Formulation and Evaluation of 5-Fluorouracil and N-Acetylcysteine Loaded Microsponges Drug Delivery System

Nasal drug delivery via polymer systems has been proposed to be prevailing in the type of controlled drug delivery devices both in present and future. For scientific as well as economic reasons, such delivery systems have potential advantages which include enhanced therapeutic response, predictable rate of release at the targeted site, less side effects and extent of absorption and better patience compliance. In the present work an nasal delivery microsponges formulation of a potent anticancer drug, 5- Fluorouracil and Chemopreventive drug N-Acetylcysteine has been developed. The study includes formulation and evaluation of 5FU-NAC microsponges. The idea behind developing a nasal polymeric microsponges delivery system of 5FU-NAC was to deliver 5FU-NAC in a controlled release pattern for a long period of time up to 12 hours in order to reduce dose frequency and improve patience compliance. Box-Behnken statistical design with 3 factors, 3 levels and 17 runs were employed for the optimization study using design-expert software version 12. The variables stirring speed, polymer Ethyl cellulose, Dichloromethane were main factors that impacted the particle size, entrapment efficiency and Mucoadhesion in our microsponges formulation in our preliminary experiments. To investigate the impact of stirring speed(A), Ethyl cellulose (B) and dichloromethane (C) were selected as independent variables and they were set at high, medium and low level on the basis of the results of initial trials. In accordance with the design, 17 microsponge formulations were prepared and characterized for particle size (R1), entrapment efficiency (R2) and Mucoadhesion (R3). However, five set of formulations were selected from given 17 runs of formulations since those five showed response.[F1,F4,F7,F11,F14]. From the five optimized formulation one formulation [F7] was selected randomly. and it was characterized. The ratio of drug: polymer for the formulation of 5FU-NAC microsponges was varied in formulation and then the microsponges were evaluated for drug content, encapsulation efficiency, FTIR, particle size, zeta potential, x -ray diffraction study, morphological study by SEM, and invitro drug diffusion study using cellophane membrane and nasal mucosal membrane of goat, mucoadhesion study by using mucosal membrane, swelling index. The results obtained from the optimization technique was incorporated in our experimental value and signified that stirring speed of 1300 rpm, Ethyl cellulose of 3g and dichloromethane of 15ml was found to produce microsponges with good physical and morphological characters. Therefore, our optimized formulation F7 was significantly in accordance with the formulation derived from the optimization technique, values varying little, The release rate of drug from varying concentrations of polymeric microsponge shows that the release of drug increase with increasing concentration of polymers. The optimized formulation F7 has the good drug diffusion rate in the treated cellophane membrane. And nasal mucosa of goat. And give prolong drug release upto 12 hours. Because ethyl cellulose polymer control the drug release rate. The microsponges diffusion profile was compared with that of pure drugs diffusion profile. This studies shows that, the drug release profile was greatly extended by microsponges formulation.it shows prolonged drug release of 5FU-NAC. The drug was released from the microsponges formulation, threw the pores present in the surface of the microsponges. The pores was characterized by the evaporation of solvent dichloromethane from the internal phase. This pores plays a vital role in drug release mechanism. The optimized formulation F7 , have good swelling index, so the microsponges formulation easily attached to the membrane. Greater swelling property is mainly due the presence of polymer concentration in higher rate. Ethyl cellulose have property of good swelling capacity. The optimized formulation F7, has good Mucoadhesion property so the microsponges formulation can be easy stick over the mucosal membrane of nasal track. This Mucoadhesion is mainly due to the ethyl cellulose polymer concentration. After the formulation it was filled in hard gelatin capsule. And it was used by dry powder inhaler device like nebulizer or rotacap. According to the patient‟s convenience. to deliver the content directly to the lung. Repeated deep inhalation minimize the dose lose due dose deposition to the surface of the DPI device. However, in vivo experiments are essential to establish the actual usefulness of these microsponges. CONCLUSION An nasal delivery microsponges formulation of 5FU-NAC was formulated using polymer Ethyl cellulose. From the study the following conclusion can be drawn. The amount of internal phase that is Dichloromethane was selected at 30ml depending on the previous researches suitable for the preparation of microsponges and the external phase was found to be distilled water of 100ml containing PVA. The concentrations of the polymers required to produce microsponges with good physical and morphological characteristics was found to be 3g of Ethyl cellulose in accordance the optimum amount derived from the optimization technique with little variation in the main formulation. The stirring speed was found out to be 1300rpm for 2 hour from the optimization technique to check how it affects the particle size, however it was not inputted in the main formulation as it can controlled while in the experiments. The ratio of drug: polymer required to produce microsponges with good encapsulation efficiency was found to be at 1:1.5 below this ratio, microsponges formed had low capacity encapsulation efficiency of drug and low production yield and above thus range, there was also further increase in the encapsulation efficiency but the particle size increased. Hence, it was concluded that at 1:1.5 drug: polymer ratio, was an optimum ratio of polymer ratio to produce good microsponges. F7 formulation shows good swelling property. so the mucoadhesion also good to produce drug release in proper way. By the drug release studies of formulation F7, It was concluded that the release profile was in controlled fashion.. Finally, we may conclude that formulation F7 was best formulation in the class of Ethyl cellulose of 3g as retarding polymers. Microsponge formulation shows better controlled drug release profile as compared to that of pure drug. It states that the duration drug release from the single dose is increased. So we can minimize the dosing frequency. We can minimize the drug wastage. By directly delivering the microsponges to the affected site (lungs) by intra nasal drug delivery device, we can minimize the drug wastage; reduce the toxic effect produced by the drug to the normal healthy tissues

Enabling ab initio Hessian and frequency calculations of large molecules

A linear scaling method, termed as cardinality guided molecular tailoring approach, is applied for the estimation of the Hessian matrix and frequency calculations of spatially extended molecules. The method is put to test on a number of molecular systems largely employing the Hartree-Fock and density functional theory for a variety of basis sets. To demonstrate its ability for correlated methods, we have also performed a few test calculations at the Moller-Plesset second order perturbation theory. A comparison of central processing unit and memory requirements for medium-sized systems with those for the corresponding full ab initio computation reveals substantial gains with negligible loss of accuracy. The technique is further employed for a set of larger molecules, Hessian and frequency calculations of which are not possible on commonly available personal-computer-type hardware.Financial support from the Center for Development of Advanced Computing C-DAC, Pune, Naval Research Board NRB, New Delhi, and Council of Scientific and Industrial Research CSIR, New Delhi is gratefully acknowledged

Ayurvedic management of pituitary macroadenoma-a case report

Pituitary macroadenoma is an infrequently encountered clinical condition, characterized by a non-metastasizing neoplasm situated within the pituitary gland. This case report endeavours to elucidate the efficacy of ayurvedic interventions in achieving symptomatic resolution. A 44-year-old female patient, residing in Thrissur, diagnosed with features suggestive of pituitary macroadenoma, sought admission to Vaidyaratnam ayurveda college hospital for complaints of generalized pain, heaviness of head, impaired peripheral vision in the left eye, and amenorrhea persisting for approximately 7 months. The case was conclusively diagnosed as Pituitary Macroadenoma and meticulously addressed through therapeutic modalities including takradhara, nasyam, and thalapothichil.  patient was already prescribed with Caberlin tablets at a dosage of 0.25 mg twice weekly, administered nocturnally. Following 21 days of treatment, notable improvement in the LBNQ-Pituitary score was observed from 60 to 21 accompanied by significant symptomatic alleviation. A specific treatment protocol for the management of pituitary macroadenoma is currently unavailable

Preparation and evaluation of chitosan based thermoreversible gels for intraperitoneal delivery of 5-fluorouracil (5-FU)

Sterile thermoreversibly gelling systems based on chitosan-glycerol phosphate were developed for intraperitoneal delivery of the antineoplastic agent 5-FU. The formulation was evaluated for gelling characteristics and in vitro drug release. Drug free gels were evaluated for in vitro cytotoxicity in L-929 mouse fibroblast cells. Drug loaded gels were subjected to acute toxicity studies in Swiss albino mice via intraperitoneal route and efficacy studies via intratumoral injections in subcutaneous colon carcinoma bearing BALB/c mice. The formulations gelled reversibly in 8 min at 37 oC and provided prolonged release of the drug. Drug free systems showed dose dependent cytotoxicity in fibroblast cells, while in vivo studies revealed a 2.8 fold increase in LD50 of 5-FU administered intraperitonealy as the developed system. Tumor volume measurements showed comparable efficacy of 5-FU administered as gel and commercial injection with greatly improved safety profile of the former as adjudged from mortality and body weight measurements

Molecular tailoring approach for exploring structures, energetics and properties of clusters

Molecular Tailoring Approach (MTA) is a method developed for enabling ab initio calculations on prohibitively large molecules or atomic/molecular clusters. A brief review of MTA, a linear scaling technique based on set inclusion and exclusion principle, is provided. The Molecular Electrostatic Potential (MESP) of smaller clusters is exploited for building initial geometries for the larger ones, followed by MTA geometry optimization. The applications of MTA are illustrated with a few test cases such as (CO2)n and Lin clusters employing Density Functional theory (DFT) and a nanocluster of orthoboric acid at the Hartree-Fock (HF) level. Further, a discussion on the geometries and energetics of benzene tetramers and pentamers, treated at the Moller-Plesset second order (MP2) perturbation theory, is given. MTA model is employed for evaluating some cluster properties viz. adiabatic ionization potential, MESP, polarizability, Hessian matrix and infrared frequencies. These property evaluations are carried out on a series of test cases and are seen to offer quite good agreement with those computed by an actual calculation. These case studies highlight the advantages of MTA model calculations vis-a-vis the actual ones with reference to the CPU-time, memory requirements and accuracy

ANTI-INFLAMMATORY AND ANALGESIC ACTIVITY OF ARENGA WIGHTII GRIFF.-AN ENDEMIC PALM OF WESTERN GHATS

Objective: The present study aims to scientifically validate the anti-inflammatory and analgesic activities of Arenga wightii.Methods: The stem pith was excised from mature palm, sliced into small pieces, shade dried and powdered. The powder was extracted with ethanol, concentrated under reduced pressure and the crude extract was referred to as AW. The anti-inflammatory and analgesic activity of AW was analyzed in Wistar rats and Swiss albino mice.Results: The results revealed that the ethanolic extract of the stem pith of A. wightii showed a dose dependent anti-inflammatory and analgesic activity, which was comparable to the standards, indomethacin and acetyl salicylic acid respectively.Conclusion: The results of the current study reveal that A. wightii possesses significant anti-inflammatory and analgesic activity.Â

A five year retrospective study on maternal and perinatal outcome in pregnancy after cardiac surgery

Background: Pregnancy is a hypercoaguable state with physiological haemodynamic changes occurring during pregnancy. There is a progressive increase in intravascular volume in second trimester of pregnancy and increase in cardiac output. Pregnancy makes a significant impact on cardiovascular system. It is important to evaluate and study the effect of pregnancy on women with surgically corrected heart conditions so as to preempt potential complications.Methods: This is a retrospective study of patients with prior history of cardiac surgery and their pregnancy outcomes in a tertiary center of Southern India over a period of five years from January 2011 to December 2016.Results: In this study, descriptive statistical analysis was done in 87 women with pregnancy following cardiac surgery. 58.6% were nulliparous. Around 52% had associated obstetric risk factors. The most common cardiac surgery in this population was Mitral valve replacement (40.2%) and Atrial septal defect closure (37.9%). Women belonged to NYHA class I in 90.8% of cases. 58.6% had vaginal delivery and 36.8% had caesarean section. 6 women had postpartum haemorrhage which was medically managed, and 6 women needed ICU care.74.7% women had term deliveries. 18.4 % of the babies were less than 2.5 kg weight at birth. 13 babies required Neonatal ICU care.Conclusions: Maternal and neonatal outcome mainly depends on the functional cardiac status of women before conception. In this study we emphasize on the importance of multidisciplinary team approach involving cardiologist, obstetrician and neonatologist in the management of women with prior cardiac surgery

A benchmark for prediction of psychiatric multimorbidity from resting EEG data in a large pediatric sample

Psychiatric disorders are among the most common and debilitating illnesses across the lifespan and begin usually during childhood and adolescence, which emphasizes the importance of studying the developing brain. Most of the previous pediatric neuroimaging studies employed traditional univariate statistics on relatively small samples. Multivariate machine learning approaches have a great potential to overcome the limitations of these approaches. On the other hand, the vast majority of existing multivariate machine learning studies have focused on differentiating between children with an isolated psychiatric disorder and typically developing children. However, this line of research does not reflect the real-life situation as the majority of children with a clinical diagnosis have multiple psychiatric disorders (multimorbidity), and consequently, a clinician has the task to choose between different diagnoses and/or the combination of multiple diagnoses. Thus, the goal of the present benchmark is to predict psychiatric multimorbidity in children and adolescents. For this purpose, we implemented two kinds of machine learning benchmark challenges: The first challenge targets the prediction of the seven most prevalent DSM-V psychiatric diagnoses for the available data set, of which each individual can exhibit multiple ones concurrently (i.e. multi-task multi-label classification). Based on behavioral and cognitive measures, a second challenge focuses on predicting psychiatric symptom severity on a dimensional level (i.e. multiple regression task). For the present benchmark challenges, we will leverage existing and future data from the biobank of the Healthy Brain Network (HBN) initiative, which offers a unique large-sample dataset (N = 2042) that provides a wide array of different psychiatric developmental disorders and true hidden data sets. Due to limited real-world practicability and economic viability of MRI measurements, the present challenge will permit only resting state EEG data and demographic information to derive predictive models. We believe that a community driven effort to derive predictive markers from these data using advanced machine learning algorithms can help to improve the diagnosis of psychiatric developmental disorders

SYNTHESIS, CHARACTERIZATION AND QUANTITATION OF REGIOISOMERIC IMPURITY IN NIMODIPINE BULK AND FORMULATION

Objective: The present research work was directed towards the synthesis characterization and quantitation of regioisomeric impurity of Nimodipine i.e. diethyl 1, 4-dihydro-2,6-dimethyl pyridine dicarboxylate in bulk and tablet formulation, by UV,IR,NMR and GC-MS techniques and a RP-HPLC method was developed as per ICH Q2B guidelines for quantitation of 1, 4-Dihydro-2, 6-Dimethyl-4-(p-nitro phenyl) pyridine-3,5 dicarboxylate (NI) from bulk and formulation. Methods: The synthesis of NI was carried out by Hantzch pyridine synthesis, by using p-nitrobenzaldehyde, ethylacetoacetate, in presence of ammonia and methanol as a catalyst. The percentage yield was found to be 89.29%. Recrystallization and purification of NI was done. The preliminary evaluation was done on laboratory scale via melting point, elemental analysis and TLC. Results: The melting point of impurity was found to be 156-1580C. The TLC of impurity was carried by using Chloroform: Methanol (9:1) and the Rf was found to be 0.79. The confirmation of structure of NI was carried out by using sophisticated techniques i.e., FT-IR, NMR (13C and 1H), GC-MS etc. The RP-HPLC method was developed to quantify the NI in Nimodipine bulk and formulation as per ICH Q2B guidelines. The method validation was done as per ICH guidelines. Conclusion: The validated optimized method was found to be linear, précised, robust, rugged and accurate. Finally NI was quantified from bulk Nimodipine and its marketed tablet formulation. It was concluded that the amount of NI, present in tablet was found to be 0.1% and in the bulk 0.067% respectively. Thus it was revealed that the NI was found to be within the limit laid down ICH guidelines (Not more than 0.1 %)