Comparison of in vitro screening methods for evaluating the effects of pharmaceutical excipients on membrane permeability.

The effects of pharmaceutical excipients on intestinal drug absorption have been highlighted and careful excipient selection is required to develop biologically equivalent formulations. This study aimed to evaluate the effects of excipients on drug permeability and compare the characteristics of in vitro screening methods. Three in vitro models, the commercial precoated parallel artificial membrane permeability assay (PAMPA), PermeaPadTM, and Caco-2 monolayer, were used to evaluate the effects of 14 excipients on the permeability of several drugs with different biopharmaceutical classification system classes. Concentration-dependent effects were analyzed to distinguish non-specific effects. The permeability of low-permeability drugs was increased by excipients such as hydroxypropyl cellulose and povidone K30 in the precoated PAMPA model, whereas PermeaPadTM maintained membrane integrity at higher concentrations. Conversely, croscarmellose sodium and sodium lauryl sulfate (SLS) decreased the permeability of highly permeable drugs in both precoated PAMPA and PermeaPadTM assays in a concentration-dependent manner. In Caco-2 monolayer assays, most excipients showed minimal effects on drug permeability. However, SLS significantly reduces the permeability of highly permeable drugs at concentrations above the critical micelle concentration, thereby compromising the integrity of the cell monolayer. Our results suggested that most of excipients, except SLS, did not affect the membrane permeation of drugs at clinically used concentrations. The pre-coated PAMPA model demonstrated high sensitivity to excipient effects, making it suitable for conservative evaluation. The PermeaPadTM and Caco-2 models allowed assessment at higher excipient concentrations, with PermeaPadTM being particularly useful for excipients that cause toxicity in Caco-2 cells.

Utilization and Evaluation of Rice Bran and Rice Bran Wax as a Tablet Lubricant.

The rice bran and rice bran wax of the KJ CMU107 rice strain were investigated as potential tablet lubricants in a directly compressed tablet formulation. Stabilized full-fatted rice bran (sFFRB), stabilized defatted rice bran (sDFRB), and rice bran wax (RBW) extracted and purified from crude rice bran oil (cRBO) were tested. Two commercial lubricants, including magnesium stearate (MGS) and hydrogenated cottonseed oil (HVO), were employed as the standards in the formulated mixtures, which contained spray-dried rice starch (SDRS) as a diluent. The tableting was carried out for each formulation, and the obtained tablets were physically and mechanically evaluated. Among the parameters investigated were the general appearance, ejection force, weight variation, hardness, friability, and disintegration time. The powder flow was also determined for each formulation. The results showed that the tablet ejection forces for all the lubricated formulations (58-259 N) were significantly lower than that of the non-lubricated control formulation (349 N). The use of sFFRB as a lubricant at 0.5-2.0% w/w could lower the ejection force up to 78%, but the hardness reduced so drastically that the formulations failed the friability test due to the chipping of the tablets' edges. Moreover, sDFRB performed significantly better as the use at 0.5-1.0% w/w in the formulation helped to lower the ejection forces by up to 80% while maintaining the changes in the tablet hardness within 10%. RBW functioned effectively as a tablet lubricant at a concentration of 0.5% w/w, yielding tablets with good strength comparable to standard HVO lubricant while helping to reduce the ejection force by 82%. In formulations with good lubrication, i.e., friability < 1%, the powder flow was improved, and the tablet disintegration times were within the same range as the control and HVO formulations. In conclusion, sDFRB displayed a lubricant property at concentrations between 0.5 and 1.0% w/w, with slightly negative effects on the tablet hardness. RBW from KJ CMU107 rice was an effective tablet lubricant at 0.5% w/w, with no effect on tablet hardness. Both materials can be further developed for use as commercial lubricants in direct compression.

Polyvinyl Alcohol, a Versatile Excipient for Pharmaceutical 3D Printing.

Three-dimensional (3D) printing in the pharmaceutical field allows rapid manufacturing of a diverse range of pharmaceutical dosage forms, including personalized items. The application of this technology in dosage form manufacturing requires the judicious selection of excipients because the selected materials must be appropriate to the working principle of each technique. Most techniques rely on the use of polymers as the main material. Among the pharmaceutically approved polymers, polyvinyl alcohol (PVA) is one of the most used, especially for fused deposition modeling (FDM) technology. This review summarizes the physical and chemical properties of pharmaceutical-grade PVA and its applications in the manufacturing of dosage forms, with a particular focus on those fabricated through FDM. The work provides evidence on the diversity of dosage forms created using this polymer, highlighting how formulation and processing difficulties may be overcome to get the dosage forms with a suitable design and release profile.

Toward a greener multifunctional pharmaceutical excipient: in vivo safety evaluation of nanofibrillated cellulose from tobacco stalk.

Tobacco stalk is a cellulose-rich material and a sustainable alternative to be applied as a plant-based nanofibrillated cellulose (NFC) source. NFC use has garnered attention in the development of oral pharmaceutical forms, despite concerns about its safety due to the adverse effects of nicotine on health. Therefore, we aimed at establishing the safety of NFC derived from tobacco stalk for its potential use as a novel pharmaceutical excipient, exploring its potential functions for tablet production. We conducted acute and subchronic oral toxicity tests in adult female Wistar rats. Initially, individual animals received sequential doses (175-5,000 mg·kg-1) for 24 hours followed by a careful observation of any toxic effects. Subsequently, 20 rats were divided into four groups for a subchronic assay, evaluating toxicity signs, body weight changes, hematological, biochemical, and histopathological parameters. No deaths or other clinical toxicity signs were observed in either the acute or the subchronic assays. We noticed a significant reduction in body weight gain (p < 0.05) after 14 days. We found statistical differences for hematological and biochemical parameters, unrelated to dosage. There were no observed toxic effects, and tobacco stalk ingestion did not adversely affect organ morphology in the histopathological evaluation. The oral administration of NFC at 5,000 mg·kg-1 per day for 28 days was well-tolerated by treated rats, with no reported deaths. In conclusion, NFC derived from tobacco stalk has shown to be a sustainable and safe alternative for use as an excipient at experimental doses, demonstrating compatibility with its proposed applications.

Crystal defects creation in Mannitol@CaCl2 metal-organic framework by induced dehydration strategy for enhanced excipient mechanical properties.

The mechanical properties of solid pharmaceutical excipients are important for assisting drug tables production, and they determine the quality of the drug tablets. The purpose of this study was to explore the potential and mechanism of crystal defect engineering to improve the mechanical properties of Mannitol@CaCl2 MOF, a pharmaceutical excipient with metal-organic framework (MOF) structure designed and prepared in our previous study. In this study, a simple and efficient "induced dehydration strategy" was proposed to prepare Mannitol@CaCl2 MOF with crystal defects (DEMOF). SEM, TEM, HRTEM, PXRD, FTIR, DSC-TGA, and N2 adsorption-desorption isotherm revealed the successful introduction of lattice vacancy and macrostructural defects while preserving MOF's skeleton structure. Tabletability profiles indicated that DEMOF presented much better mechanical properties than the original MOF at the powder level. On single crystal and atomic scales, nanoindentation and DFT calculations revealed that the defect structure increased plasticity, decreased brittleness, and improved compressibility, resulting in DEMOF tablets with much higher tensile strength that met the criteria for direct compression excipients. The achieved performance modification illustrated the capability of defect engineering to tune mechanical properties of MOFs, and the Mannitol@CaCl2 DEMOF exhibited great potential to serve as a new direct compression pharmaceutical excipient.

Potentially Harmful Excipients: State of the Art for Oral Liquid Forms Used in Neonatology and Pediatrics Units.

The pediatric population exhibits an important age-dependent heterogeneity in pharmacokinetics and pharmacodynamics parameters, resulting in differences in drug efficacy and toxicity compared to the adult population, particularly for neonates. Toxicity and efficacy divergences have been studied for active molecules, but the impact on the pharmacological parameters of excipients remains less well known. To fill this lack of knowledge, several initiatives have been started to gather information on the specific toxicity of excipients, such as the KIDS list or the STEP database. In order to contribute to this much-needed action, in this work, a compilation of the 219 formulations of oral liquid forms prescribed in pediatrics and neonatology units was established based on the summary of product characteristics. Then, for excipients found in more than 10% of the analyzed formulations, a review of their toxicity data was carried out using the STEP database. Finally, for a selection of 10 frequently used liquid forms, the amounts of excipients administered daily were calculated based on the recommended posology in the Summary of Product Characteristics (SPC) and compared with the recommended daily limits proposed by the European Medicine Agency. Pediatrics-adapted formulations are still rare, and it is not always possible to find safe alternatives to drugs containing excipients of interest.

A comprehensive review on pharmaceutical excipients.

The effectiveness of pharmaceutical drugs depends not only on their active components and manufacturing processes, but also on the role played by pharmaceutical excipients. The traditional definition of excipients as inactive and cost-effective substances has evolved significantly. They are now recognized as essential elements of drug formulations, constituting 80-90% of the final product. The rapid advancements in delivery systems, along with scientific, regulatory, financial and technological developments in biopharmaceutics, have generated renewed interest in the use and functionality of excipients, especially in solid dosage forms. This review focuses on the categorization of excipients according to the International Pharmaceutical Excipient Council (IPEC) and the establishment of guidelines for evaluating the safety of a new proposed excipient.

Excipients are matter we add to medicine when we make it. They give the medicine different qualities, like making it easier to dissolve, stick together, or slide smoothly. But if we use too many excipients, it can make the medicine less stable and more expensive. To avoid these problems, we can use special excipients that can do more than one thing. These multi-purpose excipients make the medicine work better, stay stable and cost less.

Multidimensional isotope analysis of carbon, hydrogen, and oxygen as a tool for traceability of lactose in drug products.

Lactose is one of the most commonly used pharmaceutical excipients. Depending on manufactures, the properties of lactose are very different, which could impact the pharmacokinetic behavior of drug products. Therefore, it is very important to trace the origin of pharmaceutical lactose in drug products which is valuable for prescription analysis. In this study, the carbon, hydrogen and oxygen isotope ratios (δ13C, δ2H and δ18O) of thirty-four lactose from seven manufacturers were analyzed by elemental analysis-stable isotope ratio mass spectrometry (EA-IRMS). One-way analysis of variance (ANOVA) and Duncan's test indicated significant differences in isotope ratios of lactose from different origins. To identify the lactose manufacturer, a discrimination model was generated through linear discriminant analysis (LDA). Based on this model, the manufacturers of lactose used in three drug products were successfully identified. Our results suggested that the multidimensional analysis of δ13C, δ2H and δ18O of lactose provided a fast and effective method to trace the lactose manufacturer. In conclusion, this method can be used to analyze the prescription of the drug product quickly, which could speed up the development of generic drug product.

A comprehensive review on pharmaceutical uses of plant-derived biopolysaccharides.

Biopolysaccharides extracted from plants are mainly photosynthetic byproducts found in leaves, pods, stems, fruits, grains, seeds, corms, rhizomes, roots, bark exudates, and other plant parts. Recently, these plant-derived biopolysaccharides have received a great deal of attention as pharmaceutical excipients in a range of different dosage forms because of several key advantages, such as widespread accessibility from nature as plant-based sources are readily available, sustainable production, availability of easy and cost-effective extraction methodologies, aqueous solubility, swelling capability in the aqueous medium, non-toxicity, biodegradability, etc. The current review presents a comprehensive overview of the uses of plant-derived biopolysaccharides as effective pharmaceutical excipients in the formulations of different kinds of dosage forms, for example gels, pastes, films, emulsions, suspensions, capsules, tablets, nanoparticles, microparticles, beads, buccal formulations, transdermal formulations, ocular formulations, nasal formulations, etc.

A study of solid-state epimerisation within lactose powders and implications for milk derived ingredients stored in simulated tropical environmental zones.

Isolated from milk, lactose is a food ingredient and an excipient in medicines. Its chiral forms are known to undergo epimerisation in solution but understanding whether this chemical reaction occurs in lactose powders exposed to tropical environments is of great importance for medicine stability and food quality. Thus, the aim of this study was to investigate epimerisation within lactose powders stored under specified conditions that model hot and humid climates. Powdered α-lactose monohydrate was stable under all conditions, whereas ß-lactose stored at 40 °C and 75 % RH suffered epimerisation, falling to 3.9 ± 0.3 ß-content after 6-months. Zero-order kinetics observed by NMR, indicated a shelf-life (5 % degradation) of 4.55-days for ß-lactose containing powders. Thermal analysis revealed monohydrate formation as ß-lactose epimerised, seen as tomahawk shaped α-lactose monohydrate crystals by SEM. Therefore, it is recommended ß-rich lactose containing powders, e.g., infant formula or direct compression tablet formulations, are stored hermetically in tropical zones.

Recent advances of pharmaceutical 3D printing extrusion molding technology / 药学学报

3D printing is an additive manufacturing technology with the help of digital control. Since FDA approved the first 3D printing drug in 2015, its research enthusiasm in the pharmaceutical field has been increasing year by year. In printing technology, fused deposition molding (FDM) and semi-solid extrusion (SSE) are the two most widely used extrusion molding technologies. In this review, recent advances of pharmaceutical 3D printing extrusion molding technology are reviewed from six aspects: mechanism, equipment, pharmaceutical excipients, applications, design and industrialization prospects of extrusion molding technology.

Taste masking pharmaceutical excipients and their applications / 药学学报

The taste of drugs has an important impact on the compliance of patients, but most of the active drug ingredients have an uncomfortable taste, especially traditional Chinese medicine. Through a variety of pharmaceutical excipients with taste masking properties combined with corresponding technologies can improve the taste of drugs and the characteristics of other dosage forms, so as to improve patient compliance. Here, we mainly summarize the auxiliary materials used for taste masking, explain the mechanism of taste masking from the point of view of excipients and introduces related uses, so as to provide reference for further research on taste masking of pediatric preparations.

Physicochemical and Functional Properties of Modified KJ CMU-107 Rice Starches as Pharmaceutical Excipients.

Starch extracted from KJ CMU-107 rice, with amylose content of 13.4%, was modified to yield pre-gelatinized starch (PGS), carboxymethyl starch (CMS), crosslinked carboxymethyl starch (CLCMS), crosslinked starch (CLS), and hydroxypropyl starch (HPS). Their physicochemical properties were assessed in comparison with the native starch (NS), and their functional properties were then evaluated for potential use as pharmaceutical excipients. Scanning electron microscopic (SEM) images and X-ray diffraction (XRD) patterns showed that granules of all but one of the modified starches retained the native character and crystalline arrangement. The exception, PGS, exhibited extensive granular rupture, which correlated with the loss of crystallinity suggested by the amorphous halo in XRD. Energy-dispersive X-ray (EDX) data confirmed the modification by the presence of related elements. Carboxymethylation increased solubility in unheated water, while crosslinking improved swelling. All modified starches displayed improved oil absorption capacity by 17-64%, while CMS and CLCMS also exhibited significant moisture sorption at above 75% RH PGS and HPS exhibited lower gelatinization temperature (Tg) and enthalpic change (ΔH), while CLS showed higher Tg and ΔH. CMS, CLCMS, and CLS showed adequate powder flow and compactibility, qualifying as potential tablet excipients. The 5% w/v solutions of CMS, CLMS, and HPS also formed intact films with suitable tensile strength. Overall, modified starches derived from KJ CMU-107 could potentially be developed into new pharmaceutical excipients.

Sodium alginate and alginic acid as pharmaceutical excipients for tablet formulation: Structure-function relationship.

Alginic acid and its sodium salt are well-accepted pharmaceutical excipients fulfilling several roles in the development of solid oral dosage forms. Although they have attractive advantages as safety, abundance, relatively low cost and biodegradability, these natural polysaccharides possess a high variability that may limit their use as excipients for tablet formulation. Thus, to obtain robust formulations and high-quality drug products with consistent performance a complete understanding of the structure-property relationship becomes necessary as the structure of alginates affects both, technological and biopharmaceutical properties. This review compiles the compaction studies carried out that relate the structure of alginates to their mechanical and dissolution performances. The different analytical methods used to determine the chemical composition, primary structure and molecular weight distribution, major factors affecting the behavior of alginates in direct compression, are also exposed. Finally, different strategies reported to improve the properties of alginic acid as direct compression excipient are discussed.

Spray Drying of Chitosan Acid Salts: Process Development, Scaling Up and Physicochemical Material Characterization.

We investigated a spray drying process for preparing water-soluble salts of high molecular weight chitosan (CH) intended for pharmaceutical excipient applications. CH was derived from chitin of marine lobster origin (Panulirus argus). The effects of organic acid (acetic or lactic acid) and the ratio (difference) of inlet/outlet air temperature (140/90 °C or 160/100 °C) on spray drying were studied. The yield of spray-dried CH salt powders ranged from 50% to 99% in laboratory and industrial-scale processes. The spray-dried dry powder of CH salts consisted of spherical agglomerated particles with an average diameter of 36.2 ± 7.0 µm (CH acetate) and 108.6 ± 11.5 µm (CH lactate). After dispersing the spray-dried CH salt powder samples in purified water, the mean particle sizes obtained for the CH acetate salts were 31.4 nm (batch A001), 33.0 nm (A002) and 44.2 nm (A003), and for the CH lactate salts 100.8 nm (batch L001), 103.2 nm (L002) and 121.8 nm (L003). The optimum process conditions for spray drying were found: an inlet air temperature of 160 ± 5 °C, an outlet temperature of 100 ± 5 °C and an atomizer disk rotational speed of 18,200 min-1. The X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) results confirmed the amorphous state of the CH salts. The 1H nuclear magnetic resonance (NMR) and Fourier transform infrared (FT-IR) spectra of CH acetate and lactate salts verified that the spray drying process does not affect the polymer backbone. In conclusion, both laboratory and industrial-scale spray drying methods for preparing water-soluble acid salts of CH are reproducible, and the physicochemical properties of the corresponding CH acid salts are uniform.

Identification and direct determination of fatty acids profile in oleic acid by HPLC-CAD and MS-IT-TOF.

Oleic acid is a pharmaceutical excipient and has been widely used in many dosage forms. It remains unclear in terms of the fatty acids (FAs) profile. In this study, a sensitive and direct method based on high-performance liquid chromatography coupled with charged aerosol detector (HPLC-CAD) was developed to study the compositions of oleic acid. The chromatographic conditions were optimized to achieve good separation and high sensitivity. The components of oleic acid were identified by ion trap/time of flight mass spectrometry (MS-IT-TOF). Twenty-seven FAs were identified based on the exact mass-to-charge ratio and fragments, among which 13 FAs were confirmed with the reference standards. Nine FAs in the oleic acid samples including oleic acid, linolenic acid, myristic acid, palmitoleic acid, linoleic acid, palmitic acid, stearic acid, arachidic acid and behenic acid were simultaneously determined by the developed HPLC-CAD, which showed good linearity with r2>0.999. The limit of detection (LOD) and limit of quantification (LOQ) of 9 FAs were 0.006-0.1 µg mL-1 and 0.032-0.22 µg mL-1, respectively. The components with concentration level not less than 0.03 % (referring to the sample concentration of 1.0 mg mL-1) can be quantified. The mean recovery values of 9 FAs ranged from 96.5%-103.6% at three concentration levels of 80 %, 100 % and 120 %. The repeatability and intermediate precision were less than 5.0 % for oleic acid and components with concentration levels more than 0.05 %. In contrast to the conventional pre-column derivatization gas chromatography (GC), HPLC-CAD could unbiasedly and directly detect more components, especially the FAs with long carbon chains. Overall, the developed novel HPLC-CAD method can ameliorate the deficiency of the indirect GC method recorded in current pharmacopeias, thus having great potential for the comprehensive understanding and quality control of oleic acid.

Characterization and principal component analysis of functionality-related characteristics of hydroxypropyl methylcellulose type 2208 / 药学学报

Under the guidance of Chinese Pharmacopoeia (2020 edition), the functionality-related characteristics of hydroxypropyl methylcellulose (HPMC) type 2208 from imported A manufacturer, domestic S manufacturer, domestic T manufacturer and different batches of the same manufacturer were characterized. The principal component analysis was used to comprehensively evaluate the functionality-related characteristics. The results were as follows: hydroxypropyl methylcellulose had no significant difference in viscosity and molecular weight distribution between different manufacturers, and there were significant differences in the cumulative particle size distribution of the sample reaches 50% (d50) and 90% (d90), bulk density, tap density and Carr's index. The HPMC from A manufacturer have the biggest inter-batch difference of particle size and their inter-batch difference of polydispersion coefficientis smaller than S manufacturer. Domestic manufactures have the largest inter-batch difference in other functionality-related characteristics. The three principal components were extracted by principal component analysis, and the variance contribution rate reached 89.44%, indicating that the extracted principal components can explain all the data well. By constructing a comprehensive evaluation model, the comprehensive score ranking of all HPMC samples is obtained: S manufacturer > A manufacturer > T manufacturer.

Microcrystalline Cellulose Extracted from Native Plants as an Excipient for Solid Dosage Formulations in Drug Delivery.

Excipients represent the complement of the active principle in any pharmaceutical form. Their function is to provide stability, protection, and to ensure absorption of the drug and acceptability in patients. Cellulose is a conventional excipient in many pharmaceutical solid dosage products. Most of the sources used to extract microcrystalline cellulose come from cotton or wood, which are expensive and in high demand from other industries. As plants are considered the main source of excipient production, we have taken advantage of the biodiversity of Ecuador to evaluate microcrystalline cellulose extracted from borojó (Alibertia patinoi), a native plant, as an excipient for solid dosage formulations. The method of choice for tablet manufacturing was direct compression since it is a conventional fabrication method in the pharmaceutical industry. First, we performed scanning electron microscopy (SEM), Fourier-transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD) in order to compare the structure and characteristics of the extracted cellulose with two reference commercial cellulose materials. Second, we performed quality tests to evaluate the use of the isolate as an excipient including fluidity, hardness, friability, and disintegration. Compared with commercial and microcrystalline cellulose, the extracted cellulose from the native plant showed comparable characteristics and is consequently a potential excipient that could be used in the pharmaceutical industry. Last, we performed a dissolution test in which we concluded that all tablets have a short release time of active principle.

Exploration of fulvic acid as a functional excipient in line with the regulatory requirement.

Fulvic acid, a humic substance often considered as a geopolymer, extracted from different natural resources like Shilajit, Peat, dissolved organic matters, etc. There are several reports of its pharmacological properties and its potential as pharmaceutical excipients. So, we have devised a project to strengthen its claim as a functional excipient. For the given project, lyophilized sample of a dietary supplement product (an aqueous solution of peat derived Fulvic acid) was used. The selected studies were typical for an excipient development like physicochemical properties, flow properties, compatibility with other excipient and stability studies, non-clinical safety studies (acute toxicity in mice whereas sub-acute toxicity in rats) and some functionality tests. We also suggest its ability to form co-crystal with natural phytochemicals. Our group has already reported its ability to enhance solubility and or bioavailability of different BCS class II drugs. Henceforth, we can propose that Fulvic acid appears a good candidate to be further explored as a functional excipient and should be evaluated as per the remaining recommendations of IPEC, USFDA, and USP.

Bacillus licheniformis levan as a functional biopolymer in topical drug dosage forms: From basic colloidal considerations to actual pharmaceutical application.

Ongoing demand in sustainable and biocompatible drug dosage forms is reflected in the search for novel pharmaceutical excipients with equal properties. A group of microbial exopolysaccharides offers a variety of biopolymers with many alleged uses and effects. This study aims to assess applicative properties of levan obtained from Bacillus licheniformis NS032, focusing on its potential co-stabilizing and drug release-controlling functions in pertaining emulsion systems. Despite its high molecular weight and partial existence in globular nanometric structures (180-190 nm), levan was successfully incorporated into both tested colloidal systems: those stabilized with synthetic/anionic or natural-origin/non-ionic emulsifiers. In the tested levan concentrations range (0.2-3.0% w/w) the monitored flow and thermal parameters failed to show linear concentration dependence, which prompted us to revisit certain colloidal fundamentals of this biopolymer. Being a part of the external phase of the investigated emulsion systems, levan contributed to formation of a matrix-like environment, offering additional stabilization of the microstructure and rheology modifying properties (hysteresis loop elevation as high as 4167±98 to 20792±3166 Pa•s-1), especially in case of the samples where lamellar liquid crystalline formation occurred. Apart from its good water solubility and considerable conformational flexibility, the investigated homofructan easily saturated the external phase of the samples stabilized with a conventional anionic emulsifier, leading to similar properties of 0.2% and 3.0% levan-containing samples. After closer consideration of thermal and release behavior, this was considered as a favorable property for a novel excipient, offering tailored formulation characteristics even with lower levan concentrations, consequently not compromising the potential cost of the final drug dosage form.