ABSTRACT

Peroxisome proliferator activated receptor-gamma (PPARγ) is a nuclear receptor encoded on chromosome 3p25 that plays a pivotal role in adipogenesis and insulin signaling. Differential splicing results in two main isoforms, γ1 and γ2. A number of genetic variants in the PPAR-γ gene have been identified. These include a very rare gain-of-function mutation (Pro115Gln) associated with obesity but not insulin resistance, two loss-of-function mutations (Val290Met and Pro467Leu) reported in three individuals with severe insulin resistance but normal body weight, the silent CAC478CAT mutation, and the highly prevalent Pro12Ala polymorphism in PPAR- γ2. Wild allele proline was associated with decreased insulin sensitivity and increased incidence of type II diabetes, where as mutant alanine allele improves insulin sensitivity. Hence, the present study is on studies on screening of the Pro12Ala mutation among Gujarat population and to correlate with type II diabetes.  SNP detection in PPARγ2 gene was carried out from the blood samples of 52 diabetic subjects and 22 controls followed by PCR and RFLP using restriction enzyme Hae III. The 12Ala allele frequency was 0.08 in total population. Of the 74 subjects, 62 had Pro12Pro genotype and 12 had Pro12Ala genotype. The Ala12Ala genotype was not observed. This study also found that as compared to diabetic group, non-diabetic group had significantly higher frequency of 12Ala allele in PPARγ gene (p=0.06).  Our study found higher frequency of Pro12Ala polymorphism in non-diabetic subjects, suggestive of protective role of polymorphism in risk of type II diabetes.

Key words: PPARG2, T2D, Pro12Ala, RFLP

ABSTRACT

Timolol maleate, an antihypertensive drug has a half-life of 2-3 hours and a bioavailability of about 60%. It undergoes extensive first pass metabolism. The present study aims to formulate and evaluate Transdermal drug delivery for sustained release of Timolol maleate. The partition coefficient in octanol /water system indicates that the drug is suitable for Transdermal drug delivery. The Physicochemical compatibility of the drug and polymers was studied by IR spectroscopy and the results suggested no physicochemical incompatibility between drugs and the polymers. Total 20 formulations were prepared. The transdermal patches were prepared using different polymers like Hydroxy Propyl Methyl Cellulose, Polyvinyl alcohol and Poly vinyl pyrrolidine in varied ratios, plasticizers like propylene glycol and various permeation enhancers. The patches were evaluated for various parameters like Thickness, weight variation, Water-Vapor Permeability, Tensile Strength, Percent Moisture Uptake, Drug Content, Diffusion and Dissolution studies. The interaction among various components of the matrices was studied by performing Differential Scanning Calorimetry. The Optimized formulation containing PVA: PVP (F 19) in the ratio of 3:2 and containing 30 % propylene glycol as a plasticizer and 2 % Hyaluronidase as a permeation enhancer gave a maximum release 51.68 % (4.75 mg) over a period of 8 hours. Stability studies were carried out as per ICH guidelines and formulations were found to be Stable.

Key words: Transdermal patches; Timolol maleate; Differential Scanning Calorimetry (DSC); Infrared spectroscopy (IR); Partition co-efficient.

ABSTRACT

Flurbiprofen Non-steroidal anti-inflammatory drugs (NSAIDS) drug has half-life of about 3 to 6 hrs. The present study aims to formulate and evaluate poorly soluble drug Flurbiprofen using solid dispersion based tablet. Various studies have been done in attempt to improve the solubility’s of Poorly water soluble drugs. The advent of solid dispersion technique provides a unique approach to particle size reduction and increased rates of dissolution. The compatibility studies of the drug and polymers were studied by IR spectroscopy and results suggested no interaction between drug and polymers. Solid dispersions of Flurbiprofen were prepared by common solvent method using Hydroxy Propyl Cellulose (HPC), Polyvinyl Pyrrolidone K-30(PVP) and Mannitol Fast dissolution observed with Mannitol as compared to HPC and PVP. Formulations F3, F6 and F9 containing PVP, HPC and Mannitol along with drug in 1: 6 ratios were used to formulate tablets. Formulation F9 containing drug and Mannitol showed highest dissolution of 81.11% in 1 hour  due to amorphous nature of drug in presence of polymer. Formulation F3 containing drug and PVP in 1 : 6 ratio showed 73.05% drug release  because of the formation of aggregates. Formulation F6 containing drug and HPC showed only 61.65% drug release due to the crystalline of the drug, low solubility of the drug. Results indicate that formulations prepared by the technique of solid dispersion showed increase in the dissolution of Poorly water soluble drug.

Key word: Solid dispersion; Flurbiprofen; Micronization; Compatibility studies.

ABSTRACT

Epidermal Growth Factor Receptor (EGFR) is known to play vital role in many cellular signalling pathways and hence is considered as a potent target for cancer. Inhibition of this enzyme has been reported to be beneficial by various workers. QSAR study of Quinazolines as EGFR was performed using accelrys discovery studio client (DSV-Version 3.0) as the modelling tool. A total of 67 selected molecules were considered for the development of QSAR model. Partial least square model of the data generated exhibited a very good linear relation between the training set of compounds with that of the reported activity as well as the test set of compounds with the predicted activity. The 4 statistical analysis performed revealed following observations; Training data set r²= 0.701, q² (Cross validated r²) = 0.616 validated by internal validation with correlation of coefficient (r2) of 0.848 and cross validated r2 (q2) of 0.573 and external set of compounds with a predictive correlation of coefficient of 0.900.  A total of 9 descripters pruned on the study explained the structural correlation of quinazolines with EGFR. The model developed can be used to predict bioefficacy of unknown molecules 4-[1,3-benzothiazol-2-yl]-N-[(1E)-(4-nitrophenyl)methylene]aniline as EGFR inhibitors. Further a hypothetical model to describe the interaction between the predicted molecules with EGFR is proposed and this hypothetical model explains the possibility of Met769 and Gln767 as the possible binding sites. The activity is observed in the preliminary cytotoxic activity (MTT assay). The study calls for the development of the molecules predicted as bio efficacious in this model and a quantitative inhibitory analysis of EGFR.

Key word: EGFR, QSAR, r², q²

ABSTRACT

Spleen Tyrosine Kinase (SYK) is known to play vital role in many signal transduction pathways and hence is considered as a potent target for various disorders like inflammatory, cancer and many auto immune disorders. QSAR study of Napthyridines as SYK Kinase inhibitors was performed using accelrrys discovery studio client (DSV - Version 3.0) as the modelling tool. A total of 53 selected molecules were considered for the development of QSAR model. The study was performed using the most stable confirmer fitting best to SYK Kinase enzyme binding site. The study resulted in development of cross validated QSAR models using different set of descriptors.  Partial least square model of the data generated exhibited a very good linear relation between the training set of compounds with that of the reported activity as well as the test set of compounds with the predicted activity. The 4 statistical analysis performed revealed following observations; Training data set r²= 0.848, q² (Cross validated r²) = 0.581 validated by internal validation with correlation of coefficient (r2) of 0.941 and cross validated r2 (q2) of 0.617 and external set of compounds with a predictive correlation of coefficient of 0.918.  A total of 11 descriptors pruned on the study explained the structural correlation of Napthyridines with SYK Kinase enzyme. The mode developed can be used to predict bio-efficacy of unknown molecules 7-methoxy-6-[3-morpholinopropoxy]-quinazoline as SYK Kinase inhibitors. The study calls for the development of the molecules predicted as bio efficacious in this model and a quantitative inhibitory analysis of SYK Kinase.

Key words: Napthyridines, QSAR, SYK.

ABSTRACT

Buccal mucosa is the preferred site for both systemic and local drug action. The mucosa has a rich blood supply and it relatively permeable. Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for extended periods of time by the help of interfacial forces. Mucoadhesion is a complex phenomenon which involves wetting, adsorption and interpenetration of polymer chains. Buccal mucoadhesive systems remain in close contact with the absorption tissue, the mucous membrane releasing the drug at the action site leading to increase in bioavailability (both local and systemic effects). Extending the residence time of a dosage form at a particular site and controlling the release of drug from the dosage form are useful especially for achieving controlled plasma level of the drug as well as improving bioavailability. In the present review article discusses with the buccal membrane, theory and kinetics behind buccal mucoadhesion, different types of buccal formulation advantages and disadvantages of buccal mucoadhesive drug delivery system.

Keywords: Buccal mucosa, permeable, biological origin, bioavailability.