Development of megestrol acetate solid dispersion nanoparticles for enhanced oral delivery by using a supercritical antisolvent process

Figures & data

Table 1 The formulation, particle size, and specific surface area of the megestrol acetate solid dispersion nanoparticles prepared using the SAS process

Formulation	Drug content (%)	Mean particle size (nm)	Specific surface area (m^2/g)
Megestrol acetate:HPMC =1:2	95.1±2.6	135.8±18.2	96.16±1.69
Megestrol acetate:PVP K30 =1:2	95.9±3.7	310.9±30.3	40.21±1.33
Megestrol acetate:HPMC:Gelucire 44/14 =1:2:0.5	96.1±2.1	245.9±35.9	49.22±1.09
Megestrol acetate:HPMC:poloxamer 407 =1:2:0.5	95.8±2.3	229.7±21.6	51.13±1.03
Megestrol acetate:HPMC:Ryoto sugar ester L1695 =1:2:0.5	97.1±2.0	155.3±20.1	69.31±1.25
Megestrol acetate:HPMC:TPGS =1:2:0.5	97.7±1.9	495.2±65.3	33.11±1.19
Megestrol acetate:HPMC:Ryoto sugar ester L1695 =1:2:1	98.9±1.8	180.3±29.1	57.22±1.35

Notes:

The drug content (%) = weight of the loaded drug/weight of the feeding drug ×100. Data are expressed as mean ± standard deviation (n=3).

Abbreviations: SAS, supercritical antisolvent; HPMC, hydroxypropylmethyl cellulose; PVP, polyvinylpyrrolidone; TPGS, D-α-tocopheryl polyethylene glycol 1000 succinate.

Figure 1 Scanning electron micrographs (A), differential scanning calorimetry thermograms (B), powder X-ray diffraction patterns (C), and dissolution profiles (D) of megestrol acetate solid dispersion nanoparticles prepared using the SAS process.

Abbreviations: SAS, supercritical antisolvent; HPMC, hydroxypropylmethyl cellulose; PVP, polyvinylpyrrolidone.

Figure 2 Scanning electron micrographs of megestrol acetate solid dispersion nanoparticles prepared using the SAS process.

Notes: (A) Megestrol acetate:HPMC (1:2); (B) megestrol acetate:HPMC:Gelucire 44/14 (1:2:0.5); (C) megestrol acetate:HPMC:poloxamer 407 (1:2:0.5); (D) megestrol acetate:HPMC:TPGS (1:2:0.5); (E) megestrol acetate:HPMC:Ryoto sugar ester L1695 (1:2:0.5); (F) megestrol acetate:HPMC:Ryoto sugar ester L1695 (1:2:1).
Abbreviations: SAS, supercritical antisolvent; SEI, secondary electron imaging; HPMC, hydroxypropylmethyl cellulose; TPGS, D-α-tocopheryl polyethylene glycol 1000 succinate.

Figure 3 The differential scanning calorimetry thermograms of megestrol acetate solid dispersion nanoparticles prepared using the SAS process.

Abbreviations: SAS, supercritical antisolvent; HPMC, hydroxypropylmethyl cellulose; TPGS, D-α-tocopheryl polyethylene glycol 1000 succinate.

Figure 4 Powder X-ray diffraction patterns of megestrol acetate solid dispersion nanoparticles prepared using the SAS process.

Abbreviations: SAS, supercritical antisolvent; HPMC, hydroxypropylmethyl cellulose; TPGS, D-α-tocopheryl polyethylene glycol 1000 succinate.

Table 2 The dissolution data of megestrol acetate solid dispersion nanoparticles prepared using the SAS process

Formulation	Maximum dissolution (%)	DE60a (%)	RDRb (30 minutes)
Megestrol acetate:HPMC =1:2	49.5±1.9	46.0	5.6
Megestrol acetate:PVP K30 =1:2	35.6±1.6	32.3	4.0
Megestrol acetate:HPMC:Gelucire 44/14 =1:2:0.5	61.5±2.1	55.6	6.9
Megestrol acetate:HPMC:poloxamer 407 =1:2:0.5	53.9±2.1	49.5	6.0
Megestrol acetate:HPMC:Ryoto sugar ester L1695 =1:2:0.5	81.5±2.5	76.0	9.3
Megestrol acetate:HPMC:TPGS =1:2:0.5	69.3±3.2	65.0	8.0
Megestrol acetate:HPMC:Ryoto sugar ester L1695 =1:2:1	97.3±2.3	92.4	11.1
Raw megestrol acetate	9.3±0.6	7.3	1.0

Notes:

a Dissolution efficiency was calculated from the area under the dissolution profile at 60 minutes, and is expressed as the percentage of the area of the rectangle described by 100% dissolution within the same period of time;

b relative dissolution rate is the ratio between the amount of drug dissolved from the solid dispersion nanoparticles and that dissolved from raw megestrol acetate after 30 minutes. Data expressed as mean ± standard deviation (n=4).

Abbreviations: SAS, supercritical antisolvent; DE, dissolution efficiency; HPMC, hydroxypropylmethyl cellulose; PVP, polyvinylpyrrolidone; TPGS, D-α-tocopheryl polyethylene glycol 1000 succinate; RDR, relative dissolution rate.

Table 3 The solubility of megestrol acetate in various surfactant solutions at 1% concentration (w/v)

Surfactant	Solubility (μg/mL)
No additive	2.54±0.13
Gelucire 44/14	44.83±2.31
Poloxamer 407	19.18±1.11
Ryoto sugar ester L1695	123.21±1.83
TPGS	82.28±1.01

Notes:

Data expressed as mean ± standard deviation (n=3).

Abbreviation: TPGS, D-α-tocopheryl polyethylene glycol 1000 succinate.

Figure 5 The dissolution profiles of megestrol acetate solid dispersion nanoparticles prepared using the SAS process.

Note: Data expressed as mean ± standard deviation (n=4).
Abbreviations: SAS, supercritical antisolvent; HPMC, hydroxypropylmethyl cellulose; TPGS, D-α-tocopheryl polyethylene glycol 1000 succinate.

Table 4 Pharmacokinetic parameters of megestrol acetate solid dispersion nanoparticles prepared using the SAS process

	AUC0–24(ng·h/mL)	Cmax (ng/mL)	Tmax (hours)
Raw megestrol acetate	2,029.7±407.5	234.8±42.5	2.0±0.6
Drug:HPMC =1:2	5,305.6±1,172.3a	805.7±82.5a	1.1±0.4
Drug:HPMC:Ryoto sugar ester L1695 =1:2:1	8,175.9±1,130.1a,b	1,288.2±198.0a,b	1.0±0.4

Notes:

a P<0.05 versus raw megestrol acetate;

b P<0.05 versus drug:HPMC =1:2. Data expressed as mean ± standard deviation (n=5).

Abbreviations: SAS, supercritical antisolvent; AUC, area under the concentration–time curve; C_max, peak plasma concentration; T_max, time to C_max; HPMC, hydroxypropylmethyl cellulose.

Figure 6 The plasma concentration–time profile of megestrol acetate in rats after oral administration of raw megestrol acetate powder or solid dispersion nanoparticles.

Note: Data expressed as mean ± standard deviation (n=5).
Abbreviation: HPMC, hydroxypropylmethyl cellulose.

Figure 7 Correlation between in vitro dissolution efficiency and in vivo pharmacokinetic parameters.

Notes: (A) AUC; (B) C_max.
Abbreviations: AUC, area under the concentration–time curve; C_max, peak concentration; DE, dissolution efficiency.