RECENT STRATEGIES FOR IMPROVING SOLUBILITY AND ORAL BIOAVAILABILITY OF PIPERINE

Abstract

Piperine, the main bioactive compound found in black pepper (Piper nigrum L.), has long been used in Ayurveda and traditional Chinese medicine (TCM). This compound has remarkable potential pharmacological properties, including being anti-inflammatory, antimicrobial, anticancer, anticonvulsant, antidepressant, neuroprotective, and hepatoprotective. Recent studies have reported piperine activity as an antiviral against SARS-CoV-2, which caused COVID-19. Nevertheless, the clinical use of piperine is still limited, due to its poor water solubility and bioavailability; therefore, various approaches have been developed in order to solve these limitations. This review summarises recent studies (i.e. uploaded to electronic databases in the last 10 years) regarding strategies that have been investigated to improve piperine’s solubility and pharmacokinetic properties, using ‘piperine’, ‘solubility’, ‘bioavailability’, and ‘formulation’ as keywords. Articles that have focused on piperine as the main compound were selected and sorted based on their modification and formulation types. Studies reported various approaches: from derivatives and analogue synthesis, crystal engineering, complexation, particle size reduction (micro- and nanonisation), and lipid- and polymer-based drug delivery systems, to inorganic and hybrid nanoparticles. This review also highlights limitations and challenges for these approaches and encourages further studies to optimise piperine’s potential benefits.

Keywords: Piperine; solubility; bioavailability; formulations; drug delivery systems.

References

1. Tiwari A, Mahadik KR, Gabhe SY. Piperine: A comprehensive review of methods of isolation, purification, and biological properties. Med Drug Discov 2020;7:1–18.
2. Stojanovi?-Radi? Z, Pej?i? M, Dimitrijevi? M, Aleksi? A, Anil Kumar N V., Salehi B, et al. Piperine-A Major Principle of Black Pepper: A review of its bioactivity and studies. Appl Sci 2019;9:1–29.
3. Gorgani L, Mohammadi M, Najafpour GD, Nikzad M. Piperine-The Bioactive Compound of Black Pepper: From Isolation to Medicinal Formulations. Compr Rev Food Sci Food Saf 2017;16:124–40.
4. Quijia CR, Araujo VH, Chorilli M. Piperine: Chemical, biological and nanotechnological applications. Acta Pharm 2021;71:185–213.
5. Haq IU, Imran M, Nadeem M, Tufail T, Gondal TA, Mubarak MS. Piperine: A review of its biological effects. Phytother Res 2020;1–21.
6. Rout J, Swain BC, Tripathy U. In silico investigation of spice molecules as potent inhibitor of SARS-CoV-2. J Biomol Struct Dyn 2020;1–15.
7. Kumar S, Kashyap P, Chowdhury S, Kumar S, Panwar A, Kumar A. Identification of phytochemicals as potential therapeutic agents that binds to Nsp15 protein target of coronavirus (SARS-CoV-2) that are capable of inhibiting virus replication. Phytomedicine 2020;1–10.
8. Ahmad I, Ahmed S, Anwar Z, Sheraz MA, Sikorski M. Photostability and Photostabilization of Drugs and Drug Products. Int J Photoenergy 2016;2016:1–19.
9. Kozukue N, Park MS, Choi SH, Lee SU, Ohnishi-Kameyama M, Levin CE, et al. Kinetics of light-induced cis-trans isomerization of four piperines and their levels in ground black peppers as determined by HPLC and LC/MS. J Agric Food Chem 2007;55:7131–9.
10. Hashimoto K, Yaoi T, Koshiba H, Yoshida T, Maoka T, Fujiwara Y, et al. Photochemical Isomerization of Piperine, a Pungent Constituent in Pepper. Food Sci Technol Int Tokyo 1996;2:24–9.
11. Lizarme-Salas Y, Ariawan AD, Ratnayake R, Luesch H, Finch A, Hunter L. Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity. Beilstein J Org Chem 2020;16:2663–70.
12. Censi R, Di Martino P. Polymorph impact on the bioavailability and stability of poorly soluble drugs. Molecules 2015;20:18759–76.
13. Pfund LY, Chamberlin BL, Matzger AJ. The bioenhancer piperine is at least trimorphic. Cryst Growth Des 2015;15:2047–51.
14. Zaini E, Riska D, Oktavia MD, Ismed F, Fitriani L. Improving Dissolution Rate of Piperine by Multicomponent Crystal Formation with Saccharin. Res J Pharm Technol 2019;13:1926–30.
15. Childs SL, Stahly GP, Park A. The salt-cocrystal continuum: The influence of crystal structure on ionization state. Mol Pharm 2007;4:323–38.
16. Cruz-Cabeza AJ. Acid-base crystalline complexes and the pKa rule. CrystEngComm 2012;14:6362–5.
17. Zaini E, Afriyani, Fitriani L, Ismed F, Horikawa A, Uekusa H. Improved solubility and dissolution rates in novel multicomponent crystals of piperine with succinic acid. Sci Pharm 2020;88:1–12.
18. Shao B, Cui C, Ji H, Tang J, Wang Z, Liu H, et al. Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems: In vitro, in vivo and in situ intestinal permeability studies. Drug Deliv 2015;22:740–7.
19. Patil SC, Tagalpallewar AA, Kokare CR. Natural anti-proliferative agent loaded self-microemulsifying nanoparticles for potential therapy in oral squamous carcinoma. J Pharm Investig 2019;49:527–41.
20. Etman SM, Elnaggar YSR, Abdelmonsif DA, Abdallah OY. Oral Brain-Targeted Microemulsion for Enhanced Piperine Delivery in Alzheimer’s Disease Therapy: In Vitro Appraisal, In Vivo Activity, and Nanotoxicity. AAPS PharmSciTech 2018;19:3698–711.
21. Rao Z, Si L, Guan Y, Pan H, Qiu J, Li G. Inhibitive effect of cremophor RH40 or tween 80-based self- microemulsiflying drug delivery system on cytochrome P450 3A enzymes in murine hepatocytes. J Huazhong Univ Sci Technol - Med Sci 2010;30:562–8.
22. Prabhakar K, Afzal SM, Surender G, Kishan V. Tween 80 containing lipid nanoemulsions for delivery of indinavir to brain. Acta Pharm Sin B 2013;3:345–53.
23. Yadav N, Khatak S, Singh Sara UV. Solid lipid nanoparticles- A review. Int J Appl Pharm 2013;5:8–18.
24. 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;13:288–303.
25. Yusuf M, Khan M, Khan RA, Ahmed B. Preparation, characterization, in vivo and biochemical evaluation of brain targeted Piperine solid lipid nanoparticles in an experimentally induced Alzheimer’s disease model. J Drug Target 2013;21:300–11.
26. Nobari Azar FA, Pezeshki A, Ghanbarzadeh B, Hamishehkar H, Mohammadi M. Nanostructured lipid carriers: Promising delivery systems for encapsulation of food ingredients. J Agric Food Res 2020;2:1–8.
27. Chaudhari VS, Murty US, Banerjee S. Nanostructured lipid carriers as a strategy for encapsulation of active plant constituents: Formulation and in vitro physicochemical characterizations. Chem Phys Lipids 2021;235.
28. Kalepu S, Manthina M, Padavala V. Oral lipid-based drug delivery systems – an overview. Acta Pharm Sin B 2013;3:361–72.
29. Kuche K, Bhargavi N, Dora CP, Jain S. Drug-Phospholipid Complex—a Go Through Strategy for Enhanced Oral Bioavailability. AAPS PharmSciTech 2019;20:1–13.
30. Biswas S, Mukherjee PK, Kar A, Bannerjee S, Charoensub R, Duangyod T. Optimized piperine–phospholipid complex with enhanced bioavailability and hepatoprotective activity. Pharm Dev Technol 2021;26:69–80.
31. Kalepu S, Nekkanti V. Insoluble drug delivery strategies: Review of recent advances and business prospects. Acta Pharm Sin B 2015;5:442–53.
32. Daeihamed M, Dadashzadeh S, Haeri A, Akhlaghi MF. Potential of Liposomes for Enhancement of Oral Drug Absorption. Curr Drug Deliv 2017;14:289–303.
33. Lee MK. Liposomes for enhanced bioavailability of water-insoluble drugs: In vivo evidence and recent approaches. Pharmaceutics 2020;12:264–94.
34. Dutta S, Bhattacharjee P. Nanoliposomal encapsulates of piperine-rich black pepper extract obtained by enzyme-assisted supercritical carbon dioxide extraction. J Food Eng 2017;201:49–56.
35. Pentak D. In vitro spectroscopic study of piperine-encapsulated nanosize liposomes. Eur Biophys J 2016;45:175–86.
36. Karami Z, Hamidi M. Cubosomes: Remarkable drug delivery potential. Drug Discov Today 2016;21:789–801.
37. Barriga HMG, Holme MN, Stevens MM. Cubosomes: The Next Generation of Smart Lipid Nanoparticles? Angew Chem Int Ed 2019;58:2958–78.
38. Elnaggar YSR, Etman SM, Abdelmonsif DA, Abdallah OY. Novel piperine-loaded Tween-integrated monoolein cubosomes as brain-targeted oral nanomedicine in Alzheimer’s disease: Pharmaceutical, biological, and toxicological studies. Int J Nanomedicine 2015;10:5459–73.
39. Octavia MD, Halim A, Zaini E. Preparation of Simvastatin-?-Cyclodextrin inclusion complexes using co-evaporation technique. J Chem Pharm Res 2015;7:740–7.
40. Parmar V, Patel G, Abu-Thabit NY. Responsive cyclodextrins as polymeric carriers for drug delivery applications. In: Makhlouf ASH, Abu-Thabit NY, editors. Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications: Volume 1: Types and Triggers Cambridge: Woodhead Publishing Limited; 2018. p. 555–80.
41. Alshehri S, Imam SS, Hussain A, Altamimi MA. Formulation of Piperine Ternary Inclusion Complex Using ? CD and HPMC: Physicochemical Characterization, Molecular Docking, and Antimicrobial Testing. Processes 2020;8:1450–65.
42. Imam SS, Alshehri S, Alzahrani TA, Hussain A, Altamimi MA. Formulation and Evaluation of Supramolecular Food-Grade Piperine HP ? CD and TPGS Complex: Dissolution, Physicochemical Characterization, Molecular Docking, In Vitro Antioxidant Activity, and Antimicrobial Assessment. Molecules 2020;25:4716–37.
43. Kulkarni AS, Dias RJ, Ghorpade VS, Mali KK. Freeze dried multicomponent inclusion complexes of piperine with cyclodextrin and hydrophilic polymers: Physicochemical characterization and In vivo anti-inflammatory activity . Res J Pharm Technol 2020;13:4916.
44. Ezawa T, Inoue Y, Murata I, Takao K, Sugita Y, Kanamoto I. Evaluation of the Molecular State of Piperine in Cyclodextrin Complexes by Near-Infrared Spectroscopy and Solid-State Fluorescence Measurements. Int J Med Chem 2019;2019:1–14.
45. Liu K, Liu H, Li Z, Li W, Li L. In vitro dissolution study on inclusion complex of piperine with ethylenediamine-?-cyclodextrin. J Incl Phenom Macrocycl Chem 2020;96:233–43.
46. Ezawa T, Inoue Y, Tunvichien S, Suzuki R, Kanamoto I. Changes in the Physicochemical Properties of Piperine/ ? -Cyclodextrin due to the Formation of Inclusion Complexes. Int J Med Chem 2016;2016:1–9.
47. Ezawa T, Inoue Y, Murata I, Takao K, Sugita Y, Kanamoto I. Characterization of the Dissolution Behavior of Piperine/Cyclodextrins Inclusion Complexes. AAPS PharmSciTech 2018;19:923–33.
48. Quilaqueo M, Millao S, Luzardo-Ocampo I, Campos-Vega R, Acevedo F, Shene C, et al. Inclusion of piperine in ?-cyclodextrin complexes improves their bioaccessibility and in vitro antioxidant capacity. Food Hydrocoll 2019;91:143–52.
49. Tong W-Q (Tony), Wen H. Application of Complexation in Drug Development for Insoluble Compounds. In: Liu R, editor. Water-Insoluble Drug Formulation Third edit. Boca Raton: CRC Press; 2018. p. 150–70.
50. Mohanty B, Suvitha A, Venkataramanan NS. Piperine Encapsulation within Cucurbit[n]uril (n=6,7): A Combined Experimental and Density Functional Study. ChemistrySelect 2018;3:1933–41.
51. Simanjuntak N, Levita J, Subarnas A. Inclusion of biopiperine in the kappa-carrageenan complex might improve its bioaccessibility and in vivo anti-inflammatory activity in edema-induced wistar rats. J Appl Pharm Sci 2020;10:39–43.
52. Fitriani L, Afriyanti I, Afriyani, Ismed F, Zaini E. Solid dispersion of usnic acid–HPMC 2910 prepared by spray drying and freeze drying techniques. Orient J Chem 2018;34:2083–8.
53. Deng Y, Liang Q, Wang Y, Zhang X, Yan C, He Y. The inhibiting role of hydroxypropylmethylcellulose acetate succinate on piperine crystallization to enhance its dissolution from its amorphous solid dispersion and permeability. RSC Adv 2019;9:39523–31.
54. Ashour EA, Majumdar S, Alsheteli A, Alshehri S, Alsulays B, Feng X, et al. Hot melt extrusion as an approach to improve solubility, permeability and oral absorption of a psychoactive natural product, piperine. J Pharm Pharmacol 2016;68:989–98.
55. Thenmozhi K, Yoo YJ. Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems. Drug Dev Ind Pharm 2017;43:1501–9.
56. Zhu Y, Yu J, Zhou G, Gu Z, Adu-Frimpong M, Deng W, et al. Piperine fast disintegrating tablets comprising sustained-release matrix pellets with enhanced bioavailability: formulation, in vitro and in vivo evaluation. Pharm Dev Technol 2020;25:617–24.
57. Sedeky AS, Khalil IA, Hefnawy A, El-Sherbiny IM. Development of core-shell nanocarrier system for augmenting piperine cytotoxic activity against human brain cancer cell line. Eur J Pharm Sci 2018;118:103–12.
58. Qiu LY, Bae YH. Polymer architecture and drug delivery. Pharm Res 2006;23:1–30.
59. Guineo-Alvarado J, Quilaqueo M, Hermosilla J, González S, Medina C, Rolleri A, et al. Degree of crosslinking in ?-cyclodextrin-based nanosponges and their effect on piperine encapsulation. Food Chem 2021;340:1–7.
60. Laha A, Sharma CS, Majumdar S. Electrospun gelatin nanofibers as drug carrier: Effect of crosslinking on sustained release. Mater Today Proc 2016;3:3484–91.
61. Laha A, Majumdar S, Sharma CS. Controlled drug release formulation by sequential crosslinking of multilayered electrospun gelatin nanofiber mat. MRS Adv 2016;1:2107–13.
62. Laha A, Sharma CS, Majumdar S. Sustained drug release from multi-layered sequentially crosslinked electrospun gelatin nanofiber mesh. Mater Sci Eng C 2017;76:782–6.
63. Chen S, Zhang Y, Qing J, Han Y, McClements DJ, Gao Y. Core-shell nanoparticles for co-encapsulation of coenzyme Q10 and piperine: Surface engineering of hydrogel shell around protein core. Food Hydrocoll 2020;103:1–11.
64. Paul W, Sharma CP. Inorganic nanoparticles for targeted drug delivery. In: Sharma CP, editor. Biointegration of Medical Implant Materials: Science and Design Cambridge: Woodhead Publishing Limited; 2010. p. 204–35.
65. AbouAitah K, Stefanek A, Higazy IM, Janczewska M, Swiderska-Sroda A, Chodara A, et al. Effective targeting of colon cancer cells with piperine natural anticancer prodrug using functionalized clusters of hydroxyapatite nanoparticles. Pharmaceutics 2020;12:1–28.
66. Zhu D, Zhang W guang, Nie X dan, Ding S wen, Zhang D tai, Yang L. Rational design of ultra-small photoluminescent copper nano-dots loaded PLGA micro-vessels for targeted co-delivery of natural piperine molecules for the treatment for epilepsy. J Photochem Photobiol B Biol 2020;205:1–8.
67. Murdande SB, Pikal MJ, Shanker RM, Bogner RH. Aqueous solubility of crystalline and amorphous drugs: Challenges in measurement. Pharm Dev Technol 2011;16:187–200.
68. Miller JM, Beig A, Carr RA, Spence JK, Dahan A. A win-win solution in oral delivery of lipophilic drugs: Supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability. Mol Pharm 2012;9:2009–16.
69. Miller JM, Beig A, Krieg BJ, Carr RA, Borchardt TB, Amidon GE, et al. The solubility-permeability interplay: Mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation. Mol Pharm 2011;8:1848–56.
70. Mehta M, Kothari K, Ragoonanan V, Suryanarayanan R. Effect of Water on Molecular Mobility and Physical Stability of Amorphous Pharmaceuticals. Mol Pharm 2016;13:1339–46.
71. Shi Q, Moinuddin SM, Cai T. Advances in coamorphous drug delivery systems. Acta Pharm Sin B 2019;9:19–35.
72. El-Laithy HM, Badawi A, Abdelmalak NS, Elsayyad NME. Stabilizing excipients for engineered clopidogrel bisulfate procubosome derived in situ cubosomes for enhanced intestinal dissolution: Stability and bioavailability considerations. Eur J Pharm Sci 2019;136:1–11.
73. Janga KY, Jukanti R, Velpula A, Sunkavalli S, Bandari S, Kandadi P, et al. Bioavailability enhancement of zaleplon via proliposomes: Role of surface charge. Eur J Pharm Biopharm 2012;80:347–57.
74. Nekkanti V, Venkatesan N, Betageri G. Proliposomes for Oral Delivery: Progress and Challenges. Curr Pharm Biotechnol 2015;16:303–12.
75. Rahamathulla M, H.V G, Veerapu G, Hani U, Alhamhoom Y, Alqahtani A, et al. Characterization, Optimization, In Vitro and In Vivo Evaluation of Simvastatin Proliposomes, as a Drug Delivery. AAPS PharmSciTech 2020;21:1–15.
76. Ren J, Fang Z, Jiang L, Du Q. Quercetin-containing self-assemble proliposome preparation and evaluation. J Liposome Res 2017;27:335–42.
77. Jong WH De, Paul JB. Drug delivery and nanoparticles?: Applications and hazards. Int J Nanomedicine 2008;3:133–49.
78. Nogueira DR, Carmen Morán M Del, Mitjans M, Pérez L, Ramos D, De Lapuente J, et al. Lysine-based surfactants in nanovesicle formulations: the role of cationic charge position and hydrophobicity in in vitro cytotoxicity and intracellular delivery. Nanotoxicology 2014;8:404–21.
79. Zhang XQ, Xu X, Bertrand N, Pridgen E, Swami A, Farokhzad OC. Interactions of nanomaterials and biological systems: Implications to personalized nanomedicine. Adv Drug Deliv Rev 2012;64:1363–84.
80. Watkins R, Wu L, Zhang C, Davis RM, Xu B. Natural product-based nanomedicine: Recent advances and issues. Int J Nanomedicine 2015;10:6055–74.
81. Dahan A, Zimmermann EM, Ben-Shabat S. Modern prodrug design for targeted oral drug delivery. Molecules 2014;19:16489–505.
82. Huttunen KM, Raunio H, Rautio J. Prodrugs-from serendipity to rational design. Pharmacol Rev 2011;63:750–71.
83. Stella VJ, Nti-Addae KW. Prodrug strategies to overcome poor water solubility. Adv Drug Deliv Rev 2007;59:677–94.
84. Zafar F, Jahan N, Khalil-Ur-Rahman, Bhatti HN. Increased Oral Bioavailability of Piperine from an Optimized Piper nigrum Nanosuspension. Planta Med 2019;85:249–57.
85. Ding Y, Wang C, Wang Y, Xu Y, Zhao J, Gao M, et al. Development and evaluation of a novel drug delivery: Soluplus®/TPGS mixed micelles loaded with piperine in vitro and in vivo. Drug Dev Ind Pharm 2018;44:1409–16.
86. Rani R, Kumar S, Dilbaghi N, Kumar R. Nanotechnology enabled the enhancement of antitrypanosomal activity of piperine against Trypanosoma evansi. Exp Parasitol 2020;219:1–8.
87. Chong W-H, Chin S-F, Pang S-C, Kok K-Y. Synthesis and Characterisation of Piperine-loaded Starch Nanoparticles. J Phys Sci 2020;31:57–68.
88. Pachauri M, Gupta ED, Ghosh PC. Piperine loaded PEG-PLGA nanoparticles: Preparation, characterization and targeted delivery for adjuvant breast cancer chemotherapy. J Drug Deliv Sci Technol 2015;29:269–82.
89. Abolhassani H, Shojaosadati SA. A comparative and systematic approach to desolvation and self-assembly methods for synthesis of piperine-loaded human serum albumin nanoparticles. Colloids Surfaces B Biointerfaces 2019;184:1–25.
90. Chen S, Zhang Y, Han Y, McClements DJ, Liao W, Mao L, et al. Fabrication of multilayer structural microparticles for co-encapsulating coenzyme Q10 and piperine: Effect of the encapsulation location and interface thickness. Food Hydrocoll 2020;109:1–44.
91. Ren T, Hu M, Cheng Y, Shek TL, Xiao M, Ho NJ, et al. Piperine-loaded nanoparticles with enhanced dissolution and oral bioavailability for epilepsy control. Eur J Pharm Sci 2019;137:1–8.
92. Pengpong T, Sangvanich P, Sirilertmukul K, Muangsin N. Design, synthesis and in vitro evaluation of mucoadhesive p-coumarate-thiolated-chitosan as a hydrophobic drug carriers. Eur J Pharm Biopharm 2014;86:487–97.
93. Salim AB, Chin SF, Pang SC. Hydroxypropyl starch nanoparticles as controlled release nanocarriers for piperine. J Nanostructures 2020;10:327–36.
94. Rad JG, Hoskin DW. Delivery of apoptosis-inducing piperine to triple-negative breast cancer cells via co-polymeric nanoparticles. Anticancer Res 2020;40:689–94.
95. Jain S, Meka SRK, Chatterjee K. Engineering a Piperine Eluting Nanofibrous Patch for Cancer Treatment. ACS Biomater Sci Eng 2016;2:1376–85.
96. Garrido B, González S, Hermosilla J, Millao S, Quilaqueo M, Guineo J, et al. Carbonate-?-Cyclodextrin-Based Nanosponge as a Nanoencapsulation System for Piperine: Physicochemical Characterization. J Soil Sci Plant Nutr 2019;19:620–30.
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SALSABILA, H., FITRIANI, L., & ZAINI, E. (2021). RECENT STRATEGIES FOR IMPROVING SOLUBILITY AND ORAL BIOAVAILABILITY OF PIPERINE. International Journal of Applied Pharmaceutics, 13(4). https://doi.org/10.22159/ijap.2021v13i4.41596
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