Solid lipid micro-dispersions (SLMs) based on PEGylated solidified reverse micellar solutions (SRMS): a novel carrier system for gentamicin

Figures & data

Table 1. Formulation compositions of the PEGylated SLMs.

Batches	PEG 4000 (g)	Poloxamer 188 (g)	Gentamicin (%w/w)	Lipid base (15%w/w P90G in 35% w/w DF) (g)	Distilled water, q.s. (% w/w)
A1	1.0	2.0	1.00	4.0	100
A2	2.0	2.0	1.00	3.0	100
A3	3.0	2.0	1.00	2.0	100
B1	1.0	2.0	2.00	4.0	100
B2	2.0	2.0	2.00	3.0	100
B3	3.0	2.0	2.00	2.0	100
C1	1.0	2.0	3.00	4.0	100
C2	2.0	2.0	3.00	3.0	100
C3	3.0	2.0	3.00	2.0	100
D1	1.0	2.0	–	4.0	100
D2	2.0	2.0	–	3.0	100
D3	3.0	2.0	–	2.0	100

Batches A₁–A₃, B₁–B₃ and C₁–C₃ are gentamicin-loaded PEGylated SLMs, while batches D₁–D₃ are unloaded (zero-drug) SLMs; P90G = Phospholipon® 90G, DF = dika wax.

Figure 1. DSC thermogram of dika wax.

Figure 2. DSC thermogram of Phospholipon® 90G (P90G).

Figure 3. DSC thermogram of lipid matrix (dika wax:P90G).

Figure 4. DSC thermogram of PEG 4000.

Figure 5. DSC thermogram of gentamicin.

Table 2. Thermal properties of the drug and PEGylated SLMs.

Batches	Melting point (°C)	Enthalpy (mW/mg)
Gentamicin	285.8	−10.41
A1	112.7	−164.0
A2	129.4	−312.8
A3	127.1	−254.0
B1	111.8	−173.1
B2	122.0	−213.1
B3	119.7	−205.4
C1	110.2	−215.7
C2	123.5	− 200.9
C3	125.8	− 195.0

Batches A₁–A₃, B₁–B₃ and C₁–C₃ contain 1.0, 2.0 and 3.0% w/w of gentamicin, respectively.

Figure 6. Representative photomicrographs of the SLM formulations. Batches A₁, B₁ and C₁ are gentamicin-loaded SLMs while batch D₁ is the unloaded (zero-drug) SLMs.

Table 3. Some physicochemical properties of PEGylated SLMs.

		pH^a,c
Batches	Particle size (µm)^a,b	One week	One month	Three months	EE (%)^a,c	LC (g API/100 lipid)^c
A1	34.49 ± 2.56	5.20 ± 0.05	5.25 ± 0.30	5.24 ± 0.04	52.40 ± 1.96	20.00
A2	36.56 ± 2.81	5.31 ± 0.12	5.30 ± 0.08	5.29 ± 0.05	59.61 ± 1.80	28.20
A3	37.53 ± 1.97	5.21 ± 0.17	5.27 ± 0.02	5.23 ± 0.09	62.50 ± 2.73	33.60
B1	42.53 ± 3.15	6.49 ± 0.11	6.46 ± 0.07	6.47 ± 0.25	66.43 ± 3.14	38.00
B2	45.70 ± 2.04	6.50 ± 0.02	6.49 ± 0.10	6.48 ± 0.22	71.68 ± 2.22	44.70
B3	49.54 ± 3.12	6.46 ± 0.17	6.48 ± 0.09	6.45 ± 0.03	75.40 ± 3.99	49.50
C1	50.55 ± 1.09	7.10 ± 2.45	7.13 ± 2.45	7.11 ± 2.45	80.66 ± 3.58	52.00
C2	52.50 ± 2.13	7.15 ± 0.82	7.12 ± 0.82	7.13 ± 0.82	82.52 ± 3.65	57.30
C3	53.52 ± 3.06	7.17 ± 1.97	7.20 ± 1.97	7.18 ± 1.97	84.79 ± 3.81	61.80
D1	31.49 ± 1.02	4.27 ± 0.12	4.30 ± 0.05	4.28 ± 0.07	–	–
D2	32.50 ± 1.70	4.28 ± 0.04	4.27 ± 0.12	4.29 ± 0.08	–	–
D3	33.50 ± 2.31	4.31 ± 0.03	4.30 ± 0.02	4.27 ± 0.11	–	–

^aMean ± SD, ^bn = 30, ^cn = 3; Batches A₁–A₃, B₁–B₃ and C₁–C₃ are gentamicin-loaded PEGylated SLMs, while batches D₁–D₃ are unloaded (zero-drug) SLMs; EE = encapsulation efficiency, LC = loading capacity.

Figure 7. Permeation profile of gentamicin from (a) A₁–A₃ SLMs; (b) B₁–B₃ SLMs; (c) C₁–C₃ SLMs in PBS, pH 7.4 (n = 3). A₁–A₃, B₁–B₃ and C₁–C₃ contain 1.0, 2.0 and 3.0% w/w of gentamicin, respectively, while G₁ and G₂ are commercial gentamicin injection and plain gentamicin, respectively.

Table 4. Permeation parameters of gentamicin-loaded PEGylated SLMs.

Formulation code	Flux (J) (µg/cm^2 min)	Permeation coefficient (P) (cm/min)
A1	4.761	9.522 × 10^−7
A2	4.839	9.678 × 10^−7
A3	4.961	9.857 × 10^−7
B1	4.126	9.048 × 10^−7
B2	4.572	9.395 × 10^−7
B3	4.717	9.496 × 10^−7
C1	4.917	9.834 × 10^−7
C2	5.161	1.032 × 10^−6
C3	5.239	1.781 × 10^−6
G1	3.837	8.329 × 10^−7
G2	2.354	7.106 × 10^−7

A₁–A₃, B₁–B₃ and C₁–C₃ are PEGylated SLMs containing 1.0, 2.0 and 3.0% w/w of gentamicin, respectively; G₁ and G₂ are commercial gentamicin injection and plain gentamicin, respectively.

Table 5. Susceptibility of Pseudomonas aeruginosa to gentamicin in the PEGylated SLMs.

	IZD (mm)^a,b
	Time (min)
Batches	60	120	180	240	300	360	420
A1	22.70 ± 0.19	23.89 ± 0.12	25.47 ± 0.11	26.78 ± 0.54	28.15 ± 0.96	30.37 ± 1.45	31.72 ± 1.69
A2	22.85 ± 0.43	24.07 ± 0.35	26.55 ± 0.32	27.83 ± 0.09	29.74 ± 0.85	31.91 ± 1.73	33.53 ± 1.04
A3	23.68 ± 0.81	25.97 ± 0.06	27.66 ± 0.94	29.34 ± 0.87	31.52 ± 1.06	33.81 ± 1.75	36.56 ± 1.50
B1	22.92 ± 0.09	24.37 ± 0.08	27.23 ± 0.19	30.19 ± 1.04	33.62 ± 1.53	36.89 ± 1.44	37.32 ± 1.09
B2	24.02 ± 0.50	25.98 ± 0.17	28.67 ± 0.25	31.87 ± 1.23	34.63 ± 1.09	37.95 ± 1.18	38.64 ± 1.33
B3	24.95 ± 0.67	26.62 ± 0.88	29.03 ± 0.72	32.83 ± 0.98	37.95 ± 1.82	42.56 ± 2.07	44.35 ± 1.98
C1	22.99 ± 0.45	24.59 ± 1.67	27.43 ± 2.20	30.96 ± 1.79	33.82 ± 3.10	47.19 ± 2.48	40.22 ± 3.93
C2	24.03 ± 0.78	27.29 ± 1.09	31.80 ± 1.33	35.24 ± 2.05	38.07 ± 2.41	41.26 ± 0.99	43.87 ± 1.56
C3	25.00 ± 0.82	28.57 ± 1.46	32.23 ± 1.00	36.04 ± 1.72	39.68 ± 2.15	43.80 ± 2.75	47.49 ± 2.38
G1	22.13 ± 0.98	22.46 ± 0.74	23.71 ± 0.19	25.64 ± 0.43	27.98 ± 0.95	29.16 ± 0.79	31.87 ± 1.47
G2	19.80 ± 0.62	22.28 ± 0.39	23.59 ± 0.97	24.77 ± 0.56	25.14 ± 0.79	27.81 ± 0.35	29.77 ± 0.72

^aMean ± SD, ^bn = 3, A₁–A₃, B₁–B₃ and C₁–C₃ are PEGylated SLMs containing 1.0, 2.0 and 3.0% w/w of gentamicin, respectively; G₁ and G₂ are commercial gentamicin injection and plain gentamicin, respectively.

Table 6. Susceptibility of Staphylococcus aureus to gentamicin in the PEGylated SLMs.

	IZD (mm)^a,b
	Time (min)
Batches	60	120	180	240	300	360	420
A1	22.98 ± 0.07	24.09 ± 0.02	26.00 ± 0.17	28.13 ± 0.70	30.25 ± 1.96	32.87 ± 1.04	33.72 ± 0.99
A2	23.00 ± 0.21	25.32 ± 0.45	27.19 ± 0.06	29.08 ± 0.14	31.28 ± 1.77	33.64 ± 2.05	35.00 ± 2.87
A3	24.13 ± 0.94	26.83 ± 0.17	28.08 ± 0.74	30.43 ± 1.25	32.93 ± 0.82	34.48 ± 1.90	37.30 ± 1.56
B1	23.63 ± 0.87	25.82 ± 0.59	28.53 ± 0.62	31.95 ± 0.89	34.27 ± 2.08	37.14 ± 3.00	38.63 ± 1.75
B2	24.46 ± 0.90	26.37 ± 0.67	29.19 ± 0.83	32.44 ± 2.00	35.94 ± 3.01	38.86 ± 1.98	39.46 ± 2.46
B3	25.03 ± 0.76	28.16 ± 0.45	30.62 ± 0.78	33.95 ± 0.83	38.32 ± 0.56	43.18 ± 2.14	45.53 ± 1.93
C1	23.03 ± 0.94	26.18 ± 1.02	29.75 ± 2.31	32.46 ± 1.98	36.72 ± 3.06	39.09 ± 2.84	42.87 ± 3.00
C2	24.59 ± 0.23	27.73 ± 0.94	30.10 ± 1.90	33.89 ± 2.09	37.64 ± 2.52	41.47 ± 1.88	44.59 ± 2.22
C3	25.40 ± 0.19	28.28 ± 0.08	31.98 ± 1.04	34.76 ± 1.22	39.99 ± 1.97	44.00 ± 2.55	49.40 ± 3.07
G1	22.18 ± 0.07	23.64 ± 0.71	24.99 ± 0.01	26.05 ± 0.33	28.19 ± 0.15	30.19 ± 1.07	32.47 ± 1.88
G2	22.00 ± 0.16	23.19 ± 0.05	24.07 ± 0.09	25.38 ± 0.66	26.77 ± 0.90	28.15 ± 0.03	30.98 ± 2.07

^aMean ± SD, ^bn = 3, A₁–A₃, B₁–B₃ and C₁–C₃are PEGylated SLMs containing 1.0, 2.0 and 3.0% w/w of gentamicin, respectively; G₁ and G₂ are commercial gentamicin injection and plain gentamicin, respectively.

Figure 8. Changes of gentamicin concentration in blood over 24-h study period, of rats orally administered with the optimized gentamicin-loaded PEGylated solid lipid microparticles (C₃) and gentamicin pure sample (G₂) at a dose of 5 mgkg⁻¹ (n = 5).