Solid Drug Research Articles

Self-nanoemulsifying drug delivery system (SNEDDS) of docetaxel and carvacrol synergizes the anticancer activity and enables safer toxicity profile: optimization, and in-vitro, ex-vivo and in-vivo pharmacokinetic evaluation.

Docetaxel (DTX) is a first-line chemotherapeutic molecule with a broad-spectrum anticancer activity. On the other hand, carvacrol (CV) has anti-inflammatory, antioxidant, cytotoxic, and hepatoprotective properties that could reduce undue toxicity caused by DTX chemotherapy. Thus, in order to overcome the challenges posed by DTX's poor aqueous solubility, low permeability, hepatic first pass, and systemic toxicities, we have developed a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) co-loaded with DTX and CV. In the present investigation, liquid-SNEDDS (L-SNEDDS) were fabricated using Nigella sativa oil, Cremophor RH 40, and Ethanol which was converted into solid by lyophilization using Aerosil 200. The reconstituted CV-DTX-S-SNEDDS showed an average globule size of < 200nm with promising flow properties (angle of repose θ: 33.22 ± 0.06). Additionally, 2.3-fold higher dissolution of DTX was observed from CV-DTX-S-SNEDDS after 6h as compared to free DTX. Similar trend was followed in dialysis release experiments with 1.5-fold higher release within 24h. Ex vivo permeation studies demonstrated significantly increased permeation of 1077.02 ± 12.72μg/cm2 of CV-DTX-S-SNEDDS after 12h. In vitro cell cytotoxicity studies revealed 5.2-fold reduction in IC50 as compared to free DTX in MDA-MB-231 cells. Formulation was able to induce higher apoptosis in cells treated with CV-DTX-S-SNEDDS as compared to free DTX and CV. It was evident from toxicity studies that CV-DTX-S-SNEDDS was well tolerated at higher dose where CV was able to manage the toxic effects of free DTX. In vivo pharmacokinetic study showed 3.4-fold increased Cmax and improved oral bioavailability as compared to free DTX. Thus, CV-DTX-S-SNEDDS could be an encouraging option for facilitating DTX oral therapy.

Applying Material Science Principles to Chemical Stability: Modelling Solid State Autoxidation in Mifepristone Containing Different Degrees of Crystal Disorder

Ball-milling and harsh manufacturing processes often generate crystal disorder which have practical implications on the physical and chemical stabilities of solid drugs during subsequent storage, transport, and handling. The impact of the physical state of solid drugs, containing different degrees/levels of crystal disorder, on their autoxidative stability under storage has not been widely investigated. This study investigates the impact of differing degrees of crystal disorder on the autoxidation of Mifepristone (MFP) to develop a predictive (semi-empirical) stability model. Crystalline MFP was subjected to different durations of ambient ball milling, and the resulting disorder/ amorphous content was quantified using a partial least square (PLS) regression model based on Raman spectroscopy data. Samples of MFP milled to generate varying levels of disorder were subjected to a range of (accelerated) stability conditions, and periodically sampled to examine their recrystallization and degradation extents. Crystallinity was monitored by Raman spectroscopy, and the degradation was evaluated by liquid chromatography. The analyses of milled samples demonstrated a competition between recrystallization and degradation via autoxidation of MFP, to different extents depending on stability conditions/exposure time. The degradation kinetics were analyzed by accounting for the preceding amorphous content, and fitted with a diffusion model. An extended Arrhenius equation was used to predict the degradation of stored samples under long-term (25°C/60% RH) and accelerated (40°C/75% RH, 50°C/75% RH) stability conditions. This study highlights the utility of such a predictive stability model for identifying the autoxidative instability in non-crystalline/partially crystalline MFP, owing to the degradation of the amorphous phases. This study is particularly useful for identifying drug-product instability by leveraging the concept of material sciences.

Fast and convenient delivery of fluidextracts liquorice through electrospun core-shell nanohybrids.

Introduction: As an interdisciplinary field, drug delivery relies on the developments of modern science and technology. Correspondingly, how to upgrade the traditional dosage forms for a more efficacious, safer, and convenient drug delivery poses a continuous challenge to researchers. Methods, results and discussion: In this study, a proof-of-concept demonstration was conducted to convert a popular traditional liquid dosage form (a commercial oral compound solution prepared from an intermediate licorice fluidextract) into a solid dosage form. The oral commercial solution was successfully encapsulated into the core-shell nanohybrids, and the ethanol in the oral solution was removed. The SEM and TEM evaluations showed that the prepared nanofibers had linear morphologies without any discerned spindles or beads and an obvious core-shell nanostructure. The FTIR and XRD results verified that the active ingredients in the commercial solution were compatible with the polymeric matrices and were presented in the core section in an amorphous state. Three different types of methods were developed, and the fast dissolution of the electrospun core-shell nanofibers was verified. Conclusion: Coaxial electrospinning can act as a nano pharmaceutical technique to upgrade the traditional oral solution into fast-dissolving solid drug delivery films to retain the advantages of the liquid dosage forms and the solid dosage forms.

Improvement of dissolution profile of eplerenone with solidified self-emulsifying drug delivery systems (S-SEDDS)

Context Eplerenone is a member of antihypertensives used individually or in combination with other medicines. Eplerenone exhibits poor solubility and is considered a class II drug. Objective Increasing the solubility of eplerenone by using both liquid and solid self-emulsifying drug delivery systems as an alternative to its marketed tablet product. Methods Solubility studies of eplerenone were done with different oils, surfactants, and co-surfactants to determine which one has the highest solubility for eplerenone and determine the preference in the formulations of liquid self-emulsifying drug delivery system. The solidification process was carried out with the adsorption to solid carrier method. Optimal ratios of components were specified with the pseudo-ternary phase diagram technique. Self-emulsifying drug delivery system formulations were characterized in terms of chemical interaction, droplet size/distribution, crystallization behaviors, and rheological evaluation. In vitro drug release studies were conducted and compared to pure drugs and marketed products. Results The solubility screening results showed high solubility of EPL in triacetin (11.99 mg/mL) as oil, Kolliphor®EL (≈ 2.65 mg/mL), and Tween80 (≈ 1.91 mg/mL) as surfactant and polyethylene glycol 200 (PEG200) (≈ 8.50 mg/mL), dimethyl sulfoxide (≈ 7.57 mg/mL), TranscutolP (≈ 6.03 mg/mL) as co-surfactant, respectively. Rheology studies revealed that liquid self-emulsifying drug delivery formulations exhibited non-Newtonian pseudoplastic flow. Conclusion Solid self-emulsifying drug delivery systems prepared with Aerosil and Neusilin have shown tremendous improvement in terms of eplerenone dissolution by releasing the entire dose with boosted effect within 5 and 30 min respectively compared to the marketed product and pure eplerenone (p < 0.05).

Over-blending effect of lubricants on capsules manufacturing: a simple and fast wettability technique to predict batch dissolution performance

Mixing/blending is a crucial operation in the manufacturing of solid drug products in the pharmaceutical industry. Although usually described and controlled in specific steps, blending is also inherent to other operations such as the transference of materials and equipment feeding systems. This study aimed to investigate a simple and fast wettability testing procedure capable to foresee the potential over-blending effects of lubricants occurring during the manufacturing of solid dosage forms. An industrial batch blend was submitted to two mixing mechanisms studies (diffusion and shear) during increasing time periods, and the developed wettability testing procedure was applied to assess their impact on blend water uptake. Capsules filled with these blends were tested for dissolution and disintegration. The method was applied to capsules with known dissolution results manufactured at an industrial scale. Results demonstrated that processes inducing shear stress led to less permeable blends with consequent retardation on capsules dissolution of at least 35% in the tested timepoints and obtained study metrics above 500 s. Moreover, disintegration testing was not able to detect non-compliant dissolutions, while the proposed wettability testing procedure proved to be able to identify performance failures. Wettability results correlate the effect of mixing mechanisms to capsules dissolution performance, evidencing that this technique can be applied in the pharmaceutical industry to evaluate possible over-blending effects.

Development of a sorafenib-loaded solid self-nanoemulsifying drug delivery system: Formulation optimization and characterization of enhanced properties.

Sorafenib, marketed under the brand name Nexavar®, is a multiple tyrosine kinase inhibitor drug that has been actively used in the clinical setting for the treatment of several cancers. However, the low solubility and bioavailability of sorafenib constitute a significant barrier to achieving a good therapeutic outcome. We developed a sorafenib-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation composed of capmul MCM, tween 80, and tetraglycol, and demonstrated that the SNEDDS formulation could improve drug solubility with excellent self-emulsification ability. Moreover, the sorafenib-loaded SNEDDS exhibited anticancer activity against Hep3B and KB cells, which are the most commonly used hepatocellular carcinoma and oral cancer cell lines, respectively. Subsequently, to improve the storage stability and to increase the possibility of commercialization, a solid SNEDDS for sorafenib was further developed through the spray drying method using Aerosil® 200 and PVP K 30. X-ray diffraction and differential scanning calorimeter data showed that the crystallinity of the drug was markedly reduced, and the dissolution rate of the drug was further improved in formulation in simulated gastric and intestinal fluid conditions. In vivo study, the bioavailability of the orally administered formulation increases dramatically compared to the free drug. Our results highlight the use of the solid-SNEDDS formulation to enhance sorafenib's bioavailability and outlines potential translational directions for oral drug development.

Review on Nanosuspension as a Novel Method for Solubility and Bioavailability Enhancement of Poorly Soluble Drugs

The formulation development of a drug is majorly based on the solubility of drugs. Nearly 40% of newly developed drugs show poor water solubility. Several approaches are used for the increasing solubility of such drugs for formulation development. Nanosuspension is one such attractive tactic which can be used for the enhancement of solubility, stability as well as bioavailability of such drugs. Nanosuspension can be defined as a two-phasic dosage form where solid drug particles of size less than 1 μm are dispersed in an aqueous phase with the help of a stabilizer. Particle size reduction in the nanoscale causes an increase in the surface area leading to an increase in dissolution rate and ultimately bioavailability is increased. A variety of excipients are used for the formulation of nanosuspension. Stabilizers, surfactants, co-surfactants, natural as well as organic solvents, buffers, salts, polyols, osmogents, and cryoprotectants are used in the formulation of nanosuspension. Various methods used in the formulation of nanosuspension can be classified into top-down and bottom-up approaches. Wet milling, high-pressure homogenization, anti-solvent techniques, melt emulsification, supercritical fluid extraction and ultrasonic homogenization are some of the methods for the preparation of nanosuspension. These methods are easy and appropriate for all poor water-soluble drugs. Nanosuspensions technology can be applied for the preparation of oral, pulmonary, injectable, ocular as well as targeted drug delivery. This review emphasizes various advantages and disadvantages of nanosuspension, its methods of preparation, formulation approaches, evaluation parameters, pharmaceutical applications, marketed products and patents of nanosuspension.

Dolutegravir Loaded Solid Self-Micro-Emulsifying Drug Delivery System for Enhanced Solubility and Dissolution

Dolutegravir sodium (DG) is a recently approved antiretroviral drug belonging to BCS class II having poor aqueous solubility and only 16% oral bioavailability. Hence aim of the present work was to develop solid self micro-emulsifying drug delivery system (S-SMEDDS) of Dolutegravir for enhanced solubility and dissolution behaviour. Initially, solubility of DG was checked to select oil, surfactant, and co-surfactant. Pseudo ternary phase diagram was constructed to identify microemulsion region. Liquid SMEDDS of DG were prepared using Campul MCM, Tween 80 and Transcutol P as oil, surfactant, and co-surfactant, respectively. The effect of different oil, surfactant and co-surfactant concentrations on particle size, zeta potential and %transmittance was studied using Box–Behnken factorial design. The obtained liquid SMEDDS was evaluated for its thermodynamic stability, globule size, robustness to dilution, viscosity, dye solubilization test, cloud point, etc. Satisfactory formulations of liquid SMEDDS were converted to solid form by adsorption technique using Neusilin US2 as a solid carrier. Evaluation of S-SMEDDS showed that solubility of DG in S-SMEDDS increases from 0.270 to 33.52 mg/mL. In-vitro drug release of S-DG4 showed 99.86 ± 1.47% drug release within 120 minutes while plain DG showed 32.55 ± 1.52%. Hence study revealed that S-SMEDDS is a promising approach to enhance solubility, dissolution and hence bioavailability of poorly aqueous soluble drug like DG.

Quality by Design-Based Development of Solid Self-Emulsifying Drug Delivery System (SEDDS) as a Potential Carrier for Oral Delivery of Lysozyme.

For many years, researchers have been making efforts to find a manufacturing technique, as well as a drug delivery system, that will allow for oral delivery of biopharmaceuticals to their target site of action without impairing their biological activity. Due to the positive in vivo outcomes of this formulation strategy, self-emulsifying drug delivery systems (SEDDSs) have been intensively studied in the last few years as a way of overcoming the different challenges associated with the oral delivery of macromolecules. The purpose of the present study was to examine the possibility of developing solid SEDDSs as potential carriers for the oral delivery of lysozyme (LYS) using the Quality by Design (QbD) concept. LYS was successfully ion paired with anionic surfactant, sodium dodecyl sulphate (SDS), and this complex was incorporated into a previously developed and optimized liquid SEDDS formulation comprising medium-chain triglycerides, polysorbate 80, and PEG 400. The final formulation of a liquid SEDDS carrying the LYS:SDS complex showed satisfactory in vitro characteristics as well as self-emulsifying properties (droplet size: 13.02 nm, PDI: 0.245, and zeta potential: -4.85 mV). The obtained nanoemulsions were robust to dilution in the different media and highly stable after 7 days, with a minor increase in droplet size (13.84 nm) and constant negative zeta potential (-0.49 mV). An optimized liquid SEDDS loaded with the LYS:SDS complex was further solidified into powders by adsorption onto a chosen solid carrier, followed by direct compression into self-emulsifying tablets. Solid SEDDS formulations also exhibited acceptable in vitro characteristics, while LYS preserved its therapeutic activity in all phases of the development process. On the basis of the results gathered, loading the hydrophobic ion pairs of therapeutic proteins and peptides to solid SEDDS may serve as a potential method for delivering biopharmaceuticals orally.

Formulation and Evaluation of Castor Oil Containing Self-emulsifying Pellets by Using Design of Experiment

Abstract: Background/Objectives: The objective of the study was to examine the feasibility of extrusion/ spheronization techniques for formulation of castor oil loaded self-emulsifying pellets. The study was also aimed at optimization of the self-emulsifying pellet system with design of experiments. Materials and Methods: Various surfactants and co-surfactants were tested for their ability to emulsify castor oil. The proportion of components (castor oil, surfactant and co-surfactant) in self-emulsifying pellets was optimized using a D-optimal mixture design. During optimization, the effect of composition of oil(X1), surfactant(X2) and cosurfactant(X3) blend on responses like dispersion time (Y1), resultant globule size (Y2) and polydispersity index (Y3) was studied. The developed self-emulsifying mixture was further loaded on pellet formulation using extrusion spheronization technique. Results: The application of D-optimal mixture design resulted in 16 batches, out of which the optimized batch consists of castor oil (30.92%), Cremophore EL (58.56%) and PEG 400(10.51%) having dispersion time of 53 sec, globule size of 242 nm and polydispersity index of 0.243 with desirability value of 1. All the formulation components affected the performance of pellets significantly. Free flowing pellets were obtained with 30% of oil loading. Conclusion: The self-emulsifying pellets of castor oil were successfully optimized with mixture design. The developed system containing castor oil can be used for orally for conditions like arthritis or can also serve as a carrier system for any drug or herbal active. Keywords: Solid self-emulsifying drug delivery system, Castor oil, Self-emulsifying pellets, Extrusion spheronization, Dispersion time.

Freezing process influences cake appearance of a lyophilized amorphous protein formulation with low solid content and high fill configuration

Low solid content and high fill drug product configuration pose special challenges for achieving elegant cake appearance after lyophilization. In this study, such a configuration for a protein formulation required lyophilization within a narrow primary drying operating space to obtain elegant cakes. Freezing process optimization was explored as a solution. A Design of Experiment (DoE) approach was used to evaluate the effect of shelf cooling rate, annealing temperature, and their interaction on cake appearance. The slope of product resistance (Rp) vs. dried layer thickness (Ldry) was used as the quantitative response because elegant cake appearance correlated with a lower initial Rp and positive slope. As the Rp vs. Ldry slope can be experimentally established within the first 1/6th of the total primary drying duration, partial lyophilization runs were executed, allowing for rapid screening. The DoE model revealed that a slow cooling rate (≤0.3 °C/min) and high annealing temperature (≥-10 °C) resulted in a better cake appearance. Furthermore, X-ray micro-computed tomography showed that elegant cakes exhibited uniform porous structure and larger pores, while inelegant cakes showed dense top layers with smaller pores. With the optimized freezing process, the primary drying operating space was broadened with improved cake appearance and batch homogeneity.

Screening Autoxidation Propensities of Drugs in the Solid-State Using PVP and in the Solution State Using N-Methyl Pyrrolidone.

Oxidative degradation of drugs is one of the major routes of drug substance and drug product instability. Among the diverse routes of oxidation, autoxidation is considered to be challenging to predict and control, potentially due to the multi-step mechanism involving free radicals. C-H bond dissociation energy (C-H BDE) is evidenced to be a calculated descriptor shown to predict drug autoxidation. While computational predictions for the autoxidation propensity of drugs are both swift and possible, no literature to date has highlighted the relationship between the computed C-H BDE and the experimentally-derived autoxidation propensities of solid drugs. The objective of this study is to investigate this missing relationship. The present work is an extension to the previously reported novel autoxidation approach that involves subjecting a physical mixture of pre-milled polyvinyl pyrrolidone (PVP) K-60 and a crystalline drug under high temperature and pressurized oxygen setup. The drug degradation was measured using chromatographic methods. An improved trend between the extent of solid autoxidation and C-H BDE could be observed after normalizing the effective surface area of drugs in the crystalline state, pointing to a positive relationship. Additional studies were conducted by dissolving the drug in N-methyl pyrrolidone (NMP) and exposing the solution under a pressurized oxygen setup at diverse elevated temperatures. Chromatographic results of these samples indicated a similarity in the formed degradation products to the solid-state experiments pointing to the utility of NMP, a PVP monomer surrogate, as a stressing agent for faster and relevant autoxidation screening of drugs in formulations.

Recent Advances in Improving the Bioavailability of Hydrophobic/Lipophilic Drugs and Their Delivery via Self-Emulsifying Formulations

Formulations based on emulsions for enhancing hydrophobic and lipophilic drug delivery and its bioavailability have attracted a lot of interest. As potential therapeutic agents, they are integrated with inert oils, emulsions, surfactant solubility, liposomes, etc.; drug delivering systems that use emulsion formations have emerged as a unique and commercially achievable accession to override the issue of less oral bioavailability in connection with hydrophobic and lipophilic drugs. As an ideal isotropic oil mixture of surfactants and co-solvents, it self-emulsifies and forms fine oil in water emulsions when acquainted with aqueous material. As droplets rapidly pass through the stomach, fine oil promotes the vast spread of the drug all over the GI (gastrointestinal tract) and conquers the slow disintegration commonly seen in solid drug forms. The current status of advancement in technologies for drug carrying has promulgated the expansion of innovative drug carriers for the controlled release of self-emulsifying pellets, tablets, capsules, microspheres, etc., which got a boost for drug delivery usage with self-emulsification. The present review article includes various kinds of formulations based on the size of particles and excipients utilized in emulsion formation for drug delivery mechanisms and the increase in the bioavailability of lipophilic/hydrophobic drugs in the present time.

Geriatric drug trials on solid tumor are scarce worldwide.

Conducting geriatric trials is the most feasible way to address the vast underrepresentation of older adults in clinical trials of cancer therapies. This study is a globally comprehensive examination of geriatric trials for solid tumor worldwide over the last decade. Up-to-date information on cancer drug trials in older adults aged over 59 years from the beginning of 2012 to the end of 2021 was collected from Trialtrove and Pharmaprojects. The number of identified trials was the dependent variable and corresponding analysis was conducted from the perspective of time trend, status quo and comparisons by region and country, sponsor type and cancer type, study status and phase. A total of 292 geriatric cancer drug trials were identified, of which 287 were single-region studies, 219 were initiated by academic groups, and 55 (18.8%) were terminated. Decreasing trends in the annual number of all trials (-9.2% per year) and the annual number of trials by academic groups (-9.4%) were observed over time. Of the geriatric trials, 183 were conducted in Asia; this number was significantly higher than that in Europe (74), North America (37), Oceania (4), and South America (1). Similar difference was found in participation rate in trials by academic groups ranging from 71.7% in Asia to 0.5% in South America. Of the trials, 19 and 97 were initiated before drug and indication approval, respectively, and the remaining 176 were initiated after indication approval. Phase II trials accounted for the highest proportion of trials (213, 72.9%), while phase I trials accounted for the lowest proportion (14, 4.8%). Trials by academic groups had a higher termination rate (21.5% vs. 11.0%) and fewer were phase IV trials (8.2% vs. 21.9%). Treatment was explored for 16 different cancers, with lung, colorectal and breast cancers being the most common. Geriatric trials of solid tumor drugs are scarce and partially prematurely terminated. Moreover, the number of geriatric trials has decreased and differs according to region. Global guidance and regulatory supervision are needed to facilitate the acquisition of adequate evidence on drug risk-benefit profiles in older adults, and thus to achieve high-quality care and safe medication.

Current Techniques of Water Solubility Improvement for Antioxidant Compounds and Their Correlation with Its Activity: Molecular Pharmaceutics.

The aqueous solubility of a drug is important in the oral formulation because the drug can be absorbed from intestinal sites after being dissolved in the gastrointestinal fluid, leading to its bioavailability. Almost 80% of active pharmaceutical ingredients are poorly water-soluble, including antioxidant compounds. This makes antioxidant activity inefficient in preventing disease, particularly for orally administered formulations. Although several investigations have been carried out to improve the solubility of antioxidant compounds, there is still limited research fully discussing the subject. Therefore, this study aimed to provide an overview and discussion of the issues related to the methods that have been used to improve the solubility and activity of antioxidant compounds. Articles were found using the keywords "antioxidant" and "water solubility improvement" in the Scopus, PubMed, and Google Scholar databases. The selected articles were published within the last five years to ensure all information was up-to-date with the same objectives. The most popular methods of the strategies employed were solid dispersion, co-amorphous, and nanoparticle drug delivery systems, which were used to enhance the solubility of antioxidant compounds. These investigations produced impressive results, with a detailed discussion of the mechanism of improvement in the solubility and antioxidant activity of the compounds developed. This review shows that the strategies used to increase the solubility of antioxidant compounds successfully improved their antioxidant activity with enhanced free radical scavenging abilities.

N-Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations

The potential presence of N-nitrosamines in medicinal products has become a matter of concern for health authorities and pharmaceutical companies. However, very little information is available in published literature on N-nitrosamine formation within pharmaceutical drug products. In response, experiments were undertaken to test if secondary and tertiary amines present in solid drug products could undergo nitrosation due to the presence of nitrite in the excipients used in the manufacture of the drug product. This work focused on solid dosage forms exploring several model amines of varying chemical structure, solubility and pKa which were formulated using common excipients with and without added nitrite. Monitoring the formation of the N-nitrosamines after processing and upon stressed stability conditions showed that N-nitrosamine formation can occur in solid drug product formulations. The results show that the rate and extent of N-nitrosamine formation depend upon the solubility of the amine, level of nitrite, expected local acidity in water layers within the drug product and mode of processing. Our findings agree with the rank order of dosage form risk from the published EFPIA workflows for quality risk management of N-nitrosamine risks in medicines (EFPIA, 2022): amorphous > wet granulation > direct compression > dry blends. In all cases the level of N-nitrosamine formation in solid dosage forms plateaued at a level that was significantly lower than the maximum theoretical yield based on the level of nitrite present. Trace secondary amine impurities were shown to be a significantly lower risk relative to cases containing a secondary amine present at drug substance levels. A comparison of secondary and simple tertiary alkylamine reactivity showed the tertiary amine to be significantly less reactive with nitrite.

Review on Fast Dissolving Oral Film

Oral drug carriers remain the most popular path for the delivery of drugs to date as it contains various advantages over any other delivery of therapeutics, despite a few disadvantages related to a particular category of sick people, along with elderly, neonatal, and dysphasic patients who struggle swallowing or chewing solid dosage forms because they are affiliated with many medical conditions. These sufferers also along with those who suffer from a range of infections. Many patients, both young and old, avoid taking solid drugs out of fear of choking. Even with fast dispersing pills, there is a risk of swallowing because of the tablet-like design. These patients also include those who are afflicted with many medical conditions.

An Overview and Discussion of N-nitrosamine Considerations for Orally Inhaled Drug Products and Relevance to Other Dosage Forms.

The presence of N-nitrosamines in drug products are currently an area of high regulatory and industry scrutiny, having been detected above acceptable regulatory levels in several solid oral drug products. For over 20years, there has been an expectation that N-nitrosamines be eliminated or controlled to acceptable levels in orally inhaled and nasal drug products (OINDP). As a result, the OINDP industry has developed and implemented risk management processes and considerations to address N-nitrosamines in final drug product, including management and understanding of upstream supply particularly for OINDP device and container closure systems. We provide an overview of N-nitrosamine formation, discuss key current regulatory expectations worldwide for N-nitrosamines in drug products, discuss risk management approaches relevant for drug device combination products, and share analytical "tips" with respect to handling N-nitrosamines chemical assessments.

Evaluation, preparation, and description of chitosan nanoparticles, as well as improving rivaroxaban bioavailability

The aim of the present study is the Evaluation, preparation, and description of chitosan nanoparticles and bioavilibility enhancement of rivaroxaban. Preparation of Rivaroxaban nanoparticles (RB-NPs) were prepared by the ionic gelation method. Different parameters were studied for evaluation, Preparation &amp; description of nanoparticles. The results of the present study showed that the formulation F7 showed the significant results for all the selected parameter as compared to the other formulations. The formulation F1, F5, and F6 showed the highest production yield (52.5, 52.35, and 52.35% respectively) and F7 showed the significant production yield (51.85%), zeta-potential (23.63 mV), entrapment efficiency (99.87), particle size (316.12±2.14 nm) and poly disparity index (0.32). Nanoparticles are solid colloidal drug carriers ranging from 10—1000 nm in diameter and are composed of synthetic, natural or semi-synthetic polymers encapsulating the drug molecule.

The Influence of Blonanserin Supersaturation in Liquid and Silica Stabilised Self-Nanoemulsifying Drug Delivery Systems on In Vitro Solubilisation.

Reformulating poorly water-soluble drugs as supersaturated lipid-based formulations achieves higher drug loading and potentially improves solubilisation and bioavailability. However, for the weak base blonanserin, silica solidified supersaturated lipid-based formulations have demonstrated reduced in vitro solubilisation compared to their liquid-state counterparts. Therefore, this study aimed to understand the influence of supersaturated drug load on blonanserin solubilisation from liquid and silica solidified supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) during in vitro lipolysis. Stable liquid super-SNEDDS with varying drug loads (90-300% of the equilibrium solubility) were solidified by imbibition into porous silica microparticles (1:1 lipid: silica ratio). In vitro lipolysis revealed greater blonanserin solubilisation from liquid super-SNEDDS compared to solid at equivalent drug saturation levels, owing to strong silica-BLON/lipid interactions, evidenced by a significant decrease in blonanserin solubilisation upon addition of silica to a digesting liquid super-SNEDDS. An increase in solid super-SNEDDS drug loading led to increased solubilisation, owing to the increased drug:silica and drug:lipid ratios. Solidifying SNEDDS with silica enables the fabrication of powdered formulations with higher blonanserin loading and greater stability than liquid super-SNEDDS, however at the expense of drug solubilisation. These competing parameters need careful consideration in designing optimal super-SNEDDS for pre-clinical and clinical application.