[Development of Solventless Pharmaceutical Technique for Manufacture of Pharmaceuticals].

The aim of our study was to develop a solventless drug pelletization and polymer coating technique for pharmaceutical manufacturing. This review describes a dry coating technique using a mechanical powder processor and a V-shaped blender to produce coated pellets or tablets by mechanically mixing polymer particles and core materials (such as drug pellets and uncoated tablets) without the need for a solvent. First, aqueous latexes comprising colloidal polymethacrylates and ethylcellulose were solidified by freeze drying to produce polymer particles for the dry coating process. These particles and the cores were then subjected to mechanical powder processing or V-shaped blending to provide coated formulations with controlled-release characteristics. Polymer coating was achieved by using agglomerates comprising assembled colloidal polymer. The agglomerated polymer was easily pulverized during the mixing treatments due to its loose structure (the lack of close contacts between the colloidal particles), and the resulting fine polymer with high adhesiveness was deposited on the cores. Colloidal polymer dispersed in aqueous latex tends to coagulate in the freeze-drying process due to condensation of the dispersion, yielding dense agglomerates with poor coating characteristics. The presence of surfactants (such as sodium lauryl sulfate) in the latex can prevent adhesion between colloidal particles in the freeze-drying process, providing loosely structured agglomerates suitable for dry coating. Dry coating with a V-shaped blender could thus be achieved with these polymer particles instead of having to use a mechanical powder processor.

Prolonged Skin Retention of Luliconazole from SLNs Based Topical Gel Formulation Contributing to Ameliorated Antifungal Activity.

The development of effective therapy is necessary because the patients have to contend with long-term therapy as skin fungal infections usually relapse and are hardly treated. Despite being a potent antifungal agent, luliconazole (LCZ) has certain shortcomings such as limited skin penetration, low solubility in aqueous medium, and poor skin retention. Solid Lipid Nanoparticles (SLNs) were developed using biodegradable lipids by solvent injection method and were embodied into the gel base for topical administration. After in-vitro characterizations of the formulations, molecular interactions of the drug with excipients were analyzed using in-silico studies. Ex-vivo release was determined in contrast to the pure LCZ and the commercial formulation followed by in-vivo skin localization, skin irritation index, and antifungal activity. The prepared SLNs have an average particle size of 290.7 nm with no aggregation of particles and homogenous gels containing SLNs with ideal rheology and smooth texture properties were successfully prepared. The ex-vivo LCZ release from the SLN gel was lower than the commercial formulation whereas its skin deposition and skin retention were higher as accessed by CLSM studies. The drug reaching the systemic circulation and the skin irritation potential were found to be negligible. The solubility and drug retention in the skin were both enhanced by the development of SLNs as a carrier. Thus, SLNs offer significant advantages by delivering long lasting concentrations of LCZ at the site of infection for a complete cure of the fungal load together with skin localization of the topical antifungal drug.

An Exploration of Dissolution Tests for Inhalation Aerosols.

This study aimed to establish a feasible dissolution method for inhalation aerosols. A method of collecting fine particles was investigated to capture aerosol particles less than 4 µm in diameter for dissolution tests. This dose collection method enabled the aerosol particles to be uniformly distributed on the glass fiber filter, thus considerably reducing particle agglomeration. Budesonide was used as a model drug. The aerodynamic particle size distribution (APSD) of the meter-dose inhaler (MDI) was compared by replacing actuators with different orifice sizes. Dissolution tests were conducted on fine particle doses collected using various actuators, and the dissolution profiles were modeled. The fine particle dose decreased with an increasing orifice size of the actuator. Actuators with different orifice sizes would affect the dissolution behavior of inhaled drugs. This finding was supported by similarity factor f2 analysis, suggesting the dissolution method has a discriminative capacity. The results of various model fits showed that the dissolution profiles produced by the different actuators could be fitted well using the Weibull mathematical model. The method employed in this study could offer a potential avenue for exploring the relationship between the orifice size of the actuator and the dissolution behavior of inhaled corticosteroids. This dissolution method was simple, reproducible, and suitable for determining the dissolution of inhalation aerosols.

"Enhancing Oral Drug Absorption: Overcoming Physiological and Pharmaceutical Barriers for Improved Bioavailability".

The oral route stands out as the most commonly used method for drug administration, prized for its non-invasive nature, patient compliance, and easy administration. Several elements influence the absorption of oral medications, including their solubility, permeability across mucosal membranes, and stability within the gastrointestinal (GI) environment. Research has delved into comprehending physicochemical, biochemical, metabolic, and biological obstacles that impact the bioavailability of a drug. To improve oral drug absorption, several pharmaceutical technologies and delivery methods have been studied, including cyclodextrins, micelles, nanocarriers, and lipid-based carriers. This review examines both traditional and innovative drug delivery methods, as well as the physiological and pharmacological barriers influencing medication bioavailability when taken orally. Additionally, it describes the challenges and advancements in developing formulations suitable for oral use.

Revisiting Niclosamide Formulation Approaches - a Pathway Toward Drug Repositioning.

Niclosamide (NIC), an anthelmintic drug, has garnered recent attention for its potential as an antiviral, antibacterial, and chemotherapeutic agent, among other applications. Repurposing NIC presents a current trend, offering significant time and cost savings compared to developing entirely new therapeutic chemical entities. However, its drawback lies in poor solubility, resulting in notably low oral bioavailability. This review consolidates efforts to overcome this limitation by summarizing twelve categories of formulations, spanning derivatives, amorphous solid dispersions, co-crystals, nanocrystals, micelles, nanohybrids, lipid nanoparticles and emulsions, cyclodextrins, polymeric nanoparticles, dry powders for inhalation, 3D printlets, and nanofibers. These formulations cover oral, injectable, inhalable and potentially (trans)dermal routes of administration. Additionally, we present a comprehensive overview of NIC characteristics, including physico-chemical properties, metabolism, safety, and pharmacokinetics. Moreover, we identify gaps in formulation and administration pathways that warrant further investigation to address NIC poor bioavailability.

The Use of Systemically Absorbed Drugs to Explore An In Vitro Bioequivalence Approach For Comparing Non-Systemically Absorbed Active Pharmaceutical Ingredients in Drug Products For Use in Dogs.

PURPOSE: Currently, for veterinary oral formulations containing one or more active pharmaceutical ingredient (API) that are not systemically absorbed and act locally within the gastrointestinal (GI) tract, the use of terminal clinical endpoint bioequivalence (BE) studies is the only option for evaluating product BE. This investigation explored the use of a totality of evidence approach as an alternative to these terminal studies. METHODS: Three formulations of tablets containing ivermectin plus praziquantel were manufactured to exhibit distinctly different in vitro release characteristics. Because these APIs are highly permeable, plasma drug concentrations served as a biomarker of in vivo dissolution. Tablets were administered to 27 healthy Beagle dogs (3-way crossover) and the rate and extent of exposure of each API for each formulation was compared in a pairwise manner. These results were compared to product relative in vitro dissolution profiles in 3 media. In vivo and in vitro BE predictions were compared. RESULTS: In vivo/in vitro inconsistencies in product relative performance were observed with both compounds when considering product performance across the 3 dissolution media. Formulation comparisons flagged major differences that could explain this outcome. CONCLUSIONS: The finding of an inconsistent in vivo/in vitro relationship confirmed that in vitro dissolution alone cannot assure product BE for veterinary locally acting GI products. However, when combined with a comparison of product composition and manufacturing method, this totality of evidence approach can successfully alert scientists to potential therapeutic inequivalence, thereby supporting FDA's efforts to Replace, Reduce, and/or Refine terminal animal studies.

Protein-protein interactions in cGAS-STING pathway: a medicinal chemistry perspective.

Protein-protein interactions (PPIs) play pivotal roles in biological processes and are closely linked with human diseases. Research on small molecule inhibitors targeting PPIs provides valuable insights and guidance for novel drug development. The cGAS-STING pathway plays a crucial role in regulating human innate immunity and is implicated in various pathological conditions. Therefore, modulators of the cGAS-STING pathway have garnered extensive attention. Given that this pathway involves multiple PPIs, modulating PPIs associated with the cGAS-STING pathway has emerged as a promising strategy for modulating this pathway. In this review, we summarize an overview of recent advancements in medicinal chemistry insights into cGAS-STING PPI-based modulators and propose alternative strategies for further drug discovery based on the cGAS-STING pathway.

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Novel Sustained Release Azithromycin Resinate Fabricated by One-Pot Ion-exchange Performed in Hydro-alcoholic Solution.

Drug-resin complexes usually form in the aqueous phase. For poorly water-soluble drugs, low drug loading limits the use of resin in drug formulation. In this study, we used a new method to prepare azithromycin resinates, improving the drug loading rate, shortening the preparation time and simplifying the process. We used hydro-alcoholic solution as the drug loading solvent and the ion exchange resin as the carrier, and this method enabled the resin to adsorb both the retardant and the drug. The sustained release effect of retardant Eudragit RL, RS100 was analyzed. Drug loading efficiency, release profiles, morphology, physicochemical characterization and pharmacokinetic study were assessed. Preparation of drug resinate by batch method resulted in 14% higher drug loading of azithromycin and 3.5 h shorter loading time as compared to pure water for hydroalcoholic solution as drug loading solvent. Raman mappings demonstrated that the retardant with higher molecular weight was more likely to adsorb to the outer layer of the resin compared to the drug. The in vitro release and in vivo pharmacokinetic study of azithromycin resinates showed a sustained release profile with few gastrointestinal adverse effects. Therefore, the addition of ethanol not only improved the efficiency of drug loading but also showed sustained-release effect with one-pot preparation of azithromycin resinates.

Investigation of Mirabegron-loaded Nanostructured Lipid Carriers for Improved Bioabsorption: Formulation, Statistical Optimization, and In-Vivo Evaluation.

Overactive bladder (OAB) is a usual medical syndrome that affects the bladder, and Mirabegron (MBG) is preferred medicine for its control. Currently, available marketed formulations (MYRBETRIQ® granules and MYRBETRIQ® ER tablets) suffer from low bioavailability (29-35%) hampering their therapeutic effectiveness and compromising patient compliance. By creating MBG nanostructured lipid carriers (MBG-NLCs) for improved systemic availability and drug release, specifically in oral administration of OAB treatment, this study aimed to address these issues. MBG-NLCs were fabricated using a hot-melt ultrasonication technique. MBG-GMS; MBG-oleic acid interaction was assessed by in silico molecular docking. QbD relied on the concentration of Span 80 (X1) and homogenizer speed (X2) as critical material attribute (CMA) and critical process parameter (CPP) respectively, while critical quality attributes (CQA) such as particle size (Y1) and cumulative drug release at 24 h (Y2) were estimated as dependent variables. 32 factorial design was utilized to investigate the interconnection in variables that are dependent and independents. Optimized MBG-NLCs with a particle size of 194.4 ± 2.25 nm were suitable for lymphatic uptake. A PDI score of 0.275 ± 0.02 and zeta potential of -36.2 ± 0.721 mV indicated a uniform monodisperse system with stable dispersion properties. MBG-NLCs exhibited entrapment efficiency of 77.3 ± 1.17% and a sustained release in SIF of 94.75 ± 1.60% for 24 h. MBG-NLCs exhibited the Higuchi model with diffusion as a release mechanism. A pharmacokinetic study in Wistar rats exhibited a 1.67-fold higher bioavailability as compared to MBG suspension. Hence, MBG-NLCs hold promise for treating OAB by improving MBG's oral bio absorption.

Development of Sinomenine Hydrochloride Sustained-release Pellet With Multiple Release Characteristics.

Due to the gastrointestinal side effects, the clinical application of sinomenine hydrochloride (SH) in rheumatoid arthritis is limited. The elderly population constitutes the primary group affected by this disease, and within this demographic, there are significant variations in gastric emptying time. To reduce the influence of individual differences on drug efficacy and concurrently alleviate gastrointestinal side effects, the SH sustained-release pellets with multiple release characteristics were developed, which comprised both regular sustained-release pellets and enteric-coated sustained-release pellets. The drug-loaded layer formulation was optimized by full factorial design. With the optimal formulation, the drug-loaded pellets achieved a yield of 96.05%, an encapsulation efficiency of 83.36% for SH, a relative standard deviation of 3.26% in SH content distribution, an average roundness of 0.971 for the pellets, and the particle size span of 0.808. The pellets with a 4 h SH release profile in an acidic environment and pellets displaying 4 h acid resistance followed by an 8 h SH release behavior in the intestinal environment were individually prepared through in vitro dissolution tests. The results demonstrated stable and compliant dissolution behavior of the formulation, along with excellent stability and physical appearance. This research offers novel insights and references for the innovative formulation of SH.

Buffer Screening of Protein Formulations Using a Coarse-Grained Protocol Based on Medicinal Chemistry Interactions.

In drug and vaccine development, the designed protein formulation should be highly stable against the temperature, pH, buffer, excipients, and other environmental settings. Similarly, in a sensing unit, one needs to know how strongly two biomolecules bind to guide the design of the biorecognition unit accordingly. Typically, the community performs a series of experiments to thoroughly examine the parameter space, the so-called design-of-experiment (DoE) method, to identify the optimal formulation conditions. Unfortunately, extensive physical testing entails high costs, repeatability issues, and a lack of in-depth knowledge of the underlying mechanisms that affect the final outcome. To address these challenges, we developed a physics-based simulation protocol for buffer screening of protein formulations. We are introducing a coarse-grained molecular simulation protocol that consists of six different interactions. The so-called medicinal chemistry interactions (electrostatics, hydrophobicity, hydrogen bonding propensity, disulfide bonding, and water-water) are based on the physical nature of the protein's amino acid and the partitioning/polarity of any other chemical constituent. The protocol is applied in immunoglobulin-based monoclonal antibodies. We have analyzed the protein behavior as a function of acidity (pH) to discover the isoelectric point by solving the Poisson-Boltzmann equation in a mesoscale grid. To identify the conditions under which the protein oligomerizes in a given buffer, pH, temperature, and ionic strength, we are performing dissipative particle dynamics (DPD) simulations. The protocol allows researchers to reach the high time/space scales required to study protein formulations in their full complexity. Combined with the disruptive protein folding artificial intelligence (AI) algorithms that have been recently developed, the protocol creates a powerful digital framework for cultivating advanced pharmaceutical and biological applications.

Development and Characterization of Olaparib-Loaded Solid Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) for Pharmaceutical Applications.

This study aims to enhance the solubility of Olaparib, classified as biopharmaceutical classification system (BCS) class IV due to its low solubility and bioavailability using a solid self-nanoemulsifying drug delivery system (S-SNEDDS). For this purpose, SNEDDS formulations were created using Capmul MCM as the oil, Tween 80 as the surfactant, and PEG 400 as the co-surfactant. The SNEDDS formulation containing olaparib (OLS-352), selected as the optimal formulation, showed a mean droplet size of 87.0 ± 0.4 nm and drug content of 5.53 ± 0.09%. OLS-352 also demonstrated anticancer activity against commonly studied ovarian (SK-OV-3) and breast (MCF-7) cancer cell lines. Aerosil® 200 and polyvinylpyrrolidone (PVP) K30 were selected as solid carriers, and S-SNEDDS formulations were prepared using the spray drying method. The drug concentration in S-SNEDDS showed no significant changes (98.4 ± 0.30%, 25℃) with temperature fluctuations during the 4-week period, demonstrating improved storage stability compared to liquid SNEDDS (L-SNEDDS). Dissolution tests under simulated gastric and intestinal conditions revealed enhanced drug release profiles compared to those of the raw drug. Additionally, the S-SNEDDS formulation showed a fourfold greater absorption in the Caco-2 assay than the raw drug, suggesting that S-SNEDDS could improve the oral bioavailability of poorly soluble drugs like olaparib, thus enhancing therapeutic outcomes. Furthermore, this study holds significance in crafting a potent and cost-effective pharmaceutical formulation tailored for the oral delivery of poorly soluble drugs.

An efficient RP-HPLC-based approach for simultaneous determination of sitagliptin and metformin HCl in pharmaceutical drug formulation.

This study introduces an innovative, and rapid HPLC method using reverse phase elution for the simultaneous analysis of Sitagliptin and Metformin HCl in pharmaceutical formulations. This combination was explored in bulk and solid dosage forms using Luna Phenomenex C8 column (4.6 x 250 mm, 5 µm) at ambient temperature in isocratic elution. It was found that the mobile phase comprising of 0.1% ortho-phosphoric acid, potassium dihydrogen phosphate buffer (pH 3.0) and acetonitrile in ratios 35:35:30, showed a symmetrical peak for Sitagliptin and Metformin HCl. The detection was carried out at 210nm, using a flow rate of 1.0mL/min. The method was linear over the concentration range for Sitagliptin 2.5-7.5 ppm and Metformin HCl 25-75 ppm. The assay recoveries of Sitagliptin and Metformin were found to be 100.36% and 100.20%, respectively. The LOD and LOQ for the Sitagliptin were found to be 0.201 ppm and 0.301 ppm and for Metformin HCl 0.101 ppm and 0.303 ppm, respectively. The proposed methods can be implemented for controlling quality in bulk and solid dosage forms. The analytical methods were validated as per the guideline of ICH Q2 (R2). The developed HPLC methods were effectively employed for the determination of combined dosage forms in pharmaceutical formulations.

Formulation and development of frovatriptan succinate in situ gel for nasal drug delivery: In vitro and ex vivo evaluation.

Magrain is a depleting disease that sometimes requires extensive treatment, ideally with medication that targets the brain, with minimized systemic adverse effects, preferably with a single daily medication; these properties are offered partially by the current dosage form of Frovatriptan. formulation of Frovatriptan binary ethosome into mucoadhesive nasal in situ gel to extend the drug's residence time. The particle size was 154.1±4.38 nm of the Frovatriptan binary ethosome. In situ, gel formulas were prepared to utilize the cold technique, using 18%w/v poloxamer 407 with different concentrations of Carbopol 934 and the clarity, pH, Frovatriptan content spreadability, mucoadhesive force, in vitro diffusion via nasal mucosa and the optimal formula underwent further investigations. In-situ gel F2 (0.2% Carbopol) demonstrated the best spreadability of 12.88±0.186 cm2/min, 99% drug content mucoadhesive strength of 645.32±0.054 dynes/cm2, percent release of 98.56±0.041 after 24 hours and permeability increased by around 3.68-fold compared to the pure drug and histopathologically showed favorable outcomes. Mucoadhesive Frovatriptan-binary ethosome-loaded nasal in situ gel is an effective method of treating migraines.

Enhanced bioavailability and efficacy in antimalarial treatment through QbD approach enteric encased inclusion delivery.

Aim: In this study, we aimed to prepare enteric encapsulated spheroids containing inclusion complex using quality by design approach.Methods: A Box-Behnken design was employed to determine effects of variables on selected responses. Risk assessment was conducted using Ishikawa fishbone diagram. A model with a p-value was less than 0.5 for being a significant error of model was determined based on significance 'lack of fit' value. Spheroids were formulated using the extrusion spheronization technique and were characterized using analytical techniques.Results: In vitro release was performed in both acidic (pH 1.2) and simulated intestinal (pH 6.8) conditions. Permeability studies demonstrated tenfold enhancement compared with arteether. In vivo studies further validated increase of 51.8% oral bioavailability. Ex vivo studies revealed 3.4-fold enhancement in antimalarial activity compared with arteether.Conclusion: These findings highlight effectiveness of inclusion complexation technique as a viable approach to enhance solubility and bioavailability for drugs with low aqueous solubility.

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Synthetic Approaches, Properties, and Applications of Acylals in Preparative and Medicinal Chemistry.

Diesters of geminal diols (R-CH(O-CO-R')2, RR'C(OCOR″)2, etc. with R = H, aryl or alkyl) are termed acylals according to IUPAC recommendations (Rule P-65.6.3.6 Acylals) if the acids involved are carboxylic acids. Similar condensation products can be obtained from various other acidic structures as well, but these related "non-classical acylals", as one might call them, differ in various aspects from classical acylals and will not be discussed in this article. Carboxylic acid diesters of geminal diols play a prominent role in organic chemistry, not only in their application as protective groups for aldehydes and ketones but also as precursors in the total synthesis of natural compounds and in a variety of organic reactions. What is more, acylals are useful as a key structural motif in clinically validated prodrug approaches. In this review, we summarise the syntheses and chemical properties of such classical acylals and show what potentially under-explored possibilities exist in the field of drug design, especially prodrugs, and classify this functional group in medicinal chemistry.

Solid Self Nano-Emulsifying Drug Delivery System of Dasatinib: Optimization, In-vitro, Ex-vivo and In-vivo assessment.

Aim: Dasatinib (DST) is an oral tyrosine kinase inhibitor with poor aqueous solubility. To outwit this issue, a solid self-nano emulsifying drug delivery system (S-SNEDDS) of DST was formulated.Methods: I-optimal mixture design was used for optimization of DST-loaded SNEDDS using Linalool, Cremophor RH40 and Transcutol P. S-SNEDDS underwent physicochemical characterization, in-vitro release and ex-vivo permeation, cell-based assays and pharmacokinetic study.Results: DST-S-SNEDDS showed globule size and PDI of 141.53 ± 5.371 nm and 0.282 ± 0.020, respectively. DST-S-SNEDDS revealed significantly lower IC50 (1.825 µg/mL) than free DST (7.298 µg/mL) in MDA-MB-231. In-vivo pharmacokinetic study revealed 1.94-fold increment in AUC0-t for the DST-S-SNEDDS group than free DST.Conclusion: S-SNEDDS could be promising approach for improving bioavailability and efficacy of DST.

[Box: see text].

A Comparative Mathematical Analysis of Drug Release from Lipid-Based Nanoparticles.

Mathematical modeling of drug release from drug delivery systems is crucial for understanding and optimizing formulations. This research provides a comparative mathematical analysis of drug release from lipid-based nanoparticles. Drug release profiles from various types of lipid nanoparticles, including liposomes, nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), and nano/micro-emulsions (NEMs/MEMs), were extracted from the literature and used to assess the suitability of eight conventional mathematical release models. For each dataset, several metrics were calculated, including the coefficient of determination (R2), adjusted R2, the number of errors below certain thresholds (5%, 10%, 12%, and 20%), Akaike information criterion (AIC), regression sum square (RSS), regression mean square (RMS), residual sum of square (rSS), and residual mean square (rMS). The Korsmeyer-Peppas model ranked highest among the evaluated models, with the highest adjusted R2 values of 0.95 for NLCs and 0.93 for other liposomal drug delivery systems. The Weibull model ranked second, with adjusted R2 values of 0.92 for liposomal systems, 0.94 for SLNs, and 0.82 for NEMs/MEMs. Thus, these two models appear to be more effective in forecasting and characterizing the release of lipid nanoparticle drugs, potentially making them more suitable for upcoming research endeavors.

Oral Bioavailability Enhancement of Poorly Soluble Drug by Amorphous Solid Dispersion Using Sucrose Acetate Isobutyrate.

The focus of the present work was to develop amorphous solid dispersion (ASD) formulation of aprepitant (APT) using sucrose acetate isobutyrate (SAIB) excipient, evaluate for physicochemical attributes, stability, and bioavailability, and compared with hydroxypropyl methylcellulose (HPMC) based formulation. Various formulations of APT were prepared by solvent evaporation method and characterized for physiochemical and in-vivo performance attributes such as dissolution, drug phase, stability, and bioavailability. X-ray powder diffraction indicated crystalline drug conversion into amorphous phase. Dissolution varied as a function of drug:SAIB:excipient proportion. The dissolution was more than 80% in the optimized formulation (F10) and comparable to HPMC based formulation (F13). Stability of F10 and F13 formulations stored at 25 C/60% and 40°C/75% RH for three months were comparable. Both ASD formulations (F10 and F13) were bioequivalent as indicated by the pharmacokinetic parameters Cmax and AUC0-∞. Cmax and AUC0-∞ of F10 and F13 formulations were 2.52 ± 0.39, and 2.74 ± 0.32 µg/ml, and 26.59 ± 0.39, and 24.79 ± 6.02 µg/ml.h, respectively. Furthermore, the bioavailability of ASD formulation was more than twofold of the formulation containing crystalline phase of the drug. In conclusion, stability and oral bioavailability of SAIB based ASD formulation is comparable to HPMC-based formulation of poorly soluble drugs.