Chemotherapeutic drug targeting to lungs by way of microspheres after intravenous administration

Figures & data

Figure 1 Photograph showing particles stuck to the spray-drying chamber.

Figure 2 Electron microscopy showing surface morphology of spray-dried particles.

Figure 3 Graph showing particle diameter vs % volume of sample of our powder formulation.

Figure 4 Response Surface Analysis.

Notes: Graph of the response surface graph for PS as a function of three independent variables, weight of gelatin (A) inlet temperature (B), and feed flow rate (C). Optimum response for the three variables (A, B, and C) was found to be at the point (1 g, 100°C, 25 mL/h) with a response/PS of 8.1855 µm.
Abbreviation: PS, particle size.

Table 1 Experimental data/runs showing the response (PS) for different values of the independent variables

Run	A	B	C	PS (µm)
1	1.51	95.00	25.00	7.03
2a	0.88	95.00	25.00	7.98
3	0.88	69.77	25.00	2.98
4a	0.88	95.00	25.00	8.24
5	1.25	110.00	30.00	5.25
6	0.50	110.00	30.00	5.29
7	0.88	120.23	25.00	4.47
8	0.50	110.00	20.00	4.30
9	0.24	95.00	25.00	5.71
10	1.25	80.00	30.00	4.76
11a	0.88	95.00	25.00	8.19
12	1.25	110.00	20.00	5.96
13a	0.88	95.00	25.00	8.20
14a	0.88	95.00	25.00	8.21
15	0.88	95.00	16.59	4.48
16	1.25	80.00	20.00	4.96
17	0.50	80.00	20.00	3.19
18	0.88	95.00	33.41	5.24
19	0.50	80.00	30.00	5.21
20a	0.88	95.00	25.00	8.22

Notes: A, weight of gelatin in grams; B, inlet temperature in degree; C flow rate of feed in mL/h.

a Replication of the center point.

Abbreviation: PS, particle size.

Table 2 Coefficients of the statistical model fitted to the experimental data

Response	Model equation	Model significance	Lack of fit	R^2
PS	Actual equation: −102.35872 + 14.64904A + 1.39865B + 2.83387C − 4.42371A^2 − 0.00692104B^2 − 0.046238C^2 + 0.00666667AB − 0.26133AC − 0.00256667BC Coded equation: +8.17 + 0.38A + 0.38B + 0.25C − 0.62A^2 −1.56B^2 − 1.16C^2 + 0.037AB − 0.49AC − 0.19BC	<0.0001 (significant)	0.2211 (not significant)	0.9954

Abbreviation: PS, particle size.

Table 3 ANOVA of coefficients of the quadratic model fitted to the data

	Coefficient	F	Probability < F
Independent variables
Gelatin, A	+0.38	457.10	<0.0001a
Inlet temperature, B	+0.38	136.85	<0.0001a
Feed flow, C	+0.25	138.22	<0.0001a
Interactions		58.65	<0.0001a
A^2	−0.62	391.46	<0.0001a
B^2	−1.56	2453.00	<0.0001a
C^2	−1.16	1351.66	<0.0001a
AB	0.037	0.79	0.3951
AC	−0.49	134.82	<0.0001a
BC	−0.19	20.81	0.0001a

Note:

a Significant at P < 0.05.

Abbreviation: ANOVA, analysis of variance.

Table 4 Optimization of PS using CCRD

Number	Gelatin (g)	Inlet temperature (°C)	Feed flow (mL/h)	PS (µm)	Desirability
1	1.00	100.00	25.00	8.1855	1.000

Abbreviations: PS, particle size; CCRD, central composite rotatable design.

Figure 5 In vitro drug release curves for both formulation and pure drug.

Abbreviations: 5-FU, 5-fluorouracil; 5-FUG, 5-fluorouracil gelatin.

Figure 6 Shape of the microspheres after in vitro release studies.

Figure 7 Plasma concentration profile showing 5-FU (□) and 5-FUG (◊) release.

Abbreviations: 5-FU, 5-fluorouracil; 5-FUG, 5-fluorouracil gelatin.

Figure 8 Biodistribution of 5-FU formulation in different organs.

Abbreviation: 5-FU, 5-fluorouracil.

Table 5 Plasma concentration of 5-FUG and 5-FU injection after iv administration

Parameters	5-FUG	5-FU injection
AUC (µg·h/mL^−1)	42.14	155.6
K21 (h^−1)	0.19	2.92
K12 (h^−1)	0.039	0.614
t1/2(α) (h)	1.10	0.46
K10 (h^−1)	17.2	8.11
t1/2 (β) (h)	18.9	10.1
Cmax (µg·mL^−1)	3.874	2.124
Vss (L)	0.198	0.131
CL (h^−1)	0.012	0.019

Abbreviations: 5-FU, 5-fluorouracil; 5-FUG, 5-fluorouracil gelatin; iv, intravenous; AUC, area under the curve.

Figure 9 Histology of lung tissue.

Notes: (A) Photomicrograph of H&E-stained section of lung tissue obtained after administration of intravenous 5-FUG. Note the normal cytoarchitecture with no evidence of histopathology tissue changes or gross morphology, H&E (magnification ×400), scale bar 200 µm. (B) Photomicrograph of H&E-stained section of lung tissue obtained after administration of intravenous normal saline. Note the normal cytoarchitecture with no evidence of histopathology tissue changes or gross morphology (magnification ×400), scale bar 200 µm.

Figure 10 Shelf-life of 5-FUG formulation.

Abbreviation: 5-FUG, 5-fluorouracil gelatin.