Quantitative Structure-Property Relationship Approach in Formulation Development: an Overview.

Chemoinformatics is emerging as a new trend to set drug discovery which correlates the relationship between structure and biological functions. The main aim of chemoinformatics refers to analyzing the similarity among molecules, searching the molecules in the structural database, finding potential drug molecule and their property. One of the key fields in chemoinformatics is quantitative structure-property relationship (QSPR), which is an alternative process to predict the various physicochemical and biopharmaceutical properties. This methodology expresses molecules via various numerical values or properties (descriptors), which encodes the structural characteristics of molecules and further used to calculate physicochemical properties of the molecule. The established QSPR model could be used to predict the properties of compounds that have been measured or even have been unknown, which ultimately accelerates the development process of a new molecule or the product. The formulation characteristics (drug release, transportability, bioavailability) can be predicted with the integration of QSPR approach. Therefore, QSPR modeling is an emerging trend to skip conventional drug as well as formulation development process. The current review highlights the overall process involved in the application of the QSPR approach in formulation development.

Role of Insulin Resistance in Patients of Acne Vulgaris and Hirsutism in the Western Part of India- A Cross-Sectional Study.

Background: Despite being common and easy to treat conditions, acne and hirsutism may have a striking consequence on one's perception of self. Though understanding the pathogenesis of acne and hirsutism has undergone a major paradigm shift, one of them being insulin resistance (IR), extensive research is still underway. The purpose of the study is to establish causal relationship linking IR with acne vulgaris and hirsutism, as well as to assess severity of the two with increasing IR. Materials and Methods: A cross-sectional observational study was conducted in the dermatology department. Patient's detailed clinical history and necessary parameters like height, weight, body mass index (BMI), etc., were recorded in predefined proforma, noting signs and symptoms of underlying IR, along with acne severity calculated by global acne grading system (GAGS) and hirsutism severity by modified Ferriman Gallwey score (mFG), then analyzing using Pearson's correlation test to establish correlation between IR and acne with/without hirsutism and hirsutism alone. Results: A total of 349 patients included in our study were divided into three groups, (i) Acne-only (N = 308) group showed statistically significant correlation of IR with acne severity (P < 0.0001) and recurrence (P < 0.0001). (ii) In hirsutism-only (N = 24) group, homeostatic model assessment for insulin resistance (HOMA-IR) was strongly associated with modified Ferriman-Gallwey score and recurrence suggesting raised insulin resistance with increased severity of hirsutism (P < 0.0001) and recurrence (P < 0.007). (iii) In acne + hirsutism (N = 17) group, raised BMI was found to be positively associated with IR but not with severity of both conditions. Conclusion: IR has emerged as an important contributory, if not, causative event in pathogenesis of severe, resistant acne, and hirsutism. These conditions have great deal of impact on the psychological health of those affected necessitating different approach to manage such cases.

Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants.

INTRODUCTION: Asthma complications and adverse effects associated with steroidal therapy highlight the need for non-steroidal compounds intercepting asthmatic pathophysiology at multiple targets. The present investigation was carried out to evaluate the tracheal smooth muscle relaxant effect of virtually designed, combinatorially synthesized polyfunctional N-heteroarylamides. METHODS: Virtual screening and molecular docking studies of designed compounds were performed using PyRx and AUTODOCK 4.2 software against molecular targets viz. FLAP, LTB4, and H1 receptor. Cross-validation of virtual screening results and active site, confirmation was performedusingVlife MDS software version 3.5. The combinatorial approach was used to synthesize designed compounds in which heterocyclic amines were reacted with substituted aromatic acid chlorides by nucleophilic substitution reaction to obtain a 5x5 mini-library. The structures of synthesized leads were confirmed by infrared and proton magnetic resonance spectroscopic analysis. Synthesized compounds were evaluated for their smooth muscle relaxation effect on isolated goat tracheal smooth muscle. RESULTS: Results were calculated as a percent decrease in contraction response observed using histamine and LTB4. The tested compounds produced anticipated tracheal smooth muscle relaxant activity. Based on the results of screening the structure-activity relationships (SAR) have been reported. CONCLUSION: Present study concluded that synthesized polyfunctional N-heteroarylamides have a tracheal smooth muscle relaxant effect. The mode of action is predicted from the analysis of virtual screening results. A good correlation was observed between virtual screenings and biological activities of lead molecules suggesting the rationale used to optimize the structural requirements of a ligand for selected targets is appropriate.

Discovery of pyridoindole derivatives as potential inhibitors for phosphodiesterase 5A: in silico and in vivo studies.

The aim of this work was to synthesise derivatives from identified plant based pyridoindole lead scaffold, and to assess phosphodiesterase 5A inhibitory potential by in silico and in vivo. Pyridoindole derivatives were synthesised by using six-stage reactor. In silico screening was carried out by grip-based docking methodology. In step-I, tryptophan as a starting material was reacted with different aldehydes and ketones to obtain 11 molecules. In step-II, obtained molecules were reacted with ethanol and benzyl alcohols to obtain D1 to D22 derivatives. In silico investigation resulted in best three molecules D12, D4 and D8 with promising BE score. Oral acute toxicity study of selected molecules resulted in LD50 value 500 mg/kg in rats. The result of in vivo antihypertensive study shown that molecule D12 was found to be the best antihypertensive lead molecule. This study could be a best platform to tailor novel biomolecules for inhibiting phosphodiesterase 5A enzyme in hypertension management.

Sensitive ex vivo human skin transdermal assay testing method with mass spectrometric analysis for cosmetics application.

BACKGROUND: Cosmetics manufacturers are focused on cosmetic delivery systems into the skin, but the level of diffusion of the systems in the skin tissues is not well understood. The current methods, such as Franz diffusion, assess analyte diffusion in the whole skin or artificial membranes, which has limitations for understanding skin delivery systems. AIMS: Our study aimed to create a transdermal delivery method which is based on dermal-epidermal separation of human skin, allowing us to assess each layer of skin separately for its efficacy. MATERIALS AND METHODS: During the experiment, resveratrol was used as the target analyte by applying it to the skin and then separating it into dermis and epidermis. Each layer is treated individually and subjected to a high-resolution mass spectrometry analysis to detect resveratrol levels. As a result, the efficiency of resveratrol diffusion in the dermal and epidermal layers of the skin can be evaluated. RESULTS: We found that resveratrol was detected in both the dermal and epidermal layers using our method. CONCLUSIONS: Hence, we developed a sensitive method for transdermal delivery testing that can be used to evaluate skin delivery systems for cosmetic or pharmaceutical purposes.

Hetero-Tricyclic Lead Scaffold as Novel PDE5A Inhibitor for Antihypertensive Activity: In Silico Docking Studies.

OBJECTIVE: To screen the phytochemicals for phosphodiesterase 5A (PDE5A) inhibitory potential and identify lead scaffolds of antihypertensive phytochemicals using in silico docking studies. METHODS: In this perspective, reported 269 antihypertensive phytochemicals were selected. Sildenafil, a PDE5A inhibitor was used as the standard. In silico docking study was carried out to screen and identify the inhibiting potential of the selected phytochemicals against PDE5A enzyme using vLife MDS 4.4 software. RESULTS: Based on docking score, π-stacking, H-bond and ionic interactions, 237 out of 269 molecules were selected which have shown one or more interactions. Protein residue Gln817A was involved in H-boding whereas Val782A, Phe820A and Leu804A were involved in π-stacking interaction with ligand. The selected 237 phytochemicals were structurally diverse, therefore 82 out of 237 molecules with one or more tricycles were filtered out for further analysis. Amongst tricyclic molecules, 14 molecules containing nitrogen heteroatom were selected for lead scaffold identification which finally resulted in three different basic chemical backbones like pyridoindole, tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline as lead scaffolds. CONCLUSION: In silico docking studies revealed that nitrogen-containing tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline tricyclic lead scaffolds have emerged as novel PDE5A inhibitors for antihypertensive activity. The identified lead scaffolds may provide antihypertensive lead molecules after its optimization.

Development of leads targeting ER-α in breast cancer: An in silico exploration from natural domain.

The steroid, estrogen has been recognized as being important for stimulating the growth of breast cancers primarily mediated via the steroidal estrogen receptor-α (ER-α). Inhibition of estrogen activity by small molecules with increased target specificity has proven to be an effective treatment for breast cancer. After the success stories of SERMs and fulvestrant, there is a need for the development of new small molecule modulating ER-α is due to developing resistance and side effects to current breast cancer therapy. In this pursuit, we virtually screened 227 chemically diverse bioactive natural products to get the best hits having an ER-α binding affinity. The docking scores and protein-ligand interactions of the obtained hits were emulated with the clinically used selective estrogen modulators and ER-antagonists. The results revealed 18 potential hits, which were putatively classified as hits belonging to ER agonists, modulators, and antagonists. Furthermore, as most of the hits were found to comprise the chromene nucleus, the 2D and 3D QSAR studies were performed using a set of natural products and synthesized compounds containing this scaffold, to understand the structural requirements for improving activity against breast cancer. Additionally, a pharmacophore model was generated to investigate the pharmacophoric features of the explored scaffolds for an optimal anticancer activity. The results signify that these compounds with structural modification could serve as potential leads in the drug discovery process for the treatment of breast cancer.

Computational Modeling of Polymeric Physicochemical Properties for Formulation Development of a Drug Containing Basic Functionality.

In the present research, predictive models were developed by correlating polymeric properties with characteristics of a formulation containing a drug with basic heterocycle (glipizide). Glipizide tablets containing different polymers from 3 categories (immediate, moderate, and extended release) were prepared and evaluated. Dissolution kinetics indicated Korsmeyer-Peppas as the best-fit model, whereas transportability was influenced by release rate and hydrophobicity of the drug. Calculated polymeric descriptors were correlated with formulation properties for the development of predictive quantitative structure-property relationship models. Regression coefficients and subsequent validation of developed models indicated potential predictability of the model for formulation properties containing any drug with basic heterocycle. Such models could also help to decide the formulation composition for desired characteristics with saving of time and formulation cost.

Implications of formulation design on lipid-based nanostructured carrier system for drug delivery to brain.

CONTEXT & OBJECTIVE: The aim of present investigation was to formulate and develop lipid-based nanostructured carriers (NLCs) containing Idebenone (IDE) for delivery to brain. Attempts have been made to evaluate IDE NLCs for its pharmacokinetic and pharmacodynamic profile through the objective of enhancement in bioavailability and effectivity of drug. METHODS: Nanoprecipitation technique was used for development of drug loaded NLCs. The components solid lipid Precirol ATO 5, oil Miglyol 840, surfactants Tween 80 and Labrasol have been screened out for formulation development by consideration of preformulation parameters including solubility, Required Hydrophilic lipophilic balance (HLB) of lipids and stability study. Developed IDE NLCs were subjected for particle size, zeta potential, entrapment efficiency (%EE), crystallographic investigation, transmission electron microscopy, in vitro drug release, pharmacokinetics, in vivo and stability study. RESULTS: Formulation under investigation has particle size 174.1 ± 2.6 nm, zeta potential -18.65 ± 1.13 mV and% EE 90.68 ± 2.90. Crystallographic studies exemplified for partial amorphization of IDE by molecularly dispersion within lipid crust. IDE NLCs showed drug release 93.56 ± 0.39% at end of 24 h by following Higuchi model which necessitates for appropriate drug delivery with enhancement in bioavailability of drug by 4.6-fold in plasma and 2.8-fold in brain over plain drug loaded aqueous dispersions. In vivo studies revealed that effect of drug was enhanced by prepared lipid nanocarriers. CONCLUSIONS: IDE lipid-based nanostructured carriers could have potential for efficient drug delivery to brain with enhancement in bioavailability of drug over the conventional formulations.

Quantitative structure property relationship modeling of excipient properties for prediction of formulation characteristics.

Quantitative structure property relationship (QSPR) is used to relate the excipient descriptors with the formulation properties. A QSPR model is developed by regression analysis of selected descriptors contributing towards the targeted formulation properties. Developed QSPR model is validated by the true external method where it showed good accuracy and precision in predicting the formulation composition as experimental t90% (61.35min) is observed very close to predicted t90% (67.37min). Hence, QSPR approach saves resources by predicting drug release from an unformulated formulation; avoiding repetitive trials in the development of a new formulation and/or optimization of existing one.

Proteasome inhibitors mechanism; source for design of newer therapeutic agents.

The proteasome was first identified as a high MW protease complex that gets resolved into a series of low MW protein species upon denaturation. As the dominant protease dedicated to protein turnover, the proteasome shapes the cellular protein repertoire. Our knowledge of proteasome regulation and activity has improved considerably over the past decade. Novel inhibitors, in particular, have helped to advance our understanding of proteasome biology. They range from small peptide-based structures that can be modified to vary target specificity to large macromolecular inhibitors that include proteins. Although these reagents have an important role in establishing our current knowledge of the proteasome's catalytic mechanism, many questions remain. The future lies in designing compounds that can function as drugs to target processes involved in disease progression. Our focus in this chapter is to highlight the use of various classes of inhibitors to probe the mechanism of the proteasome and to identify its physiological significance in the cell, so that the mechanism of inhibition of proteasome will work as a definite source for design of protocols for newer therapeutic agents for the treatment of inflammation and in cancer therapy.

Effects of gamma radiation on a ventricular assist device and its percutaneous lead components.

A patient supported by a left ventricular assist device (LVAD) presented with an abdominal tumor requiring consolidative radiation therapy. To assess the effects of radiation therapy on the operation of the ventricular assist device (VAD) system and assure that the treatment would be safe for the patient with regard to the operation of the VAD system, sample equipment was irradiated and then tested for functionality. Changes in the mechanical properties of components of the percutaneous lead were measured. After testing, it was concluded that radiation therapy would not impede the operation of the pump or produce deleterious alterations of mechanical properties of the various system components. The patient underwent radiation therapy with a total dose of 2,000 cGy without evident complications. There were no observed effects on the LVAD operation nor any indication of alarms or malfunctions. Subsequently, the patient recovered adequate cardiac function for explant of the LVAD and the recovered components were also analyzed confirming the absence of alterations in material properties that would endanger patient safety.

Synthesis, characterization and quantification of simvastatin metabolites and impurities.

Simvastatin is used in treatment of hypercholesterolemia because it regulates cholesterol synthesis as a result of its ß-hydroxy acid acting as an inhibitor of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA). The present communication deals with synthesis, characterization and development of accurate, precise and sensitive Reverse Phase High Performance Liquid Chromatography (RP-HPLC) method for simultaneous estimation of simvastatin and its synthetic impurities. The impurities methyl ether and ß-hydroxy acid of simvastatin were synthesized in the laboratory and characterized by MS, NMR and FT-IR spectroscopy. The separation of simvastatin and its impurities was carried out on an isocratic JASCO RP-HPLC system using KYA TECH HIQ SIL C(18) column (150 × 4.6 mm internal diameter, particle size 5 µm) operating at ambient temperature using acetonitrile:water (80:20 v/v) with 0.1% orthophosphoric acid as mobile phase. The method developed for HPLC analysis of three impurities along with simvastatin was validated using ICH Q2B (R1) guidelines and it complied with these guidelines. The results of analysis were found to be in the range of 98.14% to 101.89% for all analytes with acceptable accuracy and precision. The method can be used for detection and quantification of synthetic impurities in bulk or formulations of simvastatin.

RP-HPLC and Spectrophotometric Estimation of Ambroxol Hydrochloride and Cetirizine Hydrochloride in Combined Dosage Form.

Rapid, precise, accurate, specific and sensitive reverse phase liquid chromatographic and absorbance ratio spectrophotometric methods have been developed for the simultaneous analysis of ambroxol hydrochloride and cetirizine hydrochloride in their tablet formulation. The chromatographic methods were standardized using a HIQ SIL-C(18) column (250×4.6 mm i.d., 10 µm particle size) with UV detection at 229 nm and mobile phase consisting of methanol-acetonitrile-water (40:40:20, v/v/v). Ambroxol hydrochloride and cetirizine hydrochloride have absorbance maxima at 243 nm and 229 nm, respectively. The isoabsorptive wavelength for both the drugs was 236 nm. For absorbance ratio method developed, wavelengths selected were 243 nm and 236 nm. The proposed methods were successfully applied to the determination of ambroxol hydrochloride and cetirizine hydrochloride in tablets, with high percentage of recovery, good accuracy and acceptable precision. Different analytical performance parameters such as linearity, precision, accuracy, limit of detection, limit of quantitation and robustness were determined according to International Conference on Harmonization ICH Q2B guidelines. Results of analysis of the developed method were compared by performing ANOVA.