{"paper_id":"f5195f7d-7c07-4d34-9954-b337bd6adaf6","body_text":"Special Issue 3, 2021 Indian Journal of Pharmaceutical Sciences\n139\n Research Paper\n*Address for correspondence\nE-mail: cheng973862@163.com\nEffect of Different Ovulation Induction Regimens on  \nPregnancy Outcome of Patients with Endometriosis \nand Infertility Treated with In vitro  Fertilization and  \nTransplantation \nYU-HONG XIAO AND YUE-XIN YU*\nDepartment of Reproductive Medicine, General Hospital of Northern Theater Command, Liaoning-110016, China\nXiao et al.: Buqi Ziyin Combined with Traditional Chinese Medicine Nursing on Thyroid Cancer Patients\nTo explore the effect of different ovulation induction regimens on pregnancy outcome of patients with \nendometriosis and infertility treated with in vitro fertilization and transplantation. From December 2016 \nto December 2019, a total of 324 patients with endometriosis and infertility were selected as subjects. \nAfter the same in vitro fertilization treatment, three protocols (super long protocol, modified long protocol \nand antagonist protocol) were studied retrospectively. Baseline, total Gonadotropin dosage, Gonadotropin \ndays, Luteinizing hormone, progesterone and follicle stimulating hormone levels (U/L), oocyte retrieval \nand embryo status, clinical pregnancy rate, live birth rate and abortion rate were compared among the \nthree groups. The total number of days and total amount of Gonadotropin in the super long protocol \ngroup were lower than those in the modified long protocol group and antagonist group (p<0.05). The \nprogesterone level before oocyte retrieval was the lowest in the modified long protocol group, followed by \nthe super long protocol group, and the highest in the antagonist group (p<0.05). The number of retrieved \noocytes, mature oocytes and normal cleavage in the modified long protocol group were significantly higher \nthan those in the super long protocol group (p<0.05), but there was no significant difference in the number \nof excellent embryos (p>0.05). In addition, the number of retrieved ovums, mature ovums, normal cleavage \nand excellent embryos in the modified long protocol group was the highest (p<0.05), followed by the super \nlong protocol group (p<0.05). Compared with the other two groups, the pregnancy rate and live birth rate \nwere significantly increased (p<0.05) and the abortion rate was significantly decreased (p<0.05). Finally, \nthe pregnancy rate, live birth rate and abortion rate of the modified long protocol group were higher than \nthose of the antagonist protocol group. The pregnancy rate and live birth rate of super long protocol were \nhigher than those of modified long protocol and antagonist protocol and the abortion rate was lower. The \ntotal number of Gonadotropin days and the total amount of Gonadotropin in super long protocol group \nwere lower, which had the advantages of clinical significance. It was a kind of ovulation induction formula \nworthy of promotion for patients with endometriosis and infertility casen. \nKey words: Endometriosis, infertility, in vitro fertilization, ovulation induction program\nEndometriosis (EMT) is a kind of malignant tumor \ncharacteristic of endometrial tissue, which is implanted \nin the cervical area, and has the characteristics of \ninvasion, distant metastasis and recurrence [1], the \nincidence rate of women in childbearing age is high, \nabout 10 %~15 %[2]. Endometriosis seriously affects the \nnormal life of patients, the focus of recurrent periodic \nbleeding, cysts, dysmenorrhea and pelvic pain and other \nsymptoms, and prone to infertility[3]. The mechanism of \nEMT affecting female reproductive function is complex \nand its mechanism is not clear.\nHow to improve the pregnancy outcome of EMT \npatients with infertility has become a worldwide \nresearch hotspot. At present, the main methods include \ndrugs, surgery and in vitro fertilization and embryo \ntransfer (IVF-ET). Gonadotropin releasing hormone \nagonist (GnRHa) is commonly used in clinic. However, \nGnRHa cannot cure endometriosis, and can cause \nexcessive ovarian suppression. It is still controversial \nwhether GnRHa can improve ovum quality and clinical \npregnancy outcome. Laparoscopic surgery has become \n\nwww.ijpsonline.com\nSpecial Issue 3, 2021Indian Journal of Pharmaceutical Sciences\n140\napproved by the ethics committee of our hospital.\nDrugs: Long acting triptorelin acetate (Bayi, 3.75 \nmg/tablet, Lizhu Pharmaceutical Group Co., Ltd., \nGuoyao Zhunzi H20093852). Triptorelin acetate for \ninjection (3.75 mg/tube, daphrin, French biotechnology \ncompany, Guoyao Zhunzi H20030578). Human \nchorionic gonadotropin (Shanghai first biochemical \npharmaceutical Co., Ltd., Guoyao Zhunzi H31020520). \nRecombinant follicle stimulating hormone (guonafen, \n75 u/tube, Merck snow Co., Ltd., Registration \nNo. S20160040). Urinary follicle stimulating \nhormone (lishenbao, 75 u/piece, Lizhu group, Lizhu \npharmaceutical factory, Guoyao Zhunzi H20052130). \nUrinary gonadotropin (hMG, 75 u/tube, Ma’anshan \nFengyuan Pharmaceutical Co., Ltd., Guoyao Zhunzi \nH20045720).\nOvulation induction program:\nModified ultra-long ovulation induction protocol: the \npatient received intramuscular injection of long-acting \ntriptoreline acetate on the third day of menstruation.\nModified long protocol: on the first or second day \nof menstruation, the patient came to the hospital for \ninjection of 3.75 mg of daphnetin. Antagonist regimen: \nclomiphene citrate 100 mg/d was taken orally on the \nthird day of menstruation until the trigger day.\nOvulation induction:\nAbout 30 d after injection, B-ultrasound and serum \nhormone were used to detect the ovarian down-\nregulation. When the diameter of the largest follicle is \nless than 10 mm and the thickness of endometrium is \nless than or equal to 5 mm, we can judge that it reaches \nthe down regulation standard and start promoting \novulation. Gonadotropin is injected intramuscularly for \novulation induction. The drugs for ovulation induction \ninclude recombinant follicle stimulating hormone, \nurinary follicle stimulating hormone and urinary \ngonadotropin. The attending physician adjusts the type \nand dosage of drugs according to the hormone level \nand follicle growth of patients, and decides the starting \ndose of gonadotropin according to the age and body \nmass index of patients. When the diameter of dominant \nfollicle reached 14 mm, GnRH antagonist was injected \ndaily until the day of trigger.\nOocyte retrieval:\nWhen there are two or more dominant follicles with \na diameter greater than or equal to 18 mm, 250 μg \nrecombinant human chorionic gonadotropin was \nthe first-line treatment for endometriosis. It can be \nused for the diagnosis and staging of endometriosis, \nthe removal of ectopic lesions and the normalization of \npelvic structure. However, there is a risk of recurrence \nof ectopic cysts after surgery[4].\nEuropean Society of human reproduction and \nEmbryology guidelines recommend assisted \nreproductive technology for patients with endometriosis \nand infertility[5]. In vitro fertilization (IVF) can improve \nthe excellent embryo rate and pregnancy outcome of \npatients with endometriosis [6]. Ovulation induction \nprogram is one of the decisive steps for IVF success. \nIt is very important to control ovulation induction \ntechnology, which is closely related to improving \npregnancy outcome. In order to provide basis and \nreference for clinical research, this paper compared \nthe pregnancy outcomes of IVF treatment in patients \nwith endometriosis and infertility by three ovulation \ninduction regimens: modified long protocol, ultra-long \nprotocol and antagonist protocol.\nMATERIALS AND METHODS\nGeneral information:\nFrom December 2016 to December 2019, 324 patients \nwith endometriosis and infertility were selected as \nsubjects. The age was (32.46±3.32) y, the duration of \ninfertility was (4.24±3.07) y and the body mass index \n(BMI) was (22.20±3.35). \nInclusion criteria-In line with the EMT diagnostic criteria \nof the Chinese Medical Association of Obstetrics and \nGynecology; patients and their families are informed \nand voluntarily sign the research consent; whether the \nwoman’s uterus can bear pregnancy; Age 22-45 y; those \nwho have fertility needs and have not been pregnant for \nat least one year without contraceptive measures.\nExclusion criteria-Either male or female suffered from \nserious mental illness; either male or female suffered \nfrom acute infection of urogenital system and sexually \ntransmitted diseases; poor compliance, unable to \nreceive IVF treatment and timely review; hydrosalpinx \nwith impact on IVF pregnancy outcome, ≥4 cm \nuterine leiomyoma, severe adenomyosis; spouse with \ninfertility; parallel participants in other clinical studies.\nIn this study, patients were divided into three groups \naccording to different ovulation induction protocols, \nincluding super long protocol group, modified long \nprotocol group and antagonist protocol group. This \nstudy met the requirements of medical ethics and was \n\nwww.ijpsonline.com\nSpecial Issue 3, 2021 Indian Journal of Pharmaceutical Sciences\n141\ncompared among the three groups: total gonadotropin \n(Gn) dosage, Gn days, luteinizing hormone (LH) \nlevel (U/L), progesterone (P) level (mg/L) and follicle \nstimulating hormone (FSH) level (U/L). The number \nof retrieved oocytes, mature oocytes, normal cleavage \nand high-quality embryos were compared among the \nthree groups. Pregnancy diagnosis-blood was drawn  \n14 d after transplantation, and 30 d after transplantation, \nB-ultrasound was used to determine whether clinical \npregnancy, intrauterine and extrauterine conditions, \ngerm and heart tube pulsation were detected, and \nclinical pregnancy rate, live birth rate and abortion rate \nwere calculated.   \nStatistical analysis:\nAll data were analyzed by SPSS 22.0 software. \nContinuous variables pass the normality test to express. \nThe count variables were expressed by the number of \ncases and percentage, and the comparison between \ngroups was performed by chi square test; the test \nlevel was bilateral α=0.05. p<0.05 was considered \nstatistically significant.\nRESULTS AND DISCUSSION\nThe average age, infertility years, BMI and embryo \ntransfer number of the three groups were not statistically \nsignificant (p>0.05), indicating that the three groups \nwere comparable, as shown in Table 1.\nAccording to the statistics of IVF of three groups, we \nfound that the total number of GN days and the total \nnumber of GN in the super long protocol group were \nlower than those in the modified long protocol group \nand the antagonist group (p<0.05), and there was no \nsignificant difference in the total number of GN days \nand the total number of GN between the modified \nlong protocol group and the antagonist protocol group \n(p>0.05). For p level before oocyte retrieval, the \nmodified long protocol group was the lowest, followed \nby the super long protocol group, and the antagonist \ngroup was the highest (p<0.05), as shown in Table 2.\nThe number of retrieved oocytes, mature oocytes and \nnormal cleavage in the modified long protocol group \nwere significantly higher than those in the super long \nprotocol group (p<0.05). The number of retrieved \noocytes, mature oocytes, normal cleavage and excellent \nembryos in the modified long protocol group were \nhigher than those in the antagonist protocol group \n(p<0.05); the number of retrieved oocytes, mature \noocytes and normal cleavage in the super long protocol \ninjected intramuscularly that night. After 36-38 h, the \noocytes were removed by vaginal ultrasound. According \nto hormone level, embryo condition, endometrium \ncondition and patient’s will, ovum freezing or \ntransplantation is decided. Vitrification was used for \nfreezing. The ovums were treated with cryoprotectant \nand stored in liquid nitrogen. The ovums waiting for \ntransplantation were placed in a 5 % CO 2 incubator at \n37°.\nIVF:\nIVF was performed according to the technical \nspecification for human assisted reproduction[8]. On the \nday of in vitro fertilization, the semen of the man was \nfully liquefied, and the semen was treated by density \ngradient centrifugation. After 5 h of oocytes retrieval, \nsperm was added into the micro drop of the fertilization \ndish, and the final concentration of sperm was  \n250 000 pieces of PR grade sperm/ovums, which were \ncultured overnight in a 5 % CO2 incubator at 37°.\nThe fertilization was observed 16-20 h after \ninsemination, and the embryo quality was scored \naccording to the consensus of Istanbul experts in 2001. \nThe evaluation criteria of high-quality embryos were as \nfollows: normal fertilization on the first day, division \ninto 3-5 cells on the second day, more than 7 embryo \ncells on the third day, and the fragmentation rate was \nless than 20 %. The blastomeres were homogeneous, \nwithout vacuoles and multi-nucleation.\nFresh embryos were taken from all the above \nprograms, and all available embryos were preserved by \nvitrification. According to the patient’s menstrual cycle, \nthe endometrial preparation scheme was selected: \nthe natural cycle was selected for those with regular \nmenstruation and normal ovulation; the hormone \nreplacement cycle was selected for those with irregular \nmenstruation or ovulation disorder. Embryo transfer \nwas performed according to the routine freezing and \nresuscitation in our center. 14 d after transplantation, \nblood samples were taken to check the level of \nhuman chorionic gonadotropin (hCG). Ultrasound \nexamination was performed 4-5 w after transplantation. \nIf the gestational sac and heart tube pulsation were \nfound in the uterine cavity, it was confirmed as clinical \npregnancy.     \nObservation index:\nThe general conditions of the three groups were \ncompared: age, infertility years, BMI, and embryo \ntransfer number. Ovulation induction indexes were \n\nwww.ijpsonline.com\nSpecial Issue 3, 2021Indian Journal of Pharmaceutical Sciences142\nwill not only bring physical and mental damage to \nwomen, affect family harmony and happiness, but \nalso increase the econom ic burden of patients. The \npathological and physiological process of endometriosis \nis complex and changeable, which may be the result of \nthe synergistic effect of pelvic microenvironment and \nanatomical structure changes, oxidative stress injury, \nimmune inflammatory response, genetic factors and \nendocrine dysfunction. The method to improve the \npregnancy outcome of EMT with infertility has been \na hot and difficult point in clinical research. IVF has \nbecome an important treatment method to improve \nthe pregnancy outcome of EMT patients. One of the \nkey factors for successful pregnancy is the quality of \noocytes obtained by ovulation induction, in which \npituitary down regulation is the key process to ensure \nthe quality of oocytes\n[11]\n.\nIn this study, a retrospective analysis was used \nto compare the embryo and pregnancy status of  \n324 patients with endometriosis and infertility. Our \ngroup were higher than those in the antagonist protocol \ngroup (p<0.05), as shown in Table 3.\nStatistics of pregnancy outcomes of the three groups \nshowed that the pregnancy rate and live birth rate of \nthe super long protocol group were significantly higher \nthan those of the modified long protocol group and the \nantagonist protocol group (p<0.05), and the abortion \nrate was significantly lower than that of the other two \ngroups (p<0.05). The pregnancy rate and live birth rate \nof the modified long protocol group were higher than \nthose of the antagonist protocol group, and the abortion \nrate was lower (p<0.05), as shown in Table 4.\nEndometriosis is a common clinical gynecological \ndisease in young and middle-aged women. It means \nthat the active endometrial tissue (glands and stroma) \nis implanted outside the uterus and invades other \nnormal tissues. Its main symptoms and consequences \nare abdominal pain and infertility. EMT combined with \ninfertility has gradually become an important cause of \ninfertility in women of childbearing age. This disease \nGroups Average age Years of infertility BMI Number of embryo transfer\nModified long protocol 34.63±2.86 4.24±3.07 22.43±3.12 1.84±0.52\nUltra-long protocol 33.41±3.09 4.17±3.14 22.06±3.32 1.79±0.43\nAntagonist regimen 32.48±3.30 4.25±3.1\n7\n22.45±3.52 1.86±0.58\nTABLE 1: COMPARISON OF BASIC DATA OF THREE GROUPS OF PATIENTS (x̄ ±S)\nGroups Total Gn days Total Gn\nLH level before \noocyte retrieval \n(U/L)\nP level before \noocyte retrieval \n(mg/L)\nFSH level before \noocyte retrieval \n(U/L)\nModified long protocol 9.98±3.12\n$\n2384.40±961.33 4.52±1.32 0.52±0.15\n#$\n9.83±4.40\nUltra-long protocol 7.13±2.08\n*#\n2060.83±733.89 4.31±2.67 0.73±0.18*\n#\n10.24±4.12\nAntagonist regimen 9.55±2.22\n$\n2349.40±949.26 4.09±2.11 0.84±0.27\n$\n* 9.31±3.45\nTABLE 2: COMPARISON OF IVF OUTCOMES AMONG THE THREE GROUPS (X̄ ±S)\nNote：\n*\nmeans p<0.05 vs. Modified long protocol; \n#\nmeans p<0.05 vs. Antagonist regimem; \n$\nmeans p<0.05 vs. Ultra long protocol\nGroups N Number of  \noocytes\nNumber of mature \noocytes\nNormal oocytes \ndivision number\nNumber of excellent \nembryos\nModified long protocol 105 11.55±8.25\n#$\n10.26±7.29\n#$\n6.42±5.43\n#$\n3.23±3.19\n#\nAntagonist regimen 62 7.21±5.35$* 6.07±4.83$* 3.92±3.01$* 2.19±2.09*\nUltra-long protocol 157 9.04±5.80\n*#\n8.31±5.67\n*#\n5.11±4.08\n*#\n2.62±2.63\nTABLE 3: COMPARISON OF OOCYTE RETRIEVAL AND EMBRYO RETRIEVAL AMONG THREE GROUPS \n(X̄ ±S)\nNote: *means p<0.05 vs. Modified long protocol; \n#\nmeans p<0.05 vs. Antagonist regimem;\n $\nmeans p<0.05 vs. Ultra long protocol\nGroups N Gestation Live birth Abortion\nModified long protocol 105 76 (72.4 %)\n#$\n56 (53.3 %)\n#$\n20 (19.0 %)\n#$\nAntagonist regimen 62 42 (67.7 %)*\n$\n25 (40.3 %)*\n$\n17 (27.4 %)*\n$\nUltra long protocol 157 116 (73.9 %)\n#\n* 103 (65.6 %)\n#\n* 13 (8.3 %)\n#\n*\nTABLE 4: COMPARISON OF PREGNANCY OUTCOMES AMONG THE THREE GROUPS [N (%)]\nNote: *means p<0.05 vs. Modified long protocol; \n#\nmeans p<0.05 vs. Antagonist regimem; \n$\nmeans p<0.05 vs. Ultra long protocol\n\nwww.ijpsonline.com\nSpecial Issue 3, 2021 Indian Journal of Pharmaceutical Sciences\n143\ntotal number of GN days and the total amount of GN \nin the super long protocol group were lower than those \nin the modified long protocol group and the antagonist \ngroup, which had the advantage of clinical significance. \nIt was a worthy ovulation induction program for patients \nwith endometriosis and infertility.\nAcknowledgements:\nThis work was supported by the General Hospital of \nNorthernTheater Command.\nConflicts of interest:\nThe authors report no conflicts of interest.\nREFERENCES\n1. Zuberi NF, Rehman R. Endometriosis and subfertility. \nSubfertility 2021;135-46.\n2. Tan J, Cerrillo M, Cruz M, Cecchino GN, Garcia-Velasco JA. \nEarly Pregnancy Outcomes in Fresh Versus Deferred Embryo \nTransfer Cycles for Endometriosis-Associated Infertility: A \nRetrospective Cohort Study. J Clin Med 2021;10(2):344.\n3. Shebl O, Sifferlinger I, Habelsberger A, Oppelt P, Mayer RB, \nPetek E, et al. Oocyte competence in in vitro fertilization \nand intracytoplasmic sperm injection patients suffering from \nendometriosis and its possible association with subsequent \ntreatment outcome: a matched case–control study. Acta Obstet \nGynecol Scand 2017;96(6):736-44.\n4. Mosbrucker C, Somani A, Dulemba J. Visualization of \nendometriosis: comparative study of 3-dimensional robotic \nand 2-dimensional laparoscopic endoscopes. J Robot Surg \n2018;12(1):59-66.\n5. Haiyu T, Tianmin G. Diagnosis and treatment of endometriosis: \nInterpretation of the new guidelines of the European Society \nof human reproduction and Embryology (ESHRE). Chin J \nReproduct Health 2015;26(2):176-80.\n6. Ylmaz N, Ceran MU, Ugurlu E N. Impact of endometrioma and \nbilaterality on IVF / ICSI cycles in patients with endometriosis. \nJ Gynecol Obstetrics Human Reproduction 2020:101839.\n7. Endometriosis cooperative group, Chinese society of Obstetrics \nand gynecology. Guidelines for diagnosis and treatment of \nendometriosis. Chin J Obstetrics Gynecol 2015;10(3):161-9.\n8. Ministry of health. Notice of the Ministry of health on revising \nrelevant technical specifications, basic standards and ethical \nprinciples of human assisted reproductive technology and \nhuman sperm bank. Bulletin of the Ministry of health of the \npeople’s Republic of China, 2003;(3):1-10.\n9. Evans MB, Decherney AH. Fertility and endometriosis. Clin \nObstetrics Gynecol 2017;60(3):497-502.\n10. Miller JE, Ahn SH, Monsanto SP, Khalaj K, Koti M, Tayade \nC. Implications of immune dysfunction on endometriosis \nassociated infertility. Oncotarget 2017;8(4):7138-47.\n11. Yin Y , Mao Y , Liu A, Shu L, Yuan C, Cui Y , et al. Insufficient \nCumulus Expansion and Poor Oocyte Retrieval in \nEndometriosis-Related Infertile Women. Reproductive Sci \n2021:1-9.\n12. Khan Z. Fertility-related considerations in endometriosis. \nAbdominal Radiol 2020;45:1754-61.\n13. Danhof NA, Van Wely M, Koks CA, Gianotten J, De Bruin JP, \nsurvey results showed that the pregnancy rate and live \nbirth rate of patients treated with ultra-long protocol \nwere higher than those treated with modified long \nprotocol and antagonist protocol, and the abortion rate \nwas significantly lower than those treated with modified \nlong protocol and antagonist protocol, indicating that \nthe ultra-long protocol can significantly improve the \npregnancy outcome of patients with endometriosis \ncomplicated with infertility The transplantation rate and \nclinical pregnancy rate of fresh cycle were analyzed. \nThe results of this study also showed that the total \nnumber of days of GN and the total amount of GN in the \nsuper long protocol group were lower than those in the \nmodified long protocol group and the antagonist group, \nindicating that the super long protocol was convenient \nfor medication and less injection times, which directly \naffected the clinical compliance and patient acceptance. \nThe reason may be the decrease of estrogen level in \nthe process of promoting ovulation, which improves \nendometrial receptivity and avoids ovarian hyper \nstimulation[12].\nThe number of retrieved oocytes, mature oocytes and \nnormal cleavage in the modified long protocol group \nwas significantly higher than that in the super long \nprotocol group and the antagonist protocol group. \nThe number of retrieved oocytes, mature oocytes and \nnormal cleavage in the super long protocol group was \nhigher than that in the antagonist protocol group. This \nstudy found that the pregnancy rate and live birth rate \nof modified long protocol were high, and the abortion \nrate was low [13]. GnRH-a is a drug that can compete \nwith endogenous GnRH to act on the pituitary gland, \nwhich can make the pituitary GnRH-a receptor in a \ndesensitized state, thus inhibiting the ovarian secretion \nof related hormones[14]. In this study, GnRH-a was used \nin both modified long protocol and super long protocol \nto achieve the effect of pituitary down regulation. \nHowever, the antagonist scheme also has its clinical \nadvantages. The GN releasing hormone used in this \nscheme has a wide range of application, avoids the \ntransient increase effect of GnRH-a, does not need the \ndown-regulation process, has short treatment cycle, and \nis flexible and convenient to use[15].\nIn conclusion, modified long protocol has clinical \nadvantages in improving the number of IVF oocytes \nand laboratory embryos, but the pregnancy rate and live \nbirth rate of super long protocol are higher than those of \nmodified long protocol and antagonist protocol, and the \nabortion rate is significantly lower than that of modified \nlong protocol and antagonist protocol. In addition, the \n\nwww.ijpsonline.com\nSpecial Issue 3, 2021Indian Journal of Pharmaceutical Sciences\n144\nembryo quality in Thai native heifers. Tropical Animal Health \nand Production 2017;49(3):633-9.\nCohlen BJ, et al. The SUPER study: protocol for a randomised \ncontrolled trial comparing follicle-stimulating hormone and \nclomiphene citrate for ovarian stimulation in intrauterine \ninsemination. BMJ open 2017;7(5):e015680.\n14. Sallam HN, Garcia‐Velasco JA, Dias S, Arici A, Abou‐Setta \nAM. Long‐term pituitary down‐regulation before in vitro \nfertilization (IVF) for women with endometriosis. Cochrane \nDatabase of Sys Rev 2006;1(1):CD004635.\n15. Chankitisakul V , Pitchayapipatkul J, Chuawongboon P, \nRakwongrit D, Sakhong D, Boonkum W, et al. Comparison of \nthree superovulation protocols with or without GnRH treatment \nat the time of artificial insemination on ovarian response and \nThis article was originally published in a special issue,  \n“Evolutionary Strategies in Biomedical Research and \nPharmaceutical Sciences” Indian J Pharm Sci 2021:83(3)  \nSpl issue;139-144\nThis is an open access article distributed under the terms of the Creative \nCommons Attribution-NonCommercial-ShareAlike 3.0 License, which  \nallows others to remix, tweak, and build upon the work non-commercially,  \nas long as the author is credited and the new creations are licensed under \nthe identical terms","source_license":"CC0","license_restricted":false}