Respirable controlled release polymeric colloid (RCRPC) of bosentan for the management of pulmonary hypertension: in vitro aerosolization, histological examination and in vivo pulmonary absorption

Figures & data

Table 1. Composition and characterization of the prepared bosentan RCRPC based on central composite design.

Formulation #	PVA conc. (X2) (%)	PVA conc. (X2) (%)	Stirring rate (X3) (rpm)	Particle size (nm) Y1	PDI Y2	EE (%) Y3	Q0.5 (%) Y4	Q8 (%) Y5	Q16 (%) Y6	Zeta potential (mV)
RCRPC 1	400.00	5.00	7000.00	1225.0 ± 3.53	0.514 ± 0.01	80.49 ± 0.01	0.50	13.86	24.45	−12.20 ± 0.21
RCRPC 2	300.00	2.31	8500.00	394.2 ± 9.82	0.404 ± 0.01	35.36 ± 0.09	0.75	29.30	45.55	−25.30 ± 0.28
RCRPC 3	200.00	5.00	7000.00	913.8 ± 4.45	0.580 ± 0.01	63.12 ± 0.26	0.94	10.41	15.77	−13.30 ± 0.14
RCRPC 4	300.00	4.00	8500.00	552.3 ± 1.48	0.481 ± 0.01	47.82 ± 1.67	1.10	21.86	38.56	−18.70 ± 0.70
RCRPC 5	300.00	4.00	8500.00	373.7 ± 4.45	0.360 ± 0.01	32.18 ± 1.192	1.02	23.00	25.19	−20.80 ± 0.28
RCRPC 6	200.00	5.00	10000.00	532.6 ± 5.30	0.685 ± 0.01	82.19 ± 0.63	0.80	15.26	24.42	−16.70 ± 0.14
RCRPC 7	300.00	4.00	8500.00	438.9 ± 6.15	0.400 ± 0.01	55.32 ± 0.79	1.30	29.80	42.00	−19.10 ± 0.14
RCRPC 8	300.00	4.00	8500.00	412.3 ± 1.55	0.404 ± 0.01	55.87 ± 0.40	1.57	22.96	35.67	−18.60 ± 0.49
RCRPC 9	200.00	3.00	7000.00	1130.0 ± 1.41	0.560 ± 0.01	29.75 ± 0.18	1.10	27.10	42.20	−13.90 ± 0.14
RCRPC 10	200.00	3.00	10000.00	554.7 ± 0.84	0.530 ± 0.01	30.74 ± 0.32	0.77	10.54	19.58	−16.90 ± 0.07
RCRPC 11	400.00	5.00	10000.00	497.7 ± 0.98	0.455 ± 0.01	76.50 ± 0.70	0.52	13.74	20.03	−14.90 ± 0.42
RCRPC 12	400.00	3.00	7000.00	1259.0 ± 5.65	0.541 ± 0.01	33.66 ± 0.16	1.09	14.86	27.34	−14.80 ± 0.14
RCRPC 13	468.18	4.00	8500.00	442.6 ± 5.37	0.391 ± 0.01	43.00 ± 0.14	1.10	13.00	28.00	−22.90 ± 0.49
RCRPC 14	300.00	4.00	8500.00	508.0 ± 0.21	0.504 ± 0.02	49.00 ± 0.77	1.70	23.30	39.70	−18.90 ± 0.21
RCRPC 15	400.00	3.00	10000.00	519.7 ± 0.42	0.465 ± 0.01	60.10 ± 0.14	1.40	15.80	25.20	−18.50 ± 0.21
RCRPC 16	300.00	5.68	8500.00	491.6 ± 2.54	0.363 ± 0.01	56.52 ± 0.25	0.50	17.17	27.03	−14.60 ± 0.21
RCRPC 17	131.82	4.00	8500.00	518.4 ± 1.48	0.560 ± 0.02	55.74 ± 1.09	1.18	14.20	19.42	−16.30 ± 0.21
RCRPC 18	300.00	4.00	11022.60	432.9 ± 3.25	0.373 ± 0.021	80.24 ± 0.25	1.70	25.50	41.50	−15.40 ± 0.07
RCRPC 19	300.00	4.00	8500.00	312.2 ± 7.07	0.266 ± 0.01	38.00 ± 0.070	1.20	20.00	35.00	−23.60 ± 0.28
RCRPC 20	300.00	4.00	5977.31	1350.0 ± 0.70	0.600 ± 0.02	91.12 ± 0.72	1.30	29.20	30.60	−19.60 ± 0.35

X₁, X₂ and X₃ are the independent variables.

Y₁, Y₂, Y₃, Y₄, Y₅ and Y₆ are the dependent variables (responses).

Figure 1. Photomicrograph (a) and TEM micrograph (b) of the optimized bosentan RCRPC.

Figure 2. Aerodynamic parameters of the optimized bosentan RCRPC, drug solution and drug suspension after nebulization in a TSI.

Figure 3. The mean bosentan concentrations in plasma of rats after intratracheal delivery of the optimized bosentan RCRPC compared to the oral administration of bosentan suspension.

Table 2. The mean pharmacokinetic parameters of bosentan in plasma after intratracheal delivery of the optimized RCRPC and oral administration of bosentan suspension to rats.

Parameter	Oral drug suspension	Intratracheal RCRPC	Significance (p value)
Cmax (ng/mL)	105.1 ± 18.12	1264.8 ± 323.68	0.0003
Tmax (h)	4.0 ± 1.41	2.62 ± 1.49	0.2296
AUC0–t (ng.h/mL)	680.2 ± 133.8	8649.8 ± 3319.7	0.0030
AUC0–∞ (ng.h/mL)	760.25 ± 167.66	9592.61 ± 3551.65	0.0025
T1/2 (h)	2.8 ± 0.59	3.17 ± 0.47	0.3723

Values are expressed as mean ± SD.

Figure 4. Histological microscopic features of rat lung tissue after intratracheal administration of PBS as a negative control (i), oral administration of oral bosentan suspension (ii) and intratracheal administration of bosentan RCRPC (iii).