Microemulsions Improve Topical Protoporphyrin IX (PpIX) Delivery for Photodynamic Therapy of Skin Cancer

Leite, Paula Ângela de Souza Marinho; Miguel, Nadia Campos de Oliveira; Pierre, Maria Bernadete Riemma

doi:10.1590/s2175-97902023e21920

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 59 • 2023 • https://doi.org/10.1590/s2175-97902023e21920 copy

Microemulsions Improve Topical Protoporphyrin IX (PpIX) Delivery for Photodynamic Therapy of Skin Cancer

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

We report here microemulsions (MEs) for topical delivery of protoporphyrin IX (PpIX) for Photodynamic Therapy (PDT) of skin cancers. Selected MEs consisting of Oil/Water (O/W) bicontinuous (BC) and Water/Oil (W/O) preparations were characterized as to pH, nanometric size, zeta potential, drug content, and viscosity. Sustained in vitro PpIX release was achieved from MEs 2A (O/W), 10B (BC) and 16B (W/O) through an artificial membrane for up to 24 h, characterizing MEs as drug delivery systems. None of these MEs showed permeation through the skin, demonstrating the required topical effect. After 4 h, in vitro retention of PpIX in the stratum corneum (SC) was higher from both ME 10B and control (PpIX at 60 µg/mL in PEG 300). However, in the Epidermis + Dermis ([Ep + D]), retention from ME 10B and ME 16B was ~40 times higher compared to control. Confocal Laser Scanning Microscopy (CLSM) showed higher fluorescence intensity in the SC for both control and ME 10B, whereas ME 10B fluorescence was higher in [Ep+D]. The results indicate that ME 10B is suitable for PpIX encapsulation, showing good characteristics and a localized effect for a potential delivery system for PDT-associated treatments of skin cancers.

Keywords:
Protoporphyrin IX; Photodynamic therapy; Skin cancer; Microemulsion; In vitro skin retention.

Name	Aqueous phase (%)	Oil phase (%)	∑ S + Co-S (% )	S: Co-S
ME 1 (BC)	10	10	80	95 % :5 %
				90 % :10 %
				85 %: 15 %
				80 % :20 %
				75 % :25 % (3:1)
				66.6 %: 33.3% (2:1)
				50 % :50 % (1:1)
				40 % :60 % (2:3)
				33.3 %:66.6 % (1:2)
				25 % :75 % (1:3)
ME 2 (O/W)	20	10	70	90 %:10 %
				85 %:15 %
				80 %:20 %
				75 %:25 % (3:1)
				66.6 %:33.3 % (2:1)
				60 %:40 % (3:2)
				50 %:50 % (1:1)
				40 %:60 % (2:3)
				33.3 %:66.6 % (1:2)
				25 %:75 % (1:3)
ME 9 (W/O)	10	20	70	95 %:5 %
				90 %:10 %
				85 %:15 %
				80 %:20 %
				75 %:25 % (3:1)
				66.6 %:33.3 % (2:1)
				60 %:40 % (3:2)
				50 %:50 % (1:1)
				40 %:60 % (2:3)
				33.3 %:66.6 % (1:2)
				25 %:75 % (1:3)
ME 10 (BC)	20	20	60	95 %:5 %
				90 %:10 %
				85 %:15 %
				80 %:20 %
				75 %:25 % (3:1)
				66.6 %:33.3 % (2:1)
				60 %:40 % (3:2)
				50 %:50 % (1:1)
				40 %:60 % (2:3)
				33.3 %:66.66 % (1:2)
				25 %:75 % (1:3)
ME 16 (W/O)	10	30	60	95 %:5 %
				90 %:10 %
				85 %:15 %
				80 %:20 %
				75 %:25 % (3:1)
				66.6 %:33.3 % (2:1)
				60 %: 40 % (3:2)
				50 %:50 % (1:1)
				40 %:60 % (2:3)
				33.3 %:66.6 % (1:2)
				25 %:75 % (1:3)
ME 22 (W/O)	10	40	50	75 %:25 % (3:1)
				33.3 %:66.6 % (1:2)
				25 %:75 % (1:3)
ME 27 (W/O)	10	50	40	75 %:25 % (3:1)

Formulations	Aqueous phase (%)	Oil phase (%)	S + Co-S % and (proportion)
ME 2 (O/A)
ME 2A	20	10	70 (3:1)
ME 2B			70 (2:1)
ME 2C			70 (1:1)
ME 2D			70 (1:2)
ME 2E			70 (1:3)
ME 10 (BC)
ME 10 A	20	20	60 (3:1)
ME 10 B			60 (2:1)
ME 10 C			60 (1:1)
ME 10 D			60 (1:2)
ME 10 E			60 (1:3)
ME 16 (A/O)
ME 16 A	10	30	60 (3:1)
ME 16 B			60 (2:1)
ME 16 C			60 (1:1)
ME 16 D			60 1:2)
ME 16 E			60 (1:3)
ME 22 (A/O)
ME 22 A	10	40	50 (1:2)
ME 22 B	10	40	50 (1:3)

ME	Name	pH± S.D	R.I	Viscosity (cp)	Size (nm±S.D)	PDI± S.D	ZP (mV) ± S.D
	2A	5.53 ± 0.374	1.45	469 ± 2.455	162.8 ± 0.866	0.5 ± 0.007	-32 ± 1.210
	2B	5.62 ± 0.438	143	329 ± 1.345^**	178.3 ± 2.159	0.4 ± 0.006	-37 ± 9.151
O/A	2C	5.37 ± 0.261	1.42	282 ± 0.98^**	248.7 ± 4.813	0.5 ± 0.035	-28 ± 1.844
	2D	5.45 ± 0.318	1.42	329 ± 3.540^**	565.9 ± 14.868^**	0.5 ± 0.071	-36 ± 1.504
	2E	4.78±0.156^**	1.41^**	361 ± 2.430^**	535.9 ± 23.674^**	0.5 ± 0.047	-46 ± 1.106^*
	10A	5.04 ± 0.028	1.44	1700 ±10.250	319.3 ± 13.151	0.5 ± 0.048	-47 ± 2.000
	10B	5.01 ± 0.007	1.44	1850 ±11.750^**	301.4 ± 16.643	0.6 ± 0.051	-29 ± 0.550^**
BC	10C	4.93 ±0.049	1.43	344 ± 0.890^**	367.0 ± 19.410	0.6 ± 0.091	-35 ± 4.44^*
	10D	4.76 ± 0.169	1.35	329 ± 1.345^**	435.1 ± 40.711	0.9 ± 0.210^*	-40 ± 2.193
	10E	4.47 ±0.021	1.77^**	312 ± 3.450^**	435.8 ± 6.718	0.6 ± 0.031	-41 ± 1.473
	16A	5.00 ± 0.000	1.46	422 ±1.560	288.4 ± 2.739	0.5 ± 0.039	-43 ± 3.066
	16B	4.97 ± 0.021	1.41	548 ± 3.650^**	383.6 ± 6.819	0.6 ± 0.029	-48 ± 3.516
A/O	16C	4.89 ± 0.077	1.43	501 ± 0.560^**	385.8 ± 42.552	0.9 ± 0.097^*	-43 ± 1.137
	16D	4.83 ± 0.120	1.43	391 ±0.446^**	834.2 ± 132.646^**	0.8 ± 0.191	-47 ± 8.386
	16E	4.76±0.169	1.42	344 ± 0.848^**	517.5 ± 100.524^**	0.8 ± 0.239	-62 ± 0.200^**
	22A	4.52±0.014	1.43	361 ±0.890	635.1 ± 41.454	1.0 ± 0.000	-59 ± 0.871
	22B	4.36±0.099	1.42	329 ± 0.786^**	730.8 ± 42.733	1.0±0.000	-50 ± 5.565

Formulations	Electrical conductivity (µS/cm)
2A (O/A)	9.56
2E (O/A)	9.74
10B (BC)	8.24
10C (BC)	8.92
16B (A/O)	3.63 ^*
16C (A/O)	3.63 ^*
22B (A/O)	2.30 ^*

Formulations	pH	Size (nm)	PDI	ZP (mV)
Formulations	(blank/ME-PpIX)	(blank± S.D/ME-PpIX± S.D)	(blank± S.D /ME-PpIX± S.D)	(blank/ME-PpIX)
ME 2A	5.53 ± 0.374	162.8 ± 0.866	0.5 ± 0.057	-32 ± 1.210
ME 2A	5.83 ± 0.200	162.1 ±0.808	0.5 ± 0.006	-33 ± 1.000
ME 10B	5.01 ± 0.007	301.4 ± 16.643	0.6 ± 0.010	-29 ± 0.550
ME 10B	5.33 ± 0.350	359.9 ± 3.330	0.7 ± 0.062	-30 ± 0.450
ME 16B	4.97 ± 0.021	383.6 ± 6.819	0.6 ± 0.057	-48 ± 3.516
ME 16B	4.91 ± 0.030	605.0 ± 68.703^**	0.7 ± 0.103	-40 ± 2.890

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: M. B. R. Pierre. Faculdade de Farmácia. Universidade Federal do Rio de Janeiro. Av. Carlos Chagas Filho, 373. 21.941.590, Rio de Janeiro, Brazil. Phone/fax:+ 55 21 2260.91.92 branch 258. E-mail: bernadete@pharma.ufrj.br.