Formulation of stomach-specific floating microparticles of nizatidine and their radiographic evaluation

Rathore, Sajjan Singh Seema; Geetha, Muniyappa; Manjula, Basappa Palur; Joshi, Vijaya Gopalachar; Setty, Siddamsetty Ramachandra

doi:10.1590/s2175-97902022e191009

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 58 • 2022 • https://doi.org/10.1590/s2175-97902022e191009 copy

Formulation of stomach-specific floating microparticles of nizatidine and their radiographic evaluation

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Nizatidine is an anti-secretogogue and a gastroprotective drug with a half-life of 1-2 h and is well absorbed in the stomach. This study aimed to optimize the process and develop floating microparticles of nizatidine that are based on low methoxyl pectin. Oil-in-oil dispersion method and Taguchi orthogonal array design were employed, and the prolonged residence time of the microparticles in the stomach was demonstrated. The constraints for independent variables, viz. A-polymer, B-internal solvent volume, C-surfactant, D-stirring rate and E-stirring time were set to generate the experimental runs. Particle size, percentage yield, micromeritic properties, entrapment efficiency, in vitro buoyancy and in vitro release were characterized. Surface morphology, zeta potential, in vitro release kinetics and in vivo floating performance of the optimized formulation was examined. The microparticles were free-flowing, irregular in shape and had a mean particle size distribution of 73-187 μ. Low methoxyl pectin played a predominant role in achieving buoyancy and optimum gastric retention for the modified release of the drug, suggesting Korsmeyer-Peppas model as the possible release mechanism. In vivo radiographic study in rabbits revealed that the drug was retained in the stomach for a period of 6 h. These results indicate that nizatidine floating microparticulate system provides modified drug release for the effective treatment of gastric ulcer.

Keywords:
Floating microparticles; Nizatidine; Low methoxyl pectin; Oil-in-oil dispersion; Solvent evaporation; Modified release

Formulation	Polymer (LMP) (%)	(Internal phase volume) Acetone (ml)	Surfactant (%)	Stirring rate (rpm)	Stirring time (min)
FMN1	5.5	20	1.5	1200	60
FMN2	0.5	30	1	600	60
FMN3	3	20	1	900	180
FMN4	5.5	50	1	300	120
FMN5	0.5	40	1.5	900	120
FMN6	3	30	0.5	1200	120
FMN7	8	20	2	600	120
FMN8	3	50	1.5	600	30
FMN9	5.5	40	0.5	600	180
FMN10	3	40	2	300	60
FMN11	5.5	30	2	900	30
FMN12	0.5	20	0.5	300	30
FMN13	8	50	0.5	900	60
FMN14	0.5	50	2	1200	180
FMN15	8	40	1	1200	30
FMN16	8	30	1.5	300	180
FMN1 (Optimized)	5.5	20	1.5	1200	60

FORMULATION	% YIELD	PARTICLE SIZE ± SD (μm)	BULK DENSITY±SD (g/cm³)	TAPPEDDENSITY±SD (g/ cm³)
FMN1	84.61	86.67±0.03	0.312±0.01	0.361±0.02
FMN2	75.46	90.51±0.08	0.348±0.02	0.439±0.03
FMN3	84.25	128.89±0.07	0.407±0.06	0.493±0.09
FMN4	82.3	97.88±0.05	0.332±0.03	0.393±0.03
FMN5	79.03	105.64±0.19	0.344±0.02	0.401±0.004
FMN6	85.25	115.96±0.08	0.21±0.01	0.231±0.05
FMN7	78.11	114.2±0.06	0.262±0.01	0.305±0.05
FMN8	76	106.66±0.18	0.357±0.03	0.435±0.05
FMN9	77.98	119.3 +0.09	0.435±0.03	0.532±0.16
FMN10	80.75	74.57±0.06	0.32±0.04	0.372±0.01
FMN11	85.38	108.61±0.05	0.53±0.11	0.636±0.09
FMN12	80.05	97.2±0.06	0.354±0.01	0.426±0.04
FMN13	83	101.79±0.08	0.453±0.06	0.53±0.06
FMN14	79.98	187.05±0.09	0.346±0.01	0.385±0.03
FMN15	83.22	79.53±0.07	0.407±0.05	0.457±0.05
FMN16	86.77	130.14±0.05	0.374±0.04	0.41±0.08

FORMULATION	TRUE DENSITY±SD(g/cm³)	HAUSNER’S RATIO±SD	CARR’S INDEX±SD (%)	ANGLE OF REPOSE±SD(θ)
FMN1	0.22±0.04	1.157±0.009	12.5±0.0	24.13±1.09
FMN2	0.24±0.07	1.238±0.124	25±1.08	22.86±0.95
FMN3	0.3±0.05	1.205±0.04	14.28±4.98	21.46±1.74
FMN4	0.26±0.07	1.182±0.01	16.66±1.76	20.91±3.78
FMN5	0.29±0.04	1.168±0.01	28.57±1.67	24.12±0.16
FMN6	0.35±0.17	1.099±0.18	8.33±1.45	20.41±1.90
FMN7	0.181±0.07	1.122±0.05	15±5.89	23.7±1.67
FMN8	0.34±0.05	1.217±0.02	16.66±2.56	24.26±2.87
FMN9	0.138±0.05	1.22±0.02	16.66±2.76	32.08±1.67
FMN10	0.19±0.03	1.169±0.01	12.5±2.34	30.97±1.59
FMN11	0.35±0.07	1.202±0.04	16.66±4.87	36.31±2.06
FMN12	0.27±0.18	1.12±0.06	28.57±1.09	25.58±0.78
FMN13	0.45±0.05	1.165±0.17	12.5±2.89	21.29±1.65
FMN14	0.3±0.08	1.14±0.05	22.22±1.98	22.02±1.89
FMN15	0.3±0.04	1.12±0.03	11.11±4.67	30.61±2.94
FMN16	0.43±0.06	1.096±0.05	10±2.56	29.46±3.45

FORMULATION	ENTRAPPMENT EFFICIENCY (%)	FLOATING ABILITY (%)
FMN1	95±0.00	96±2.00
FMN2	83.33±0.57	80.67±1.52
FMN3	89.67±1.15	84±1.00
FMN4	91±1.00	94±1.00
FMN5	87.67±1.52	82±1.00
FMN6	91.67±2.08	92.33±1.54
FMN7	95.33±0.57	90±2.00
FMN8	94.67±1.52	88±1.00
FMN9	93.33±0.57	94.33±0.57
FMN10	86.33±1.15	90±1.00
FMN11	94.67±0.57	90±1.52
FMN12	87.33±1.52	80.67±1.54
FMN13	97.67±1.52	82±1.00
FMN14	84.33±1.52	78.67±1.54
FMN15	99±0.00	90±1.00
FMN16	97.33±1.52	84±1.15

Response	Source	Sum of square	df	Mean square	F-value	p- value
Particle size	Factorial model	8328.01	6	1388.00	5.15	0.0146^*
	A-Polymer	4457.10	3	1485.70	5.52	0.0199^*
	C-Surfactant	3870.91	3	1290.30	4.79	0.0292^*
	Residual	2424.43	9	269.38	-	-
	Cor Total	10752.44	15	-	-	-
Drug entrapment efficiency	Factorial model	333.68	6	55.61	12.14	0.0007^*
	A-Polymer	303.71	3	101.24	22.10	0.0002^*
	C-Surfactant	29.97	3	9.99	2.18	0.1601^NS
	Residual	41.23	9	4.58	-	-
	Cor Total	374.91	15	-	-	-
Floating ability	Factorial model	419.50	6	69.92	9.22	0.0020^*
	A-Polymer	374.75	3	124.92	16.47	0.0005^*
	D-Stirring rate	44.75	3	14.92	1.97	0.1896^NS
	Residual	68.25	9	7.58	-	-
	Cor Total	487.75	15	-	-	-
%CDR 15min	Factorial model	2.48	6	0.41	1.90	0.1852^NS
	A-Polymer	1.13	3	0.38	1.74	0.2286^NS
	C-Surfactant	1.35	3	0.45	2.07	0.1750^NS
	Residual	1.96	9	0.22	-	-
	Cor Total	4.44	15	-	-	-
%CDR 2h	Factorial model	1040.35	6	173.39	2.94	0.0710^*
	A-Polymer	589.29	3	196.43	3.33	0.0700^*
	C-Surfactant	451.06	3	150.35	2.55	0.1208^NS
	Residual	530.29	9	58.92	-	-
	Cor Total	1570.64	15	-	-	-
%CDR 7h	Factorial model	279.46	6	46.58	3.24	0.0555^*
	A-Polymer	173.21	3	57.74	4.02	0.0454^*
	E-Stirring time	106.25	3	35.42	2.47	0.1287^NS
	Residual	129.25	9	14.36	-	-
	Cor Total	408.72	15	-	-	-
%CDR 24h	Factorial model	99.09	6	16.51	5.44	0.0123^*
	A-Polymer	77.43	3	25.81	8.51	0.0054^*
	C-Surfactant	21.66	3	7.22	2.38	0.1374^NS
	Residual	27.30	9	3.03	-	-
	Cor Total	126.39	15	-	-	-

	Predicted	Actual
Particle size (μm)	100	86.67±0.03
% Drug entrapment efficiency	95.31	95±0.00
% Floating ability	95.37	96±2.00
% CDR 15 min	0.66	0.473±0.02
% CDR 2 h	10.98	9.531±0.64
% CDR 7 h	77.43	76.821±3.89
% CDR 24 h	96.95	97.294±5.02

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: Dr. Geetha M. Department of Pharmaceutics. Government College of Pharmacy. No. 2, P. Kalinga Rao Road, Subbaiah Circle. Bengaluru - 560027, Karnataka, India. Phone: +91-990-1844877. Fax: +91-080-22270666. Email: geetha.rohinimalavika@gmail.com