Development and Evaluation of Self-Emulsifying Drug-Delivery System-Based Tablets for Simvastatin, a BCS Class II Drug.

Background: Self-emulsifying drug-delivery systems (SEDDSs) are designed to improve the oral bioavailability of poorly water-soluble drugs. This study aimed at formulating and characterization of SEDDS-based tablets for simvastatin using castor and olive oils as solvents and Tween 60 as surfactant. Methods: The liquids were adsorbed on microcrystalline cellulose, and all developed formulations were compressed using 10.5 mm shallow concave round punches. Results: The resulting tablets were evaluated for different quality-control parameters at pre- and postcompression levels. Simvastatin showed better solubility in a mixture of oils and Tween 60 (10:1). All the developed formulations showed lower self-emulsification time (˂200 seconds) and higher cloud point (˃60°C). They were free of physical defects and had drug content within the acceptable range (98.5%-101%). The crushing strength of all formulations was in the range of 58-96 N, and the results of the friability test were within the range of USP (≤1). Disintegration time was within the official limits (NMT 15 min), and complete drug release was achieved within 30 min. Conclusion: Using commonly available excipients and machinery, SEDDS-based tablets with better dissolution profile and bioavailability can be prepared by direct compression. These S-SEDDSs could be a better alternative to conventional tablets of simvastatin.

Influence of Prunus domestica gum on the release profiles of propranolol HCl floating tablets.

Propranolol hydrochloride is a beta-blocker used for the management and treatment of hypertension, angina, coronary artery disease, heart failure, fibrillation, tremors, migraine etc. The objective of the present study was to design Propranolol Hydrochloride floating tablets by direct compression method and to explore the role of a new gum as a matrix former. A 22 full factorial design was selected for the present study. Prunus domestica gum and HPMC (K4M) were used as independent variables, swelling index and drug dissolution at 12 hours as dependent variables. Formulations were subjected to pre- and post-compression tests that showed good micromeritics and buoyancy characteristics (Carr's index 11.76%-14.00%, Hausner's ratio 1.13°-1.16°, angle of repose 22.67°-25.21°, floating lag time 56-76 seconds, total floating time 18-25 hours and swelling index 59.87%-139.66%). The cumulative drug release in 0.1 N HCl at 12 hours was 72%-90% (p<0.05). Weibull model was found to be the best fit model (R2>0.99) among all other studied models. Multiple regression showed a significant effect of Prunus domestica gum and HPMC K4M on the swelling index and dissolution profiles of propranolol HCl (p<0.05). On the basis of better in-vitro performance and cost-effectiveness, formulation F4 was the best formulation. It is evident from the results that Prunus domestica gum possesses excellent drug release retardant potential for the floating drug delivery system and this new gum should be further explored alone or with other natural and synthetic polymers in future studies.

Preparation and Characterization of Hydrophilic Polymer Based Sustained-Release Matrix Tablets of a High Dose Hydrophobic Drug.

The objective of this study was the preparation and characterization of a sustained-release matrix tablet containing a high-dose hydrophobic drug and its comparison with marketed products. In the present study, HPMC was applied as the matrix-forming polymer for the sustained release of clarithromycin (500 mg). The compatibility of clarithromycin and excipients was studied using a binary mixture approach and compatible excipients were selected. Matrix tablets were prepared using the high-shear wet granulation technique. Tablets were compressed using oblong (19 mm), shallow concave punches, under a compression weight of 900 mg/tablet. The flow of granules was evaluated by determining their bulk density, tapped density, angle of repose, Hausner ratio, and Car's index. Compressed tablets were tested for their physical parameters, mechanical characteristics, drug content, and in vitro drug release, as per United States Pharmacopeia (USP). Clarithromycin is a drug having poor water solubility and showed compatibility with all the excipients used in the formulation of polymeric matrix tablets. FTIR spectra of clarithromycin, before and after being subjected to the stress conditions, confirmed the compatibility of clarithromycin and other ingredients of the matrix tablets. All the formulations exhibited good rheological characteristics and all the parameters related to flow showed results in the acceptable range. Physically, matrix tablets were smooth and shiny, without any surface defects. Weight variation (±5%) and drug content of the tablets (95-102%) were within the pharmacopeial limits. HPMC successfully sustained the drug release for 24 h. It is concluded from the study that dissolution rate of clarithromycin can be sustained using hydrophilic polymer (HPMC) as a release-controlling agent.

Evaluation of the effect of carrier material on modification of release characteristics of poor water soluble drug from liquisolid compacts.

Liquisolid compact is a novel dosage form in which a liquid medication (liquid drug, drug solution/dispersion in non-volatile solvent/solvent system) is converted to a dry, free flowing powder and compressed. Objective of the study was to elucidate the effect of carrier material on release characteristics of clopidogrel from liquisolid compacts. Different formulations of liquisolid compacts were developed using microcrystalline cellulose, starch maize, polyvinyl pyrollidone and hydroxypropyl methylcellulose as carrier material in three concentrations (40, 30 and 20%, w/w). Liquid vehicle was selected on the basis of solubility of clopidogrel. Colloidal silicondioxide was used as coating material and ratio of carrier to coating material was kept 10. A control formulation comprised of microcrystalline cellulose (diluents), tabletose-80 (diluents), primojel (disintegrant) and magnesium stearate (lubricant) was prepared by direct compression technique and was used for comparison. All the formulations were evaluated at pre and post compression level. Acid solubility profile showed higher solubility in HCl buffer pH2 (296.89±3.49 µg/mL). Mixture of propylene glycol and water (2:1, v/v) was selected as liquid vehicle. Drug content was in the range of 99-101% of the claimed quantity. All the formulations showed better mechanical strength and their friability was within the official limits (<1%). Microcrystalline cellulose and starch maize resulted in faster drug release while polyvinyl pyrollidone and HPMC resulted in sustaining drug release by gel formation. It is concluded from results that both fast release and sustained release of clopidogrel can be achieved by proper selection of carrier material.

Effect of varying quantities of polymer on preparation and stability evaluation of carbamazepine cocrystals with dicarboxylic acid coformers.

The current study is an attempt to explore the effect of varying quantities of hydroxypropyl cellulose (HPC) polymer on carbamazepine (CBZ) cocrystal formation with dicarboxylic acid coformers i.e., malonic acid (MA), succinic acid (SA), glutaric acid (GA), and adipic acid (AA). The cocrystals were first prepared without polymer by slurry crystallization method and then tried with different quantities of the polymer. The prepared samples were characterized by Powder X-ray Diffraction (XRPD). The characterization results indicate that in methanol pure carbamazepine-malonic (CBZ-MA) and carbamazepine-adipic acid (CBZ-AA) cocrystal can be prepared, while in ethanol and acetone pure carbamazepine-succinic (CBZ-SA) and carbamazepine-glutaric acid (CBZ-GA) cocrystals can be obtained respectively. The same cocrystals were tried using HPC polymer in three different quantities. The characterization results showed that a higher quantity of HPC polymer transforms CBZ-MA cocrystal polymorph-I to polymorph-II. The CBZ-SA and CBZ-GA cocrystal formation somehow inhibited as the concentration of HPC polymer increases. But on the other side, the formation of CBZ-AA cocrystal utterly not inhibited in the presence of varying quantities of HPC polymer. Furthermore, 11 different quantities of HPC were tried to know about the inhibitory concentration of HPC on CBZ-AA cocrystal formation. The CBZ-AA cocrystal preparation was not inhibited even at higher quantities of HPC compared to the coformer. Additionally, the effect of three different quantities of HPC on the thermal stability of the CBZ-AA cocrystal was investigated. Moreover, the stability of pure CBZ at 92% relative humidity (RH) condition was compared to CBZ-AA cocrystal with and without HPC polymer. The CBZ-AA cocrystal with and without HPC polymer was more stable than pure CBZ.

Understanding impact of pre-dissolved polymers on dissolution behavior of soluble carbamazepine cocrystal.

Cocrystallization is a novel approach for tackling the lower solubility concerns when they can yield solution concentration a lot better than their corresponding parent drug in crystalline form. To get the actual solubility and dissolution gains offered by the cocrystals, phase changes in solution (dissolution) has to be interrupted. In current study, we selected commonly used polymers in order to study their effects on the super saturation of carbamezepine-succinic acid (CBZ-SUC) cocrystal during dissolution studies. To observe solid phase changes during dissolution in situ Raman spectroscopy was used. At the completion of each test the solid phase was analyzed by Fourier-transform infrared spectroscopy (FTIR) and powder X-Ray diffractometry. In polymers absence, no dissolution improvement was achieved by the cocrystal owing to its quick transformation to the stable carbamazepine dihydrate (CBZDH). Pre-dissolved PVP at 2% w/v concentration did not inhibit CBZ crystallization as a dihydrate, whereas at 0.025% w/v pre-dissolved hydroxypropyl methyl cellulose acetate succinate (HPMCAS) did stabilize the cocrystal in buffer solution (pH 6.8) for the course of time studied. This cocrystal stabilization resulted in enhanced CBZ solubility ( Ì´ 4fold) caused by cocrystal super saturation state. Seeding of this stable supersaturated state with 1% w/v CBZDH resulted in CBZ crystallization as dihydrate with ultimate loss of solubility advantage.

Review: Therapeutic potential of carbonic anhydrase inhibitors.

Enzymes are biological catalyst involve in different biochemical reactions. But over activation of these biomolecules can cause disease thus different inhibitors and knockout therapies are use in current clinical practice. Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens. In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that CAIs could have potential as novel anti-obesity, anticancer and anti-infective drugs. Furthermore, recent studies suggest that CA activation may provide a novel therapy for Alzheimer's disease. This article discusses the biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases, and highlights progress in the development of specific modulators of the relevant CA isoforms, some of which are now being evaluated in clinical trials.

Lethal toxic Dose (i.p LD50), total protein contents and comparative hemolytic potential of (99mTc labeled & non-labeled) Naja naja karachiensis venom.

Recent recognition about snake bite envenomation on June, 2017 as neglected tropical disease under category-A by World Health Organization advocated again its undeniable importance. Present circumstances reasoned to work on a neglected subspecies of Naja naja, i.e., Naja naja karachiensis (N. n. karachensis) has been documented for frequent deaths in Pakistan. In this study median lethal toxic dose (LD50) was determined intraperitoneally in Swiss albino mice and was found to be 2.0µg/g (2.0mg/kg) equal in potency to Naja pallida (red spitting African cobra). Total protein contents (188±0.011µg / 200µg of dry weight) were high enough (94%) to represent an arsenal of proteins. Furthermore, 99mTc was labeled 99.9% with venom and didn't find to alter hemolytic activity of venom in dose dependent manner at 125µg/ml (p>0.5), 250 µg/ml (p>0.1) and 500 µg/ml (p>0.1) when compared with its crude form. Present work will pave the way for proteomics study in effective production of antidote against specific species of snakes as dare demand of it has been felt since long period of time in Pakistan.

Improved in vitro and in vivo performance of carbamazepine enabled by using a succinic acid cocrystal in a stable suspension formulation.

Currently cocrystals are considered as an established approach for making crystalline solids with overall improved physico-chemical properties. However, some otherwise well behaving cocrystals undergo rapid dissociation during dissolution, with ultimate conversion to parent drug and thus apparent loss of improved solubility. The polymeric carriers are long known to manipulate this conversion during dissolution to parent crystalline drug, which may hinder or accelerate the dissolution process if used in a dosage form. The goal of this study was to deliver in vivo a more soluble carbamazepine-succinic acid (CBZ-SUC) cocrystal in suspension formulation utilizing Hydroxypropyl methyl cellulose (HPMC-AS) as a crystallization inhibitor and Polyvinyl carpolactam-polyvinyl acetate-polyethylene glycol graft copolymer ® as solubilizer. The concentration of these polymers were systemically varied during in vitro dissolution studies, while selected formulations from dissolution studies were tested in vivo. Pharmacokinetic studies (PK) in rabbits demonstrated that formulation F7-X (1% cocrystal, 1% HPMC-AS and 2% Polyvinyl carpolactam-polyvinyl acetatepolyethylene glycol graft co-polymer®) caused almost 6fold improvement in AUC0-72 (***P k 0.05) as well as much higher Cmax of 4.73µ.mL-1 to that of 1.07µ.mL-1 of unformulated 'neat' cocrystal given orally. When reference formulation of CBZ (F5-X) with similar composition to F7-X were given to rabbits, cocrystal formulation gave 1.37fold (***P k 0.05) bioavailability than CBZ reference formulation. Cmax of reference formulation observed was 3.9µmL-1.

The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance.

The use of soluble cocrystal for delivering drugs with low solubility, although a potentially effective approach, often suffers the problem of rapid disproportionation during dissolution, which negates the solubility advantages offered by the cocrystal. This necessitates their robust stabilization in order for successful use in a tablet dosage form. The cocrystal between carbamezepine and succinic acid (CBZ-SUC) exhibits a higher aqueous solubility than its dihydrate, which is the stable form of CBZ in water. Using this model system, we demonstrate an efficient and material-sparing tablet formulation screening approach enabled by intrinsic dissolution rate measurements. Three tablet formulations capable of stabilizing the cocrystal both under accelerated condition of 40 °C and 75% RH and during dissolution were developed using three different polymers, Soluplus® (F1), Kollidon VA/64 (F2) and Hydroxypropyl methyl cellulose acetate succinate (F3). When compared to a marketed product, Epitol® 200 mg tablets (F0), drug release after 60 min from formulations F1 (∼82%), F2 (∼95%) and F3 (∼95%) was all higher than that from Epitol® (79%) in a modified simulated intestinal fluid. Studies in albino rabbits show correspondingly better bioavailability of F1-F3 than Epitol.

RELATIVE BIOAVAILABILITY STUDY OF SUCCINIC ACID COCRYSTAL TABLET AND MARKETED CONVENTIONAL IMMEDIATE RELEASE TABLET FORMULATION OF CARBAMAZEPINE 200 MG IN RABBITS.

A single-dose study was performed to observe the bioequivalence of the newly formulated carbamazepine-succinic cocrystal (CBZ-SUC) immediate release tablet (F(1)) with marketed immediate release formulation Epitoll 200 mg tablet (F(0)). In this study on albino rabbits, the plasma levels resulting from 250 mg cocrystal equivalent to 200 mg of carbamazepine and conventional tablets 200 mg immediate release tablets were compared. An open-label, randomized 2 x 2 crossover study design, with a 1-week washout period, was used. Carbamazapine (CBZ) plasma concentrations were determined by a high-performance liquid chromatography validated method using ultraviolet detection. CBZ plasma levels were measured at predose and various postdose time points up to 72 h and the following pharmacokinetic parameters were used for evaluation: area under the curve (AUC), maximum plasma drug concentration (C(max)), time to achieve C(max), and elimination rate constant. (K(e)). By applying paired t-test to AUC2(0-72) (calculated by linear trapezoidal rule), the experimental formulation F(1), was found to have statistically significant (***p < 0.05) improvement in bioavailability of CBZ. However, these statistical differences do not have practical implications and the two formulations (F(0) and F(1)) were found to be bioequivalent as the relative bioavailability of both formulations (106.9%) falls with- in the acceptable FDA set range of two bioequivalent products 80-125%.

Evaluation of Influence of Various Polymers on Dissolution and Phase Behavior of Carbamazepine-Succinic Acid Cocrystal in Matrix Tablets.

The aim of current study was to explore the influence of three commonly used polymers, that is, cellulosics and noncellulosics, for example, Methocel K4M, Kollidon VA/64, and Soluplus, on the phase disproportionation and drug release profile of carbamazepine-succinic acid (CBZ-SUC) cocrystal at varying drug to polymer ratios (1 : 1 to 1 : 0.25) in matrix tablets. The polymorphic phase disproportionation during in-depth dissolution studies of CBZ-SUC cocrystals and its crystalline properties were scrutinized by X-ray powder diffractrometry and Raman spectroscopy. The percent drug release from HPMC formulations (CSH) showed inverse relation with the concentration of polymer; that is, drug release increased with decrease in polymer concentration. On contrary, direct relation was observed between percent drug release and polymer concentrations of Kollidon VA 64/Soluplus (CSK, CSS). At similar polymer concentration, drug release from pure carbamazepine was slightly lower with HPMC formulations than that of cocrystal; however, opposite trend in release rate was observed with Kollidon VA/64 and Soluplus. The significant increase in dissolution rate of cocrystal occurred with Kollidon VA/64 and Soluplus at higher polymer concentration. Moreover, no phase change took place in Methocel and Kollidon formulations. No tablet residue was left for Soluplus formulation so the impact of polymer on cocrystal integrity cannot be predicted.

Anti-inflammatory activities of Taxusabietane A isolated from Taxus wallichiana Zucc.

Current study was conducted to identify constituents of Taxus wallichiana Zucc. that might be responsible for its folk use in anti-inflammatory conditions. Taxusabietane A was isolated from the bark extract of Taxus wallichiana Zucc. Taxusabietane A was analyzed for in-vitro and in-vivo anti-inflammatory activities using Lipoxygenase (LOX) inhibition assay and carrageenan-induced paw edema model. Taxusabietane A revealed considerable LOX inhibitory activity with the IC(50) value being 57 ± 0.31. Standard compound Baicalein showed the IC(50) value being 22.1 ± 0.03 µM. Taxusabietane A also showed significant (5 and 10 mg/kg) anti-inflammatory activity induced by carrageenan. However, this study highlighted the potential of Taxusabietane A to be further explored as a new lead compound for management of conditions associated with inflammation.