INTRODUCTION:

Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage forms. Conventional dosage forms have drawbacks like frequent administration and fluctuation of plasma drug concentration¹. Controlled release dosage form covers a wide range of prolonged action formulation which provides continuous release of their active ingredient at a predetermined rate and time.

Sustained or controlled drug delivery system is to reduce the frequency of dosing or to increase the effectiveness of drug by localization at the site of action, reducing dose required, providing continuous drug delivery, reduce incidence of adverse effect and maintain drug concentration in system.

Acrivastine is a triprolidine analog antihistamine indicated for the treatment of allergies and hay fever. As an H1 receptor antagonist, it functions by blocking the action of histamine at this receptor thereby preventing the symptoms associated with histamine release such as pruritis, vasodilation, hypotension, edema, bronchoconstriction, and tachycardia^2,3.

Acrivastine has a short biological half life of 1.9-3.5 hour and having less bioavailability which necessitates multiple daily dosing, hence the present study was aimed to develop a controlled release formulation of Acrivastine^4,5. The aim of this present work is to formulate a controlled release matrix tablet of Acrivastine by direct compression method using various polymers such as HPMC K-4M, HPMC K-15M and Carbopol 940.

MATERIALS AND METHODS:

Acrivastine purchased from B.M.R Chemicals, Hyderabad. HPMC K-4M, HPMC K-15M obtained gift sample from Strides arcolab, Bangalore. Carbopol 940 obtained from Himedia laboratory. Mumbai. Micro crystalline cellulose, Lactose, Magnesium stearate and PVP K 30 obtained from Loba chemie pvt.ltd, Mumbai.

Methods:

Preformulation studies:

Solubility of Acrivastine was determined in pH 1.2 and pH 7.4 and 6.8 phosphate buffers.

Solubility studies were performed by taking excess amount of Acrivastine in beakers containing the solvents. The mixtures were shaken for 24 hrs at regular intervals. The solutions were filtered by using whattmann’s filter paper grade no. 41. The filtered solutions are analyzed by spectrophotometrically.

Compatibility Studies⁶:

Compatibility study with excipients was carried out by FTIR. The pure drug and its formulations along with excipients were subjected to FTIR studies. In the present study, the potassium bromide disc (pellet) method was employed.

Determination of UV spectrum of Acrivastine:

10mg of Acrivastine was dissolved in 10ml of buffers so as to get a stock solution of 1000µg/ml concentration. From the above stock solution pipette out 1ml of the solution and makeup the volume to 10ml using buffer to get the concentration of 100µg/ml concentration. From this stock solution pipette out 1ml of the solution and makeup the volume to 10ml using buffer to get the concentration of 10µg/ml concentration, this solution was scanned under UV Spectroscopy using 200-400nm.

Preparation of Stock Solution:

10mg of Acrivastine was dissolved in 10ml of buffers so as to get a stock solution of 1000µg/ml concentration.

Preparation Standard Solution:

1ml of stock solution was diluted to 10ml with buffer in 10ml volumetric flask this gives a concentration of 10µg/ml. Aliquot of standard drug solutions were prepared by withdrawing 0.2, 0.4, 0.6, 0.8, 1.0 and 1.2ml and transferred in to 10ml volumetric flask and were diluted up to the mark with pH 1.2 buffer. This gives the final concentration of 2, 4, 6, 8, 10and 12µg/ml of Acrivastine respectively. The absorbances of the solution were measured against as blank using UV visible spectrophotometer. The absorbance values were plotted against concentration (µg/ml) to obtain the standard calibration curve.

Preparation of Acrivastine Controlled Release Matrix Tablets. Direct Compression:

Controlled release tablets of Acrivastine were prepared by Direct compression technique using variable concentrations of different polymers like HPMC K4M, HPMC K15M, Carbapol 940 used.

In this process the tablets are compressed directly from powder blends of active ingredient and all the excipients, which will flow the die cavity and forms a firm compact.

Brief manufacturing procedure for the preparation of tablets:

Weighed all the ingredients separately. The drug and the other excipients were passed through 40# sieve, blended for 10 minutes. The magnesium stearate was passed through 60# sieve and added to the powder blend of drug and excipients. Compressed into tablets by using 9mm flat punches^7,8.

Evaluation Parameters:

Precompression Parameters⁹: Controlled release powder blend of acrivastine with excipients were performed Precompression parameters such as angle of repose, bulk density, tapped density, carr’s index and hausner’s ratio.

Table 1: Tablet composition of different formulations of Acrivastine matrix tablets

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
Acrivastine	100	100	100	100	100	100	100	100	100
Lactose	50	50	50	50	50	50	50	50	50
HPMCK4M	50	100	150	-	_	_	_	_	_
Carbapol 940	_	_	_	50	100	150	_	_	_
HPMCK15M	_	_	_	_	_	_	50	100	150
MCC	276	226	176	276	226	176	276	226	176
PVP K30	20	20	20	20	20	20	20	20	20
Talc	2	2	2	2	2	2	2	2	2
Mg.Stearate	2	2	2	2	2	2	2	2	2
Total(mg)	500	500	500	500	500	500	500	500	500

From the drug excipients compatibility studies we observe that there are no interactions between the pure drug and optimized controlled release formulation of Acrivastine, which indicates there are no interaction between drug and polymers.

Table 2: Pre Compression Parameters of _Acrivastine controlled release matrix Tablets:

_FC	_{Angle of Repose}	_{Bulk density}	_{Tapped density}	_{Hausners ratio}	_{Carrs index}
_F1	26.21±0.54	0.282±0.44	0.324±0.36	1.14±0.22	12.96±0.54
_F2	29.84±0.46	0.270±0.16	0.316±0.24	1.17±0.54	14.55±0.26
_F3	26.96±0.28	0.266±0.84	0.327±0.21	1.22±0.26	18.65±0.33
_F4	28.85±0.32	0.270±0.26	0.330±0.22	1.22±0.87	18.18±0.20
_F5	26.46±0.65	0.264±0.22	0.325±0.18	1.20±0.62	18.76±0.14
_F6	28.64±0.24	0.268±0.14	0.334±0.54	1.24±0.48	19.76±0.02
_F7	27.64±0.10	0.252±0.02	0.320±0.26	1.26±0.34	21.25±0.54
_F8	25.85±0.24	0.268±0.97	0.330±0.24	1.23±0.22	18.78±0.62
_F9	26.54±0.89	0.266±0.24	0.320±0.52	1.20±0.04	16.87±0.10

The angle of repose of different formulations (F1-F9) was found to be in the range of 26.21 to 29.54 which indicates that material had excellent flow property. So it was confirmed that the flow property of blends were free flowing. The bulk density of blend was found between 0.324 to 0.320. Tapped density was found between 0.324 to 0.320.These values indicate that the blends had good flow property. Carr’s index for all the formulations was found to be between 12.96 to 16.87 and Hausner’s ratio from 1.14 to 1.20 which reveals that the blends have good flow character and compressability suitable for formulation development

Table 3: Post Compression Parameters of _Acrivastine controlled release matrix Tablets:

_FC	_Avg.Wt _(mg)	_Thickness _(mm)	_Hardness _(kg/cm2)	_Friability _(%)	_{Drug Content} _(%)
_F1	_499.28±1.54	_4.12±1.66	_8.54±0.74	_0.22±0.18	_92.14±0.92
_F2	_498.02±0.26	_4.02±0.78	_8.92±0.62	_0.16±0.82	_91.54±0.48
_F3	_501.56±0.54	_4.22±0.88	_9.12±0.95	_0.54±0.66	_90.26±0.84
_F4	_498.28±0.11	_4.28±0.74	_8.26±0.76	_0.28±0.38	_93.64±0.55
_F5	_500.64±0.78	_4.10±0.82	_8.54±0.88	_0.10±0.65	_92.41±0.18
_F6	_497.14±0.86	_4.03±0.79	_9.20±0.94	_0.46±0.26	_88.26±0.94
_F7	_499.01±0.24	_4.00±072	_8.86±0.37	_0.29±0.72	_90.14±0.79
_F8	_502.87±0.54	_4.52±0.36	_8.24±0.72	_0.84±0.58	_95.12±0.49
_F9	_500.54±0.18	_4.26±0.84	_8.26±0.49	_0.12±0.45	_96.64±0.84

The average weight of the _{Acrivastine
tablets were found to be in the range of 497.14 to 502.87mg. Thickness of the
Acrivastine tablets were found to be in the range of 4.00 to 4.52mm. Hardness
of the Acrivastine tablets were found to be in the range of 8.10 to 9.33kg/cm2.}Friability_{of the Acrivastine tablets were found to be in the range of 0.10 to 0.84% .Drug
content of the Acrivastine tablets were found to be in the range of}

In Vitro Drug Release Studies:

Figure 7: In Vitro Drug Release Studies Of F1-F9 Formulations

From the in vitro drug release studies of Acrivastine controlled release tablets using HPMC K4M, Carbapol 940 and HPMC K15M in three different polymer ratios using lactose as a diluent, MCC as a filler and PVP K30 as binder.

Among the all 9 trails F1-F3 trails were formulated using HPMC K 4M in three different ratios like 50mg, 100mg and 150mg, the drug release was decreased with increase in the polymer concentration. But F3 formulation fails to control the drug release up to 12 hours as HPMC K4M has less viscosity.

Then F4-F6 trails were formulated using carbapol in three different ratios like 50mg, 100mg and 150mg, the drug release was decreased with increase in the polymer concentration. Then F7-F9 trails were formulated using HPMC K15M in three different ratios like 50mg, 100mg and 150mg, the drug release was decreased with increase in the polymer concentration. Among the all three formulations F9 formulation containing 150mg of HPMC K15M controls the drug release up to 12 hours controlled release tablets at 150mg concentration. So the drug release kinetics was performed for the F9 formulation.

Drug Release Kinetics:

Zero Order:

Figure 8: Zero order plot of optimized Acrivastine controlled release formulation (F9)

Figure 9: First order plot of Acrivastine controlled release optimized formulation (F9)

Figure 10: Higuchi plot of Acrivastine controlled release optimized formulation (F9)

Figure 11: Peppas plot of Acrivastine controlled release optimized formulation(F9)

Table 4: Drug release kinetics of Acrivastine controlled release optimized formulation.

R² values					n values
Formulation	Zero order	First order	Higuchi	Korsmeyer - Peppas	Korsmeyer- Peppas (n)
F9	0.986	0.743	0.871	0.973	1.965

The invitro dissolution data for best formulation F9 were fitted in different kinetic models i.e, zero order, first order, Higuchi and korsemeyer-peppas equation. Optimized formulation F9 shows R²value 0.986. As its value nearer to the ‘1’ it is conformed as it follows the Zero order release. The mechanism of drug release is further confirmed by the korsmeyer and peppas plot, if n = 0.45 it is called Case I or Fickian diffusion, 0.45 < n < 0.89 is for anomalous behavior or non-Fickian transport, n = 0.89 for case II transport and n > 0.89 for Super case II transport.

The ‘n’ value is 1.965 for the optimised formulation (F9) i.e., n value was > 0.89 this indicates super case transport. The release kinetics for the optimized formula are shown in table.

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Received on 21.02.2023 Modified on 06.03.2023

Asian J. Pharm. Tech. 2023; 13(2):95-100.

DOI: 10.52711/2231-5713.2023.00018