Abstract
The gut microbiome is involved in the pathogenesis of many diseases including polycystic ovarian syndrome (PCOS). Modulating the gut microbiome can lead to eubiosis and treatment of various metabolic conditions. However, there is no proper study assessing the delivery of microbial technology for the treatment of such conditions. The present study involves the development of guar gum-pectin-based solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing curcumin (CCM) and fecal microbiota extract (FME) for the treatment of PCOS. The optimized S-SNEDDS containing FME and CCM was prepared by dissolving CCM (25 mg) in an isotropic mixture consisting of Labrafil M 1944 CS, Transcutol P, and Tween-80 and solidified using lactose monohydrate, aerosil-200, guar gum, and pectin (colon-targeted CCM solid self-nanoemulsifying drug delivery system [CCM-CT-S-SNEDDS]). Pharmacokinetic and pharmacodynamic evaluation was carried out on letrozole-induced female Wistar rats. The results of pharmacokinetic studies indicated about 13.11 and 23.48-fold increase in AUC of CCM-loaded colon-targeted S-SNEDDS without FME (CCM-CT-S-SNEDDS (WFME)) and CCM-loaded colon-targeted S-SNEDDS with FME [(CCM-CT-S-SNEDDS (FME)) as compared to unprocessed CCM. The pharmacodynamic study indicated excellent recovery/reversal in the rats treated with CCM-CT-S-SNEDDS low and high dose containing FME (group 13 and group 14) in a dose-dependent manner. The developed formulation showcasing its improved bioavailability, targeted action, and therapeutic activity in ameliorating PCOS can be utilized as an adjuvant therapy for developing a dosage form, scale-up, and technology transfer.
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References
Aebi H (1984) Catalase in vitro. In: Methods in enzymology. Elsevier, pp 121–126
Bo-Jeong P, Yang H, Sohn E et al (2018) Tetragonia tetragonioides (pall.) kuntze regulates androgen production in a letrozole-induced polycystic ovary syndrome model. Molecules 23:1173. https://doi.org/10.3390/molecules23051173
Choi HY, Lim JE, Hong JH (2010) Curcumin interrupts the interaction between the androgen receptor and Wnt/β-catenin signaling pathway in LNCaP prostate cancer cells. Prostate Cancer Prostatic Dis 13:343–349
Corrie L, Gulati M, Singh SK et al (2021a) Recent updates on animal models for understanding the etiopathogenesis of polycystic ovarian syndrome. Life Sci 280:119753. https://doi.org/10.1016/j.lfs.2021.119753
Corrie L, Gulati M, Vishwas S et al (2021b) Combination therapy of curcumin and fecal microbiota transplant: potential treatment of polycystic ovarian syndrome. Med Hypotheses 154:110644. https://doi.org/10.1016/j.mehy.2021.110644
Corrie L, Gulati M, Awasthi A et al (2022a) Polysaccharide, fecal microbiota, and curcumin-based novel oral colon-targeted solid self-nanoemulsifying delivery system: formulation, characterization, and in-vitro anticancer evaluation. Mater Today Chem 26:101165. https://doi.org/10.1016/j.mtchem.2022.101165
Corrie L, Gulati M, Awasthi A et al (2022b) Harnessing the dual role of polysaccharides in treating gastrointestinal diseases: as therapeutics and polymers for drug delivery. Chem Biol Interact 368:110238. https://doi.org/10.1016/j.cbi.2022.110238
Corrie L, Kaur J, Awasthi A et al (2022c) Multivariate data analysis and central composite design-oriented optimization of solid carriers for formulation of curcumin-loaded solid SNEDDS: dissolution and bioavailability assessment. Pharmaceutics 14:2395. https://doi.org/10.3390/pharmaceutics14112395
Corrie L, Singh SK, Gulati M et al (2022d) Improvement in polycystic ovarian syndrome using pharmacological and non-pharmacological approaches: current perspectives and principles. Curr Womens Health Rev 19:11–18. https://doi.org/10.2174/1573404818666220329123334
Corrie L, Gulati M, Kaur J et al (2023b) Quality by design-based RP-HPLC method for estimation of curcumin in rat plasma and fecal microbiota extract-based solid self-nano emulsifying drug delivery system. Curr Drug Res Rev 15:272–285. https://doi.org/10.2174/2589977515666230120140543
Corrie L, Awasthi A, Kaur J et al (2023a) Interplay of gut microbiota in polycystic ovarian syndrome: role of gut microbiota, mechanistic pathways and potential treatment strategies. Pharmaceuticals 16(2):197–221
Das K, Roychoudhury A (2014) Reactive oxygen species (ROS) and response of antioxidants as ROS-scavengers during environmental stress in plants. Front Environ Sci 2:1–13. https://doi.org/10.3389/fenvs.2014.00053
Derosa G, Maffioli P, Simental-Mendía LE et al (2016) Effect of curcumin on circulating interleukin-6 concentrations: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res 111:394–404. https://doi.org/10.1016/j.phrs.2016.07.004
Desai BN, Maharjan RH, Nampoothiri LP (2012) Aloe barbadensis Mill. formulation restores lipid profile to normal in a letrozole-induced polycystic ovarian syndrome rat model. Pharmacognosy Res 4:109–115. https://doi.org/10.4103/0974-8490.94736
di Bella S, Gouliouris T, Petrosillo N (2015) Fecal microbiota transplantation (FMT) for Clostridium difficile infection: focus on immunocompromised patients. J Infect Chemother 21:230–237. https://doi.org/10.1016/j.jiac.2015.01.011
Escobar-Morreale HF (2018) Polycystic ovary syndrome: Definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol 14:270–284. https://doi.org/10.1038/nrendo.2018.24
Firmansyah A, Chalid MT, Farid RB, Abdullah N (2018) The correlation between insulin-like growth factor binding protein 1 (IGFBP-1) and homeostasis model assessment of insulin resistance (HOMA-IR) in polycystic ovarian syndrome with insulin resistance. Int J Reprod Biomed 16:679–682
Ghasemiyeh P, Mohammadi-Samani S (2018) Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: applications, advantages and disadvantages. Res Pharm Sci 13:288–303. https://doi.org/10.4103/1735-5362.235156
Gulati M, Singh SK, Corrie L et al (2020) Delivery routes for faecal microbiota transplants: available, anticipated and aspired. Pharmacol Res 159:104954. https://doi.org/10.1016/j.phrs.2020.104954
Haschke M, Schuster M, Poglitsch M et al (2013) Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet 52:783–792. https://doi.org/10.1007/s40262-013-0072-7
Heshmati J, Farsi F, Yosaee S et al (2019) The effects of probiotics or synbiotics supplementation in women with polycystic ovarian syndrome: a systematic review and meta-analysis of randomized clinical trials. Probiotics Antimicrob Proteins 11:1236–1247. https://doi.org/10.1007/s12602-018-9493-9
Heshmati J, Golab F, Morvaridzadeh M et al (2020) The effects of curcumin supplementation on oxidative stress, sirtuin-1 and peroxisome proliferator activated receptor γ coactivator 1α gene expression in polycystic ovarian syndrome (PCOS) patients: a randomized placebo-controlled clinical trial. Diabetes Metab Syndr 14:77–82. https://doi.org/10.1016/j.dsx.2020.01.002
Hirsch BE, Saraiya N, Poeth K et al (2015) Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection. BMC Infect Dis 15:191. https://doi.org/10.1186/s12879-015-0930-z
Hong Y, Yin Y, Tan Y et al (2019) The flavanone, naringenin, modifies antioxidant and steroidogenic enzyme activity in a rat model of letrozole-induced polycystic ovary syndrome. Med Sci Monit 25:395–401. https://doi.org/10.12659/MSM.912341
Hoseinpour MJ, Ghanbari A, Azad N et al (2019) Ulmus minor bark hydro-alcoholic extract ameliorates histological parameters and testosterone level in an experimental model of PCOS rats. Endocr Regul 53:146–153. https://doi.org/10.2478/enr-2019-0015
Hu T, Yuan X, Ye R et al (2017) Brown adipose tissue activation by rutin ameliorates polycystic ovary syndrome in rat. J Nutr Biochem 47:21–28. https://doi.org/10.1016/j.jnutbio.2017.04.012
Jahan S, Abid A, Khalid S et al (2018) Therapeutic potentials of Quercetin in management of polycystic ovarian syndrome using Letrozole induced rat model: a histological and a biochemical study. J Ovarian Res 11:1–10. https://doi.org/10.1186/s13048-018-0400-5
Kafali H, Iriadam M, Ozardali I, Demir N (2004) Letrozole-induced polycystic ovaries in the rat: a new model for cystic ovarian disease. Arch Med Res 35:103–108. https://doi.org/10.1016/j.arcmed.2003.10.005
Kang H, Mintri S, Menon AV et al (2015) Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles graphical abstract HHS public access. Nanoscale 7:18848–18862. https://doi.org/10.1039/c5nr05264e.Pharmacokinetics
Kang D-W, Adams JB, Vargason T et al (2020) Distinct fecal and plasma metabolites in children with autism spectrum disorders and their modulation after microbiota transfer therapy. mSphere 5:1–17. https://doi.org/10.1128/msphere.00314-20
Kapoor B, Gupta R, Gulati M et al (2019) The why, where, who, how, and what of the vesicular delivery systems. Adv Colloid Interface Sci 271:101985. https://doi.org/10.1016/j.cis.2019.07.006
Kaur R, Gulati M, Singh SK (2017) Role of synbiotics in polysaccharide assisted colon targeted microspheres of mesalamine for the treatment of ulcerative colitis. Int J Biol Macromol 95:438–450. https://doi.org/10.1016/j.ijbiomac.2016.11.066
Kaur J, Gulati M, Famta P et al (2022) Polymeric micelles loaded with glyburide and vanillic acid : I. Formulation development, in-vitro characterization and bioavailability studies. Int J Pharm 624:121987. https://doi.org/10.1016/j.ijpharm.2022.121987
Kaźmierczak-Siedlecka K, Daca A, Fic M et al (2020) Therapeutic methods of gut microbiota modification in colorectal cancer management–fecal microbiota transplantation, prebiotics, probiotics, and synbiotics. Gut Microbes 11:1518–1530. https://doi.org/10.1080/19490976.2020.1764309
Kelley ST, Skarra DV, Rivera AJ, Thackray VG (2016) The gut microbiome is altered in a Letrozole-Induced mouse model of polycystic ovary syndrome. PLoS One 11. https://doi.org/10.1371/journal.pone.0146509
Khursheed R, Singh SK, Wadhwa S et al (2020) Exploring role of probiotics and Ganoderma lucidum extract powder as solid carriers to solidify liquid self-nanoemulsifying delivery systems loaded with curcumin. Carbohydr Polym 250:116996. https://doi.org/10.1016/j.carbpol.2020.116996
Khursheed R, Singh SK, Wadhwa S et al (2021) Development of mushroom polysaccharide and probiotics based solid self-nanoemulsifying drug delivery system loaded with curcumin and quercetin to improve their dissolution rate and permeability: State of the art. Int J Biol Macromol 189:744–757. https://doi.org/10.1016/j.ijbiomac.2021.08.170
Khursheed R, Singh SK, Kumar B et al (2022) Self-nanoemulsifying composition containing curcumin, quercetin, Ganoderma lucidum extract powder and probiotics for effective treatment of type 2 diabetes mellitus in streptozotocin induced rats. Int J Pharm 612:121306. https://doi.org/10.1016/j.ijpharm.2021.121306
Kotla NG, Gulati M, Singh SK, Shivapooja A (2014) Facts, fallacies and future of dissolution testing of polysaccharide based colon-specific drug delivery. J Control Release 178:55–62
Konturek PC, Koziel J, Dieterich W et al (2016) Successful therapy of Clostridium difficile infection with fecal microbiota transplantation. J Physiol Pharmacol 67:859–866
Kumar R, Kumar R, Khursheed R et al (2021) Development and validation of RP-HPLC method for estimation of fisetin in rat plasma. S Afr J Bot 140:284–289. https://doi.org/10.1016/j.sajb.2020.05.010
Kumar B, Malik AH, Sharma P et al (2017) Validated reversed-phase high-performance liquid chromatography method for simultaneous estimation of curcumin and duloxetine hydrochloride in tablet and self-nanoemulsifying drug delivery systems. J Pharm Res 11:1166–1178
Lee YH, Yang H, Lee SR et al (2018) Welsh onion root (Allium fistulosum) restores ovarian functions from letrozole induced-polycystic ovary syndrome. Nutrients 10:1430. https://doi.org/10.3390/nu10101430
Li S, Zhai J, Chu W et al (2020) Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome. Transl Res 219:13–29. https://doi.org/10.1016/j.trsl.2020.02.003
Li G, Liu Z, Ren F et al (2022) Alterations of gut microbiome and fecal fatty acids in patients with polycystic ovary syndrome in central China. Front Microbiol 13:1–12. https://doi.org/10.3389/fmicb.2022.911992
Lian Y, Zhao F, Wang W (2016) Central leptin resistance and hypothalamic inflammation are involved in letrozole-induced polycystic ovary syndrome rats. Biochem Biophys Res Commun 476:306–312. https://doi.org/10.1016/j.bbrc.2016.05.117
Liu H, Xie M, Nie S (2020) Recent trends and applications of polysaccharides for microencapsulation of probiotics. Food Front 1:45–59. https://doi.org/10.1002/fft2.11
Lowry OH (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Ndeingang EC, Defo Deeh PB, Watcho P, Kamanyi A (2019) Phyllanthus muellerianus (Euphorbiaceae) restores ovarian functions in letrozole-induced polycystic ovarian syndrome in rats. Evid-Based Complement Altern Med 2019:2965821. https://doi.org/10.1155/2019/2965821
Neyrinck AM, Sánchez CR, Rodriguez J et al (2021) Prebiotic effect of berberine and curcumin is associated with the improvement of obesity in mice. Nutrients 13:1436
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358. https://doi.org/10.1016/0003-2697(79)90738-3
Pandey KR, Naik SR, Vakil BV (2015) Probiotics, prebiotics and synbiotics-a review. J Food Sci Technol 52:7577–7587. https://doi.org/10.1007/s13197-015-1921-1
Raja MA, Maldonado M, Chen J et al (2021) Development and evaluation of curcumin encapsulated self-assembled nanoparticles as potential remedial treatment for pcos in a female rat model. Int J Nanomedicine 16:6231–6247. https://doi.org/10.2147/IJN.S302161
Reddy PS, Begum N, Mutha S, Bakshi V (2016) Beneficial effect of curcumin in letrozole induced polycystic ovary syndrome. Asian Pac J Reprod 5:116–122. https://doi.org/10.1016/j.apjr.2016.01.006
Risma KA, Clay CM, Nett TM et al (1995) Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci U S A 92:1322–1326. https://doi.org/10.1073/pnas.92.5.1322
Romo-Vaquero M, Selma MV, Larrosa M et al (2014) A rosemary extract rich in carnosic acid selectively modulates caecum microbiota and inhibits β-glucosidase activity, altering fiber and short chain fatty acids fecal excretion in lean and obese female rats. PLoS ONE 9:e94687. https://doi.org/10.1371/journal.pone.0094687
Sáez-Lara MJ, Robles-Sanchez C, Ruiz-Ojeda FJ et al (2016) Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: a review of human clinical trials. Int J Mol Sci 17:1–15. https://doi.org/10.3390/ijms17060928
Sahebkar A, Cicero AFG, Simental-Mendía LE et al (2016) Curcumin downregulates human tumor necrosis factor-α levels: a systematic review and meta-analysis ofrandomized controlled trials. Pharmacol Res 107:234–242. https://doi.org/10.1016/j.phrs.2016.03.026
Shabani A, Noshadian M, Jamilian M et al (2018) The effects of a novel combination of selenium and probiotic on weight loss, glycemic control and markers of cardio-metabolic risk in women with polycystic ovary syndrome. J Funct Foods 46:329–334. https://doi.org/10.1016/j.jff.2018.04.071
Shen JD, Wei Y, Li YJ et al (2017) Curcumin reverses the depressive-like behavior and insulin resistance induced by chronic mild stress. Metab Brain Dis 32:1163–1172. https://doi.org/10.1007/s11011-017-0017-1
Staley C, Hamilton MJ, Vaughn BP et al (2017) Successful resolution of recurrent clostridium difficile infection using freeze-dried, encapsulated fecal microbiota; pragmatic cohort study. Am J Gastroenterol 112:940–947. https://doi.org/10.1038/ajg.2017.6
Sun W, Guo Y, Zhang S et al (2018) Fecal microbiota transplantation can alleviate gastrointestinal transit in rats with high-fat diet-induced obesity via regulation of serotonin biosynthesis. Biomed Res Int 2018:8308671. https://doi.org/10.1155/2018/8308671
Wang ET, Calderon-Margalit R, Cedars MI et al (2011) Polycystic ovary syndrome and risk for long-term diabetes and dyslipidemia. Obstet Gynecol 117:6–13. https://doi.org/10.1097/AOG.0b013e31820209bb
Weingarden AR, Vaughn BP (2017) Intestinal microbiota, fecal microbiota transplantation, and inflammatory bowel disease. Gut Microbes 8:238–252
Wilson BC, Vatanen T, Cutfield WS, O’Sullivan JM (2019) The super-donor phenomenon in fecal microbiota transplantation. Front Cell Infect Microbiol 9:1–11
Yang H, Lee YH, Lee SR et al (2020) Traditional medicine (Mahuang-Tang) improves ovarian dysfunction and the regulation of steroidogenic genes in letrozole-induced PCOS rats. J Ethnopharmacol 248:112300. https://doi.org/10.1016/j.jep.2019.112300
Zhang N, Zhang F, Xu S et al (2020) Formulation and evaluation of luteolin supersaturatable self-nanoemulsifying drug delivery system (S-SNEDDS) for enhanced oral bioavailability. J Drug Deliv Sci Technol 58:101783. https://doi.org/10.1016/j.jddst.2020.101783
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Leander Corrie: methodology, data curation, and writing—original draft
Hardeep Singh: methodology
Monica Gulati: supervision and writing—review and editing
Sukriti Vishwas: methodology
Dinesh Kumar Chellappan: methodology
Gaurav Gupta: methodology
Ana Cláudia Paiva-Santos: methodology, writing—review and editing
Francisco Veiga: methodology, writing—review and editing
Faisal Alotaibi: methodology
Aftab Alam: methodology, writing—review and editing
Rajaraman D. Eri: writing—review and editing, methodology
Parteek Prasher: methodology
Jon Adams: methodology
Keshav Raj Paudel: methodology
Kamal Dua: methodology
Sachin Kumar Singh: methodology, supervision, and writing—review and editing
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Corrie, L., Singh, H., Gulati, M. et al. Polysaccharide-fecal microbiota-based colon-targeted self-nanoemulsifying drug delivery system of curcumin for treating polycystic ovarian syndrome. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03029-3
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DOI: https://doi.org/10.1007/s00210-024-03029-3