Effect of Variability of Physical Properties of Povidone K30 on Crystallization and Drug-Polymer Miscibility of Celecoxib-Povidone K30 Amorphous Solid Dispersions.

In the present study, we have investigated the variability in physical properties of povidone K30 (PVP K30) and its impact on crystallization and drug-polymer miscibility of celecoxib-PVP K30 (CLB-PVP K30) amorphous solid dispersions (ASDs). CLB-PVP K30 ASDs were prepared using nine batches of PVP K30, in situ on glass slides by quench-cooling using the hot and cold stage of a microscope. Crystallization of the ASDs stored at 40 ± 2 °C/75 ± 5% relative humidity was captured using polarized light microscopy for up to 24 h and quantified using mean pixel counts of images. The quantitative drug-polymer miscibility of nine CLB-PVP K30 systems was determined using melting point depression. Pearson's correlation analysis was used to find the correlation between (i) % crystallization with drug-polymer miscibility and physical properties and (ii) drug-polymer miscibility and physical properties, of PVP K30. The % crystallization was significantly variable (p < 0.05) among the nine CLB-PVP K30 ASDs. The nine PVP K30 batches exhibited significant variability (p < 0.05) from batch to batch and/or source to source in physical properties. The % crystallization showed correlation to particle size distribution (PSD) (weak positive), glass transition (Tg) (weak positive), drug-polymer miscibility (moderate negative), true density, and porosity (moderate positive) and hygroscopicity (strong positive). Miscibility showed correlation between Tg (weak positive), hygroscopicity (weak negative), PSD (moderate negative), and true density and porosity (strong negative). The study suggests PSD, hygroscopicity, true density, and porosity of PVP K30 as the functionality related characteristics for its intended functionality of physical stability when it is used as a stabilizer in ASDs.

Impact of Drug-Polymer Miscibility on Enthalpy Relaxation of Irbesartan Amorphous Solid Dispersions.

PURPOSE: Drug-polymer miscibility has been proposed to play a critical role in physical stability of amorphous solid dispersions (ASDs). The purpose of the current work was to investigate the role of drug-polymer miscibility on molecular mobility, measured as enthalpy relaxation (ER) of amorphous irbesartan (IBS) in ASDs. METHODS: Two polymers, i.e. polyvinylpyrrolidone K30 (PVP K30) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), were used to generate ASDs with 10% w/w of the polymer. Drug-polymer miscibility was determined using melting point depression (MPD) method. Molecular mobility was assessed from ER studies at a common degree of undercooling (DOU) (Tg - 13.0°C ± 0.5°C). RESULTS: IBS exhibited higher miscibility in PVP K30 as compared to HPMCAS at temperature > 140°C. However, extrapolation of miscibility data to storage temperature (62°C) using Flory-Huggins (F-H) theory revealed a reversal of the trend. Miscibility of IBS was found to be higher in HPMCAS (2.6%) than PVP K30 (1.3%) at 62°C. Stretched relaxation time (τß) of 17.4365 h and 7.0886 h was obtained for IBS-HPMCAS and IBS-PVP K30 ASDs, respectively. CONCLUSION: Miscibility of drug-polymer at storage temperature explained the behavior of the molecular mobility, while miscibility near the melting point provided a reverse trend. Results suggest that drug-polymer miscibility determined at temperatures higher than the storage temperature should be viewed cautiously.

Biocompatible Human Placental Extracellular Matrix Derived Hydrogels.

Solubilizing extracellular matrix (ECM) materials and transforming them into hydrogels has expanded their potential applications both in vitro and in vivo. In this study, hydrogels are prepared by decellularization of human placental tissue using detergent and enzymes and by the subsequent creation of a homogenized acellular placental tissue powder (P-ECM). A perfusion-based decellularization approach is employed using detergent and enzymes. The P-ECM with and without gamma irradiation is then utilized to prepare P-ECM hydrogels. Physical and biological evaluations are conducted to assess the suitability of the P-ECM hydrogels for biocompatibility. The decellularized tissue has significantly reduced cellular content and retains the major ECM proteins. Increasing the concentration of P-ECM leads to improved mechanical properties of the P-ECM hydrogels. The biocompatibility of the P-ECM hydrogel is demonstrated through cell proliferation and viability assays. Notably, gamma-sterilized P-ECM does not support the formation of a stable hydrogel. Nonetheless, the use of HCl during the digestion process effectively decreases spore growth and bacterial bioburden. The study demonstrates that P-ECM hydrogels exhibit physical and biological attributes conducive to soft tissue reconstruction. These hydrogels establish a favorable microenvironment for cell growth and the need for investigating innovative sterilization methods.

Status of Contraceptive Use for Birth Spacing After a Teenage Pregnancy: Where Do We Stand?

BACKGROUND: Adolescence is the most complex stage of reproductive health. The knowledge and awareness of adolescent-related reproductive issues are limited, particularly in lower-middle-income countries. Adolescent pregnancies are associated with major maternal and neonatal complications. Effective contraception use can prevent teenage pregnancy and subsequent complications. METHODS: It was a cross-sectional study conducted in a tertiary care hospital and teaching institute over a period of one year. Through this study, we aimed to assess the prevalence of postpartum use of approved standard methods of contraception for birth spacing among teenage mothers and to assess the reasons for their non-acceptance. A total of 133 consecutive consenting postpartum teenage mothers were recruited in the study. Participants were asked about their age at the time of marriage and delivery, marital status, parity, education and economic status, the number of antenatal visits, mode of delivery, and antenatal complications. Compliance with postpartum contraception was noted, and reasons for its non-acceptance were asked in detail. RESULTS: Among the 133 participants, contraceptive users were categorized into Group A and non-users into Group B. The mean age at the time of marriage was 17.6±0.4 and 17.5±0.6 years in Group A and Group B, respectively. Mothers in Group A were more educated than their counterparts in Group B (82.2% of mothers were educated up to 12th standard in Group A compared to 46.6% in Group B). Among the contraception users, 70% had four or more antenatal visits compared to 7.9% of the non-users. Reasons for non-acceptance of postpartum contraception were elicited in Group B: 42.0% had fear of becoming infertile, 38.6% feared that contraceptives interfere with breastfeeding and quality of breastmilk, 13.6% had opposition from family members, and 5.8% did not mention any reason. CONCLUSION: Teenage pregnancy is associated with increased feto-maternal complications. It also accounts for an increased incidence of unsafe abortions and maternal mortality. So it is crucial to make the adolescent group aware of effective methods of postpartum contraceptives to prevent adolescent pregnancies. Collaborative larger multicentric studies from different countries will help to reach a better, generalized conclusion regarding the same.

Synchronous Occurrence of Adult Granulosa Cell Tumor with Fibroma in One Ovary and Brenner Tumor in Other Ovary: An Extremely Unusual Case.

Ovarian tumors are a common form of neoplasia in women and it accounts for about 30% of female genital cancers. A coexistence of ovarian tumors with the same histogenetic origin such as germ cell or epithelial or sex cord stromal, but different histologic subtype is relatively common, whereas a synchronous occurrence of tumors with different histogenetic origin is rare. We report a case of 58-year-old woman with the synchronous presentation of adult granulosa cell tumor with fibroma (ovarian tumors with the same origin (sex cord stromal) but different histologic type) in one ovary and Brenner tumor (epithelial origin) in other ovary. Our patient presented with postmenopausal bleeding and was diagnosed with this rare combination of ovarian tumors on histopathology supplemented with immunohistochemistry. On extensive literary search, there is only a single report of mixed ovarian tumor composed of Brenner tumor and adult-type granulosa cell tumor. Our case is different from the above-mentioned report as although, in our patient both tumors coexisted, but in contralateral ovaries.

Compassionate Use of Remdesivir in Pregnancy: A Case Series From a COVID-19 Dedicated Center and Review of Literature.

Pregnancy is associated with immunological changes that could render an individual vulnerable to the severe coronavirus disease 2019 (COVID-19) disease. Even as we witnessed the third and most widespread pandemic wave, a conclusively advantageous treatment option still remained elusive. Remdesivir was one of the front-running therapeutic options that received emergency use authorization (EUA) and subsequent approval for the management of moderate to severe COVID-19 infections. Here, we report a series of moderate to severe COVID-19-infected pregnancies and the experience of remdesivir use on a compassionate basis. Four cases of pregnancy complicated with moderate to severe COVID-19 infections where remdesivir was administered were recruited into the study, and their outcome was assessed objectively. Of these cases, three women received remdesivir in addition to standard SARS-CoV-2 treatment in the antenatal period. One woman received remdesivir after delivery. One woman received tocilizumab in addition to remdesivir and standard SARS-CoV-2 care. Two women survived and were subsequently discharged to home care. Two succumbed to the disease. One baby who was exposed to remdesivir in utero is doing well at six months post-delivery. Remdesivir had been granted EUA for the treatment of suspected or laboratory-confirmed COVID-19 infection in adults and children who were hospitalized with severe disease or requiring supplemental oxygen and mechanical ventilation or extracorporeal membrane oxygenation (ECMO) in May 2020. This issuance allowed the use of the same dosing regimen in pregnant and parturient women as in the general adult population. Thus, this series of cases tried to assess the outcome of this drug among COVID-19-infected pregnant women. Early initiation of remdesivir in pregnancy in the viremic phase seems to provide some advantages in the survival outcome. Its use may be associated with transient elevation in hepatic transaminases in some cases. No detrimental effects on the ongoing pregnancies, fetuses, or neonates have been observed. Further large-scale studies may provide more conclusive evidence.

Assessment of Fertility Outcomes Following Combined Clomiphene and Letrozole Versus Letrozole Therapy for the Treatment of Polycystic Ovarian Syndrome Subfertility.

BACKGROUND: Poly Cystic Ovarian Syndrome (PCOS) affects 8-13% of women in their reproductive age and is one of the foremost causes of female subfertility. Traditionally, clomiphene citrate has been the first-line treatment for ovulation induction in PCOS. However, the European Society of Human Reproduction and Embryology (ESHRE) international evidence-based guidelines in 2018 recommended the use of letrozole as first-line therapy for ovulation induction in anovulatory PCOS women, due to better pregnancy and live birth rates. Here we aimed to evaluate the effect of combined - clomiphene and letrozole versus letrozole for the treatment of PCOS subfertility. METHODS: It was a retrospective cohort study conducted on reproductive-age women fulfilling Rotterdam Criteria for PCOS with a history of subfertility. All participants receiving at least one cycle of letrozole and clomiphene combination were recruited as cases. However, women receiving letrozole only for ovulation induction were taken as controls. Hospital records were abstracted for data on baseline characteristics such as age, duration of infertility, PCOS phenotype, body mass index (BMI), past medical and fertility history, treatment with ovulation induction agents, and metformin use. The mean size of the largest follicle, number of dominant follicles of size greater than 15 mm and endometrial thickness on Days 12-14 or on the day of the luteinizing hormone (LH) surge were recorded. A cycle was termed ovulatory if serum progesterone levels were > 5.0 ng/ml on the seventh day after the LH surge or day 22 in the absence of the LH surge. Data pertaining to therapy-associated side effects were also abstracted from the clinical records. RESULTS: Amongst the ovulatory cycles in both groups, there was no significant difference in the day of the LH surge. Serum progesterone levels on the seventh day post-ovulation were higher with combination therapy (19.35 v/s 26.71, p=0.004). The number of ovulatory cycles was also greater with combination therapy, but the difference was just short of significant (25 vs 18, p=0.08). The mean diameter of the largest follicle, incidence of multi-follicular ovulation, and thin endometrium were similar in both groups. The adverse effect profile was similar in both groups. CONCLUSION: Combination treatment of clomiphene citrate with letrozole may potentially improve fertility outcomes in PCOS subfertility in terms of the likelihood of ovulation and higher post-ovulatory progesterone levels, however, larger studies are required.

Application of a Negative Intrauterine Pressure Suction Device for Prophylactic Management of Atonic Postpartum Hemorrhage: A Quality Improvement Study.

BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide. PPH-preventing interventions need to be prioritized and can be integrated with conventional methods of PPH prevention. The introduction of negative intrauterine pressure using a suction cannula can be one of the cheapest modalities to decrease PPH secondary to uterine atonicity. This method has brought a renaissance to practical obstetrics in low-middle income countries (LMIC), where the cost and availability of uterotonics are major health issues. METHODS: It was a prospective quality improvement (QI) study conducted in the labor and delivery wards of a tertiary care medical institute and teaching center over the duration of one year. We aimed to assess the decrease in the incidence of atonic PPH with a negative intrauterine pressure suction device (NIPSD) integrated with active management of the third stage of labor (AMTSL) in the prevention of atonic PPH following normal vaginal delivery in low-risk antenatal women. In the initial six months, routine AMTSL was instituted for all consenting women (group 1). In the next six months, NIPSD was integrated with AMTSL (group 2). Data pertaining to the amount of blood loss, the incidence of primary PPH, uterine tone, fall in hemoglobin and hematocrit levels post-delivery, need for blood transfusion, and doctor and patient satisfaction were tabulated for all patients. RESULTS: A total of 1324 consenting women were eligible for enrollment during the study time frame. In the initial six months (baseline period, group 1), 715 participants were subjected to routine AMTSL in the third stage of labor. During the intervention phase (group 2), 609 parturient women were recruited. There was no significant difference in baseline parameters between the two groups. With the introduction of NIPSD to routine AMTSL, there was a significant decrease in the average volume of blood loss during vaginal delivery (group 1 = 389.45+65.42 ml, group 2 = 216.66+34.27 ml; p-value = 0.012). The incidence of atonic PPH was reduced by more than 75% (group 1 = 13 women, group 2 = 3 women; p-value = 0.001) after the introduction of NIPSD complementing routine AMTSL. The introduction of NIPSD has also been instrumental in reducing the cost burden on patient and hospital expenditures. The net benefit of its introduction resulted in a reduction of the overall cost burden of blood transfusions by around 70%. CONCLUSION: PPH is a public health problem, and measures to reduce PPH must be implemented to decrease this health burden. In countries with low resources, complementing routine AMTSL with NIPSD can be instrumental in decreasing the incidence of PPH. Considering its cost-effectiveness and reusability, LMIC can adopt NIPSD as a routine measure in all vaginal deliveries.

Assessment of Risk Factors and Obstetric Outcome of Adolescent Pregnancies Through a Prospective Observational Analysis.

Background Adolescence is the most crucial stage of life. Early marriage and teenage pregnancy infringe on adolescent girls' social and humanitarian rights. Moreover, it leads to school dropouts and decreased self-autonomy. Through this study, we aimed to analyze the risk factors and obstetric and neonatal outcomes resulting from adolescent pregnancies conceived by Indian girls less than 20 years of age. Materials and methods It was a prospective observational study conducted over a period of two years. Consecutive consenting adolescent mothers visiting the antenatal clinic or the delivery wards were recruited into the study. Adolescent pregnancies constituted all pregnancies where the maternal age was between 14 and 19 years at the time of presentation. Participants were followed prospectively till delivery and postpartum visit at six weeks to assess the obstetric and puerperal outcomes. Treating obstetricians asked about the causes responsible for current teenage pregnancy. At the time of delivery, data pertaining to antenatal complications, pregnancy outcome, mode of delivery, and birth weight were noted. All women were counseled for postpartum contraception at the time of delivery. Compliance with postpartum contraception was noted, and reasons for non-acceptance were asked. Results A total of 133 antenatal women in the adolescent age group were recruited during the study time frame. The mean age at the time of delivery was 18.4 years. Most of the women were educated between the sixth and 12th standards and belonged to the upper-lower economic class. Early marriage, increased family pressure, and school dropout at a young age were the predominant risk factors for teenage pregnancy in the study population. The majority of them suffered from anemia. Pregnancy-induced hypertension, hypothyroidism, fetal growth restriction, and oligohydramnios were a few other complications seen in adolescent pregnancies. Despite counseling, only 33.8% of adolescent mothers accepted postpartum contraception (any of the standard methods). Conclusion Pregnancy has concerning health consequences on adolescent girls and their babies. For example, adolescent mothers face increased risks of pregnancy-induced hypertension, obstructed labor, and puerperal sepsis. So, it is time to create awareness through mass educational campaigns and widespread family planning services.

Laparoscopic Sacrocervicopexy Using Ethibond Suture Graft: A Very Economic Yet Effective Fertility Preserving Surgery for Pelvic Organ Prolapse.

BACKGROUND: The modern era has witnessed a transition to a phase of uterus-preserving surgeries and so holds true for pelvic organ prolapse (POP) surgeries as well. Laparoscopic sacrocervicopexy has become a preferred surgical modality for moderate to severe degrees of POP in most women of the childbearing age group. With the alarming incidences of mesh erosion, synthetic mesh has almost gone off the market. We advocate a very simple and cost-effective technique of laparoscopic sacrocervicopexy using an Ethibond suture graft. MATERIALS AND METHODS: It was a pilot prospective observational study over one year. Consecutive consenting women with symptomatic prolapsed uterus Stage-II of the central component of the quantitative POP classification (POP-Q) were recruited. Laparoscopic sacrocervicopexy was performed under general anesthesia using the standard protocols, and patients were prospectively followed for six months after surgery. The duration of surgery and hospital stay were noted. Patient satisfaction was rated using a five-point Likert scale. The vaginal length was measured immediately after and six months post-surgery. Sexual function was assessed using the validated female sexual function index (FSFI) scale six months after sacrocervicopexy. RESULTS: Out of 28 recruited women, the majority were multiparous, highly qualified, and belonged to the middle socio-economic class. Seven patients had co-morbidity in the form of hypertension (17.8%), diabetes (7.1%), and cardiovascular diseases (7.1%). The mean duration of surgery was 105.8±7.2 minutes in the study population. The mean duration of hospital stay was 2.2±0.6 days. No surgical site infection was noted in any of the cases. Most patients rated "very satisfied" experiences following surgery (67.9%). The mean vaginal length after surgery was 7.6±1.2 centimeters. After a follow-up period of six months, the mean vaginal length was 7.4±0.8 centimeters. The mean FSFI score was 30.8±2.4. CONCLUSION: Laparoscopic sacrocervicopexy with Ethibond suture graft is a cost-effective and safe surgical technique for POP in resource-limited settings. It also obviates the additional cost of synthetic mesh and the long-term risks of mesh erosion.

Correlationship of Drug-Polymer Miscibility, Molecular Relaxation and Phase Behavior of Dipyridamole Amorphous Solid Dispersions.

In present work, a correlationship among quantitative drug-polymer miscibility, molecular relaxation and phase behavior of the dipyridamole (DPD) amorphous solid dispersions (ASDs), prepared with co-povidone (CP), hydroxypropyl methylcellulose phthalate (HPMC P) and hydroxypropyl methylcellulose acetate succinate (HPMC AS) has been investigated. Miscibility predicted using melting point depression approach for DPD with CP, HPMC P and HPMC AS at 25 °C was 0.93% w/w, 0.55% w/w and 0.40% w/w, respectively. Stretched relaxation time (τß) for DPD ASDs, measured using modulated differential scanning calorimetry (MDSC) at common degree of undercooling, was in the order of DPD- CP > DPD-HPMC P > DPD-HPMC AS ASDs. Phase behavior of 12 months aged (25 ± 5 °C and 0% RH) spray dried 60% w/w ASDs was tracked using MDSC. Initial ASD samples had homogeneous phase revealed by single glass transition temperature (Tg) in the MDSC. MDSC study of aged ASDs revealed single-phase DPD-CP ASD, amorphous-amorphous and amorphous-crystalline phase separated DPD-HPMC P and DPD-HPMC AS ASDs, respectively. The results were supported by X-ray micro computed tomography and confocal laser scanning microscopy studies. This study demonstrated a profound influence of drug-polymer miscibility on molecular mobility and phase behavior of ASDs. This knowledge can help in designing "physical stable" ASDs.

Surface-stabilized lopinavir nanoparticles enhance oral bioavailability without coadministration of ritonavir.

AIM: The aim of the present study was to prepare surface-stabilized nanoparticles (NPs) for oral bioavailability enhancement of lopinavir (LPN), a Biopharmaceutics Classification System class II antiretroviral drug that possesses low oral bioavailability due to its poor aqueous solubility and extensive metabolism by liver microsomal enzymes. MATERIALS & METHODS: Surfactant-stabilized LPN-NPs were prepared by combination of antisolvent precipitation and high-pressure homogenization techniques using polyvinyl alcohol as a suitable stabilizer. LPN-NPs were freeze dried by a universal stepwise freeze-drying cycle using mannitol as the cryoprotectant. Pharmacokinetics after oral administration of LPN-NPs were evaluated in male Sprague-Dawley rats and were compared with free LPN coadministered with ritonavir (conventional formulation). RESULTS & CONCLUSION: Freeze-dried stabilized LPN-NPs possessed particle sizes of approximately 320 nm and a narrow particle size distribution (polydispersity index <0.2). The surface-stabilized LPN-NPs (without ritonavir) demonstrated a 3.11-fold enhancement in bioavailability in comparison to free LPN with ritonavir (conventional formulation).

Surface stabilized efavirenz nanoparticles for oral bioavailability enhancement.

The aim of the present study was to prepare surface stabilized nanoparticles for oral bioavailability enhancement of efavirenz (EFZ). EFZ nanoparticles (EFZ-NPs) were prepared by combination of anti-solvent precipitation and high pressure homogenization technique, using hydroxy propyl methyl cellulose as stabilizer which resulted in formation of EFZ-NPs of average particle size -350 nm with excellent particles size distribution (< 0.2). EFZ-NPs were freeze dried using trehalose as cryoprotectant and found to be quite stable against storage at 25 +/- 2 degrees C/60 +/- 5% RH and 40 +/- 2 degrees C/75 +/- 5% RH as evidenced from particle size, particle size distribution and drug content. EFZ-NPs demonstrated an increase in saturation solubility by 5.16 folds in comparison with free EFZ. In vitro dissolution studies established advantage of EFZ-NPs over free EFZ as more than 75% drug was dissolved within 5 min in case of EFZ-NPs while it was approx 20% in case of free EFZ. In vivo pharmacokinetic studies further confirmed the potential of EFZ-NPs as 2.02 folds increase in peak plasma concentration and 2.29 folds increase in AUC(0-infinity) were observed in comparison to free EFZ. The In vitro-In vivo relationship of the formulations further suggested higher correlation coefficient of 0.9995 for EFZ-NPs in Levys plot as compared to 0.8726 for free EFZ.