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Preparation and optimization of berberine phospholipid complexes using QbD approach and in vivo evaluation for anti-inflammatory, analgesic and antipyretic activity

Yıl 2022, Cilt: 26 Sayı: 2, 370 - 382, 28.06.2025

Ayça Güngör-ak Esra Küpeli Akkol , Buket Aksu , Ayşegül Karataş

Öz

Berberine (BER) is a benzylisoquinoline alkaloid found in many plants. It has high water solubilitybut its bioavailability is low in oral administration due to the first-pass effect in the liver and intestine. Phytosomesare are prepared by complexing herbal active ingredients and phospholipids (PLs). The aim of this study is to prepare BERphospholipidcomplexes (BPCs) using the reverse phase evaporation method. In the preparation of the formulations, the effects of BER:PL ratio (w/w), reaction temperature (°C) and reaction time (h) on the specifications of the complexes such as particle size (PS), zeta potential (ZP) and encapsulation efficiency (EE%) were investigated. The distribution of PS of obtained complexes was ranging between 339 -1259 nm and their ZP were within -4,27- -5,15 mV. The drug EE% was relatively high. Quality by Design (QbD) methods have been used in the formulation design and selection of the optimum formulation. BPCs anti-inflammatory, analgesic and antipyretic activities are evaluated by using in vivo methods.Carrageenan-, Prostaglandin E2 (PGE2)- and serotonin-induced hind paw edema, acetic acid-induced increase in capillary permeability and subcutaneous air-pouch models for the anti-inflammatory activity, inhibition of pbenzoquinone-induced abdominal constriction and hot plate test for the analgesic activity, Freund’s complete adjuvantinduced pyrexia model for the antipyretic activity were used in mice and rats. Results showed that BPCs showed potent anti-inflammatory, analgesic and antipyretic activities at the dose of 209 mg/kg.

Anahtar Kelimeler

Berberine phytosomes analgesic anti-inflammatory qbd approach

Kaynakça

  • [1] Lu M, Qiu Q, Luo X, Liu X, Sun J, Wang C, Song Y. Phyto-phospholipid complexes (phytosomes): A novel strategy to improve the bioavailability of active constituents. Asian J Pharm Sci. 2019; 14 (3): 265-274. [CrossRef]
  • [2] Singh RP, Gangadharappa HV, Mruthunjaya K. Phospholipids: Unique carriers for drug delivery systems. J Drug Deliv Sci Technol. 2017; 39: 166-179. [CrossRef]
  • [3] Hüsch J, Bohnet J, Fricker G, Skarke C, Artaria C, Appendino G, Abdel-Tawab M. Enhanced absorption of boswellic acids by a lecithin delivery form (Phytosome®) of Boswellia extract. Fitoterapia. 2013; 84: 89-98. [CrossRef]
  • [4] Shivanand P, Kinjal P. Phytosomes: Technical Revolution in Phytomedicine. Int J PharmTech Res. 2010; 2: 627–631.
  • [5] Raju TP, Reddy MS, Reddy VP. Phytosomes: A Novel Phyto-Phospholipid Carrier for Herbal Drug Delivery. Int Res J Pharm. 2011; 2: 28–33.
  • [6] Bombardelli E, Curri SB, Dellaloggia R, Del Negro P, Gariboldi P, Tubaro A. Complexes between phospholipids and vegetal derivates of biological interest. Fitoterapia. 1989;60:1-9.
  • [7] Mota AH, Rijo P, Molpeceres J, Reis CP. Broad overview of engineering of functional nanosystems for skin delivery. Int J Pharm. 2017; 532(2): 710-728. [CrossRef]
  • [8] Virtanen JA, Cheng KH, Somerharju P. Phospholipid Composition of the Mammalian Red Cell Membrane Can Be Rationalized by a Superlattice Model.Proc Natl Acad Sci USA. 1998; 95: 4964–4969. [CrossRef]
  • [9] Ghanbarzadeh B, Babazadeh A, Hamishehkar H. Nano-phytosome as a potential food-grade delivery system. Food Biosci. 2016; 15: 126-135. [CrossRef]
  • [10] Gnananath K, Nataraj KS, Rao BG. Phospholipid complex technique for superior bioavailability of phytoconstituents. Adv Pharm Bull. 2017; 7 (1): 35-42. [CrossRef]
  • [11] Semalty A, Semalty M, Rawat MSM, Franceschi F. Supramolecular phospholipids–polyphenolics interactions: The PHYTOSOME® strategy to improve the bioavailability of phytochemicals. Fitoterapia. 2010; 81 (5): 306-314. [CrossRef]
  • [12] Yu F, Ao M, Zheng X, Li N, Xia J, Li Y, Chen XD. PEG–lipid–PLGA hybrid nanoparticles loaded with berberine–phospholipid complex to facilitate the oral delivery efficiency. Drug Deliv. 2017; 24 (1): 825-833. [CrossRef]
  • [13] Güngör S, Akbal-Dağıstan Ö, Algın-Yapar E, Kartal M, Özsoy Y. Phytosomes as Novel Carriers of Herbal Extracts. In: Gupta M, Chauhan DN, Sharma V, Chauhan NS. (Eds). Novel Drug Delivery Systems for Phytoconstituents. Inc, New York, 2019, pp. 69-81.
  • [14] Zhang Y, Cui YL, Gao LN, Jiang HL. Effects of β-cyclodextrin on the intestinal absorption of berberine hydrochloride P-Glycoprotein Substrate. Int J Biol Macromol. 2013;59: 363–371. [CrossRef]
  • [15] Sut S, Faggian M, Baldan V, Poloniato G, Castagliuolo I, Grabnar I, Peron G. Natural deep eutectic solvents (NADES) to enhance berberine absorption: an in vivo pharmacokinetic study. Molecules. 2017; 22 (11): 1921. [CrossRef]
  • [16] Liang YP, Xu XJ, Yin MJ, Zhang Y, Huang L, Chen R, Ni J. Effects of berberine on blood glucose in patients with type 2 diabetes mellitus: a systematic literature review and a meta-analysis. Endocr J. 2019;66 (1): 51-63. [CrossRef]
  • [17] Wang ZC, Wang J, Chen H, Tang J, Bian AW, Liu T, Yang F. Synthesis and anticancer activity of novel 9, 13-disubstituted berberine derivatives. Bioorg Med Chem Lett. 2020; 30 (2): 126821. [CrossRef]
  • [18] Kulkarni SK, Dhir A. Berberine: A plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res. 2010; 24 (3): 317-324. [CrossRef]
  • [19] Zhao Z, Wei Q, Hua W, Liu Y, Liu X, Zhu Y. Hepatoprotective effects of berberine on acetaminophen-induced hepatotoxicity in mice. BiomedPharmacother. 2018;103: 1319-1326. [CrossRef]
  • [20] Cicero AFG, Baggioni A. Berberine and Its Role in Chronic Disease. In: Gupta S, Prasad S, Aggarwal B. (Eds). Anti-inflammatory Nutraceuticals and Chronic Diseases. Advances in Experimental Medicine and Biology. Springer, Cham, 2016, vol 928, 27-45. [CrossRef]
  • [21] Tanaka T, Metori K, Mineo S, Hirotani M, Furuya T, Kobayashi S. Inhibitory Effects of Berberine-Type Alkaloids on Elastase. Planta Med. 1993;3: 200-202. [CrossRef]
  • [22] Pallagi E, Jójárt-Laczkovich O, Németh Z, Szabó-Révész P, Csóka I. Application of the QbD-based approach in the early development of liposomes for nasal administration. Int J Pharm. 2019; 562: 11-22. [CrossRef]
  • [23] www.ich.org. Available from: https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf, 2009 (accessed on 18 August 2020).
  • [24] Aksu B, Coskunmerıc N, Yegen G, Ozalp Y, Okur N. Quality by design approach for optimizing preparation and characterization of buccal film formulation with different polymers. Int J Pharm Res. 2019; 11(1): 1153-1160. [CrossRef]
  • [25] Aksu B, Yegen G, Purisa S, Cevher E, OzsoyY. Optimisation of ondansetron orally disintegrating tablets using artificial neural networks. Trop J Pharm Res. 2014; 13(9): 1374-1383. [CrossRef]
  • [26] Aksu B, Yeğen G. Benefits of Computerized Technologies in Pharmaceutical Development with Quality by Design Approach. J Comput Eng Inf Technol. 2017; 6(1). [CrossRef]
  • [27] Kasahara Y, Hikino H, Tsurufuji S, Watanabe M, Ohuhi K. Antiinflammatory Actions of Ephedrines in Acute Inflammations. Planta Med. 1985; 51: 325-331. PMID: 4070447.
  • [28] Whittle BA. The ise of capillary permeability in mice to distinguish between narcotic and nonnarcotic analgesics. Br J Pharmacol. 1964; 22: 246-253. [CrossRef]
  • [29] Yesilada E, Küpeli E. Clematis vitalba L. aerial part exhibits potent anti-inflammatory, antinociceptive and antipyretic effects. J Ethnopharmacol. 2007; 110: 504–515. [CrossRef]
  • [30] Okun R, Liddon SC, Lasagnal L. The effect of aggregation, electric shock and adrenergic bloking drugs on inhibition of the “writhing syndrome”. J Pharm Exp Ther. 1963; 139: 107-114.
  • [31] Eddy NB, Leimback D. Synthetic analgesic. II. Dithienyl-butenyl and dithienylbutylamines. J Pharmacol ExpTher. 1953; 107: 385-393.
  • [32] Yesilada E, Küpeli E. Berberis crataegina DC. root exhibits potent anti-inflammatory, analgesic and febrifuge effects in mice and rats. J Ethnopharmacol. 2002; 79: 237-248. [CrossRef]
  • [33] Food And Drug Administration. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/reviewer-guidance-validation-chromatographic-methods, 1994 (accessed on 18 August 2020).
  • [34] Olajide OA, Makinde MJ, Awe SO. Effects of the aquous extract of Brideliaferruginea stem bark on carrageenan-induced oedema and granuloma tissue formation in rats and mice. J Ethnopharmacol. 1999; 66, 113-117.[CrossRef] [35] Singh B, Pandey VB, Joshi VK, Gambhir SS. Anti-inflammatory studies on Polygonum glabrum. J Ethnopharmacol. 1987; 19 (3): 255-267. [CrossRef]
  • [36] Flower R, Vane JR. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol. Nature. 1972; 240: 410–411.[CrossRef]
  • [37] Le Bars D, Gozariu M, Cadden SW. Animal Models of Nociception. Pharmacol Rev. 2001; 53: 597-652.
  • [38] Yıldız A, Genç Ö, Bektaş S. EnstrümantalAnalizYöntemleri. Hacettepe University publications. Ankara, 1997.
  • [39] Sartorious. Available from: https://umetrics.com/product/modde?page=1, 2017 (accessed on 18 August 2020).
  • [40] Suciu S, Iurian CB, Iovanov R, Rus L, Moldovan M, Tomuta I. Qbd approach in the development of oral lyophilisateswıth ibuprofen for paediatric use. Farmacia. 2018; 66: 514-523.
  • [41] KupeliAkkol E, Ercil D. Antinociceptive and Anti-inflammatory Activities of Some Linaria species from Turkey, Pharm Biol. 2009; 47 (3): 188-194. [CrossRef]

Yıl 2022, Cilt: 26 Sayı: 2, 370 - 382, 28.06.2025

Ayça Güngör-ak Esra Küpeli Akkol , Buket Aksu , Ayşegül Karataş

Öz

Kaynakça

  • [1] Lu M, Qiu Q, Luo X, Liu X, Sun J, Wang C, Song Y. Phyto-phospholipid complexes (phytosomes): A novel strategy to improve the bioavailability of active constituents. Asian J Pharm Sci. 2019; 14 (3): 265-274. [CrossRef]
  • [2] Singh RP, Gangadharappa HV, Mruthunjaya K. Phospholipids: Unique carriers for drug delivery systems. J Drug Deliv Sci Technol. 2017; 39: 166-179. [CrossRef]
  • [3] Hüsch J, Bohnet J, Fricker G, Skarke C, Artaria C, Appendino G, Abdel-Tawab M. Enhanced absorption of boswellic acids by a lecithin delivery form (Phytosome®) of Boswellia extract. Fitoterapia. 2013; 84: 89-98. [CrossRef]
  • [4] Shivanand P, Kinjal P. Phytosomes: Technical Revolution in Phytomedicine. Int J PharmTech Res. 2010; 2: 627–631.
  • [5] Raju TP, Reddy MS, Reddy VP. Phytosomes: A Novel Phyto-Phospholipid Carrier for Herbal Drug Delivery. Int Res J Pharm. 2011; 2: 28–33.
  • [6] Bombardelli E, Curri SB, Dellaloggia R, Del Negro P, Gariboldi P, Tubaro A. Complexes between phospholipids and vegetal derivates of biological interest. Fitoterapia. 1989;60:1-9.
  • [7] Mota AH, Rijo P, Molpeceres J, Reis CP. Broad overview of engineering of functional nanosystems for skin delivery. Int J Pharm. 2017; 532(2): 710-728. [CrossRef]
  • [8] Virtanen JA, Cheng KH, Somerharju P. Phospholipid Composition of the Mammalian Red Cell Membrane Can Be Rationalized by a Superlattice Model.Proc Natl Acad Sci USA. 1998; 95: 4964–4969. [CrossRef]
  • [9] Ghanbarzadeh B, Babazadeh A, Hamishehkar H. Nano-phytosome as a potential food-grade delivery system. Food Biosci. 2016; 15: 126-135. [CrossRef]
  • [10] Gnananath K, Nataraj KS, Rao BG. Phospholipid complex technique for superior bioavailability of phytoconstituents. Adv Pharm Bull. 2017; 7 (1): 35-42. [CrossRef]
  • [11] Semalty A, Semalty M, Rawat MSM, Franceschi F. Supramolecular phospholipids–polyphenolics interactions: The PHYTOSOME® strategy to improve the bioavailability of phytochemicals. Fitoterapia. 2010; 81 (5): 306-314. [CrossRef]
  • [12] Yu F, Ao M, Zheng X, Li N, Xia J, Li Y, Chen XD. PEG–lipid–PLGA hybrid nanoparticles loaded with berberine–phospholipid complex to facilitate the oral delivery efficiency. Drug Deliv. 2017; 24 (1): 825-833. [CrossRef]
  • [13] Güngör S, Akbal-Dağıstan Ö, Algın-Yapar E, Kartal M, Özsoy Y. Phytosomes as Novel Carriers of Herbal Extracts. In: Gupta M, Chauhan DN, Sharma V, Chauhan NS. (Eds). Novel Drug Delivery Systems for Phytoconstituents. Inc, New York, 2019, pp. 69-81.
  • [14] Zhang Y, Cui YL, Gao LN, Jiang HL. Effects of β-cyclodextrin on the intestinal absorption of berberine hydrochloride P-Glycoprotein Substrate. Int J Biol Macromol. 2013;59: 363–371. [CrossRef]
  • [15] Sut S, Faggian M, Baldan V, Poloniato G, Castagliuolo I, Grabnar I, Peron G. Natural deep eutectic solvents (NADES) to enhance berberine absorption: an in vivo pharmacokinetic study. Molecules. 2017; 22 (11): 1921. [CrossRef]
  • [16] Liang YP, Xu XJ, Yin MJ, Zhang Y, Huang L, Chen R, Ni J. Effects of berberine on blood glucose in patients with type 2 diabetes mellitus: a systematic literature review and a meta-analysis. Endocr J. 2019;66 (1): 51-63. [CrossRef]
  • [17] Wang ZC, Wang J, Chen H, Tang J, Bian AW, Liu T, Yang F. Synthesis and anticancer activity of novel 9, 13-disubstituted berberine derivatives. Bioorg Med Chem Lett. 2020; 30 (2): 126821. [CrossRef]
  • [18] Kulkarni SK, Dhir A. Berberine: A plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res. 2010; 24 (3): 317-324. [CrossRef]
  • [19] Zhao Z, Wei Q, Hua W, Liu Y, Liu X, Zhu Y. Hepatoprotective effects of berberine on acetaminophen-induced hepatotoxicity in mice. BiomedPharmacother. 2018;103: 1319-1326. [CrossRef]
  • [20] Cicero AFG, Baggioni A. Berberine and Its Role in Chronic Disease. In: Gupta S, Prasad S, Aggarwal B. (Eds). Anti-inflammatory Nutraceuticals and Chronic Diseases. Advances in Experimental Medicine and Biology. Springer, Cham, 2016, vol 928, 27-45. [CrossRef]
  • [21] Tanaka T, Metori K, Mineo S, Hirotani M, Furuya T, Kobayashi S. Inhibitory Effects of Berberine-Type Alkaloids on Elastase. Planta Med. 1993;3: 200-202. [CrossRef]
  • [22] Pallagi E, Jójárt-Laczkovich O, Németh Z, Szabó-Révész P, Csóka I. Application of the QbD-based approach in the early development of liposomes for nasal administration. Int J Pharm. 2019; 562: 11-22. [CrossRef]
  • [23] www.ich.org. Available from: https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf, 2009 (accessed on 18 August 2020).
  • [24] Aksu B, Coskunmerıc N, Yegen G, Ozalp Y, Okur N. Quality by design approach for optimizing preparation and characterization of buccal film formulation with different polymers. Int J Pharm Res. 2019; 11(1): 1153-1160. [CrossRef]
  • [25] Aksu B, Yegen G, Purisa S, Cevher E, OzsoyY. Optimisation of ondansetron orally disintegrating tablets using artificial neural networks. Trop J Pharm Res. 2014; 13(9): 1374-1383. [CrossRef]
  • [26] Aksu B, Yeğen G. Benefits of Computerized Technologies in Pharmaceutical Development with Quality by Design Approach. J Comput Eng Inf Technol. 2017; 6(1). [CrossRef]
  • [27] Kasahara Y, Hikino H, Tsurufuji S, Watanabe M, Ohuhi K. Antiinflammatory Actions of Ephedrines in Acute Inflammations. Planta Med. 1985; 51: 325-331. PMID: 4070447.
  • [28] Whittle BA. The ise of capillary permeability in mice to distinguish between narcotic and nonnarcotic analgesics. Br J Pharmacol. 1964; 22: 246-253. [CrossRef]
  • [29] Yesilada E, Küpeli E. Clematis vitalba L. aerial part exhibits potent anti-inflammatory, antinociceptive and antipyretic effects. J Ethnopharmacol. 2007; 110: 504–515. [CrossRef]
  • [30] Okun R, Liddon SC, Lasagnal L. The effect of aggregation, electric shock and adrenergic bloking drugs on inhibition of the “writhing syndrome”. J Pharm Exp Ther. 1963; 139: 107-114.
  • [31] Eddy NB, Leimback D. Synthetic analgesic. II. Dithienyl-butenyl and dithienylbutylamines. J Pharmacol ExpTher. 1953; 107: 385-393.
  • [32] Yesilada E, Küpeli E. Berberis crataegina DC. root exhibits potent anti-inflammatory, analgesic and febrifuge effects in mice and rats. J Ethnopharmacol. 2002; 79: 237-248. [CrossRef]
  • [33] Food And Drug Administration. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/reviewer-guidance-validation-chromatographic-methods, 1994 (accessed on 18 August 2020).
  • [34] Olajide OA, Makinde MJ, Awe SO. Effects of the aquous extract of Brideliaferruginea stem bark on carrageenan-induced oedema and granuloma tissue formation in rats and mice. J Ethnopharmacol. 1999; 66, 113-117.[CrossRef] [35] Singh B, Pandey VB, Joshi VK, Gambhir SS. Anti-inflammatory studies on Polygonum glabrum. J Ethnopharmacol. 1987; 19 (3): 255-267. [CrossRef]
  • [36] Flower R, Vane JR. Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol. Nature. 1972; 240: 410–411.[CrossRef]
  • [37] Le Bars D, Gozariu M, Cadden SW. Animal Models of Nociception. Pharmacol Rev. 2001; 53: 597-652.
  • [38] Yıldız A, Genç Ö, Bektaş S. EnstrümantalAnalizYöntemleri. Hacettepe University publications. Ankara, 1997.
  • [39] Sartorious. Available from: https://umetrics.com/product/modde?page=1, 2017 (accessed on 18 August 2020).
  • [40] Suciu S, Iurian CB, Iovanov R, Rus L, Moldovan M, Tomuta I. Qbd approach in the development of oral lyophilisateswıth ibuprofen for paediatric use. Farmacia. 2018; 66: 514-523.
  • [41] KupeliAkkol E, Ercil D. Antinociceptive and Anti-inflammatory Activities of Some Linaria species from Turkey, Pharm Biol. 2009; 47 (3): 188-194. [CrossRef]
Toplam 40 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Farmakogenomik
Bölüm Articles
Yazarlar

Ayça Güngör-ak 0000-0002-7002-5209

Esra Küpeli Akkol 0000-0002-5829-7869

Buket Aksu

Ayşegül Karataş 0000-0001-5157-5187

Yayımlanma Tarihi 28 Haziran 2025
Yayımlandığı Sayı Yıl 2022 Cilt: 26 Sayı: 2

Kaynak Göster

APA Güngör-ak, A., Küpeli Akkol, E., Aksu, B., Karataş, A. (2025). Preparation and optimization of berberine phospholipid complexes using QbD approach and in vivo evaluation for anti-inflammatory, analgesic and antipyretic activity. Journal of Research in Pharmacy, 26(2), 370-382.
AMA Güngör-ak A, Küpeli Akkol E, Aksu B, Karataş A. Preparation and optimization of berberine phospholipid complexes using QbD approach and in vivo evaluation for anti-inflammatory, analgesic and antipyretic activity. J. Res. Pharm. Haziran 2025;26(2):370-382.
Chicago Güngör-ak, Ayça, Esra Küpeli Akkol, Buket Aksu, ve Ayşegül Karataş. “Preparation and Optimization of Berberine Phospholipid Complexes Using QbD Approach and in Vivo Evaluation for Anti-Inflammatory, Analgesic and Antipyretic Activity”. Journal of Research in Pharmacy 26, sy. 2 (Haziran 2025): 370-82.
EndNote Güngör-ak A, Küpeli Akkol E, Aksu B, Karataş A (01 Haziran 2025) Preparation and optimization of berberine phospholipid complexes using QbD approach and in vivo evaluation for anti-inflammatory, analgesic and antipyretic activity. Journal of Research in Pharmacy 26 2 370–382.
IEEE A. Güngör-ak, E. Küpeli Akkol, B. Aksu, ve A. Karataş, “Preparation and optimization of berberine phospholipid complexes using QbD approach and in vivo evaluation for anti-inflammatory, analgesic and antipyretic activity”, J. Res. Pharm., c. 26, sy. 2, ss. 370–382, 2025.
ISNAD Güngör-ak, Ayça vd. “Preparation and Optimization of Berberine Phospholipid Complexes Using QbD Approach and in Vivo Evaluation for Anti-Inflammatory, Analgesic and Antipyretic Activity”. Journal of Research in Pharmacy 26/2 (Haziran 2025), 370-382.
JAMA Güngör-ak A, Küpeli Akkol E, Aksu B, Karataş A. Preparation and optimization of berberine phospholipid complexes using QbD approach and in vivo evaluation for anti-inflammatory, analgesic and antipyretic activity. J. Res. Pharm. 2025;26:370–382.
MLA Güngör-ak, Ayça vd. “Preparation and Optimization of Berberine Phospholipid Complexes Using QbD Approach and in Vivo Evaluation for Anti-Inflammatory, Analgesic and Antipyretic Activity”. Journal of Research in Pharmacy, c. 26, sy. 2, 2025, ss. 370-82.
Vancouver Güngör-ak A, Küpeli Akkol E, Aksu B, Karataş A. Preparation and optimization of berberine phospholipid complexes using QbD approach and in vivo evaluation for anti-inflammatory, analgesic and antipyretic activity. J. Res. Pharm. 2025;26(2):370-82.