Development Of Drug Formulations Research Articles

The Anti-Melanoma Effect of Betulinic Acid Functionalized Gold Nanoparticles: A Mechanistic In Vitro Approach.

Implementing metallic nanoparticles as research instruments for the transport of therapeutically active compounds remains a fundamentally vital work direction that can still potentially generate novelties in the field of drug formulation development. Gold nanoparticles (GNP) are easily tunable carriers for active phytocompounds like pentacyclic triterpenes. These formulations can boost the bioavailability of a lipophilic structure and, in some instances, can also enhance its therapeutic efficacy. In our work, we proposed a biological in vitro assessment of betulinic acid (BA)-functionalized GNP. BA-GNP were obtained by grafting BA onto previously synthesized citrate-capped GNP through the use of cysteamine as a linker. The nanoformulation was tested in HaCaT human keratinocytes and RPMI-7951 human melanoma cells, revealing selective cytotoxic properties and stronger antiproliferative effects compared to free BA. Further examinations revealed a pro-apoptotic effect, as evidenced by morphological changes in melanoma cells and supported by western blot data showing the downregulation of anti-apoptotic Bcl-2 expression coupled with the upregulation of pro-apoptotic Bax. GNP also significantly inhibited mitochondrial respiration, confirming its mitochondrial-targeted activity.

Cutaneous/Mucocutaneous Leishmaniasis Treatment for Wound Healing: Classical versus New Treatment Approaches

Cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (ML) show clinical spectra that can range from a localized lesion (with a spontaneous healing process) to cases that progress to a generalized systemic disease with a risk of death. The treatment of leishmaniasis is complex since most of the available drugs show high toxicity. The development of an effective topical drug formulation for CL and ML treatment offers advantages as it will improve patient’s compliance to the therapy given the possibility for self-administration, as well as overcoming the first pass metabolism and the high costs of currently available alternatives. The most common dosage forms include solid formulations, such as membranes and semi-solid formulations (e.g., ointments, creams, gels, and pastes). Topical treatment has been used as a new route of administration for conventional drugs against leishmaniasis and its combinations, as well as to exploit new substances. In this review, we discuss the advantages and limitations of using topical drug delivery for the treatment of these two forms of leishmaniasis and the relevance of combining this approach with other pharmaceutical dosage forms. Emphasis will also be given to the use of nanomaterials for site-specific delivery.

Challenges and potentials of developing domperidone into the transdermal delivery

Nausea, which often coexists with vomiting, is an uneasy sensation in the stomach caused by several factors. Oral domperidone is widely prescribed in nausea treatment. The low bioavailability of oral domperidone makes a patient take the drug more frequently, even though some patients have difficulty swallowing the drug when suffering nausea. Recently, the drug formulation development for transdermal delivery systems is expected to increase in the future. Practical and increase patient comfortable is the notable advantages of using transdermal dosage form. Domperidone is currently being studied into various pharmaceutical dosage forms with the transdermal route. This present article provides summaries of the constraints also the current formulation development of domperidone which shows the potential of domperidone in transdermal delivery.

Effect of Primary Packaging Material on the Stability Characteristics of Diazepam and Midazolam Parenteral Formulations.

Diazepam and midazolam are formulated in autoinjectors for parenteral administration to decrease seizures in the case of emergency. However, the compatibility of these lipophilic drugs with the primary packaging material is a key part of drug formulation development. In this work, diazepam and midazolam were packaged in glass syringes as parenteral solutions using two different elastomeric sealing materials (PH 701/50 C BLACK and 4023/50 GRAY). Syringes were stored at three different storage temperatures: 4, 25, and 40 °C. At different time points over 3 years, physical appearance, benzodiazepine sorption on the sealing elastomeric materials, and drug content in solution were assayed. A detailed study on the adsorption profile of both benzodiazepines on the elastomeric gaskets was performed, indicating that the novel rubber material made of bromobutyl derivatives (4023/50 GRAY) is a better choice for manufacturing autoinjectors due to lower drug adsorption. Diazepam showed a better stability profile than midazolam, with the latter solubilised as a hydrochloride salt in an acidic pH that can affect the integrity of the elastomer over time. The amount of drug adsorbed on the surface of the elastomer was measured by NIR and correlated using chemometric models with the amount retained in the elastomeric gaskets quantified by HPLC.

Formulation Development and Evaluation of Drug Loaded Microsponges of Sulindac Sodium

Formulation Development and Evaluation of Drug Loaded Microsponges of Sulindac Sodium

A Review on the Concept of Superfluity Mechanism in Solubility Enhancement

Superfluity drug delivery system (SFDDS) is an auspicious conception to obtain adequate oral bioavailability of poorly soluble drugs especially those drugs which are belongs to Biopharmaceutical Classification System II. The drug is in the form of high energy or otherwise swiftly dissolving form such that generated the drug in intraluminal concentrations above the saturation solubility which is liable for desired pharmacological response to the systemic circulation due to superfluity mechanism. The mechanism is based upon spring-parachute and hang-glider effect which involves the inhibition of nucleation with the help of precipitation inhibitors which will act as parachute and glider effect in superfluity formulations and the spring and hang will act as technology used to formulated the dosage form such as amorphous solid dispersion, co-crystals, supersaturated self-emulsifying drug-delivery system correlating to want the biological response is inadequate in the aqueous solubility of drug encountered with formulation development of new drug and existing drug as well as for the new formulation development of existing drug. The methods related to solubilization process are not necessarily improving the absorption in GIT i.e., the free fraction of drug molecules in the inter-micellar phase is limited at the time of dissolution process of the intestinal barrier. This review articles belongs to mechanism of superfluity strategy which overcomes many of the obstacles and limitations of solubilization methods especially very poorly water-soluble drug.

A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis

Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires strict adherence to drug regimens for prolonged periods of time. Long-acting (LA) delivery systems have the potential to improve adherence. Here, we show the development of LA injectable drug formulations of the anti-TB drug rifabutin made of biodegradable polymers and biocompatible solvents that solidifies after subcutaneous injection. Addition of amphiphilic compounds increases drug solubility, allowing to significantly increase formulation drug load. Solidified implants have organized microstructures that change with formulation composition. Higher drug load results in smaller pore size that alters implant erosion and allows sustained drug release. The translational relevance of these observations in BALB/c mice is demonstrated by (1) delivering high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb infection, and (3) clearing acute Mtb infection from the lung and other tissues.

A comprehensive analysis of meloxicam particles produced by nanosecond laser ablation as a wet milling technique

Recently, the number of water insoluble and poorly soluble drug compounds has increased significantly. Therefore, growing interest has been witnessed in different particle size reduction techniques to improve the dissolution rates, transport characteristics and bioavailability of drugs. Laser ablation has proven to be an alternative method to the production of nano- and micrometre-sized drug particles without considerable chemical damage. We present the nanosecond laser ablation of drug pastilles in distilled water, targeting meloxicam, a poorly water soluble nonsteroidal anti-inflammatory drug, at different laser wavelengths (248 nm, 532 nm and 1064 nm). Besides chemical characterization, crystallinity, morphology and particle size studies, the mechanism of the particle generation process was examined. The applicability of ablated particles in drug formulation was investigated by solubility, cytotoxicity and anti-inflammatory effect measurements. We showed that laser ablation is a clean, efficient and chemically non-damaging method to reduce the size of meloxicam particles to the sub-micrometre–few micrometre size range, which is optimal for pulmonary drug delivery. Complemented by the excellent solubility (four to nine times higher) and anti-inflammatory (four to five times better) properties of the particles compared to the initial drug, laser ablation is predicted to have wider applications in the development of drug formulations.

Computational Screening of Medicinal Plant Phytochemicals to Discover Potent Inhibitors against Hepatitis B Virus

Hepatitis B virus (HBV) infections are infamous to cause liver damage, hepatocellular carcinoma, and cirrhosis, all of which can be fatal in nature. Nucleotide analogues, which target viral reverse transcriptase, and interferon therapy, which is known to have side effects in recipients, are currently being used to treat such infections. Increasingly, the growing viral resistance towards the first line of drugs has been a concern for the healthcare system worldwide, and therefore the need for new therapeutic interventions has been noted and novel viral targets are being explored. The HBV core protein (HBc), which regulates several viral replication checkpoints in the host cell, is one such possible target for therapeutic development. In this study, we use in silico approach to investigate the potential of various phytochemicals and natural compounds to be developed as antiviral medicines that target HBc protein. For which, the compounds were collected from databases and potential candidates were screened and shortlisted based on their pharmacokinetics and drug-likeness using Lipinski’s rule of five. Further, the chosen phytochemicals were subjected to docking analysis, and binding affinities were evaluated to set a cut-off value for selecting the best interactions, which showed better binding energy values compared to standard anti-HBV drugs. Further, the two- and three-dimensional interactions of the ligand and target protein complexes were studied to gain insights into the ligand-target bonding patterns, and bioavailability and toxicity profiles were analyzed to understand the safety and efficacy of the selected compounds to be developed as anti-HBV interventions. Upon complete inspection, Ingenol was identified as the best candidate among the chosen phytochemicals, followed by I-asarinin and Withaferin. We hope that the findings from this study will be useful in the development of anti-HBV drug candidates or formulations.

Silica hydrogel composites as a platform for soft drug formulations and cosmetic compositions

In this work, silica hydrogels are considered as potential basis for the development of new soft drug formulations and cosmetic products. For this purpose, the hydrogel drug-silica composites having pH ∼7 were synthesized by two-step sol-gel method under different synthesis conditions (concentration of acidic catalyst, addition of co-solvent (DMSO), drug loading). Lipoamide, a powerful antioxidant, was used as the drug. Since biomedical functionality of the hydrogel materials is largely determined by their mechanical properties, response of the hydrogels to deformation under compression, tension and shear was measured, and their thixotropic behavior was also studied. The release kinetics of the drug from the hydrogel composites was investigated in vitro. It was shown that the synthesis conditions influenced significantly on the indicated properties of the synthesized hydrogels. The compression Young's moduli and the thixotropic indexes decreased with increasing catalyst concentration and drug loading due to the destabilizing effect of these factors on microstructure of the hydrogels. However, DMSO promoted improvement of the mechanical properties of the hydrogels. The tensile properties of the hydrogels were very low. It was found that the drug release from the hydrogel composites followed zero order kinetic for two days due to mechanism of anomalous diffusion. The drug release from the hydrogel composites prepared using the highest catalyst concentration and high drug loading is characterized by higher rate constants.

The Role of in silico Research in Developing Nanoparticle-Based Therapeutics.

Nanoparticles (NPs) hold great potential as therapeutics, particularly in the realm of drug delivery. They are effective at functional cargo delivery and offer a great degree of amenability that can be used to offset toxic side effects or to target drugs to specific regions in the body. However, there are many challenges associated with the development of NP-based drug formulations that hamper their successful clinical translation. Arguably, the most significant barrier in the way of efficacious NP-based drug delivery systems is the tedious and time-consuming nature of NP formulation—a process that needs to account for downstream effects, such as the onset of potential toxicity or immunogenicity, in vivo biodistribution and overall pharmacokinetic profiles, all while maintaining desirable therapeutic outcomes. Computational and AI-based approaches have shown promise in alleviating some of these restrictions. Via predictive modeling and deep learning, in silico approaches have shown the ability to accurately model NP-membrane interactions and cellular uptake based on minimal data, such as the physicochemical characteristics of a given NP. More importantly, machine learning allows computational models to predict how specific changes could be made to the physicochemical characteristics of a NP to improve functional aspects, such as drug retention or endocytosis. On a larger scale, they are also able to predict the in vivo pharmacokinetics of NP-encapsulated drugs, predicting aspects such as circulatory half-life, toxicity, and biodistribution. However, the convergence of nanomedicine and computational approaches is still in its infancy and limited in its applicability. The interactions between NPs, the encapsulated drug and the body form an intricate network of interactions that cannot be modeled with absolute certainty. Despite this, rapid advancements in the area promise to deliver increasingly powerful tools capable of accelerating the development of advanced nanoscale therapeutics. Here, we describe computational approaches that have been utilized in the field of nanomedicine, focusing on approaches for NP design and engineering.

Practical and operational considerations related to paediatric oral drug formulation: An industry survey

For over 15 years, US and EU regulations ensure that medicines developed for children are explicitly authorised for such use with age-appropriate forms and formulations, implying dedicated research. To shed light on how these regulations have been adopted by pharmaceutical companies and how various aspects of paediatric oral drug formulation development are currently handled, an exploratory survey was conducted. Topics included: general company policy, regulatory aspects, dosage form selection, in-vitro, in-silico and (non-)clinical in-vivo methods, and food effects assessment. The survey results clearly underline the positive impact of the paediatric regulations and their overall uptake across the pharmaceutical industry. Even though significant improvements have been made in paediatric product development, major challenges remain. In this respect, dosage form selection faces a discrepancy between the youngest age groups (liquid products preference) and older subpopulations (adult formulation preference). Additionally, concerted research is needed in the development and validation of in-vitro tools and physiology based pharmacokinetic models tailored to the paediatric population, and in estimating the effect of non-standard and paediatric relevant foods. The current momentum in paediatric drug development and research should allow for an evolution in standardised methodology and guidance to develop paediatric formulations, which would benefit pharmaceutical industry and regulators.

Sex-specific and concentration-dependent influence of Cremophor RH 40 on ampicillin absorption via its effect on intestinal membrane transporters in rats.

Pharmaceutical excipients are the basic materials and important components of pharmaceutical preparations, and play an important role in improving the efficacy of drugs and reducing adverse reactions. Therefore, selecting suitable excipients for dosage form is an important step in formulation development. An increasing number of studies have revealed that the traditionally regarded "inert" excipients can, however, influence the bioavailability of drugs. Moreover, these effects on the bioavailability of drugs caused by pharmaceutical excipients may differ in between males and females. In this study, the in situ effect of the widely-used pharmaceutical excipient Cremophor RH 40 spanning from 0.001% to 0.1% on the intestinal absorption of ampicillin in male and female rats using closed-loop models was investigated. Cremophor RH 40 ranging from 0.03% to 0.07% increased the absorption of ampicillin in females, however, was decreased in male rats. The mechanism of such an effect on drug absorption is suggested to be due to the interaction between Cremophor RH 40 and two main membrane transporters P-gp and PepT1. Cremophor RH 40 altered the PepT1 protein content in a sex-dependent manner, showing an increase in female rats but a decrease in males. No modification on the PepT1 mRNA abundance was found with Cremophor RH 40, indicating that the excipient may regulate the protein recruitment of the plasma membrane from the preformed cytoplasm pool to alter the PepT1 function. This influence, however, may differ between males and females. As such, the study herein shows that supposedly inert excipient Cremophor RH 40 can influence membrane fluidity, uptake and efflux transporters in a sex- and concentration-dependent manner. These findings, therefore, highlight the need for sex-specific studies in the application of solubilizing excipients in drug formulation development.

Potential of the capillary electrophoresis method for PLGA analysis in nano-sized drug formulations

This study demonstrated applications of the capillary electrophoresis technique for various tasks related to polymer analysis when developing nano-sized drug formulations based on the copolymer of lactic and glycolic acids (PLGA). The focus of this study was to find the appropriate method for PLGA analysis that would address the numerous tasks related to the development of a PLGA-based nano-sized drug formulation. Capillary zone electrophoresis (CZE) was successfully applied for both assessment of PLGA quality (i.e. determination of the PLGA content, content and composition of the water-soluble fraction and lactide/glycolide molar ratio) and for PLGA quantification in a drug nanoformulation, as well as the monitoring of polymer hydrolytic degradation in biorelevant media. This technique enabled selective quantification of the polymer by its lactate or glycolate peaks with high sensitivity (LOD = 0.04 μg PLGA/ml). The study also addresses methodological aspects of applying capillary zone electrophoresis (CZE) for PLGA analysis. Also, the opportunity to quantify PLGA in a nano-sized drug formulation by the nanoparticle peak area in electropherograms was investigated.

Emerging Landscape of Computational Modeling in Pharmaceutical Development.

Computational chemistry applications have become an integral part of the drug discovery workflow over the past 35 years. However, computational modeling in support of drug development has remained a relatively uncharted territory for a significant part of both academic and industrial communities. This review considers the computational modeling workflows for three key components of drug preclinical and clinical development, namely, process chemistry, analytical research and development, as well as drug product and formulation development. An overview of the computational support for each step of the respective workflows is presented. Additionally, in context of solid form design, special consideration is given to modern physics-based virtual screening methods. This covers rational approaches to polymorph, coformer, counterion, and solvent virtual screening in support of solid form selection and design.

Biogenic Synthesis of Nanoparticles and their Role in Drug delivery

The development of nanoparticle-based drug formulations has yielded the opportunities to deal with and treat diseases. Nanoparticles in drug delivery vary in size but are generally ranging from 10 to 100 nm. Through the manipulation of size, surface characteristics and material used, the nanoparticles will be developed into smart systems, encasing therapeutic and imaging agents in addition to bearing stealth property. Further, these systems can deliver drug to specific tissues and provide controlled release therapy. However, for these novel delivery methods to succeed and compete with those already on the market, the prime issues that require consideration include device design and safety, efficacy, ease of handling and costeffectiveness. Nanotechnology has proven beneficial in the treatment of cancer and many other diseases, also providing advancement in diagnostic testing. Drug delivery systems have an important role to play in the administration of drugs, vaccines and diagnostic agents. This review provides a detail of the next generation of active constituent delivery technologies.

Drug-Biopolymer Dispersions: Morphology- and Temperature- Dependent (Anti)Plasticizer Effect of the Drug and Component-Specific Johari-Goldstein Relaxations.

Amorphous molecule-macromolecule mixtures are ubiquitous in polymer technology and are one of the most studied routes for the development of amorphous drug formulations. For these applications it is crucial to understand how the preparation method affects the properties of the mixtures. Here, we employ differential scanning calorimetry and broadband dielectric spectroscopy to investigate dispersions of a small-molecule drug (the Nordazepam anxiolytic) in biodegradable polylactide, both in the form of solvent-cast films and electrospun microfibres. We show that the dispersion of the same small-molecule compound can have opposite (plasticizing or antiplasticizing) effects on the segmental mobility of a biopolymer depending on preparation method, temperature, and polymer enantiomerism. We compare two different chiral forms of the polymer, namely, the enantiomeric pure, semicrystalline L-polymer (PLLA), and a random, fully amorphous copolymer containing both L and D monomers (PDLLA), both of which have lower glass transition temperature (Tg) than the drug. While the drug has a weak antiplasticizing effect on the films, consistent with its higher Tg, we find that it actually acts as a plasticizer for the PLLA microfibres, reducing their Tg by as much as 14 K at 30%-weight drug loading, namely, to a value that is lower than the Tg of fully amorphous films. The structural relaxation time of the samples similarly depends on chemical composition and morphology. Most mixtures displayed a single structural relaxation, as expected for homogeneous samples. In the PLLA microfibres, the presence of crystalline domains increases the structural relaxation time of the amorphous fraction, while the presence of the drug lowers the structural relaxation time of the (partially stretched) chains in the microfibres, increasing chain mobility well above that of the fully amorphous polymer matrix. Even fully amorphous homogeneous mixtures exhibit two distinct Johari–Goldstein relaxation processes, one for each chemical component. Our findings have important implications for the interpretation of the Johari–Goldstein process as well as for the physical stability and mechanical properties of microfibres with small-molecule additives.

DEFORMATION PROPERTIES OF HYDROGEL COMPOSITESOF Α-LIPOIC ACID WITH COLLOID SILICA

Hydrogels are widely used as the basis of soft drug formulations and cosmetic compositions (ointments, creams, gels, masks, dermal fillers, etc.). Deformation properties of these products are very important from the point of view of the convenience and safety of their application, as well as optimization of their production process. In this work, inorganic silica hydrogels are considered as a promising basis for the development of new soft drug formulations and products for cosmetology. The hydrogel composites of colloid silica with α-lipoic acid which is a well-known powerful anti-oxidant used for treatment of various skin diseases were synthesized. Besides, the drug has a reju-venating effect on the skin. Taking into account the indicated potential application of the hydrogels and the methods of their administration (transdermal, injection), the hydrogels had a pH of 6.6-7.4. Pure silica hydrogels and their composites with α-lipoic acid were synthesized by a two-step sol-gel method. Using the method of optical microscopy, it was shown that they have a highly po-rous surface. The deformation properties of the synthesized hydrogels under compression, tension, and shear were determined. It is shown that the synthesized hydrogels have a certain elasticity under axial compression, thixotropy and exhibit pseudoplasticity. The effects ofthe synthesis con-ditions (concentration of the catalyst for silica sol formation, the amount of the introduced drug) on the deformation properties of the composites have been established. The effects were explained in terms of the influence of these factors on the strength of the three-dimensional silica framework of the hydrogel materials. The discovered deformation properties of silica hydrogels make them promising for the development of new soft drug formulations for topical application.

Release Mechanisms and Practical Percolation Threshold for Long-acting Biodegradable Implants: An Image to Simulation Study

The development of long-acting drug formulations requires efficient characterization technique as the designed 6–12 months release duration renders real-time in vitro and in vivo experiments cost and time prohibitive. Using a novel image-based release modeling method, release profiles were predicted from X-Ray Microscopy (XRM) of T0 samples. A validation study with the in vitro release test shows good prediction accuracy of the initial burst release. Through fast T0 image-based release prediction, the impact of formulation and process parameters on burst release rate was investigated. Recognizing the limitations of XRM, correlative imaging with Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) was introduced. A water stress test was designed to directly elucidate the formation of pores through polymer-drug-water interplay. Through an iterative correction method that considers poly(lactic-co-glycolic acid) (PLGA) polymer degradation, good agreement was achieved between release predictions using FIB-SEM images acquired from T0 samples and in vitro testing data. Furthermore, using image-based release simulations, a practical percolation threshold was identified that has profound influence on the implant performance. It is proposed as an important critical quality attribute for biodegradable long-acting delivery system, that needs to be investigated and quantified.

Polysorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy

Polysorbates (PSs) are synthetic nonionic surfactants consisting of polyethoxy sorbitan fatty acid esters. PSs have been widely employed as emulsifiers and stabilizers in various drug formulations and food additives. Recently, various PS-based formulations have been developed for safe and efficient drug delivery. This review introduces the general features of PSs and PS-based drug carriers, summarizes recent progress in the development of PS-based drug formulations, and discusses the physicochemical properties, biological safety, P-glycoprotein inhibitory properties, and therapeutic applications of PS-based drug formulations. Additionally, recent advances in brain-targeted drug delivery using PS-based drug formulations have been highlighted. This review will help researchers understand the potential of PSs as effective drug formulation agents.