Solubility-permeability interplay of hydrotropic solubilization of piroxicam.

OBJECTIVES: In this research paper, an investigation has been made to assess the simultaneous effect of a solubility enhancement approach, i.e., hydrotropy on the solubility and apparent permeability of piroxicam. The solubility of piroxicam (PRX) a BCS (biopharmaceutics classification system) class II drug has been increased using a mixed hydrotropy approach. This study is based on identifying the pattern of solubility-permeability interplay and confirming whether every solubility gain results in a concomitant decrease in permeability or permeability remains unaffected. METHOD: Solid dispersions of PRX were formulated using two hydrotropes, viz., sodium benzoate (SB) and piperazine (PP) by solvent evaporation method. A comprehensive 32factorial design was employed to study the effect of hydrotropes on the solubility and permeability of PRX. Subsequently, PRX tablets containing these solid dispersions were formulated and evaluated. KEY FINDINGS: SB and PP displayed a significant increase in the solubility of PRX ranging from 0.99 to 2.21 mg/mL for F1-F9 batches attributed to the synergistic effect of hydrotropes. However, there is a reduction in PRX permeability with increasing hydrotrope levels. The decline in permeability was notably less pronounced compared to the simultaneous rise in aqueous solubility of PRX. CONCLUSION: An evident tradeoff between permeability and solubility emerged through the mixed hydrotropic solubilization for PRX. As PRX has generally higher intrinsic permeability, it has been assumed that this permeability loss will not affect the overall absorption of PRX. However, it may affect the absorption of drugs with limited permeability. Therefore, solubility permeability interplay should be investigated during solubility enhancement.

A Clinical Insight on New Discovered Molecules and Repurposed Drugs for the Treatment of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began churning out incredulous terror in December 2019. Within several months from its first detection in Wuhan, SARS-CoV-2 spread to the rest of the world through droplet infection, making it a pandemic situation and a healthcare emergency across the globe. The available treatment of COVID-19 was only symptomatic as the disease was new and no approved drug or vaccine was available. Another challenge with COVID-19 was the continuous mutation of the SARS-CoV-2 virus. Some repurposed drugs, such as hydroxychloroquine, chloroquine, and remdesivir, received emergency use authorization in various countries, but their clinical use is compromised with either severe and fatal adverse effects or nonavailability of sufficient clinical data. Molnupiravir was the first molecule approved for the treatment of COVID-19, followed by Paxlovid™, monoclonal antibodies (MAbs), and others. New molecules have variable therapeutic efficacy against different variants or strains of SARS-CoV-2, which require further investigations. The aim of this review is to provide in-depth information on new molecules and repurposed drugs with emphasis on their general description, mechanism of action (MOA), correlates of protection, dose and dosage form, route of administration, clinical trials, regulatory approval, and marketing authorizations.

A Comprehensive Investigation Regarding the Differentiation of the Procurable COVID-19 Vaccines.

COVID-19 caused by coronavirus SARS-CoV-2 became a serious threat to humankind for the past couple of years. The development of vaccine and its immediate application might be the only to escape from the grasp of this demoniac pandemic. Approximately 343 clinical trials on COVID-19 vaccines are ongoing currently, and almost all countries are motivating ongoing researches at warp speed for the development of vaccines against COVID-19. This review explores the progress in the development of the vaccines, their current status of ongoing clinical research, mechanisms, and regulatory approvals. Many pharmaceutical companies are already in the endgame for manufacturing various vaccines of which some are already being marketed across the globe, while others are yet to get approval for marketing. The primary aim of this review is to compare regulatory accepted vaccines in terms of their composition, doses, regulatory status, and efficacy. The study is conducted by grouping into approved and unapproved vaccines for marketing. Different routes of administration of vaccines along with the efficacy of the routes are also presented in the review. A wide range of database and clinical trial data is reviewed for sorting out the information on different vaccines. Unfortunately, many mutations (alpha, beta, gamma, delta, kappa, omicron etc.) of SARS-CoV-2 have attacked people in very short time, which is the great challenge for investigational vaccines. Moreover, some vaccines like Pfizer's BNT162, Oxford's ChAdOx1, Moderna's mRNA-1273, and Bharat Biotech's Covaxin have got regulatory approval in some countries for its distribution which may prove to stand tall against the pandemic.

Lipids for Taste masking and Taste assessment in pharmaceutical formulations.

Pharmaceutical products often have drawbacks of unacceptable taste and palatability which makes it quite difficult for oral administration to some special populations like pediatrics and geriatrics. To curb this issue different approaches like coating, granulation, extrusion, inclusion complexation, ion-exchange resins, etc for taste masking are employed and among them use of lipids have drawn special attention of researchers. Lipids have a lower melting point which is ideal for incorporating drugs in some of these methods like hot-melt extrusion, melt granulation, spray drying/congealing and emulsification. Lipids play a significant role as a barrier to sustain the release of drugs and biocompatible nature of lipids increases their acceptability by the human body. Further, lipids provide vast opportunities of altering pharmacokinetics of the active ingredients by modulating release profiles. In taste sensors, also known as electronic tongue or e-tongue, lipids are used in preparing taste sensing membranes which are subsequently used in preparing taste sensors. Lipid membrane taste sensors have been widely used in assessing taste and palatability of pharmaceutical and food formulations. This review explores applications of lipids in masking the bitter taste in pharmaceutical formulations and significant role of lipids in evaluation of taste and palatability.

Lipid Drug Carriers for Cancer Therapeutics: An Insight into Lymphatic Targeting, P-gp, CYP3A4 Modulation and Bioavailability Enhancement.

In the treatment of cancer, chemotherapy plays an important role though the efficacy of anti-cancer drug administered orally is limited, due to their poor solubility in physiological medium, inability to cross biological membrane, high Para-glycoprotein (P-gp) mediated drug efflux, and pre-systemic metabolism. These all factors cumulatively reduce drug exposure at the target site leading to multidrug resistance (MDR). Lipid based carriers systems has been explored to overcome solubility and permeability related issues of anti-cancer drugs. The lipid based formulations have also been reported to circumvent the effect of P-gp and CYP3A4. Further long chain triglycerides (LCT) has shown their ability to access Lymphatic route over Medium Chain Triglycerides, as the former has been extensively used for targeting anti-cancer drugs at proliferating cells through lymphatic route. Therefore this review tries to reflect the usefulness of lipid based drug carriers systems (viz. liposome, solid lipid nanoparticle, nano-lipid carriers, self-emulsifying, lipidic pro-drugs) in targeting lymphatic system and overcoming issues related to solubility and permeability of anti-cancer drugs. Moreover, we have also tried to reflect how critically lipid based carriers are important in maximizing therapeutic safety and efficacy of anti-cancer drugs.

Fast Dissolving/Disintegrating Dosage Forms of Natural Active Compounds and Alternative Medicines.

Fast Dissolving/Disintegrating Dosage Forms (FDDFs) are a group of dosage forms which dissolve or disintegrate quickly, leading to fast distribution of active ingredients at the site of administration; thereby providing ease of oral ingestion of solid unit dosage forms and have the potential to enhance transmucosal absorption. With time, the use of FDDFs in alternative systems has significantly increased. Homeopathic systems and traditional Chinese medicine have embraced FDDFs for the delivery of active compounds. Most of the patents in this area are from China or by the Chinese innovators. In Europe and US, FDDFs have been extensively studied for the delivery of natural active compounds. It was fascinating to know that some new dosage forms and new routes of delivering active compounds are also making their way to the family of FDDFs. The dose of active compound, size of dosage forms, standardization of extracts, polyherbal mixtures, stability of active compounds, safety, efficacy and pharmacokinetics are challenging issues for developing FDDF herbal formulations or phytopharmaceuticals.

The Solubility-Permeability Interplay for Solubility-Enabling Oral Formulations.

The Biopharmaceutical classification system (BCS) classifies the drugs based on their intrinsic solubility and intestinal permeability. The drugs with good solubility and intestinal permeability have good bioavailability. The drugs with poor solubility and poor permeability have solubility dependent and permeability dependent bioavailability, respectively. In the current pharmaceutical field, most of the drugs have poor solubility. To solve the problem of poor solubility, various solubility enhancement approaches have been successfully used. The effects of these solubility enhancing approaches on the intestinal permeability of the drugs are a matter of concern, and must not be overlooked. The current review article focuses on the effect of various solubility enhancing approaches viz. cyclodextrin, surfactant, cosolvent, hydrotropes, and amorphous solid dispersion, on the intestinal permeability of drugs. This article will help in the designing of the optimized formulations having balanced solubility enhancement without affecting the permeability of drugs.

Transdermal applications of ethosomes - a detailed review.

Skin, the largest organ of the body serves as a potential route of drug delivery for local and systemic effects. However, the outermost layer of skin, the stratum corneum (SC) acts as a tough barrier that prevents penetration of hydrophilic and high molecular weight drugs. Ethosomes are a novel phospholipid vesicular carrier containing high ethanol concentrations and offer improved skin permeability and efficient bioavailability due to their structure and composition. This article gives a review of ethosomes including their compositions, types, mechanism of drug delivery, stability, and safety behaviour. This article also provides a detailed overview of drug delivery applications of ethosomes in various diseases.

A Comparative Study of Different Proportions of Superdisintegrants: Formulation and Evaluation of Orally Disintegrating Tablets of Salbutamol Sulphate.

OBJECTIVES: Superdisintegrants play important role in disintegration of orally disintegrating tablets (ODTs). Action of three different superdisintegrants, viz. croscarmellose sodium, sodium starch glycolate and Indion 414, were studied individually or in their binary combinations for their fast disintegrant action in ODTs of salbutamol sulphate prepared by direct compression. MATERIALS AND METHODS: ODTs were prepared in three different superdisintegrant combinations A, B and C. In each combination, five formulations were prepared with superdisintegrants in ratios 10:90, 25:75, 50:50, 75:25, and 90:10. Three ODT formulations were prepared with single superdisintegrant and two ODT batches were prepared from marketed ODT excipient blends, viz. Prosolv-ODT and F-Melt. Prepared ODT formulations were evaluated and compared for weight variation, hardness, friability, wetting time, disintegration and drug release. RESULTS: All ODTs disintegrated quickly in 32 s or less. ODT formulation F3, containing croscarmellose sodium and sodium starch glycolate, disintegrated very quickly in 19.28±3.11 s. Results of F3 were compared with the batches (F19 and F20) containing marketed coprocessed excipients and found in good agreement for various evaluation parameters. Formulation F20 was hygroscopic, while F3 did not suffer this disadvantage. CONCLUSION: Thus, we may conclude that superdisintegrants in combinations may offer additive and/or synergistic disintegration possible due to their different mechanism.

Formulation and characterization of taste masked ondansetron-magnesium aluminum silicate adsorption systems.

CONTEXT: Taste masking greatly influences the acceptability of bitter tasting formulation; moreover, it governs the commercial and therapeutic success of drug products. OBJECTIVE: This work is directed toward masking the bitter taste of ondansetron HCl (ONS) utilizing the excipient, which can delay the reach of drug to the taste buds. MATERIAL AND METHODS: Magnesium aluminum silicate (Veegum F), a clay material having capability to adsorb the drugs onto it, was used. The adsorption systems of ONS with Veegum were obtained by dynamic adsorption technique and examined by scanning electron microscopy, differential scanning calorimetry, Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD) for morphology, thermal behavior, and interactions. The taste assessment of prepared systems was done by in vitro method based on drug release. RESULTS: The molecular interaction between ONS and Veegum in the system was revealed by FTIR spectroscopy. A change in thermal behavior of the system was observed owing to interaction or replacement of the cationic groups of Veegum with that of ONS. XRD studies revealed that the prepared system was having lower crystallinity as compared to ONS. The in vitro drug release study showed that ONS release from the system was relatively slow in basic environment than the acidic one. DISCUSSION: Adsorption of ONS on the surface of Veegum was mainly due to electrostatic interactions and hydrogen bonding. CONCLUSION: The experimental results reveal the successful intercalation of ONS into the space available between the layers of Veegum. Furthermore, this resulted in a control on drug release in salivary pH resulting in a concentration lower than bitterness threshold.

Formulation and evaluation of lipid based taste masked granules of ondansetron HCl.

INTRODUCTION AND AIM: Various taste masking approaches comprising the excipients which delay the reach of the drug to taste buds are reported. Lipidic substances can act as release retarding agent and provides a matrix base responsible for suppressing the bitter taste of drug. This work was aimed to study the influence of different proportions of a lipid carrier on the inhibition of bitterness of the drug vis-a-vis in vitro release of drug from the granules. METHODS: The lipid-matrix granules of ondansetron HCl with Geleol pellets (glycerol monostearate) were obtained by manual hot melt fusion technique. The prepared granules were characterized by SEM, DSC and XRD. The taste assessment of prepared granules was done by in vitro method based on drug release. RESULTS: Distribution of drug inside the lipid-matrix granules was not properly analyzed by DSC and XRD, moreover these studies revealed no interaction between the drug and lipid. The dissolution tests displayed the significant retardation of drug release from the granules compared to pure drug and additionally indicated the attainment of matrix system via appearance of unbroken granules during in vitro testing. Higuchi relationship for drug release was obtained by drug release kinetics, which also revealed the functioning drug release mechanism, as diffusion controlled but the addition of hydrophilic substance (Cab-o-sil) has changed the mechanism of drug release. CONCLUSION: The proportions of Geleol and Cab-o-sil taken in granules had affected the dissolution profile. Higher amount of GE resulted in high taste masking ability.

Formulation, evaluation and 3(2) full factorial design-based optimization of ondansetron hydrochloride incorporated taste masked microspheres.

CONTEXT: Masking the bitter taste of Ondansetron hydrochloride (ONS) may improve palatability, acceptance and compliance of ONS products. OBJECTIVE: ONS-loaded, taste-masked microspheres were prepared with a polycationic pH-sensitive polymer and 3(2) full factorial design (FFD) was applied to optimize microsphere batches. MATERIALS AND METHODS: Solvent evaporation, in acetone--methanol/liquid paraffin system, was used to prepare taste-masked ONS microspheres. The effect of varying drug/polymer (D/P) ratios on microspheres characteristics were studied by 3(2) FFD. Desirability function was used to search the optimum formulation. Microspheres were evaluated by FTIR, XRD and DSC to examine interaction and effect of microencapsulation process. In vitro taste assessment approach based on bitterness threshold and drug release was used to assess bitterness scores. RESULTS: Prepared ONS microspheres were spherical and surface was wrinkled. ONS was molecularly dispersed in microspheres without any incompatibility with EE100. In hydrochloric acid buffer pH 1.2, ONS released completely from microsphere in just 10 min. Contrary to this, ONS release at initial 5 min from taste-masked microspheres was less than the bitterness threshold. CONCLUSION: Full factorial design and in vitro taste assessment approach, coupled together, was successfully applied to develop and optimize batches of ONS incorporated taste-masked microspheres.

Pharmacognostic standardization with various plant parts of Desmostachya bipinnata.

CONTEXT: Desmostachya bipinnata (L.) Stapf [Gramineae (Poaceae)] has been traditionally used to treat various disorders such as asthma, kidney stone, diarrhea, wound healing, etc. OBJECTIVE: The present study involves pharmacognostic, botanical, and preliminary phytochemical examination of various plant parts and powders of D. bipinnata. MATERIALS AND METHODS: Leaves, stem, roots, underground and aerial part powders were microscopically examined. Pharmacognostic standardization parameters were determined as per the WHO guidelines. Parameters, including extractive value in different solvents, ash values, and loss on drying, were determined. Preliminary phytochemical studies, fluorescence analysis, and chromatographic profiling were performed for the correct identification of this crude drug and some of its phytoconstituents. RESULTS: Microscopical studies showed various characteristic features including, collateral vascular bundle, bundle sheath cells, and bulliform cells in leaf, conjoint, collateral and closed vascular bundles, and sclerenchymatous sheath in stem; and silica bodies in root. Phytochemical screening and chromatographic profile of aerial plant parts revealed the presence of alkaloids, tannins, flavonoids, steroids, glycosides, and coumarins. Underground plants parts indicated the presence of glycosides, steroids, flavonoids, coumarins, and alkaloids. DISCUSSION AND CONCLUSION: The results of the performed studies are helpful in correct identification, characterisation of D. bipinnata. Preliminary phytochemical studies and chromatographic profiling may be helpful in further isolation and purification of lead compounds from different extracts.

Strychnos nux-vomica seeds: Pharmacognostical standardization, extraction, and antidiabetic activity.

BACKGROUND: Strychnos nux-vomica, commonly known as kuchla, contains strychnine and brucine as main constituents. Minor alkaloids present in the seeds are protostrychnine, vomicine, n-oxystrychnine, pseudostrychnine, isostrychnine, chlorogenic acid, and a glycoside. Seeds are used traditionally to treat diabetes, asthma, aphrodisiac and to improve appetite. OBJECTIVE: The present study was aimed to evaluate the various pharmacognostical characters and antidiabetic activity of S. nux-vomica seed. MATERIALS AND METHODS: Pharmacognostical characters were performed as per the WHO guideline. Extraction was carried out in petroleum ether, chloroform, alcohol, hydroalcoholic, aqueous, and phytochemical constituents present in extracts were detected by different chemical tests. Among these extracts hydroalcoholic, aqueous extracts were evaluated for antidiabetic activity on the basis of extractive yield and phytoconstituents, in alloxan-induced diabetic rats using gliclazide as standard. RESULTS: Various analytical values of S. nux-vomica extract were established. Phytoconstituents present in S. nux-vomica extracts were detected. CONCLUSION: S. nux-vomica extracts show antihyperglycemic activity in experimental animals.

Dissolution rate enhancement of piroxicam by ordered mixing.

Micronized piroxicam was mixed with lactose, mannitol, sorbitol, maltitol and sodium chloride to produce ordered mixture in a glass vial by manual hand shaking method. The effect of excipients, surfactant, superdisintegrant, drug concentration and carrier particle size on dissolution rate was investigated. Dissolution rate studies of the prepared ordered mixtures revealed that all water soluble excipients increased the dissolution rate of piroxicam when compared to the dissolution rate of piroxicam or its suspension. Ordered mixture formulation PLF4, consisting of lactose as water soluble excipient, SSG (8% w/s) and SLS (1% w/w), released piroxcam at a very fast rate so much so that about 90% of the composition had passed into solution within 2 min. The order of the dissolution rate enhancement for ordered mixtures of various water soluble excipients was: lactose > mannitol > maltitol > sorbitol > sodium chloride. Carrier granules of size 355-710 µm were most effective in increasing the dissolution rate of drug from ordered mixtures. Decreasing the carrier particle size reduced drug dissolution from ordered mixtures. The dissolution rate of ordered mixtures consisting of 1-5% w/w piroxicam was superior to dissolution rate of piroxicam suspension. The dissolution data fitting and the resulting regression parameters indicated Hixson Crowell, cube root law, as the best fit to drug release data of ordered mixtures.