Design and Development of a Self-nanoemulsifying Drug Delivery System for Co-delivery of Curcumin and Naringin for Improved Wound Healing Activity in an Animal Model

Ajmal Hayat; Ismail Shah; Abdul Jabbar; Shafi Ullah; Muhammad Raza Shah; Muhammad Shafique; Aziz Balouch; Farah Gul

doi:10.1055/a-2376-6380

Planta Medica, Table of Contents

Planta Med 2024; 90(12): 959-970
DOI: 10.1055/a-2376-6380

Formulation and Delivery Systems

Original Papers

Design and Development of a Self-nanoemulsifying Drug Delivery System for Co-delivery of Curcumin and Naringin for Improved Wound Healing Activity in an Animal Model

Ajmal Hayat

¹Department of Pharmacy, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan

,

Ismail Shah‡

¹Department of Pharmacy, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan

,

Abdul Jabbar

²International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan

,

Shafi Ullah

³Department of Pharmaceutical Sciences, Faculty of Pharmacy, Superior University, Lahore, Pakistan

,

Muhammad Raza Shah

²International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan

,

Muhammad Shafique‡

⁴Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, Saudi Arabia

,

Aziz Balouch

²International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan

,

Farah Gul

⁵Pharmacology Section MBC, PCSIR Laboratories Complex, Peshawar, Pakistan

› Author Affiliations

Abstract

The present study endeavored to design and develop a self-nanoemulsifying drug delivery system to improve the solubility and dermatological absorption of curcumin and naringin. Curcumin and naringin-loaded self-nanoemulsifying drug delivery system formulations were developed using aqueous phase titration. Phase diagrams were used to pinpoint the self-nanoemulsifying drug delivery system zones. Tween 80 and Labrasol (surfactants), Transcutol (cosurfactant), and cinnamon oil were chosen from a large pool of surfactants, cosurfactants, and oils based on their solubility and greatest nano-emulsion region. Fourier transform infrared spectroscopy, zeta sizer, and atomic force microscopy were used to characterize the optimized formulations and test for dilution and thermodynamic stability. The optimized curcumin-naringin-self-nanoemulsifying drug delivery system demonstrated the following characteristics: polydispersity index (0.412 ± 0.03), % transmittance (97%), particle size (212.5 ± 05 nm), zeta potential (− 25.7 ± 1.80 mV) and having a smooth and spherical droplet shape, as shown by atomic force microscopy. The ability of their combined formulation to cure wounds was tested in comparison to pure curcumin suspension, empty self-nanoemulsifying drug delivery system, and standard fusidic acid. Upon topical administration, the optimized curcumin-naringin-self-nanoemulsifying drug delivery system demonstrated significant wound healing activity in comparison with a pure curcumin suspension, empty self-nanoemulsifying drug delivery system, and standard fusidic acid. Based upon this result, we assume that skin penetration was increased by using the optimized curcumin-naringin-self-nanoemulsifying drug delivery system with enhanced solubility.

Keywords

SNEDDS - curcumin - Curcuma longa - Zingiberaceae - naringin - Citrus reticulata - Rutaceae - wound healing - phase diagrams - thermodynamic stability - topical administration

Full Text

References

References
1 Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT. Human skin wounds: A major and snowballing threat to public health and the economy. Wound Repair Regen 2009; 17: 763-771
2 Cañedo-Dorantes L, Cañedo-Ayala M. Skin acute wound healing: A comprehensive review. Int J Inflam 2019; 2019: 3706315
3 Wilkinson HN, Hardman MJ. Wound healing: cellular mechanisms and pathological outcomes. Open biol 2020; 10 (09) 200223
4 Saghazadeh S, Rinoldi C, Schot M, Kashaf SS, Sharifi F, Jalilian E, Nuutila K, Giatsidis G, Mostafalu P, Derakhshandeh H. Drug delivery systems and materials for wound healing applications. Adv Drug Deliv Rev 2018; 127: 138-166
5 Pereira RF, Bartolo PJ. Traditional therapies for skin wound healing. Adv Wound Care (New Rochelle) 2016; 5: 208-229
6 Bodeker G, Ryan T, Ong CK. Traditional approaches to wound healing. Clin Dermatol 1999; 17: 93-98
7 Gopinath D, Ahmed MR, Gomathi K, Chitra K, Sehgal P, Jayakumar R. Dermal wound healing processes with curcumin incorporated collagen films. Biomaterials 2004; 25: 1911-1917
8 Sidhu GS, Singh AK, Thaloor D, Banaudha KK, Patnaik GK, Srimal RC, Maheshwari RK. Enhancement of wound healing by curcumin in animals. Wound Repair Regen 1998; 6: 167-177
9 Shirani K, Yousefsani BS, Shirani M, Karimi G. Protective effects of naringin against drugs and chemical toxins induced hepatotoxicity: A review. Phytother Res 2020; 34: 1734-1744
10 El-Desoky AH, Abdel-Rahman RF, Ahmed OK, El-Beltagi HS, Hattori M. Anti-inflammatory and antioxidant activities of naringin isolated from Carissa carandas L.: In vitro and in vivo evidence. Phytomedicine 2018; 42: 126-134
11 Kanta J. The role of hydrogen peroxide and other reactive oxygen species in wound healing. Acta Medica (Hradec Kralove) 2011; 54: 97-101
12 Kandhare AD, Ghosh P, Bodhankar SL. Naringin, a flavanone glycoside, promotes angiogenesis and inhibits endothelial apoptosis through modulation of inflammatory and growth factor expression in diabetic foot ulcer in rats. Chem Biol Interact 2014; 219: 101-112
13 Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: Problems and promises. Mol Pharm 2007; 4: 807-818
14 Wang MJ, Chao PD, Hou YC, Hsiu SL, Wen KC, Tsai SY. Pharmacokinetics and conjugation metabolism of naringin and naringenin in rats after single dose and multiple dose administrations. J Food Drug Anal 2006; 14: 4
15 Budel RG, da Silva DA, Moreira MP, Dalcin AJF, da Silva AF, Nazario LR, Majolo JH, Lopes LQS, Santos RCV, Soares FAA. Toxicological evaluation of naringin-loaded nanocapsules in vitro and in vivo . Colloids Surf B Biointerfaces 2020; 188: 110754
16 Enrico C. Nanotechnology-based drug delivery of natural compounds and phytochemicals for the treatment of cancer and other diseases. Studies in natural products chemistry. Amsterdam: Elsevier; 2019; 62: 91-123
17 Jamil A, Aamir Mirza M, Anwer MK, Thakur PS, Alshahrani SM, Alshetaili AS, Telegaonkar S, Panda AK, Iqbal Z. Co-delivery of gemcitabine and simvastatin through PLGA polymeric nanoparticles for the treatment of pancreatic cancer: In-vitro characterization, cellular uptake, and pharmacokinetic studies. Drug Dev Ind Pharm 2019; 45: 745-753
18 Almutairy BK, Alshetaili A, Alali AS, Ahmed MM, Anwer MK, Aboudzadeh MA. Design of olmesartan medoxomil-loaded nanosponges for hypertension and lung cancer treatments. Polymers (Basel) 2021; 13: 2272
19 Bisht D, Verma D, Mirza MA, Anwer MK, Iqbal Z. Development of ethosomal gel of ranolazine for improved topical delivery: In vitro and ex vivo evaluation. J Mol Liq 2017; 225: 475-481
20 Alam P, Shakeel F, Anwer MK, Foudah AI, Alqarni MH. Wound healing study of eucalyptus essential oil containing nanoemulsion in rat model. J Oleo Sci 2018; 67: 957-968
21 Ponto T, Latter G, Luna G, Leite-Silva VR, Wright A, Benson HA. Novel self-nano-emulsifying drug delivery systems containing astaxanthin for topical skin delivery. Pharmaceutics 2021; 13: 649
22 Shakeel F, Shazly GA, Raish M, Ahmad A, Kalam MA, Ali N, Ansari MA, Elosaily GM. Biological investigation of a supersaturated self-nanoemulsifying drug delivery system of Piper cubeba essential oil. RSC Adv 2015; 5: 105206-105217
23 Van Staden D, du Plessis J, Viljoen J. Development of topical/transdermal self-emulsifying drug delivery systems, not as simple as expected. Sci Pharm 2020; 88: 17
24 Pouton CW. Formulation of self-emulsifying drug delivery systems. Adv Drug Deliv Rev 1997; 25: 47-58
25 Pouton CW. Lipid formulations for oral administration of drugs: Non-emulsifying, self-emulsifying and ʼself-microemulsifyingʼdrug delivery systems. Eur J Pharm Sci 2000; 11: S93-S98
26 Kurisawa M, Chung JE, Uyama H, Kobayashi SJB. Enzymatic synthesis and antioxidant properties of poly (rutin). Biomacromolecules 2003; 4: 1394-1399
27 Nepal PR, Han HK, Choi HK. Preparation and in vitro–in vivo evaluation of Witepsol H35 based self-nanoemulsifying drug delivery systems (SNEDDS) of coenzyme Q10. Eur J Pharm Sci 2010; 39: 224-232
28 Kommuru T, Gurley B, Khan M, Reddy IK. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: Formulation development and bioavailability assessment. Int J Pharm 2001; 212: 233-246
29 Elnaggar YS, El-Massik MA, Abdallah OY. Self-nanoemulsifying drug delivery systems of tamoxifen citrate: Design and optimization. Int J Pharm 2009; 380: 133-141
30 Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: Physical and biopharmaceutical aspects. Pharm Res 1995; 12: 1561-1572
31 Pouton CW, Porter CJ. Formulation of lipid-based delivery systems for oral administration: Materials, methods and strategies. Adv Drug Deliv Rev 2008; 60: 625-637
32 Porter CJ, Pouton CW, Cuine JF, Charman WN. Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev 2008; 60: 673-691
33 Liu Y, Zhang P, Feng N, Zhang X, Wu S, Zhao JJ. Optimization and in situ intestinal absorption of self-microemulsifying drug delivery system of oridonin. Int J Pharm 2009; 365: 136-142
34 Parmar N, Singla N, Amin S, Kohli K. Study of cosurfactant effect on nanoemulsifying area and development of lercanidipine loaded (SNEDDS) self nanoemulsifying drug delivery system. Colloids Surf B Biointerfaces 2011; 86: 327-338
35 Khan AW, Kotta S, Ansari SH, Sharma RK, Ali J. Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid Naringenin: design, characterization, in vitro and in vivo evaluation. Drug Deliv 2015; 22: 552-561
36 Hakim A, Loka IN, Prastiwi NWWS. New method for isolation of naringin compound from Citrus maxima . Nat Resour 2019; 10: 299
37 Kolev TM, Velcheva EA, Stamboliyska BA, Spiteller M. DFT and experimental studies of the structure and vibrational spectra of curcumin. Int J Quantum Chem 2005; 102: 1069-1079
38 Jabbar A, Rehman K, Jabri T, Kanwal T, Perveen S, Rashid MA, Kazi M, Ahmad Khan S, Saifullah S, Shah MR. Improving curcumin bactericidal potential against multi-drug resistant bacteria via its loading in polydopamine coated zinc-based metal–organic frameworks. Drug Delivery 2023; 30: 2159587
39 Kandhare AD, Alam J, Patil MV, Sinha A, Bodhankar SL. Wound healing potential of naringin ointment formulation via regulating the expression of inflammatory, apoptotic and growth mediators in experimental rats. Pharm Biol 2016; 54: 419-432
40 Kumari SD, Chevala NT, Jitta SR, Kumar L, Verma R, Jose J. Design and development of naringin‐loaded proposomal gel for wound healing. J Cosmet Dermatol 2022; 21: 5187-5202
41 Salehi B, Rodrigues CF, Peron G, DallʼAcqua S, Sharifi-Rad J, Azmi L, Shukla I, Singh Baghel U, Prakash Mishra A, Elissawy AM, Singab AN, Pezzani R, Redaelli M, Patra JK, Kulandaisamy Venil C, Das G, Singh D, Kriplani P, Venditti A, Fokou PVT, Iriti M, Amarowicz R, Martorell M, Cruz-Martins N. Curcumin nanoformulations for antimicrobial and wound healing purposes. Phytother Res 2021; 35: 2487-2499
42 Altamimi MA, Kazi M, Hadi Albgomi M, Ahad A, Raish M. Development and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for curcumin transdermal delivery: An anti-inflammatory exposure. Drug Dev Ind Pharm 2019; 45: 1073-1078
43 Velnar T, Bailey T, Smrkolj V. The wound healing process: An overview of the cellular and molecular mechanisms. J Int Med Res 2009; 37: 1528-1542
44 Singh B, Bandopadhyay S, Kapil R, Singh R, Katare OP. Self-emulsifying drug delivery systems (SEDDS): Formulation development, characterization, and applications. Crit Rev Ther Drug Carrier Syst 2009; 26: 427-521
45 Villar AMS, Naveros BC, Campmany ACC, Trenchs MA, Rocabert CB, Bellowa LH. Design and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for enhanced dissolution of gemfibrozil. Int J Pharm 2012; 431: 161-175
46 Taha EI, Ak-Suwayeh SA, Tayel MM, Badran MM. Fast ultra-fine self-nanoemulsifying drug delivery system for improving in vitro gastric dissolution of poor water soluble drug. Acta Pol Pharm 2015; 72: 171-178
47 Date AA, Nagarsenker MS. Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for cefpodoxime proxetil. Int J Pharm 2007; 329: 166-172
48 Kanwal T, Saifullah S, ur Rehman J, Kawish M, Razzak A, Maharjan R, Imran M, Ali I, Roome T, Simjee SU. Design of absorption enhancer containing self-nanoemulsifying drug delivery system (SNEDDS) for curcumin improved anti-cancer activity and oral bioavailability. J Mol Liq 2021; 324: 114774
49 Koshak AE, Algandaby MM, Mujallid MI, Abdel-Naim AB, Alhakamy NA, Fahmy UA, Alfarsi A, Badr-Eldin SM, Neamatallah T, Nasrullah MZ. Wound healing activity of Opuntia ficus-indica fixed oil formulated in a self-nanoemulsifying formulation. Int J Nanomedicine 2021; 16: 3889-3905