Formulation and Evaluation of Floating and Mucoadhesive Tablets containing Repaglinide

 

Dharmajit Pattanayak¹*,  Jagdish K Arun¹,  Ramesh Adepu², B. Shrivastava¹, C.M Hossain³, Saumya Das³

¹School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan

²Vikas College of Pharmaceutical Sciences, Rayanigudem, Suryapet, TS

³Bengal School of Technology, Sugandha, Hooghly, WB

 

ABSTRACT:

In the present study, Repaglinide an anti-diabetic drug is formulated in the form of floating mucoadhesive tablets to improve its bioavailability. Hydroxy Propyl Methyl Cellulose K200M, Sodium Carboxy Methyl Cellulose, Carbopol 974P, Karaya gum, Chitosan, Xanthan gum were used as rate controlling and mucoadhesive polymers in designing the tablets.Various formulations were prepared by using different concentration of polymers. The pre-compression blend of Repaglinide mucoadhesive tablets were characterized with respect to angle of repose, bulk density, tapped density, carr’s index and hausner’s ratio and all the results indicated that the blend had good flow property and better compressibility.The swelling studies were performed and the results indicated that all the formulations had good swelling index. The results of floating lag time and buoyancy studies suggested that formulations had good floating ability. The drug release studies indicated a controlled and enhanced drug release for a period of 12hrs. In-vivo study was carried out using the optimized formulation.Based on the in-vitro drug release and other related evaluation tests, formulation RT11 containing drug: karaya gum in the ratio 1:2 was optimized. The drug release of the formulation RT11 followed Higuchi model with regression value of 0.984.

 

 

 

INTRODUCTION:

The most acceptable route of drug administration to achieve a desired systemic action is oral route. There is a probability that at least 90% of all the drugs are administered through an oral route.In conventional oral drug delivery, the drug resides for a shorter period of time in the absorption window, so the bioavailability is hampered. Oral controlled drug delivery system represents the most popular form of controlled and prolonged drug delivery for the various advantages minimizing the cons of conventional therapy. This type of drug delivery systems releases the drug with constant or variable release rates^1-3.

 

Gastric emptying of a dosage forms can be modified by different parameters and can increase the gastric residence time of the dosage forms, by which the dosage form can remain in the stomach for a prolong period of time than the normal conventional dosage forms⁴. The most popular approach of oral controlled drug delivery is gastroretentive dosage form retain in stomach prolong period of drug profile and control the Gastric residence time in the stomach⁵. GRDDS can be elaborated as a modified technique of dosage form which can remain in the stomach for a long duration of time by altering the gastric emptying time as well as release the drug in a controlled manner, and then metabolized⁶. In the present scenario the different approaches for GRDDS have been designed to increase GRT. The primary objective of formulating GRDDS is to overcome the problems associated with existing oral conventional and sustained release dosage form and to design a drug delivery which will be more benefit towards the patients^7-9.

 

There are different parameters listed out which effects on the GRT of a dosage form among theme one parameter is ‘fluid level’. The fluid level in the stomach is not constant always. This creates problem for GRDDS to float for a desired period of time and release the drug in stomach.¹⁰ Floating drug delivery is effective for drug which give local action in the stomach or for the drug which unstable in alkaline pH due to poor solubility and a narrow of absorption window¹¹. The bulk density for the GRDDS is less than gastric fluids due to which it remain buoyant in the stomach for long duration without affecting the gastric emptying rate. Due to prolong floating time in the gastric fluid, the desired amount of drug can release from the dosage form slowly¹². So to overcome the problems of low gastric retention time, a new delivery system is designed which is a combination of Floating and Mucoadhesive technique. In the present work Repaglinide, an antidiabetic drug is formulated with different type of controlled release and mucoadhesive polymers in different concentration to optimize a formulation which will help to overcome the above said problems.

 

MATERIAL AND METHODS:

Repaglinide was obtained from Triveni Chemicals through the supplier. The polymers like HPMC K200M¹³, sodium carboxy methyl  cellulose (NaCMC), Carbopol 974P, Karaya gum, Chitosan, Xanthan gum and other reaming excipients like sodium bicarbonate, magnesium stearate, talc, lactose too obtained from S. D Fine Chemicals. All the excipients used were of laboratory grade.

 

Pre compression evaluation:^14,15

Solubility Studies:

The solubility of Repaglinide, in 0.1 N HCl solution pH 1.2 was studied by phase equilibrium method. In a 20ml vial 10mL of 0.1 N HCl (pH 1.2) and excessive amount of drug was taken. The above vials were sealed by rubber caps and shaken at room temperature for 24 hrs using rotary shaker. After 24 h, the solution was strained through 0.2µm Whatmann’s filter paper. The amount of dissolved drug was then determined by taking the absorbance at 281 nm using a UV spectrophotometer.

 

The standard graph of Repaglinide was established in 0.1 N HCl and solubility of Repaglinide was estimated from the slope of the calibration curve. The studies were repeated in triplicate (n = 3), and mean was calculated.

 

Drug-excipient compatibility studies:

Fourier transforminfra red spectroscopic studies:

A Fourier transform – infra red spectrophotometer was performed to check the compatibility drug-excipient (binary mixture of drug: excipient 1:1 ratio) by the non-thermal analysis. The spectrum of the sample was recorded in the range of 450-4000 cm^-1.

Pre-compression Evaluation:

Preformulation studies is a group studies which deals with the physicochemical parameter of drug, also helps in dosage form design and provides a outline for the selection of pharmaceutical additives or excipients.

 

Compressibility index:

It is an important parameter which decides the method of tablet manufacturing. It is determined from the apparent bulk density and tapped density. The compressibility index (percentage compressibility) of the API was calculated by using the following formula.

 

I = (D_T – D_b / D_T )100

 

Where, I = Compressibility index

Dt= Tapped density of the powder

D_b= Bulk density of the powder.

 

Hausner’s ratio:

It takes in account the flow of the powders and is measured by the ratio of tapped density to the bulk density

 

H = D_t / D_b

 

Where, H =Hausner’s ratio

D_t= tapped density of the powder

D_b= bulk density of the powder.

 

Angle of repose:

It is the Maximum angle possible between the surface of the pile or powder and horizontal plane. The tangent of Angle of repose is equal to the coefficient friction between the particles. It is expressed as

 

θ = tan^-1 (h / r)

 

Where, θ= angle of repose; h = height in cm; r = radius in cm.

 

Preparation of Floating mucoadhesive tablets:¹⁶

The Floating mucoadhesive tablets containing Repaglinide, were prepared by direct compression method. Various batches were developed by changing the ratio of HPMC K200M, Na CMC, Carbopol 974P, Karaya gum, Chitosan and Xanthan gum. Sodium bicarbonate is used to enhance the floating behavior of tablets. Talc and Magnesium stearate are used as lubricant and glidant. Lactose is used as a filler to maintain the bulk of the formulations.

 

The drug, polymers, sodium bicarbonate and lactose were mixed homogeneouslyin a glass mortar for 15 min. The powder blend is lubricated with talc and Magnesium Stearate. The final powder blend is mixed homogeneously by using a polyethylene bag. The mixture was then compressed using a 6 mm diameter die in a 9-station rotary punching machine (Lab Press, India). Table No. 1 shows the different formulation approaches.

 

Table No. 1: The Composition of Floating Mucoadhesive Tablets of Repaglinide

 

Table No. 1: continued

 

 

Post- compression Evaluation:^17-19

Physicochemical characterization of tablets:

The prepared Repaglinide Floating mucoadhesive tablets were studied for their physicochemical properties like weight variation, hardness, thickness, friability and drug content.

 

A. Weight variation:

This test is carried out by using 20 tablets selected randomly and weighed accurately. The composite weight divided by 20 provides an average weight of tablet. The individual weight of the tablet (Not more than two) should not deviate from the average weight by ± 7.5 % and none should deviate by more than twice that percentage. The percent deviation was determined using the following formula:

 

% Deviation = (Individual weight – Average weight / Average weight) X 100

 

The average weight of tablets in each formulation was calculated and represented with standard deviation.

 

Table No. 2: Pharmacopoeiastandards for the weight variation of tablet

 

 

B. Tablet Thickness:

The Thickness and diameter of the tablets from production run is carefully controlled. Thickness of the tablet can vary without change in weight due to different parameters like density of granulation and force of the punches applied on the tablets, as well as the speed of the tablet compression machine. Hence this parameter are important for consumer acceptance, tablet uniformity and packaging. The Digital Vernier caliper²⁰ was used to examine the thickness and diameter of the tablets. The tablets (10 tablets for each formulation) were randomly selected and the average values were calculated. The average thickness for tablet is calculated and presented with standard deviation.

 

C. Tablet Hardness:

Tablet hardness is defined as the force necessitate for breaking a tablet in a diametric compression test. Tablets need a certain amount of strength and resistance to friability, to withstand the mechanical shocks during handling, manufacturing, packaging and shipping. From every formulation tablets were taken (6 tablets) and hardness was determined using Monsanto hardness tester²¹ and the average was calculated. It is expressed in Kg/cm².

 

D. Friability:

Hardness of a tablet is not an absolute indicator to express the strength because some formulations during compression in to tablets may loosen their crown positions. Accordingly to cross check the strength of tablet other measure for the tablet was proposed i.e. friability. It is measured by using Roche friabilator. The number of tablets selected for the test is subject to the combined effect of mechanical force (shock and abrasion) by utilizing a plastic chamber of Roche friabilator which revolves at 25rpm speed for 4 minutes, dropping the tablets to a distance of 6 inches in each revolution²².

 

Preweighed tablets sample was placed in Roche friabilator which was then operated 25rpm for 4 minutes. The tablets were then de-dusted and reweighed. Percent friability (% F) was calculated as

 

                    Initial weight of 10 tablets – final weight of 10 tablets (W)

Friability (%) = --------------------------------------------------------- X 100

                                      Initial weight of 10 tablets(Wo)

Where,

W_o is the initial weight of the tablets (Preweighed)

W is the final weight of the tablets (Reweighed)

 

E. Assay²³:

The tablets (6 tablets for each formulation) were randomly selected and amount of drug present in each tablet was determined. Equivalent to weight of one tablet, powder was taken and dissolved in 100ml of 0.1N HCl by stirring for 10 min. The membrane filter (0.45μ) was used for straining the above solution and diluted suitably followed bymeasuring absorbance by using UV-Visible spectrophotometer at 281 0.1N HCl nm using.

 

In vitro Buoyancy studies:

The in vitro buoyancy was determined by two parameters i.e. floating lag time and total floating time. These are measured by placing the tablet in a 100ml beaker containing 0.1N HCl. The Floating Lag Time (FLT) was checked by measuring time required for the tablet to rise to the surface and the Total Floating Time (TFT)¹¹ was determined by noting down the duration of time that tablet constantly floats on the dissolution medium.

 

In vitro release studies:^24,25

The USP type II dissolution test apparatus was used to measured drug release rate from Floating mucoadhesive tablets. In Floating mucoadhesive tablets were supposed to release the drug from one side, so to maintain  in- vitro gastric condition an impermeable backing membrane was placed on the one side of the tablet and followed by it was further fixed to a 2x2cm glass slide with a solution of cyanoacrylate adhesive. Then it was placed in the dissolution apparatus. The dissolution medium selected was 900 ml of pH 1.2 HCl buffer and paddle speed was 50rpm at a temperature of 37 ± 0.5°C. Samples of 5ml were withdrawn at different time intervals up to 12 h and analyzed after appropriate dilution by using UV Spectrophotometer at 281nm.

 

In vitro bioadhesion strength:

Microprocessor based on advanced force gauge equipped with a motorized test stand (Ultra Test Tensile strength tester, Mecmesin, West Sussex, UK) was used to measure the bioadhesion strength of tablets. 25kg load cell was set. Porcine membrane was placed tightly to a circular stainless steel adaptor and the Floating mucoadhesive tablet (sample tablet) was attached to another cylindrical stainless steel adaptor having similar in diameter using a cyanoacrylate bioadhesive. 100 µl of 1% w/v mucin solution was spread on the surface of the mucosa and immediately the tablet was allowed to come in contact with the mucosa. After certain period of time time,the upper support was withdrawn at 0.5 mm/sec until the tablet was completely detached from the mucosa. The area under the force distance curve was helped to determine the work of adhesion. The peak detachment force was maximum force to detach the tablet from the mucosa.

 

                                    Bioadhesion strength x 9.8

Force of adhesion = -------------------------------------

                                                   1000                  

                                       Force of adhesion

Bond strength  =  ----------------------------------------

                                              Surface area         

 

Moisture absorption²⁶:

Agar (5% m/v) was dissolved in hot water. It was transferred into petridishes and allowed to solidify. Prior to the study Floating mucoadhesive tablets (6 from each formulation) were placed in a vacuum oven overnight to remove moisture, if any, followed by immediately laminated on one side with a water impermeable backing membrane. The above tablets were incubated at 37°C for one hour by placing on the surface of the agar media. After one hour the tablets were taken out and weighed and the percentage of moisture absorption was calculated by using following formula:

 

                            Final weight – Initial weight

% Moisture = ---------------------------------------------x100

Absorption                        Initial weight

                                                

Kinetic analysis of dissolution data^27,28,29:

To analyze the in vitro release data various kinetic models were used like Zero order model (Cumulative % drug released versus time), First order model (Log cumulative percent drug remaining versus time), Higuchi’s model –Cumulative percent drug released versus square root of time, Korsmeyer equation/ Peppa’s model – Log cumulative % drug released versus log time.

 

 

 

 

In vivo studies - Pharmacokinetic studies:

To determine the peak plasma concentration pharmacokinetic studies were carried out. The In vivo studies were carried out on male Wistar rats weighing range from 250-300gm. They were housed in polypropylene cages and had free access to food and water. The formulation for the test was formulated according to the doses of anti-diabetic drugs whichwere calculated as per the body weight of animals. The protocol for the animal study was approved by the Institutional Animal Ethical Committee (IEAC), which is recognized by Committee for the Purpose of Control and Supervision of Experiments on Animal (CPCSEA). The optimized Floating mucoadhesive matrix tablets were administered orally. Blood samples were collected for over 24 h according to a predetermined sample collection schedule. Various pharmacokinetic parameters like C max, T max, AUC were  determined^30,31.

 

RESULT AND DICSUSSION:

The solubility studies indicated that the drug is having less solubility in water as compared to methanol and 0.1N HCl.

 

Drug –Polymer Compatibility Studies by FTIR

 

Figure No.1: FTIR of Repaglinide pure drug.

 

 

Figure No. 2: FTIR Spectra of Drug+Polymer Physical Mixture.

Pre-compression Evaluation:

 

Figure No.3: Angle of repose for obtained formulation

 

 

Figure No.4: Carr’s Index for obtained formulation

 

 

Figure No.5: Hausner’s Ratio for obtained formulation

 

The angle of repose for all formulations was in the range of 22.29 to 37.39. This suggested that the powder blend has excellent to moderate flow property. The results of Carr’s Index and Hausner’s ratio showed that the powder has a good compressibility index. This is an indication that the tablets can be prepared by direct compression method.

 

The thickness of the prepared tablets was in range between 3.01mm to 3.92mm. The weight variation was in the limit as specified in I.P. The maximum and minimum hardness of tablets was 4.9Kg/cm² and 4Kg/cm² respectively. This is an optimum hardness for floating mucoadhesive tablet. The friability study depicted that all formulations have tendency to withstand handling and packing. The maximum floating lag time was 2.17min

 

Post-compression Evaluation:

Table No.3: Evaluation of floating mucoadhesive tablets of Repaglinide

Formulation Code	Thickness (mm)	Average Weight (mg)	Hardness (Kg/cm2)	Friability (%)	Content uniformity (%)	Total Floating Time (h)	Floating lag time (Min-s)
RT1	3.15±0.29	98.21±0.11	4.1±0.08	0.15±0.09	98.30±0.35	>12	1:06±0..5
RT2	3.56±0.21	95.13±0.18	4.3±0.07	0.36±0.04	99.16±0.31	>12	2:17±0.04
RT3	3.48±0.22	99.45±0.17	4.9±0.03	0.14±0.06	97.91±0.24	>12	2:16±0.06
RT4	3.92±0.19	98.26±0.09	4.2±0.05	0.24±0.04	99.38±0.31	>12	1:19±0.05
RT5	3.68±0.34	99.12±0.12	4.8±0.04	0.61±0.06	96.63±0.27	>12	1:02±0.07
RT6	3.17±0.27	100.0±0.19	4.0±0.09	0.39±0.07	99.12±0.26	>12	1:18±0.01
RT7	3.86±0.28	98.75±0.14	4.8±0.11	0.18±0.09	99.10±0.24	>12	1:15±0.09
RT8	3.92±0.27	99.86±0.17	4.9±0.07	0.45±0.04	98.34±0.22	>12	1:20±0.05
RT9	3.67±0.21	99.48±0.14	4.6±0.02	0.98±0.06	95.61±0.24	>12	1:40±0.03
RT10	3.29±0.19	96.38±0.04	4.3±0.06	0.14±0.08	98.74±0.29	>12	1:53±0.09
RT11	3.48±0.31	97.49±0.15	4.7±0.05	0.61±0.12	97.62±0.24	>12	1:01±0.10
RT12	3.26±0.25	98.29±0.21	4.0±0.09	0.75±0.05	100.2±0.24	>12	1:06±0.08
RT13	3.54±0.29	97.90±0.14	4.1±0.05	0.31±0.06	95.26±0.28	>12	2:12±0.04
RT14	3.24±0.33	99.67±0.09	4.9±0.13	0.62±0.04	99.12±0.29	>12	1:19±0.11
RT15	3.48±0.28	98.64±0.10	4.2±0.08	0.34±0.06	98.61±0.21	>12	1:41±0.06
RT16	3.10±0.21	100.1±0.18	4.4±0.15	0.42±0.03	97.31±0.29	>12	1:15±0.02
RT17	3.01±0.24	98.78±0.14	4.3±0.04	0.11±0.04	98.85±0.23	>12	1:09±0.13
RT18	3.65±0.28	99.73±0.13	4.5±0.06	0.52±0.05	99.69±0.36	>12	1:24±0.04

Each value represents the mean±SD (n=3)

 

In vitro release studies:

 

Figure No.6: In vitro Dissolution study of RT 1 to RT 9

 

 

Figure No.7: In vitro Dissolution study of RT 10 to RT 18

 

The minimum drug release was observed for formulation RT3 which contains drug: carbopol 974P in ratio of 1:3. This may be due to the high concentration of rate controlling polymer. The maximum drug release is found in formulation RT7 which contains drug: carbopol 974P in ratio 1:1. This shows that the drug: carbopol 974P in ratio 1:1 is optimum to achieve a mucoadhesive and floating tablet.

 

Table No. 4: Moisture absorption, bioadhesion strength values of selected formulations.

Formulation Code	Moisture absorption	Bioadhesion strength
		Peak detachment force (N)	Work of adhesion (mJ)
RT11	44±0.25	3.8±0.41	17.42±6.10

Each value represents the mean±SD (n=3)

 

Release kinetics:

Data of in vitro release studies of formulations which were showing better drug release were fit into different equations to explain the release kinetics of Repaglinide release from mucoadhesive tablets. The data was fitted into various kinetic models such as zero, first order kinetics,higuchi and korsmeyerpeppas mechanisms and the results were shown in below table.

 

Figure No.8: Zero order plot of optimized formulation

 

Table No 5: Table of release kinetics and correlation factors

Cumulative (%) release q	Time (t)	Root (t)	Log (%) release	Log (t)	Log (%) remain	Release   rate (cumulative % release / t)	1/Cum% release	Peppas  log q/100	% Drug Remaining	Q01/3	Qt1/3	Q01/3-Qt1/3
0	0	0			2				100	4.642	4.642	0
18.19	0.5	0.707	1.26	0.301	1.913	36.38	0.055	-0.74	81.81	4.642	4.341	0.3
23.46	1	1	1.37	0	1.884	23.46	0.0426	-0.63	76.54	4.642	4.246	0.396
31.37	2	1.414	1.497	0.301	1.837	15.685	0.0319	-0.503	68.63	4.642	4.094	0.547
37.31	3	1.732	1.572	0.477	1.797	12.437	0.0268	-0.428	62.69	4.642	3.973	0.669
44.19	4	2	1.645	0.602	1.747	11.048	0.0226	-0.355	55.81	4.642	3.822	0.82
52.84	5	2.236	1.723	0.699	1.674	10.568	0.0189	-0.277	47.16	4.642	3.613	1.029
60.57	6	2.449	1.782	0.778	1.596	10.095	0.0165	-0.218	39.43	4.642	3.404	1.238
66.72	7	2.646	1.824	0.845	1.522	9.531	0.015	-0.176	33.28	4.642	3.217	1.425
73.64	8	2.828	1.867	0.903	1.421	9.205	0.0136	-0.133	26.36	4.642	2.976	1.665
79.52	9	3	1.9	0.954	1.311	8.836	0.0126	-0.1	20.48	4.642	2.736	1.906
83.75	10	3.162	1.923	1	1.211	8.375	0.0119	-0.077	16.25	4.642	2.533	2.109
95.67	11	3.317	1.981	1.041	0.636	8.697	0.0105	-0.019	4.33	4.642	1.63	3.012
98.64	12	3.464	1.994	1.079	0.134	8.22	0.0101	-0.006	1.36	4.642	1.108	3.534

 

 

Figure No.9: Higuchi plot of optimized formulation

 

 

Figure No.10: Koresmeyer-peppas plot of optimized formulation

 

Based on the all studies RT11 formulation was found to be better when compared with all other formulations. This formulation was following Higuchi mechanism with regression value of 0.984.

 

In vivo Studies - Pharmacokinetic Studies:

All the pharmacokinetics parameters displayed in Table. 6 Mean time to reach peak drug concentration (T_max) was 0.8 hours, while mean maximum drug concentration (Cmax) was 30.24µg/ml. The values for C_max, T_max, AUC were found to be comparable indicating that their sustained release patterns were similar.

Table No 6: Pharmacokinetic parameters ofoptimizedformulation

S. No	Parameter	Repaglinide
1	Cmax	30.24µg/ml(±0.67)
2	T max (hr)	0.8 hours(±0.27)
3	AUC	40.54μg.h/ml (±2.94)

 

 

Figure No.11: First order plot of optimized formulation

 

CONCLUSION:

Repaglinide, was formulated as Floating mucoadhesive tablets to improve its bioavailability. HPMC K200 M, Na CMC, Carbopol 974P, Karaya gum, Chitosan, Xanthan gum were selected as polymers. The pre-compression blend of Repaglinide Floating mucoadhesive tablets were characterized with respect to all the parameter(angle of repose, bulk density, tapped density, carr’s index and hausner’s ratio) and all the results reflected that the blend was having good flow nature and better compression properties.Peak detachment force (N) and work of adhesion were calculated and they were found to be good.

 

Repaglinide RT11 formulation was considered as optimised formulation because good drug release (98.64 %) in 12 hours, Moisture absorption (44±0.25), Peak detachment force (N) (3.8±0.41N), Work of adhesion (17.42±6.10mJ). RT11 formulation follows the Higuchi mechanism with regression value of 0.984. The in-vivo pharmacokinetics studies showed that the drug reaches the maximum concentration in 0.8 hr. The C_max and AUC data predicts that the drug has a good oral bioavailabilty. Further studies can be carried out using different drugs to correlate the data.

 

ACKNOWLEDGEMENT:

The authors would like to express sincere gratitude to Vikas College of Pharmaceutical Sciences and Bengal School of Technology for their esteemed support towards this work.

 

AUTHORS CONTRIBUTION:

All the authors have equal contribution in making this research a success.

 

CONFLICT OF INTEREST:

Declared None

 

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Accepted on 08.11.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(3):1277-1284.