Ageratum conyzoides L. and Its Secondary Metabolites in the Management of Different Fungal Pathogens.

Ageratum conyzoides L. (Family-Asteraceae) is an annual aromatic invasive herb, mainly distributed over the tropical and subtropical regions of the world. It owns a reputed history of indigenous remedial uses, including as a wound dressing, an antimicrobial, and mouthwash as well as in treatment of dysentery, diarrhea, skin diseases, etc. In this review, the core idea is to present the antifungal potential of the selected medicinal plant and its secondary metabolites against different fungal pathogens. Additionally, toxicological studies (safety profile) conducted on the amazing plant A. conyzoides L. are discussed for the possible clinical development of this medicinal herb. Articles available from 2000 to 2020 were reviewed in detail to exhibit recent appraisals of the antifungal properties of A. conyzoides. Efforts were aimed at delivering evidences for the medicinal application of A. conyzoides by using globally recognized scientific search engines and databases so that an efficient approach for filling the lacunae in the research and development of antifungal drugs can be adopted. After analyzing the literature, it can be reported that the selected medicinal plant effectively suppressed the growth of numerous fungal species, such as Aspergillus, Alternaria, Candida, Fusarium, Phytophthora, and Pythium, owing to the presence of various secondary metabolites, particularly chromenes, terpenoids, flavonoids and coumarins. The possible mechanism of action of different secondary metabolites of the plant against fungal pathogens is also discussed briefly. However, it was found that only a few studies have been performed to demonstrate the plant's dosage and safety profile in humans. Considered all together, A. conyzoides extract and its constituents may act as a promising biosource for the development of effective antifungal formulations for clinical use. However, in order to establish safety and efficacy, additional scientific research is required to explore chronic toxicological effects of ageratum, to determine the probability of interactions when used with different herbs, and to identify safe dosage. The particulars presented here not only bridge this gap but also furnish future research strategies for the investigators in microbiology, ethno-pharmacology, and drug discovery.

Intensification of marrubiin concentration by optimization of microwave-assisted (low CO2 yielding) extraction process for Marrubium vulgare using central composite design and antioxidant evaluation.

CONTEXT: Marrubium vulgare Linn (Lamiaceae) was generally extracted by conventional methods with low yield of marrubiin; these processes were not considered environment friendly. OBJECTIVE: This study extracts the whole plant of M. vulgare by microwave assisted extraction (MAE) and optimizes the effect of various extraction parameters on the marrubiin yield by using Central Composite Design (CCD). MATERIALS AND METHODS: The selected medicinal plant was extracted using ethanol: water (1:1) as solvent by MAE. The plant material was also extracted using a Soxhlet and the various extracts were analyzed by HPTLC to quantify the marrubiin concentration. RESULTS: The optimized conditions for the microwave-assisted extraction of selected medicinal plant was microwave power of 539 W, irradiation time of 373 s and solvent to drug ratio, 32 mL per g of the drug. The marrubiin concentration in MAE almost doubled relative to the traditional method (0.69 ± 0.08 to 1.35 ± 0.04%). The IC50 for DPPH was reduced to 66.28 ± 0.6 µg/mL as compared to conventional extract (84.14 ± 0.7 µg/mL). The scanning electron micrographs of the treated and untreated drug samples further support the results. DISCUSSION AND CONCLUSION: The CCD can be successfully applied to optimize the extraction parameters (MAE) for M. vulgare. Moreover, in terms of environmental impact, the MAE technique could be assumed as a 'Green approach' because the MAE approach for extraction of plant released only 92.3 g of CO2 as compared to 3207.6 g CO2 using the Soxhlet method of extraction.

Impact of spontaneous prophage induction on the fitness of bacterial populations and host-microbe interactions.

Bacteriophages and genetic elements, such as prophage-like elements, pathogenicity islands, and phage morons, make up a considerable amount of bacterial genomes. Their transfer and subsequent activity within the host's genetic circuitry have had a significant impact on bacterial evolution. In this review, we consider what underlying mechanisms might cause the spontaneous activity of lysogenic phages in single bacterial cells and how the spontaneous induction of prophages can lead to competitive advantages for and influence the lifestyle of bacterial populations or the virulence of pathogenic strains.

Spatiotemporal microbial single-cell analysis using a high-throughput microfluidics cultivation platform.

Cell-to-cell heterogeneity typically evolves due to a manifold of biological and environmental factors and special phenotypes are often relevant for the fate of the whole population but challenging to detect during conventional analysis. We demonstrate a microfluidic single-cell cultivation platform that incorporates several hundred growth chambers, in which isogenic bacteria microcolonies growing in cell monolayers are tracked by automated time-lapse microscopy with spatiotemporal resolution. The device was not explicitly developed for a specific organism, but has a very generic configuration suitable for various different microbial organisms. In the present study, we analyzed Corynebacterium glutamicum microcolonies, thereby generating complete lineage trees and detailed single-cell data on division behavior and morphology in order to demonstrate the platform's overall capabilities. Furthermore, the occurrence of spontaneously induced stress in individual C. glutamicum cells was investigated by analyzing strains with genetically encoded reporter systems and optically visualizing SOS response. The experiments revealed spontaneous SOS induction in the absence of any external trigger comparable to results obtained by flow cytometry (FC) analyzing cell samples from conventional shake flask cultivation. Our microfluidic setup delivers detailed single-cell data with spatial and temporal resolution; complementary information to conventional FC results.

Analysis of SOS-induced spontaneous prophage induction in Corynebacterium glutamicum at the single-cell level.

The genome of the Gram-positive soil bacterium Corynebacterium glutamicum ATCC 13032 contains three integrated prophage elements (CGP1 to -3). Recently, it was shown that the large lysogenic prophage CGP3 (∼187 kbp) is excised spontaneously in a small number of cells. In this study, we provide evidence that a spontaneously induced SOS response is partly responsible for the observed spontaneous CGP3 induction. Whereas previous studies focused mainly on the induction of prophages at the population level, we analyzed the spontaneous CGP3 induction at the single-cell level using promoters of phage genes (Pint2 and Plysin) fused to reporter genes encoding fluorescent proteins. Flow-cytometric analysis revealed a spontaneous CGP3 activity in about 0.01 to 0.08% of the cells grown in standard minimal medium, which displayed a significantly reduced viability. A PrecA-eyfp promoter fusion revealed that a small fraction of C. glutamicum cells (∼0.2%) exhibited a spontaneous induction of the SOS response. Correlation of PrecA to the activity of downstream SOS genes (PdivS and PrecN) confirmed a bona fide induction of this stress response rather than stochastic gene expression. Interestingly, the reporter output of PrecA and CGP3 promoter fusions displayed a positive correlation at the single-cell level (ρ = 0.44 to 0.77). Furthermore, analysis of the PrecA-eyfp/Pint2-e2-crimson strain during growth revealed the highest percentage of spontaneous PrecA and Pint2 activity in the early exponential phase, when fast replication occurs. Based on these studies, we postulate that spontaneously occurring DNA damage induces the SOS response, which in turn triggers the induction of lysogenic prophages.

Comparative evaluation of the anti-diabetic activity of Pterocarpus marsupium Roxb. heartwood in alloxan induced diabetic rats using extracts obtained by optimized conventional and non conventional extraction methods.

The aim of the present study was to assess the anti-diabetic activity of Pterocarpus marsupium Roxb. heartwood in alloxan induced diabetic rats using extracts obtained by optimized conventional and non conventional extraction methods. Aqueous and ethanol extracts of Pterocarpus marsupium heartwood were prepared by conventional methods (infusion, decoction, maceration and percolation) and non conventional methods, such as ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE). The crude aqueous extracts were administered orally to both normal and alloxan induced male albino rats (Sprague-Dawley strain). The experimental set up consisted of 48 male albino rats divided into 6 groups: Normal control, diabetic control (sterile normal saline, 1 ml/100 g body weight), standard (gliclazide, 25 mg/1000g of body weight), groups 4-6 (crude aqueous percolation, optimized UAE and MAE extract, 250 mg/1000g of body weight). In acute treatment, the reduction of blood glucose level was statistically significant with the oral administration of UAE and percolation aqueous extracts to the hyperglycemic rats. In sub-acute treatment, the UAE aqueous extract led to consistent and statistically significant (p<0.001) reduction in the blood glucose levels. There was no abnormal change in body weight of the hyperglycemic animals after 10 days of administration of plant extracts and gliclazide. This study justifies the traditional claim and provides a rationale for the use of Pterocarpus marsupium to treat diabetes mellitus. The antidiabetic activity of Pterocarpus marsupium can be enhanced by extracting the heartwood by non conventional method of UAE.

A Comprehensive Insight on Recent Advancements in Self-emulsifying Drug Delivery Systems.

A large proportion of new chemical moieties are poorly water-soluble. As a result, the biggest challenge for researchers is to enhance the solubility and oral bioavailability of lipophilic drugs. Self-emulsifying systems offer immense potential for improving lipophilic drugs' oral bioavailability and solubility through various mechanisms such as: inhibiting efflux transporters, absorption of the lipophilic drug through the lymphatic system, and bypassing hepatic first-pass metabolism. These systems dissolve hydrophobic drugs, allowing them to be delivered in a unit dose form for oral administration. Despite much potential, issues like stability, low drug loading, packaging, etc., are associated with the self-emulsifying technique. This review discusses conventional Self-Emulsifying Drug Delivery Systems (SEDDS), which deliver poorly water-soluble drugs. Recent advancements in self-emulsifying systems to solve the issues associated with conventional SEDDS are described exhaustively, including their methodologies and excipients utilized for preparation. The current article also furnishes a literature review on recent advancements in self-emulsifying systems. Recent advances in SEDDS are a great option for overcoming oral bioavailability, stability, and solubility issues of lipophilic drugs. Solid-self emulsifying system can be used to improve the stability of the formulation, hydrophobic ion-pairing for improving mucus permeation properties, while supersaturated self-emulsifying systems with a low concentration of surfactant to overcome issues such as precipitation of drug after dilution and gastrointestinal related side effects. The day will come when medicine companies will see the value of selfemulsifying system developments and adopt this technology for next-generation product releases.

A Comprehensive Insight on Pharmaceutical Co-crystals for Improvement of Aqueous Solubility.

Various drugs are not able to reach the market due to their poor bioavailability and poor solubility in aqueous media. Hence, several approaches are used to enhance the solubility of poorly water-soluble drugs. Co-crystallization is one of the approaches used to enhance the solubility of poorly water-soluble drugs. Co-crystals are solid crystalline substances consisting of two or more ingredients in a stoichiometric ratio in which one of the ingredients is an active pharmaceutical ingredient (API) and the other is a co-former. API and co-former mix with one another in a co-crystal through intermolecular interactions. This review represents an overview of co-crystals, a comparison of co-crystals and other solid forms, mechanisms of solubility enhancement by co-crystals in brief, techniques of co-former selection, a list of co-formers used during various co-crystals formation and a list of marketed co-crystals formulation, method of co-crystals preparation and characterization techniques of co-crystals.

Development, optimization and evaluation of solid lipid nanoparticles of Celecoxib.

BACKGROUND: As indicated by the biopharmaceutical classification system, Celecoxib is a class II moiety. Many endeavors have been made to improve its solubility and consequently its dissolution rate, thus enhancing its overall bioavailability. In the present investigation, the nano-lipid technology was exploited to control the release of celecoxib (CXB) to overcome its dissolution problem. Solid lipid nanoparticles (SLNs) have a small particle size (50-1000 nm) that results in a large surface area-to-volume ratio, which further enhances the contact between the drug and the dissolution medium. This leads to improved drug release and absorption. Moreover, SLNs can solubilize hydrophobic drugs within the lipid matrix, increasing their effective solubility and facilitating their dissolution in an aqueous environment. AIM AND OBJECTIVE: The objective of the study was to enhance the solubility and bioavailability of a BCS Class-II drug-celecoxib formulating it as solid lipid nanoparticles. In order to overcome all its limitations, solid lipid nanoparticles of Celecoxib were developed, optimized, and evaluated for in-vitro and in-vivo parameters. METHODS: The CXB loaded-SLNs were prepared by solvent emulsification-diffusion technique. SLN was characterized using Fourier transform infra spectroscopy (FTIR) and evaluated for entrapment efficiency, drug loading, particle size, Polydispersity index (PDI), zeta potential, In-vitro release studies as well as in- vivoanti-inflammatory studies using rat paw edema method. The SLN formulations were optimized by central composite design (Design Expert 11- trial version). RESULTS: On the basis of outcomes of CCD the optimized formulation OF1 was selected as a desirable formulation. Its particle size, PDI, and zeta potential were found to be 314 nm, 0.204, and -18.73 respectively. It exhibited high entrapment efficiency (79±0.18 %) and drug loading (44.38±0.21 %). In-vitro release studies of the optimized formulation displayed the Korsemeyer-Peppas model with a maximum drug release of 89.42 ±0.12 % in 24 h. In-vivo studies also revealed that OF1 formulation reduced the rat paw volume to a minimum (1±0.32) in 24 h when compared to pure API (2±0.62) and marketed preparation (2±0.42). CONCLUSION: The results revealed that in-vitro release studies of optimized formulation exhibited a sustained drug release delivery. In-vivo anti-inflammatory studies proved that the CXB-loaded SLNs enhance the oral bioavailability more than pure API.

Comparison of conventional and non conventional methods of extraction of heartwood of Pterocarpus marsupium Roxb.

The renewed interest in plant-derived drugs has led to an increased need for efficient extraction methods. The present investigation was an attempt to evaluate and compare the conventional methods of extraction with non conventional methods of extraction, such as ultrasonic-assisted extraction (UAE) and microwave-assisted extraction (MAE) methods. Pterocarpus marsupium Roxb. has been reported to contain bioactive phytochemicals, e.g., pterostilbene (3',5'-dimethoxy-4-stilbenol). The results showed that among the conventional extraction methods, percolation gave the highest yield. The non conventional methods were optimized. The extraction yield was the highest in case of MAE. The phytochemical screening of the extracts indicated similar groups of compounds in all the extracts. The thin layer chromatography showed the presence of pterostilbene in the extracts obtained by using percolation, MAE and UAE. In these extracts the quantification of pterostilbene was conducted by high performance liquid chromatography and the method was validated. The MAE method extracted significantly higher amount of pterostilbene.

A recent update in research on the antihepatotoxic potential of medicinal plants.

Hepatic damage is a global metabolic and epidemic disease, affecting essential biochemical activities in almost every age group. Conventional drugs used in the treatment of liver disorders are often inadequate. Also, the spectrum of liver abnormalities caused by allopathic drugs is found to be broad. In view of severely undesirable side effects of synthetic agents, it is necessary to search for alternative drugs for the treatment of liver diseases to replace the currently used drugs, which are of doubtful efficacy and safety. Therefore, there is growing focus to follow systematic research methodology and to evaluate scientific basis for the traditional herbal medicines that are claimed to possess hepatoprotective activities. Use of herbal drugs in the treatment of liver diseases has a long tradition, especially in Eastern medicine and can be traced back as far as 2100 B.C. in ancient China (Xia Dynasty) and India (Vedic period), but evidence for efficacy is sparse. The current study is aimed at providing an overview of clinical and experimental studies carried out on the most effective and commonly used hepatoprotective plants and their beneficial aspects.

A Comprehensive Insight on Self Emulsifying Drug Delivery Systems.

BACKGROUND: The oral route is a highly recommended route for the delivery of a drug. But most lipophilic drugs are difficult to deliver via this route due to their low aqueous solubility. Selfemulsifying drug delivery systems (SEDDS) have emerged as a potential approach of increasing dissolution of a hydrophobic drug due to spontaneous dispersion in micron or nano sized globules in the GI tract under mild agitation. OBJECTIVE: The main motive of this review article is to describe the mechanisms, advantages, disadvantages, factors affecting, effects of excipients, possible mechanisms of enhancing bioavailability, and evaluation of self-emulsifying drug delivery systems. RESULTS: Self emulsifying systems incorporate the hydrophobic drug inside the oil globules, and a monolayer is formed by surfactants to provide the low interfacial tension, which leads to improvement in the dissolution rate of hydrophobic drugs. The globule size of self-emulsifying systems depends upon the type and ratio of excipients in which they are used. The ternary phase diagram is constructed to find out the range of concentration of excipients used. This review article also presents recent and updated patents on self-emulsifying drug delivery systems. Self-emulsifying systems have the ability to enhance the oral bioavailability and solubility of lipophilic drugs. CONCLUSION: This technique offers further advantages such as bypassing the first pass metabolism via absorption of drugs through the lymphatic system, easy manufacturing, reducing enzymatic hydrolysis, inter and intra subject variability, and food effects.

A manually curated compendium of expression profiles for the microbial cell factory Corynebacterium glutamicum.

Corynebacterium glutamicum is the major host for the industrial production of amino acids and has become one of the best studied model organisms in microbial biotechnology. Rational strain construction has led to an improvement of producer strains and to a variety of novel producer strains with a broad substrate and product spectrum. A key factor for the success of these approaches is detailed knowledge of transcriptional regulation in C. glutamicum. Here, we present a large compendium of 927 manually curated microarray-based transcriptional profiles for wild-type and engineered strains detecting genome-wide expression changes of the 3,047 annotated genes in response to various environmental conditions or in response to genetic modifications. The replicates within the 927 experiments were combined to 304 microarray sets ordered into six categories that were used for differential gene expression analysis. Hierarchical clustering confirmed that no outliers were present in the sets. The compendium provides a valuable resource for future fundamental and applied research with C. glutamicum and contributes to a systemic understanding of this microbial cell factory. Measurement(s) Gene Expression Analysis Technology Type(s) Two Color Microarray Factor Type(s) WT condition A vs. WT condition B • Plasmid-based gene overexpression in parental strain vs. parental strain with empty vector control • Deletion mutant vs. parental strain Sample Characteristic - Organism Corynebacterium glutamicum Sample Characteristic - Environment laboratory environment Sample Characteristic - Location Germany.

Nano Cocrystals: Crystal Engineering from a Nanotechnological Perspective.

Low aqueous solubility and poor bioavailability are the major hurdles during drug development for the oral route. A large number of the newly discovered drug molecules fall under the BCS II class and have solubility related issues and hence pose low oral bioavailability, which, in turn, render them non-suitable candidates for further development. A multitude of solubility enhancement approaches are available. Notable among them are salt formation, solid dispersions, inclusion complexes, cocrystallization, nanonization, etc. Cocrystallization and nanonization are among the most widely used approaches in the pharmaceutical field that offer multiple enhancements to the active pharmaceutical ingredients. This review endeavours to cover the recent work, important findings, advantages offered by nano-sized cocrystals, future aspects and challenges in the implementation of this newer approach in pharmaceutical research and development.

Recent Advancements in Pharmaceutical Cocrystals, Preparation Methods, and their Applications.

The issue of poor aqueous solubility is a major hurdle in pharmaceutical dosage form design. A large number of active molecules in the research and development pipeline possess poor aqueous solubility and, hence, are not suitable for further development. Therefore, the pharmaceutical industry is continuously in search of techniques to tackle the issue of poor solubility. Cocrystallization has gained popularity as one such technique for the modulation of physicochemical properties of an active pharmaceutical ingredient (API). Pharmaceutical cocrystals consist of an API non-covalently linked to a crystal former or coformer that plays an important role in imparting the desired properties to the cocrystal. Cocrystallization of an API with a suitable coformer not only enhances solubility but also helps in improving physicochemical properties such as stability, bioavailability, mechanical properties, etc., without changing the pharmacological activity of the API. The past decade has experienced enormous growth in cocrystal research which paved the way for drug-drug, higherorder, and nano-sized cocrystals, and further exploration of the applications of cocrystals is still going on. Recently FDA and EMA have released regulatory guidelines for pharmaceutical cocrystals, which grant them a status similar to that of polymorphs and salts, which in turn opens a wider prospect for pharmaceutical cocrystals in terms of intellectual property.

Statistically Designed Extraction of Herbs Using Ultrasound Waves: A Review.

BACKGROUND: Extraction is the foremost step to isolate the natural constituents from a medicinal plant and leads the process of development of herbal formulation from bench to bed. INTRODUCTION: In the field of extraction, the optimization approach helps in achieving better yield and quality where a response of concern is determined or influenced by various variables. This review aimed at congregating the application of different statistical designs (CCD/BBD) to optimize the Ultrasound assisted extraction (UAE) parameters for the recovery of various plant actives belonging to different categories. METHODOLOGY: The literature published during the last decade in the various reputed databases (Web of Science, Pubmed, Scopus) was reviewed and compiled to reveal the role of response surface methodology in optimizing the influential parameters involved in the ultrasound assisted extraction of herbs. CONCLUSION: From the present investigations, it can be concluded that the different variables, such as sonication power, temperature, time, solute to solvent ratio are generally optimized in UAE of herbs. Moreover, it has also been evidenced from the review of published data that the flavonoids/phenolic acids (>50%) leads the race for the extraction of plants using sound waves. It can be said that the statistically designed UAE has a vast prospective in bringing about a green mutiny in the herbal drug industry and the modeling of various parameters shall be able to absolutely build up a complete drug innovation course (bench to bed).

Hot stage microscopy and its applications in pharmaceutical characterization.

Hot stage microscopy (HSM) is a thermal analysis technique that combines the best properties of thermal analysis and microscopy. HSM is rapidly gaining interest in pharmaceuticals as well as in other fields as a regular characterization technique. In pharmaceuticals HSM is used to support differential scanning calorimetry (DSC) and thermo-gravimetric analysis (TGA) observations and to detect small changes in the sample that may be missed by DSC and TGA during a thermal experiment. Study of various physical and chemical properties such sample morphology, crystalline nature, polymorphism, desolvation, miscibility, melting, solid state transitions and incompatibility between various pharmaceutical compounds can be carried out using HSM. HSM is also widely used to screen cocrystals, excipients and polymers for solid dispersions. With the advancements in research methodologies, it is now possible to use HSM in conjunction with other characterization techniques such as Fourier transform infrared spectroscopy (FTIR), DSC, Raman spectroscopy, scanning electron microscopy (SEM) which may have additional benefits over traditional characterization techniques for rapid and comprehensive solid state characterization.

Comparative Evaluation of Conventional and Novel Extracts of Stem Bark of Terminalia arjuna for Antihypertensive Activity in BSO Induced Oxidative Stress based Rat Model.

BACKGROUND: Terminalia arjuna (TA) has been reported and explored traditionally for its cardiotonic properties while the mechanism of antihypertensive effect of TA has not been clearly reported. METHOD: The oxidative stress is a major cause for hypertension, hence different extracts of TA having variable marker yield were evaluated for their antihypertensive effect in buthionine sulfoxamine (BSO) induced oxidative stress based model. Soxhlet extraction (SE), room temperature extraction (RTE), microwave assisted extraction (MAE), and ultrasound assisted extraction (USAE) were quantitatively estimated for marker compounds arjunolic acid and arjunic acid through HPTLC. RESULTS: The hypertension was induced using buthionine sulfoxamine (2 mmol/kg b.w. i.p.) and results suggested that the MAE and USAE showed better recovery of systolic blood pressure (110.33±0.10 and 118.33±0.10) and GSH level (3.62±0.07 nmoles/mL and 3.22±0.13 nmoles/mL), respectively as compared to the positive control group treated with ascorbic acid (Systolic BP: 119.67±0.10, GSH level: 3.11±0.10 nmoles/mL). The RTE and SE also showed a decrease in hypertension but were having moderate effect as compared with the standard positive control. CONCLUSION: The total percentage yield, the yield of the marker compounds arjunolic and arjunic acid, the IC50 values for antioxidant activity as well as the antihypertensive effect were in order: MAE>USAE>SE>RTE that suggested the role of biomarkers arjunolic acid and arjunic acid in reversing the effect of buthionine sulfoxamine.

A Review about Regulatory Status and Recent Patents of Pharmaceutical Co-Crystals.

Pharmaceutical Co-crystals are not new, they have gained much attention since the last decade among scientists and pharmaceutical industry. Pharmaceutical co-crystals are multicomponent systems composed of two or more molecules and held together by non-covalent interactions. The development of pharmaceutical co-crystals, a new solid crystalline form, offer superior physico-chemical properties (such as melting point, stability, solubility, permeability, bioavailability, taste masking, etc.) without altering the pharmacological properties. Recently, with the upsurge in the growth of Pharmaceutical co-crystals, the major concern is over the regulatory status of co-crystals. With the new guidelines from United States Food and Drug Administration (USFDA) and European Medicines Agency (EMA), the status has become even more complicated due to significantly different opinions. This review highlights whether co-crystals fulfil the requirements for the grant of a patent or not and how cocrystals are going to affect the present scenario of pharmaceuticals.

Self-Emulsifying Drug Delivery System of Simvastatin: Formulation Development, Optimization by Box- Behnken Design, In-Vitro and In-Situ Single-Pass Intestinal Perfusion (SPIP) Studies.

PURPOSE: The purpose of the study was formulation development, optimization and evaluation of a Self-Emulsifying Drug Delivery System (SEDDS) of Simvastatin (SIM) for improvement in dissolution and bioavailability of SIM. Solubility enhancement of Biopharmaceutical Classification System (BCS) Class-II drugs is a burning topic and attracting various publications and patents regarding different strategies employed for improvement of dissolution viz., USOO5340591A (Solid dispersion), US005472954A, US005646131A (complexation), USOO5858410A (Nanosuspensions), USOO5874029A (micronization) US2008.00095O2A1 (Solid composites), US2008O146640A1 (Prodrug) US 2009001 1009 A1 (nanocapsules), etc. Methods: SEDDS was prepared on the basis of solubility studies employing Capmul MCM EP as lipid and Cremophor ELP as surfactant. Box-Behnken design was implemented for optimization by using lipid concentration, surfactant concentration and mixing time as dependent variables and their impact was observed on particle size, poly dispersity index (PDI) and drug released in 15min. Optimized formulation was evaluated for particle size, PDI, zeta potential, emulsification time, transmittance, invitro drug release and in situ Single-Pass Intestinal Perfusion (SPIP) studies. RESULTS: For optimized formulation, OF1 value of particle size, PDI, zeta potential, emulsification time, transmittance and percent in-vitro release were 162±14.32nm, 0.19±0.01, -22.3 ±1.1mV, 93±3.11 sec, 99.45±4.35 % and 99.43± 5.6 % in 30 min respectively. In-situ SPIP studies were performed on Wistar rats and the value of predicted fraction absorbed for humans was found to be 0.98. CONCLUSION: SIM SEDDS was successfully developed and evaluated for in-vitro & in-vivo parameters. All the evaluated parameters were in tolerable limits. In vitro release studies from optimized formulation, OF1, exhibited maximum drug release when compared to SIM API and marketed preparation. Moreover, the predicted value of fraction absorbed (Fa) in humans by in-situ SPIP method was also in agreement with in-vitro dissolution studies thus, confirming SEDDS as a suitable drug delivery system for solubility enhancement of SIM.