Effect of Formulation Variables of Gastroretentive Floating Tablets of an Anti-Hypertensive agent using different Grades of Hydrophillic Polymers

Vamshi Krishna Lekkala¹*, N Siva Subramanian², K Srikanth Gupta³

¹Research Scholar, Himalayan University, Itanagar, Arunachal Pradesh, India.

²Research Guide, Himalayan University, Itanagar, Arunachal Pradesh, India.

³Scientist, Formulation Research and Development, Aizant Drug Research Solutions,

Hyderabad, Telangana, India.

*Corresponding Author E-mail: vamsilekkala84@gmail.com

ABSTRACT:

Losartan potassium (LP) is an orally active non-peptide angiotensin -II receptor antagonist, used in the treatment of hypertension and have narrow therapeutic index, short biological half-life (1-2h), poor bio availability (25-35%), Due to these reasons conventional tablets should administer 3-4 times per day to maintain plasma drug concentrations within the therapeutic window. To overcome these drawbacks, sustained release gastro retentive floating tablets were prepared to enhance the patient compliance. Floating tablets were prepared with different grades of Hypromellose polymers along with Sodium bicarbonate, citric acid and characterized (Pre and post compression parameters) to optimize the best formulation. Lubricated blend was characterized for angle of repose, bulk density, tapped density and compressibility index. Compressed tablets were characterized for Hardness, friability, assay, related substances, in vitro drug release, etc. Based on the results, it was concluded that LFT10 formulation prepared with combination of Metolose 90SH-4000SR and Metolose 90SH-100000SR was optimized as best formulation. In vitro dissolution data of best formulation fitted in different mathematical models like zero, first orders, Higuchi, Hixon Crowell and Korsmeyer Peppas models and found that the drug release following zero order, non fickian diffusion mechanism. The optimized formulation (LFT10) also exposed to accelerated stability condition (40°C/ 75%RH) and found satisfactory as per ICH guidelines.

KEYWORDS: Hypromellose, Sodium bicarbonate, citric acid, hypertension, losartan potassium, conventional tablets, floating tablets, patient compliance.

INTRODUCTION:

Losartan potassium (LP) is an orally active, nonpeptide angiotensin II (AII) receptor antagonist and is well approved to treat the hypertension¹. It acts by binding competitively and selectively to the AII subtype 1 (AT1) receptor, thereby blocks the all-induced physiological effects and is very well tolerable drug². In clinical trials it has not been reported any adverse events except dizziness.

Its novel mechanism of action, good efficacy and favorable tolerability profile, losartan potassium is considered as the best spectacular drug in the management of patients with essential hypertension.  However, it is well accepted, its acceptance is limited because of low therapeutic effectiveness. Its therapeutic effectiveness was narrowed because of constrictive therapeutic index, poor bioavailability, and short biological half-life (1-2h)³. The bioavailability of Losartan potassium is about 33%⁴ and its less bioavailability is in consequence of first-pass metabolism⁵ and is not altered significantly in presence of food⁶. Time to achieve peak plasma concentration is about 1 hour for losartan potassium and the volume of distribution is about 34L⁷.

Conventional tablets should be administered 3-4 times to maintain plasma drug concentration. So, to increase therapeutic efficacy, reduce frequency of administration and thereby to increase the patient compliance an attempt was made by developing the sustained release tablets of losartan potassium^8,9,10. Sustained release floating matrix tablets of Losartan Potassium were prepared^11,12,13. Present study demonstrates the formulation of sustained release floating matrix tablets of Losartan Potassium with various grades of hydroxyl propyl methylcellulose to restrict the drug release preferably in upper part of intestine, to improve its bioavailability and to provide constant drug plasma levels for longer period thereby improving the patient compliance by decreasing the number of doses^14,15,16.

MATERIALS AND METHODS:

Materials:

Losartan potassium was a generous gift from Hetero Labs Limited. Hyderabad, India. Hydroxypropyl Methylcellulose 4000 cPs (Metolose 90SH-4000 SR), Hydroxypropyl Methylcellulose 15000 cPs (Metolose 90SH-15000 SR) and Hydroxypropyl Methylcellulose 100000 cPs (Metolose 90SH-100000 SR) were obtained from Shin-etsu. Sodium bicarbonate and citric acid were purchased from Merck. Microcrystalline cellulose, Talc and Magnesium stearate obtained as gift samples from Hetero Labs Limited.

Methods:

Preparation of gastro retentive floating tablets of Losartan potassium:

The Losartan potassium (LP) floating tablets were prepared by using direct compression method.  Blend was prepared by uniform mixing of polymer (Metolose 90SH-4000 SR / Metolose 90SH-15000 SR / Metolose 90SH-100000 SR) and Microcrystalline Cellulose in different proportions as mentioned in table 1. To this, accurately weighed quantity of Sodium bicarbonate, Citric acid and API were added and blended well. The entire mixture was passed through sieve no 30. Prelubrication and lubrication was carried out with ASTM# 40 passed talc and ASTM# 60 passed Magnesium stearate respectively. Finally, the blend was compressed as tablet at a hardness of 6 kg/cm^2.  Based on previous formulation experience, different grades of Hydroxypropyl Methylcellulose found to be key critical material attributes and formulation variables.  Therefore, the present study was mainly focused on concentration of different viscosities of Metolose grades. The composition of all formulations were mentioned in          table 1.

Characterization:

The lubricated blend and the compressed tablets are characterized as follows.

Evaluation of pre-compression parameters:

The following pre compression¹⁷ were studied with lubricated blend. 

Angle of repose:

The height and the radius of the pile were measured and the angle of repose was calculated using the equation,

θ = tan^-1(h/r)

Where, is the angle of repose, h and r are the height and radius of the pile respectively.

A funnel was filled to the brim and the lubricated blend was allowed to flow smoothly through the orifice under gravity. The blend allowed to fall on graph sheet and the height and the radius of the pile was measured to calculate the angle of repose.

Bulk density:

Bulk density defined as mass of powder divided by the bulk volume and is depends on particle size distribution, particle shape, and tendency of particle to adhere to each other. A quantity of weighed granules was filled in a 50ml measuring cylinder and the initial volume was noted. The Loose bulk density (LBD) was calculated using the following formula.

Bulk density (b) =

Weight of granules(g)/Bulk volume (ml)(Vb)

Table 1. Composition of Losartan potassium gastro retentive floating tablets

S No	Name of the Ingredient	Formulation Code
		LFT1	LFT2	LFT3	LFT4	LFT5	LFT6	LFT7	LFT8	LFT9	LFT10	LFT11
1	LP	50	50	50	50	50	50	50	50	50	50	50
2	Metolose 90SH-4000 SR	60	80	100	-	-	-	-	-	-	40	60
3	Metolose 90SH-15000 SR	-	-	-	60	80	100	-	-	-	-	-
4	Metolose 90SH-100000 SR	-	-	-	-	-	-	60	80	100	60	40
5	Sodium bicarbonate	20	20	20	20	20	20	20	20	20	20	20
6	Citric acid	15	15	15	15	15	15	15	15	15	15	15
7	MCC pH 102	145	125	105	145	125	105	145	125	105	105	105
8	Talc	5	5	5	5	5	5	5	5	5	5	5
9	Magnesium stearate	5	5	5	5	5	5	5	5	5	5	5
Tablet weight (mg)		300	300	300	300	300	300	300	300	300	300	300

Table 2. Physical properties of the lubricated blend

Physical properties of lubricated blend
S No	Formulation code	Angle of repose	Bulk density	Tapped Density	Carrs index	Hausners ratio
1	LFT1	26.8	0.471	0.541	12.9	1.15
2	LFT2	27.5	0.482	0.562	14.2	1.17
3	LFT3	28.0	0.455	0.528	13.8	1.16
4	LFT4	29.4	0.452	0.535	15.5	1.18
5	LFT5	28.5	0.470	0.535	12.1	1.14
6	LFT6	29.4	0.458	0.515	11.1	1.12
7	LFT7	28.4	0.465	0.540	13.9	1.16
8	LFT8	26.9	0.453	0.518	12.5	1.14
9	LFT9	27.5	0.449	0.526	14.6	1.17
10	LFT10	27.1	0.472	0.542	12.9	1.15
11	LFT11	28.6	0.462	0.528	12.5	1.14

Tap density:

After measuring the bulk density the same measuring cylinder was fixed into tap density apparatus. The apparatus was adjusted to tap 300 times per minute and operated for 500 taps. Volume was recorded and again tapped for 750 taps. The tapped density (TD) was calculated using the following formula.

                                         Weight of granules (g)

Tapped density (ρt) = ––––––––––––––––––––––––

                                        tapped volume (ml)(Vt)

Carr’s index and Hausner’s ratio:

Carr’s index and Hausner’s ratio are calculated using following formula. 

                         Tapped density – Bulk density

Carr’s index =–––––––––––––––––––––––––––– X 100

                                     Tapped density

Hausner’s ratio = ρt / ρb

Where ρt is tapped density, ρb is bulk density.

Pre compression i.e. Physical properties of the lubricated blend are reported in the table 2.

Evaluation of post-compression parameters:

Various post compression parameters¹⁸ were evaluated after compressing the lubricated blend. 

Hardness:

The tablets should have adequate hardness to withstand during handling, transportation, storage, etc and is also influence on the drug release. Hence evaluation of tablet hardness is mandatory and was measured the hardness using Pfizer hardness tester.

Tablet thickness:

Thickness of tablets was important for maintaining the uniformity of tablet size and was measured using vernier caliper.

Friability:

Friability is the measure of tablet strength. Roche Friabilator was used to determine the friability of all formulations. Twenty tablets were weighed accurately and placed in the plastic drum which revolves at 25 rpm for 4 minutes dropping the tablets from a height of six inches in each revolution. After 100 revolutions the tablets were reweighed and the percentage loss of weight in tablets was calculated.                

Initial wt. of tablets – Final wt. of tablets

% loss = –––––––––––––––––––––––––––––––– X 100

Initial wt. of tablets

Weight variation:

Twenty tablets were weighed individually from each batch and the average weight was calculated. Percentage deviation from the average weight was calculated.

Table 3. Physical properties of the compressed tablets

Physical properties of compressed tablets
S No	Formulation code	Weight variation (mg)	Hardness (kg/cm2)	Thickness (mm)	Friability (%)	Assay (%)	Floating lag time (Sec)	Total floating time (hrs)
1	LFT1	298.38±3.84	6.5±0.3	4.84±0.05	0.32	98.23	95	>12
2	LFT2	301.52±2.87	6.6±0.5	4.76±0.06	0.19	99.65	78	>12
3	LFT3	299.23±2.73	6.8±0.4	4.86±0.03	0.26	99.12	87	>12
4	LFT4	302.6±2.13	6.0±0.5	4.76±0.04	0.33	98.44	97	>12
5	LFT5	300.19±3.48	7.0±0.2	4.63±0.06	0.29	99.23	89	>12
6	LFT6	301.71±2.3	6.8±0.4	4.65±0.06	0.22	98.63	99	>12
7	LFT7	297.2±1.19	6.8±0.5	4.68±0.05	0.37	99.65	101	>12
8	LFT8	299.46±2.27	5.9±0.2	4.55±0.25	0.23	98.65	98	>12
9	LFT9	300.67±3.84	6.8±0.5	4.51±0.04	0.29	98.45	94	>12
10	LFT10	298.38±3.84	6.5±0.3	4.62±0.07	0.37	99.64	103	>12
11	LFT11	298.38±3.94	6.8±0.5	4.78±0.02	0.41	98.12	84	>12

In vitro buoyancy studies:

In vitro buoyancy¹⁹ of the compressed tablets of all batches were determined as described below. The tablets (n = 3) were placed in 900 ml of 0.1 N HCl in USP type II dissolution apparatus (37 ± 0.5°C, 50 rpm). Floating lag time is the time required for the tablet to rise to the surface and float. The duration of time for which the dosage form constantly remained on the surface of medium was determined as the total floating time.

Drug Content:

Twenty tablets were taken randomly, powdered and the powder equivalent to one dose each was transferred to a 100 ml volumetric flask and 0.1N HCl was added. The volume was then made up to the mark with 0.1N HCl.  The solution was filtered and diluted suitably and drug content²⁰ in the samples was estimated using UV-spectrophotometer at 220 nm²¹.

Post compression properties of the tablets are reported in the table 3.

In vitro Drug Release Studies:

The release rate²² of Losartan Potassium from sustained matrix tablets were determined using USP dissolution testing apparatus II (paddle type) at 50 rpm. The dissolution test was performed using 900 ml of 0.1 N HCl (pH 1.2) for 12 h at 37±0.5ºC. 5ml of the sample was withdrawn at regular intervals and replaced with the same volume of fresh dissolution medium. The solution was filtered and diluted suitably and drug content in the samples was estimated using UV-Spectrophotometer at 220 nm.

The results are presented in table 4 and figure 1.

Release kinetics:

The dissolution profile of optimized formulation was fitted in zero order (Cumulative percent drug released versus time), first order (Log cumulative percent drug remaining versus time), Higuchi model (Cumulative percent drug released versus square root of time), Hixson-crowell model (Cube root of drug percentage remaining in matrix versus time) and Korsmeyer peppas models (Cumulative percent drug released versus log time) to determine the kinetic modeling of the drug release. The release kinetics²³ of the optimized formulation was presented in table 5 and graphically represented in figure 2.

Table 4. Cumulative % drug released from all formulations

S No	Time (Hrs)	Cumulative % drug released
		LFT1	LFT2	LFT3	LFT4	LFT5	LFT6	LFT7	LFT8	LFT9	LFT10	LFT11
1	0	0	0	0	0	0	0	0	0	0	0	0
2	0.5	33.52	23.45	19.23	28.92	21.75	18.95	17.40	15.48	12.09	11.20	22.07
3	1	41.76	36.72	30.23	37.80	32.94	28.94	27.80	26.50	19.92	16.30	32.58
4	2	55.45	51.32	46.78	51.39	45.45	41.50	42.30	37.68	27.35	23.50	45.32
5	3	69.76	66.40	61.34	66.57	61.34	58.92	53.80	44.81	34.14	34.90	62.89
6	4	82.43	77.90	71.80	78.92	72.98	69.53	69.54	59.45	40.26	42.20	75.67
7	6	97.86	93.40	89.20	95.36	87.50	85.64	80.79	67.66	54.78	55.30	95.67
8	8	99.78	98.90	96.70	99.23	98.90	99.30	89.35	71.23	64.03	69.30	99.71
9	10	99.92	100.20	99.83	100.23	99.78	100.88	99.95	85.30	75.30	88.00	99.93
10	12	99.89	100.10	100.20	100.15	100.60	100.72	99.89	95.30	86.40	99.50	99.81

Figure 1. Cumulative % drug release from tablets prepared with Metolose 90 SH-4000 SR, 15000 SR and 100000 SR (alone and combinations)

Figure 2. Release kinetics of Optimized formulation (LFT10) a. Zero order  b. First Order c. Higuchi d. Hixon crowel and e. Korsmeyer peppas

Zero order:

In most of the modified release dosage forms viz Sustained or controlled release dosage forms, Zero order kinetic was followed when the dosage form releases the drug in predictable, planned and slowed than normal²⁴. Zero order is a plot of cumulative percent drug released versus time which is linear.

First order:

Many if the conventional release dosage forms exhibits this dissolution mechanism. Few modified release preparation, especially prolonged release formulations, follow this type of dissolution model. This model assumes that the drug molecules, diffuses out through the gel membrane formed around the drug during the dissolution program. First order is a plot of log cumulative percent drug remaining versus time which is linear.

Higuchi model:

A big number of modified release dosage form contain some sort of matrix based system. For few instance, the drug dissolves from matrix²⁵. The dissolution model of the drug is dictated by water penetration rate (diffusion controlled). In Higuchi model, a plot of cumulative percent drug released versus square root of time is linear.

Hixson-crowell model:

This law describes the release from systems where there are changes in surface area and diameter of particles/tablets. Therefore, Hixson-Crowell model recognized that the particle regular area to the cubic root of its volume. A graph has been plotted between cube root of drug percentage remaining in matrix versus time to study the release kinetics. In this model, the rate of dissolution depends on the surface of solvent, the larger is the area, the faster is the dissolution.

Table 5. Results of Different mathematical models of LFT10 in terms of R² and slope

Formulation	Zero order	First Order	Higuchi	Hixon crowel	Korsemeyer peppas
LFT10	R^2	R^2	R^2	R^2	R^2	n
	0.9967	0.745	0.9765	0.9065	0.9918	0.6991

Table 6. Stability data of LFT10 formulation subjected to 40±2°C / 75±5 % RH

Physical properties
S No	Parameter	Initial	1 Month	2 Month	3 month	6 month
1	Thickness (mm)	4.62±0.07	4.69±0.16	4.70±0.08	4.68±0.13	4.65±0.15
2	Hardness (kg/cm2)	6.5±0.3	6.6±0.8	6.6±0.4	6.7±0.4	6.6±0.7
3	Friability (%)	0.37	0.18	0.18	0.19	0.18
4	Assay (%)	99.64	99.42	99.40	99.33	99.22
Cumulative % Drug released
S No	Time (Hrs)	Initial	1 Month	2 Month	3 month	6 month
1	0	0	0	0	0	0
2	0.5	11.2	10.6	11.9	12.4	11.8
3	1	16.3	16.7	17.0	15.6	16.1
4	2	23.5	22.6	24.2	22.8	22.9
5	3	34.9	36.7	35.4	34.4	35.2
6	4	42.2	44.1	43.1	41.9	43.6
7	6	55.3	53.4	54.3	56.4	54.9
8	8	69.3	68.1	69.9	70.2	68.9
9	10	88.0	89.7	88.8	88.1	88.6
10	12	99.5	99.9	99.5	99.7	99.8

Korsmeyer-Peppas model:

Korsmeyer-Peppas model equation is used when the linearization of release data from several formulations of microspheres and microcapsules. It describes the release of a drug from a polymeric system. The empirical expression relates the function of time for diffusion controlled mechanism.

Mt / M∞ = Ktⁿ

where Mt / M∞ is a fraction of drug released at time t, k is the release rate constant and n is the release exponent which is indicative of drug release mechanism. The n value is used to characterize different release for cylindrical shaped matrices and also release mechanism of drug. If n value is 0.45 ≤ n corresponds to a Fickian diffusion mechanism, 0.45 < n < 0.89 to non-Fickian transport, n = 0.89 to Case II (relaxational) transport, and n > 0.89 to super case II transport²⁶. In order to study the release kinetics, in vitro drug release studies from promising batch were plotted as log cumulative percentage drug release versus log time.

Stability Studies:

To assess the drug and formulation stability, stability studies²⁷ were done according to ICH guidelines. The stability studies were carried out of the most satisfactory formulation (LFT10) as per ICH guidelines. The most satisfactory formulation sealed in aluminum packaging and kept in stability chamber maintained at 40±2°C / 75±5 % RH for six months. After six months the samples were analyzed for the drug content, in vitro dissolution and other physicochemical parameters.

The results are presented in table 6.

RESULTS:

Pre-compression Flow Properties:

All the formulations showed good flow properties with angle of repose values between 26^∘ and30^∘ and Hausner’s ratio ranged between 1.12 and 1.18, whereas Carr’s index values ranged between 11 and 16.

Evaluation of Post compression properties:

The tablets were visually evaluated and free from defects like sticking, lamination, chipping and capping. Core tablets passed all the in-process tests. The weights of the tablets are within the range. Hardness of the tablets was in the range of 6.0–7.0kg/cm², thickness of the tablets is within 4.50–4.86 mm and the friability ranges between 0.19 and 0.41 percent.

Drug Content:

Drug content of all formulations were estimated as described earlier and % drug content of all formulation was found in the range of 98.12 – 99.65%. This stating that all the formulations were qualified in the drug content study as the results are within the acceptance range. (100±5% w/w).

In vitro Drug Release Studies and release kinetics:

Figure 1 explains the drug release from formulations prepared with Metolose 90SH-4000 SR, Metolose 90SH-15000 SR and Metolose 90SH-100000 SR respectively. All three figures explain that three polymers sustaining the release of drug from the floating matrix tablets. Sodium bicarbonate and citric acid acts as Carbon dioxide generating agents due to acid base reaction. The resulted Carbon dioxide helps in floating of the tablet in dissolution medium. The variation in drug release from all formulations may be because of differences in the grades of the polymers and their concentrations. It is also observed that increased polymer concentration leads decrease in the drug release. Formulations LFT1 to LFT7 drug release completely took out between 8-10hours and are not achieved 12hours profile whereas LFT8 and LFT9 not releases the drug completely in 12hours. Early release of drug from formulations LFT1 to LFT7 may be because of either the low polymer concentration or viscosity and incomplete release of drug from Formulations LFT8 and LFT9 may be because of the polymer high viscosity.

The percent of drug release from formulations LFT1, LFT2 and LFT3 was 97.86, 93.4 and 89.2 at 6 hours respectively. This authenticate that with increased concentration of the polymer decreases the drug release from tablets. Similar kind of trend was observed in LFT 4 to LFT6 and LFT7 to LFT9 Formulations.

Formulations LFT1 and LFT9 where the polymer used alone at different drug polymer ratios to achieve the desired drug release profile and the objective has not been fulfilled. When the polymer used alone either the drug release profile was faster or delayed when compared with optimized release profile. Hence to achieve desired release profile combination of polymers and release profiles was observed.

Though the drug release in LFT3 and LFT5 formulations met 12 Hr dissolution profile, Initial release was not controlled. To achieve this, combination of low and high viscosity polymers were used in different ratios. Drug release from Formulation LFT10 where combination of Metolose 90SH-4000 SR and Metolose 90SH-100000 SR used at a ratio of 40:60 respectively and is achieved 12hours profile satisfactorily whereas the drug release from formulation LFT11 was not exhibited 12hours drug release profile where the polymers concentrations interchanged.

Formulation LFT10 has shown sustained the drug release for desired period of time (12 hrs) and also exhibited good buoyancy properties (floating lag time: 103 sec and floating time >12 hrs). Hence it was considered as best among all formulations prepared with Metolose 90SH-4000 SR, Metolose 90SH-15000 SR and Metolose 90SH-100000 SR alone or in combination.

Figure 2 and Table 5 explains the different mathematical models of the optimized formulation drug release. The drug release was fitted in different mathematical models and R² value and n value was observed. The R² value of 0.9967 substantiated that the formulation following zero order. Based on R² value of 0.9765 obtained from Higuchi graph, it follows diffusion mechanism. The n value (0.69) of Korsmeyer-Peppas model confirms that the optimized formulation (LFT10) following Non-Fickian transport.

Stability Studies:

Stability samples of LFT10 formulation was analysed at predetermined intervals (1, 2, 3 and 6 Months) and compared the data with initial data. There was no significant change in the physical properties. Also observed that there is no significant change in the % assay and in vitro drug release. All the stability data of LFT10 formulation complies with ICH guidelines.

CONCLUSION:

Present study demonstrated that all formulations achieved sustained drug release. LFT10 formulation has considered as optimized formulation as it has shown maximum floating time compared with other formulations.  Hydroxyl propyl methylcellulose grades in combination can act as good control release polymer. However, the formulation has to be analysed further by performing the in vivo studies to demonstrate that the formulations will give longer MRT there by decreases the no of doses in a day and increases the patient compliance.

ABBREVIATIONS:

RH – Relative Humidity

ICH- International Conference on Harmonization

cPs – Centipoise

ASTM – American society for testing and materials

MRT – Mean Residence Time.

ACKNOWLEDGEMENT:

The authors report no conflicts of interest.

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Received on 25.10.2019            Modified on 21.12.2019

Accepted on 19.01.2020          © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(6): 2893-2900.

DOI: 10.5958/0974-360X.2020.00516.8