Enhancing acne treatment with novel ternary metal complexes embedded in solid lipid nanoparticles: Development, in vitro characterization, and clinical evaluation

Document Type : Research Paper


1 Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Future University in Egypt, 11835 Cairo, Egypt

2 Chemistry Department, Faculty of Science, Ain Shams University, 11566, Abbassia, Cairo, Egypt

3 2Chemistry Department, Faculty of Science, Ain Shams University, 11566, Abbassia, Cairo, Egypt

4 Eva Cosmetics Manufacturing Facility, Cairo, Egypt


Objective(s): The aim of this study is to investigate the potential of Solid lipid nanoparticles (SLNs) to enhance the therapeutic effectiveness of ternary metal complexes of hydroxy acids in the treatment of acne.
Materials and Methods: Ternary complexes of Cu (II) and Zn (II) with glycine amino acid (Gly) as a primary ligand, and Hydroxy acids (salicylic acid (L1), lactic acid (L2) or glycolic acid (L3)) as a secondary ligand, were synthesized in a slightly acidic medium and isolated in different ratios. These ternary complexes were loaded into SLNs and evaluated for particle size, polydispersity index, Zeta potential, entrapment efficiency and in vitro release studies. SLN-encapsulated ternary metal complexes were clinically evaluated in acne patients.
Results: Scanning Electron Microscopy revealed that SLNs were spherical in shape and varied in size from 115 to 210 nm when measured with a Malvern Zetasizer. The zeta potential was ranged from -41.33 ± -2.5 to -47.32 ± -2.1 mV. The calculated entrapment efficiency (EE%) was 79 - 83% with slow release of the ternary complexes from the prepared SLNs. The in-vivo clinical study disclosed that Zn(L1)(Gly) SLNs outperformed Cu(L1)(Gly) SLNs in terms of acne spot reduction and patient satisfaction.
Conclusion: In conclusion, this study demonstrated that SLNs-encapsulated ternary metal complexes are a promising new treatment for acne.


1.  Antimisiaris SG, Marazioti A, Kannavou M, Natsaridis E, Gkartziou F, Kogkos G, et al. Overcoming barriers by local drug delivery with liposomes. Adv Drug Deliv Rev. 2021; 174: 53-86. 
2. De Jong WH, Borm PJ. Drug delivery and nanoparticles:applications and hazards. Int J Nanomedicine. 2008; 3(2): 133-149.
3.    Mazayen ZM, Ghoneim AM, Elbatanony RS, Basalious EB, Bendas ER. Pharmaceutical nanotechnology: from the bench to the market. Futur J Pharm Sci. 2022; 8(1): 12, 1-11.
4.    Patil-Sen Y. Advances in nano-biomaterials and their applications in biomedicine. Emerg Top Life Sci. 2021; 5(1): 169-176. 
5.    Scioli Montoto S, Muraca G, Ruiz ME. Solid Lipid Nanoparticles for Drug Delivery: Pharmacological and Biopharmaceutical Aspects. Front Mol Biosci. 2020; 7: 1-24.
6.    Rajpoot K. Solid Lipid Nanoparticles: A Promising Nanomaterial in Drug Delivery. Curr Pharm Des. 2019; 25(37):3943-3959. 
7.    Ghasemiyeh P, Mohammadi-Samani S. Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: applications, advantages and disadvantages. Res Pharm Sci. 2018; 13(4): 288-303.
8.    Patil H, Kulkarni V, Majumdar S, Repka MA. Continuous manufacturing of solid lipid nanoparticles by hot melt extrusion. Int J Pharm. 2014; 25;471(1-2): 153-156.
9.    Khairnar SV, Pagare P, Thakre A, Nambiar AR, Junnuthula V, Abraham MC, et al. Review on the Scale-Up Methods for the Preparation of Solid Lipid Nanoparticles. Pharmaceutics. 2022; 14(9): 1-22.
10.    Geszke-Moritz M, Moritz M. Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies. Mater Sci Eng C Mater Biol Appl. 2016; 68: 982-994. 
11.    Tapeinos C, Battaglini M, Ciofani G. Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases. J Control Release. 2017; 264: 306-332. 
12.    Lazăr LF, Olteanu ED, Iuga R, Burz C, Achim M, Clichici S, et al. Solid Lipid Nanoparticles: Vital Characteristics and Prospective Applications in Cancer Treatment. Crit Rev Ther Drug Carrier Syst. 2019; 36(6): 537-581. 
13.    González-Paredes A, Sitia L, Ruyra A, Morris CJ, Wheeler GN, McArthur M, et al. Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides. Eur J Pharm Biopharm. 2019; 134: 166-177. 
14.    Wang F, Chen L, Jiang S, He J, Zhang X, Peng J, et al. Optimization of methazolamide-loaded solid lipid nanoparticles for ophthalmic delivery using Box-Behnken design. J Liposome Res. 2014; 24(3): 171-181. 
15.    Jenning V, Gysler A, Schäfer-Korting M, Gohla SH. Vitamin A loaded solid lipid nanoparticles for topical use: occlusive properties and drug targeting to the upper skin. Eur J Pharm Biopharm. 2000; 49(3): 211-218. 
16.    Fox L, Csongradi C, Aucamp M, du Plessis J, Gerber M. Treatment Modalities for Acne. Molecules. 2016; 21(8): 1-20. 
17.    Toyoda M, Morohashi M. Pathogenesis of acne. Med Electron Microsc. 2001; 34(1): 29-40. 
18.    Cervantes J, Eber AE, Perper M, Nascimento VM, Nouri K, Keri JE. The role of zinc in the treatment of acne: A review of the literature. Dermatol Ther. 2018; 31(1): 1-17. 
19.    Gupta M, Mahajan VK, Mehta KS, Chauhan PS. Zinc therapy in dermatology: a review. Dermatol Res Pract. 2014; 709152: 1-11. 
20.    Ikaraoha CI, Mbadiwe NC, Anyanwu CJ, Odekhian J, Nwadike CN, Amah HC. The Role of Blood Lead, Cadmium, Zinc and Copper in Development and Severity of Acne Vulgaris in a Nigerian Population. Biol Trace Elem Res. 2017; 176(2): 251-257. 
21.    Parsons HH. The Use of Copper in Acne. Cal West Med. 1933; 38(1):42-43. 
22.    Paiva-Santos AC, Herdade AM, Guerra C, Peixoto D, Pereira-Silva M, Zeinali M, et al. Plant-mediated green synthesis of metal-based nanoparticles for dermopharmaceutical and cosmetic applications. Int J Pharm. 2021; 597:120311. 
23.    Kapuścińska A, Nowak I. Use of organic acids in acne and skin discolorations therapy. Postepy Hig Med Dosw. 2015; 69: 374-383. 
24.    Kristensen B, Kristensen O. Topical salicylic acid interferes with UVB therapy for psoriasis. Acta Derm Venereol. 1991; 71(1): 37-40. 
25.    Herrmann M. Salicylic acid: an old dog, new tricks, and staphylococcal disease. J Clin Invest. 2003; 112(2): 149-151. 
26.    Souaya ER, Khalil MMH, Ismail EH, Bendas ER, Neaz OS. Synthesis and Characterization of Ternary Complexes of certain Hydroxyl Acids and their Biological Applications. Res J Pharm Biol Chem Sci. 2014; 5(4): 18-30.
27.    Isamil EH, AlBlewi FF, Soliman N, Khalil MMH. Thermal studies and mass loss inhibition for some new mixed amino acid metal complexes with their applications. J Therm Anal Calorim. 2016; 125: 289-300.
28.    Farsani PA, Mahjub R, Mohammadi M, Oliaei SS, Mahboobian MM. Development of Perphenazine-Loaded Solid Lipid Nanoparticles: Statistical Optimization and Cytotoxicity Studies. Biomed Res Int. 2021; 6619195: 1-14. 
29.    Peng L-H, Wei W, Shan Y-H, Chong Y-S, Yu L, Gao J-Q. Sustained release of piroxicam from solid lipid nanoparticle as an effective anti-inflammatory therapeutics in vivo. Drug Dev Ind Pharm. 2017; 43(1): 55-66.
30.    Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010; 67(3): 217-223. 
31.    Ritger PL, Peppas NA. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. J Control Release. 1987; 5(1): 37-42.
32.    Kessler E, Flanagan K, Chia C, Rogers C, Glaser DA. Comparison of alpha- and beta-hydroxy acid chemical peels in the treatment of mild to moderately severe facial acne vulgaris. Dermatol Surg. 2008; 34(1): 45-50.
33.    Kootiratrakarn T, Kampirapap K, Chunhasewee C. Epidermal permeability barrier in the treatment of keratosis pilaris. Dermatol Res Pract. 2015; 205012: 1-5. 
34.    Dixon JR, Jr. The International Conference on Harmonization Good Clinical Practice guideline. Qual Assur. 1998; 6(2): 65-74. 
35.    Zhang L, Shao X, Chen Y, Wang J, Ariyawati A, Zhang Y, et al. 30% supramolecular salicylic acid peels effectively treats acne vulgaris and reduces facial sebum. J Cosmet Dermatol. 2022; 21(8): 3398-3405. 
36.    Schlager JG, Rosumeck S, Werner RN, Jacobs A, Schmitt J, Schlager C, et al. Topical treatments for scalp psoriasis. Cochrane Database Syst Rev. 2016;2(2): 1-215. 
37.    Dall’Oglio F, Nasca MR, Gerbino C, Micali G. An Overview of the Diagnosis and Management of Seborrheic Dermatitis. Clin Cosmet Investig Dermatol. 2022; 15: 1537-1548. 
38.    Zander E, Weisman S. Treatment of acne vulgaris with salicylic acid pads. Clinical therapeutics. 1992; 14(2): 247-253. 
39.    da Rocha Neto AC, Maraschin M, Di Piero RM. Antifungal activity of salicylic acid against Penicillium expansum and its possible mechanisms of action. Int J Food Microbiol. 2015; 215: 64-70.
40.    Madan RK, Levitt J. A review of toxicity from topical salicylic acid preparations. J Am Acad Dermatol. 2014; 70(4): 788-792. 
41.    Arif T. Salicylic acid as a peeling agent: a comprehensive review. Clin Cosmet Investig Dermatol. 2015; 8: 455-461. 
42.    Yang M, Song WJ. Diverse protein assembly driven by metal and chelating amino acids with selectivity and tunability. Nat Commun. 2019; 10(1): 1-11. 
43.    Mudavath R, Vuradi RK, Bathini U, Narsimha N, Kunche S, Sunitha S, et al. Design, synthesis, in vitro anticancer, antioxidant and antibacterial activity; DNA/BSA binding, photoleavage and docking studies of Cu(II) ternary metal complexes. Nucleosides Nucleotides Nucleic Acids. 2019; 38(11): 874-900. 
44.    Thanavelan R, Ramalingam G, Manikandan G, Thanikachalam V. Stability constants of mixed ligand complexes of lead(II) with 1-(aminomethyl) cyclohexane acetic acid and α-amino acids.  J Saudi Chem Soc. 2014; 18(3): 227-233.