ABSTRACT
This study outlines a practical approach for assessing chemical instability by heating the drug-excipient binary mixtures or multi-excipient formulations at 75°C for 3 days before characterization. Differentiating itself from other excipient compatibility methods, our methodology necessitates a saturated aqueous slurry rather than arbitrarily fixed water content. This allows bulk and surface water in the excipient to contribute to drug degradation. The synergistic impact of surface water and elevated temperature expedites degradation kinetics, resulting in accelerated data generation. Among excipient compatibility methods available, our method is quantitative and merges with traditionally used methodologies. The devised nomograph enables extrapolation of shelf life at 20°C from experimental data obtained at 75°C. This methodology also helped identify stabilizers for the drug NVS-1 where traditional excipient compatibility programs had failed. Incorporation of monovalent salts, such as sodium/potassium chloride and sodium bicarbonate at 5% w/w, significantly enhanced the chemical stability of NVS-1, ensuring stable tablet formulations. Our hypothesis posits that stabilization is due to increased ionic strength in the slurry, which stabilizes an induced dipole within the polar NVS-1 drug. Additionally, the presence of ions in the moisture layer is anticipated to stabilize π-π stacking of two planar aromatic NVS-1 molecules. The expedited generation of experimental data allowed the identification of inorganic salts to supplement a standard excipient compatibility screening panel. Considering the economic implications of stability testing methodologies in effort, cost, and duration, a faster turnaround in chemical stability data enhances formulation selection. This ultimately facilitates the development of drug formulations with greater efficiency without delays.
Subject(s)
Excipients , Salts , Dietary Supplements , Heating , WaterABSTRACT
Assessing the robustness of a drug product formulation and manufacturing process to variations in raw material (RM) properties is an essential aspect of pharmaceutical product development. Motivated by the need to demonstrate understanding of attribute-performance relationships at the time of new product registration and for subsequent process maintenance, we review practices to explore RM variations. We describe limitations that can arise when active ingredients and excipients invariably undergo changes during a drug product lifecycle. Historical approaches, such as Quality-by-Design (QbD) experiments, are useful for initial evaluations but can be inefficient and cumbersome to maintain once commercial manufacturing commences. The relatively miniscule data sets accessible in product development - used to predict response to a hypothetical risk of variation - become less relevant as real-world experience of actual variability in the commercial landscape grows. Based on our observations of development and manufacturing, we instead propose a holistic framework exploiting a hierarchy of RM variability, and challenge this with common failure modes. By explicitly incorporating higher ranking RM variations as perturbations, material-conserving experiments are shown to provide powerful and enduring robustness data. Case studies illustrate how correctly contextualizing such data in formulation and process development can avoid the traps of historical QbD approaches and become valuable for evaluating changes occurring later in the drug product lifecycle.
Subject(s)
Chemistry, Pharmaceutical , Technology, Pharmaceutical , Technology, Pharmaceutical/methods , Chemistry, Pharmaceutical/methods , ExcipientsABSTRACT
Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the development of a unique formulation for our first-in-class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimer's disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulation's long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, confirmed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) Spectroscopy. Three rapid freeze-thaw cycles at -80 °C/25 °C or -80 °C/37 °C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4°C and 25°C. Finally, the unfolding temperature (Tm) for formulated MS-Hu6 increased by >4.80 °C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.
Subject(s)
Antibodies, Monoclonal , Follicle Stimulating Hormone , Antibodies, Monoclonal/chemistry , Temperature , Calorimetry, Differential Scanning , Viscosity , Protein StabilityABSTRACT
This study fabricated a novel excipient emulsion by adding dark tea polysaccharides to improve the bioaccessibility of lycopene from tomatoes. Results indicated that addition of tea polysaccharides greatly increased the antioxidant activity of excipient emulsions. Additionally, tea polysaccharides markedly improved the physical stability of excipient emulsion when being mixed with tomato puree and passing through a simulated gastrointestinal tract, contributing to an increase in electrostatic and steric repulsion between the droplets. Besides, certain amount of tea polysaccharides (0.05 - 0.2 wt%) could increase the rate and extent of lipid digestion in tomato-emulsion mixtures. Finally, lycopene bioaccessibility was significantly increased (from 16.95 % to 26.21 %) when 0.1 wt% tea polysaccharides were included, which was mainly ascribed to the ability of tea polysaccharides to increase lipid digestion and reduce carotenoid oxidation within the gastrointestinal tract. These results suggest that well-designed excipient emulsions may increase carotenoids bioavailability in the complex food matrices.
Subject(s)
Solanum lycopersicum , Lycopene , Emulsions , Excipients , Carotenoids , Dietary Supplements/analysis , Lipids , TeaABSTRACT
The influence of the carrier oil type on the bioavailability and bioactivity of flavonoids (quercetin, kaempferol, and apigenin) was examined using in vitro digestion, in situ intestinal perfusion, and pharmacokinetic studies. Here, medium-chain triglycerides (MCTs), long-chain triglycerides (LCTs), or MCT/LCT mixtures (1:1, w/w) served as the oil phase of excipient emulsions. Overall, the bioavailability and antioxidant activity of flavonoids increased when they were coingested with excipient emulsions. The in vitro bioaccessibility of flavonoids was affected by the carrier oil: LCT (17.9-22.8%) > MCT/LCT (12.1-13.7%) > MCT (9.2-12.6%). These differences were mainly attributed to the fact that the mixed micelles formed after the digestion of LCTs had larger hydrophobic domains to solubilize more flavonoids. However, in vivo pharmacokinetic experiments showed that the flavonoid concentrations in rat serum were comparable for all carrier oils (p > 0.05). Our results assist in formulating excipient emulsions to enhance the efficacy of flavonoids.
Subject(s)
Antioxidants , Excipients , Rats , Animals , Emulsions/chemistry , Excipients/chemistry , Flavonoids , Biological Availability , Triglycerides/chemistry , Dietary Supplements , OilsABSTRACT
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.
ABSTRACT
AIM: The aim of this study was the synthesis and evaluation of entirely S-protected thiolated hydroxyethylcellulose (HEC) with low and high viscosity, as well as thiolated poly-L-lysine (poly-L-Lys) used as dual-acting ionic as well as thiol-disulfide exchange mediated cross-linking hydrogel. METHODS: Bis(mercaptosuccinic acid) was covalently attached to low and high viscous HECs via Fisher esterification, obtaining S-protected polymers. Poly-L-Lys-cysteine was synthesized via amidation of poly-L-Lys-HBr with cysteine (Cys). Thiolated polymers were examined in terms of cytotoxicity and rheological behavior of hydrogels containing these thiomers was evaluated with a cone-plate rheometer. RESULTS: Thiomers showed less cytotoxicity compared to the corresponding unmodified polymers. Rheological studies showed that cross-linking occurred between the two polymers via thiol-disulfide exchange reactions facilitated by the complementary charges. Employing poly-L-Lys-Cys in a concentration of either 0.5 or 5% (m/v) resulted in a 34.5-fold or 17.3-fold as well as a 53.6-fold or 29.6-fold improvement in dynamic viscosity within 5 min at 37 °C on S-protected thiolated low and high viscous HEC, compared to the corresponding unmodified HECs, respectively. CONCLUSION: By the combination of anionic S-protected thiolated polymers with a cationic thiolated polymer, dual-acting hydrogels exhibiting a time dependent increase in viscosity can be designed.
Subject(s)
Cysteine , Hydrogels , Rheology , DisulfidesABSTRACT
This study demonstrated the combination of black pepper and a canola oil-based emulsion synergistically enhanced carotenoid bioavailability of raw vegetables in humans. In a randomized crossover design, healthy young adults consumed (1) vegetable salad (control), (2) salad with canola oil emulsion (COE), (3) salad with black pepper (BP), and (4) salad with canola oil emulsion and black pepper (COE + BP). COE + BP led to a higher AUC0-10h of total plasma carotenoids (p < 0.0005) than the control (6.1-fold), BP (2.1-fold), and COE (3.0-fold). COE + BP increased AUC0-10h of plasma lutein, α-carotene, ß-carotene, and lycopene by 4.8, 9.7, 7.6, and 5.5-fold than the control, respectively (p < 0.0001). COE + BP produced a significant synergy in increasing both Cmax and AUC0-10h of total carotenoids, α-carotene, ß-carotene, and lycopene. Moreover, COE + BP produced a stronger enhancement on AUC0-10h of total carotenoids, α-carotene, ß-carotene, and lycopene in females than in males.
Subject(s)
Piper nigrum , Vegetables , Biological Availability , Carotenoids , Emulsions , Humans , Lutein , Plant Oils , Young AdultABSTRACT
Low bioavailability currently limits the potential of curcumin as a health-promoting dietary compound. This study therefore explored the potential of excipient emulsions to improve curcumin bioavailability. Oil-in-water excipient emulsions were prepared using different types of oils: corn oil, olive oil, and medium chain triglycerides (MCT). The excipient emulsions increased the transportation rate of curcumin across the Caco-2 cell monolayer and showed ability to protect curcumin from metabolism in the enterocytes, with the olive oil-based systems exhibiting the highest efficacy. In addition, most of curcumin metabolites were present as hexahydro-curcumin (HHC) and its conjugates. Our results show that excipient emulsions can improve curcumin bioavailability by increasing its trans-enterocyte absorption and reducing cellular metabolism. Moreover, they show that these effects depend on the type of oil used to produce them. These findings have important implications for the rational design of lipid-based delivery systems to enhance the bioavailability of hydrophobic nutraceuticals like curcumin.
Subject(s)
Curcumin , Excipients , Biological Availability , Caco-2 Cells , Corn Oil , Curcumin/metabolism , Emulsions/metabolism , Excipients/metabolism , Gastrointestinal Tract/metabolism , HumansABSTRACT
Abstract The objective of this study was to determine the influence of nonionic surfactants on the effectiveness of preservatives used in emulsions containing high surfactant content. Mixtures of different concentrations were prepared between polyethoxylated (40) hydrogenated castor oil (PHCO) and polyoxyethylene sorbitan monooleate (PSO), with methylparaben, phenoxyethanol, methylparaben, ethylparaben, propylparaben, and isobutylparaben (PMEPBI) blend, phenoxyethanol and benzoic acid (BP) blend, and phenoxyethanol and caprylyl glycol (PC) blend. Subsequently, the compatibility of the formulation ingredients and the effectiveness of the preservatives were evaluated by the challenge test. It was found that PHCO and PSO inactivated the antimicrobial action of methylparaben and PMEPBI. Paraben-free preservatives BP and PC had less influence on surfactants than systems containing parabens. When incorporated into microemulsions and nanoemulsions containing 40% and 20% surfactants, methylparaben and BP 0.2% and 0.5% were only effective against Aspergillus niger. The PMEPBI 0.2% was effective as a preservative in nanoemulsified formulations against A. niger, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The results demonstrate that the efficacy of the preservative system in formulations containing nonionic surfactant excipients depends on the type of excipient, the components of the formulation, the preservative systems composition, the excipient to preservative ratio, and the availability in the formulation.
Subject(s)
Polysorbates/pharmacology , Surface-Active Agents/pharmacology , Castor Oil/pharmacology , Additives in Cosmetics , Excipients/pharmacology , Effectiveness , Colony Count, Microbial , Microbial Sensitivity Tests , Cosmetic StabilityABSTRACT
The impact of lutein-loaded nanoemulsions and excipient nanoemulsions mixed with lutein-based dietary supplements (capsules and soft gels) on the bioaccessibility of lutein was explored using a simulated gastrointestinal tract (GIT). The particle size, particle size distribution, ζ-potential, microstructure, lipid digestibility, and lutein bioaccessibility of all the samples were measured after they were exposed to different environments (stomach and small intestine environments) within a simulated GIT. As expected, the bioaccessibility of lutein from the capsules (1.5%) and soft gels (3.2%) was relatively low when they were administered alone. However, the co-administration of excipient nanoemulsions significantly increased the bioaccessibility of lutein from both the capsules (35.2%) and soft gels (28.7%). This phenomenon was attributed to the fast digestion of the small oil droplets in the excipient nanoemulsions and the further formation of mixed micelles to solubilize any lutein molecules released from the supplements. The lutein-loaded nanoemulsions exhibited a much higher lutein bioaccessibility (86.8%) than any of the supplements, which was attributed to the rapid release and solubilization of lutein when the lipid droplets were rapidly and extensively digested within the small intestine. This study indicates that the bioaccessibility of lutein is much higher in nanoemulsion droplets than that in dietary supplements. However, consuming dietary supplements in the presence of nanoemulsion droplets can greatly increase lutein bioavailability. The results of this study have important guiding significance for the design of more effective lutein supplements.
Subject(s)
Excipients , Lutein , Biological Availability , Dietary Supplements/analysis , Digestion , Emulsions , Particle SizeABSTRACT
This paper explores Mongolian medicine processing methods and the use regularity of excipient by text mining techniques. Relevant books of Mongolian medicine processing were consulted to collect data on Mongolian medicine processing methods and excipient, and select data based on processing methods and excipient noun frequency statistics. Microsoft Excel 2010 software was used for statistical analysis and mining for the usage regularity of different types of Mongolian medicinal materials in different periods. And Cytoscape 3.6.1 software was used for visual presentation. The topological analysis showed the top five processing methods were net production, development, frying, calcining and cooking, and the top five processing excipient were fresh milk, wine, urine, cream and mineral borax. Frequency analysis showed that the plant medicinal materials were mostly recorded in the 18~(th) and 21~(st) centuries, especially in the 21 st century; the processing methods mostly contained water processing, repair processing and other methods. The mineral medicinal materials were mostly recorded in the 18~(th), 19~(th) and 21~(st) centuries; most of the processing methods were the fire processing method. The animal medicinal materials were recorded in the 18~(th), 19~(th) and 21~(st) century; the fire processing method occupied a major position, and the repair processing and the grinding processing were markedly increased in the 21~(st) century. In the use of excipient, liquid excipient were mostly used in plant medicines. Solid excipient were most commonly used in the 18~(th) century. Animal excipient were mostly used during the processing in the 18~(th) century. The use of liquid excipient gradually increased in the 19~(th) and 21~(st) centuries. This study summarizes the traditional processing methods of Mongolian medicine and the usage regularity of excipient, defines the characteristics of Mongolian medicine processing methods and excipient, and the characteristics of the combination of medicinal materials and excipient, so as to provide reference for the clinical use of Mongolian medicine.
Subject(s)
Excipients , Medicine, Mongolian Traditional , Data Mining , Records , SoftwareABSTRACT
Mechanistic-understanding-based selection of excipients may improve formulation development strategies for generic drug products and potentially accelerate their approval. Our study aimed at investigating the effects of molecular excipients present in orally administered FDA-approved drug products on the intestinal efflux transporter, BCRP (ABCG2), which plays a critical role in drug absorption with potential implications on drug safety and efficacy. We determined the interactions of 136 oral molecular excipients with BCRP in isolated membrane vesicles and identified 26 excipients as BCRP inhibitors with IC50 values less than 5 µM using 3H-cholecystokinin octapeptide (3H-CCK8). These BCRP inhibitors belonged to three functional categories of excipients: dyes, surfactants, and flavoring agents. Compared with noninhibitors, BCRP inhibitors had significantly higher molecular weights and SLogP values. The inhibitory effects of excipients identified in membrane vesicles were also evaluated in BCRP-overexpressing HEK293 cells at similar concentrations. Only 1 of the 26 inhibitors of BCRP identified in vesicles inhibited BCRP-mediated 3H-oxypurinol uptake by more than 50%, consistent with the notion that BCRP inhibition depends on transmembrane or intracellular availability of the inhibitors. Collectively, the results of this study provide new information on excipient selection during the development of drug products with active pharmaceutical ingredients that are BCRP substrates.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Coloring Agents/metabolism , Excipients/metabolism , Flavoring Agents/metabolism , Neoplasm Proteins/metabolism , Surface-Active Agents/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Administration, Oral , Coloring Agents/chemistry , Coloring Agents/pharmacology , Drug Compounding/methods , Drug Evaluation, Preclinical/methods , Excipients/chemistry , Excipients/pharmacology , Female , Flavoring Agents/chemistry , Flavoring Agents/pharmacology , HEK293 Cells , Humans , Inhibitory Concentration 50 , Intestinal Absorption/drug effects , Molecular Weight , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Signal Transduction/genetics , Surface-Active Agents/chemistry , Surface-Active Agents/pharmacology , TransfectionABSTRACT
This paper explores Mongolian medicine processing methods and the use regularity of excipient by text mining techniques. Relevant books of Mongolian medicine processing were consulted to collect data on Mongolian medicine processing methods and excipient, and select data based on processing methods and excipient noun frequency statistics. Microsoft Excel 2010 software was used for statistical analysis and mining for the usage regularity of different types of Mongolian medicinal materials in different periods. And Cytoscape 3.6.1 software was used for visual presentation. The topological analysis showed the top five processing methods were net production, development, frying, calcining and cooking, and the top five processing excipient were fresh milk, wine, urine, cream and mineral borax. Frequency analysis showed that the plant medicinal materials were mostly recorded in the 18~(th) and 21~(st) centuries, especially in the 21 st century; the processing methods mostly contained water processing, repair processing and other methods. The mineral medicinal materials were mostly recorded in the 18~(th), 19~(th) and 21~(st) centuries; most of the processing methods were the fire processing method. The animal medicinal materials were recorded in the 18~(th), 19~(th) and 21~(st) century; the fire processing method occupied a major position, and the repair processing and the grinding processing were markedly increased in the 21~(st) century. In the use of excipient, liquid excipient were mostly used in plant medicines. Solid excipient were most commonly used in the 18~(th) century. Animal excipient were mostly used during the processing in the 18~(th) century. The use of liquid excipient gradually increased in the 19~(th) and 21~(st) centuries. This study summarizes the traditional processing methods of Mongolian medicine and the usage regularity of excipient, defines the characteristics of Mongolian medicine processing methods and excipient, and the characteristics of the combination of medicinal materials and excipient, so as to provide reference for the clinical use of Mongolian medicine.
Subject(s)
Data Mining , Excipients , Medicine, Mongolian Traditional , Records , SoftwareABSTRACT
The present work demonstrates the utility of temperature controlled set up with pressurized headspace oxygen as an approach to effectively reduce the time required for solid-state drug-excipient compatibility study. To illustrate the utility, the incompatibility of polyethylene glycol (PEG) and polyethylene oxide (PEO) with Famotidine (Fam) was shown. Owing to thermal and oxidative stress, polyethylene ether moieties of PEG generated reactive impurities, resulting in the degradation of Fam. The chemical degradation was evaluated via liquid chromatography. Around 20% of degradation was observed in the pressurized oxygen set up, whereas, no degradation was found in the absence of oxidative stress. On increasing the excipient fraction, the Fam degradation increased proportionally. Formation of aldehydes and free radicals from excipients were proposed as the precursors for Fam degradation. The generation of aldehydes and free radicals was confirmed by infrared and Electron Spin Resonance (ESR) spectroscopic analysis, respectively. Overall, the present study demonstrated the utility of pressurized oxygen set up as a rapid and routine tool for studying drug-excipient incompatibility at temperatures relevant drug-product manufacture.
Subject(s)
Drug Incompatibility , Excipients/chemistry , Famotidine/chemistry , Polyethylene Glycols/chemistry , Chemistry, Pharmaceutical/methods , Chromatography, Liquid/methods , Feasibility Studies , Oxidative Stress , Oxygen/chemistry , TemperatureABSTRACT
Graviola leaves contain much vitamin U (vit U), but their sensory quality is not good enough for them to be developed as food ingredients. Addition of excipient natural ingredients formulated alongside vit U as active ingredients could enhance not only its sensory quality but also its bioavailability. The objectives of this study were to measure the bioaccessibility and intestinal cellular uptake of bioactive components, including rutin, kaempferol-rutinoside, and vit U, from steamed extract of graviola leaves (SGV) and SGV enriched with kale extract (SGK), and to examine how much they can detoxify nicotine in HepG2 cells. The bioaccessibility of vit U from SGV and SGK was 82.40% and 68.03%, respectively. The cellular uptake of vit U in SGK by Caco-2 cells was higher than that in SGV. Cotinine content converted from nicotine in HepG2 cells for 120 min was 0.22 and 0.25 µg/mg protein in 50 µg/mL of SGV and SGK, respectively, which were 2.86 and 3.57 times higher than the no-treatment control. SGK treatment of HepG2 cells upregulated CYP2A6 three times as much as did that of SGV. Our results suggest that graviola leaf extract enriched with excipient ingredients such as kale could improve vit U absorption and provide a natural therapy for detoxifying nicotine.
Subject(s)
Annona/chemistry , Inactivation, Metabolic/drug effects , Intestinal Absorption/physiology , Nicotine/metabolism , Plant Extracts , Vitamin U , Caco-2 Cells , Cell Survival/drug effects , Hep G2 Cells , Humans , Plant Extracts/chemistry , Plant Extracts/metabolism , Plant Extracts/pharmacokinetics , Plant Extracts/pharmacology , Vitamin U/chemistry , Vitamin U/metabolism , Vitamin U/pharmacokinetics , Vitamin U/pharmacologyABSTRACT
In the typical Western diet, fruits and vegetables are often consumed with food products that exist as oil-in-water emulsions, such as creams, dressings, and sauces. Studies have shown that coingestion of fruits and vegetables with emulsions can increase the bioavailability of beneficial lipophilic bioactive agents, such as nutraceuticals or vitamins. Agricultural produce, however, may also be contaminated with low levels of detrimental lipophilic agents, such as hydrophobic pesticides. We therefore examined the impact of coingesting a common agricultural product (tomatoes) with model food emulsions on the bioaccessibility of a hydrophobic pesticide (chlorpyrifos). The impact of emulsifier types (phospholipids, whey protein, Tween 80) and dietary fiber types (xanthan, chitosan, ß-glucan) on the bioaccessibility of the pesticide was measured using a simulated gastrointestinal model. Chlorpyrifos bioaccessibility depended on the type of emulsifier used to formulate the emulsions: phospholipids > Tween 80 > whey protein. Dietary fiber type also influenced pesticide bioaccessibility by an amount that depended on the nature of the emulsifier used. Overall, our results suggest that the bioaccessibility of undesirable pesticides on fruits and vegetables will depend on the nature of the emulsions they are consumed with.
Subject(s)
Biological Products/metabolism , Dietary Fiber/metabolism , Emulsifying Agents/chemistry , Pesticide Residues/metabolism , Solanum lycopersicum/metabolism , Biological Availability , Biological Products/chemistry , Corn Oil/chemistry , Corn Oil/metabolism , Dietary Fiber/analysis , Digestion , Emulsifying Agents/metabolism , Emulsions/chemistry , Emulsions/metabolism , Food Contamination/analysis , Gastrointestinal Tract/metabolism , Humans , Solanum lycopersicum/chemistry , Models, Biological , Particle Size , Pesticide Residues/chemistryABSTRACT
Mast cell activation syndrome (MCAS) is a complex disorder hallmarked by chronic multisystem inflammatory, allergic and growth dystrophic phenomena caused by inappropriate mast cell activation. MCAS has been estimated to affect as many as 17% of the population with a severity ranging from mild to life-threatening. MCAS patients are more sensitive than the average person to chemicals in the environment, including the nondrug ("inactive") ingredients (excipients) in medications and supplements. Excipient reactivity may explain unusual side effects to medications health professionals often find puzzling, such as the patient who appears intolerant of prednisone, acetaminophen, levothyroxine, or a vitamin. We present a series of patients with MCAS to illustrate important points regarding excipient reactivity which may be useful in everyday practice.
Subject(s)
Excipients/adverse effects , Mastocytosis/chemically induced , Adolescent , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
The influence of chiral excipient D-chitosan (CS) on the stereoselective release of racemic ketoprofen (rac-KET) microspheres has been investigated in comparison to those microspheres containing individual enantiomers in vitro and in vivo. Stereoselectivity was observed in vitro release test, with R-KET release slightly higher than that of S-KET, especially in 3% rac-KET loading microspheres. Stereoselectivity is dependent on the content of chiral excipient and pH of release medium. A molecular docking study between CS and KET enantiomers further revealed that S-KET has a stronger interaction with CS compared to R-KET. Moreover, the plasma concentration of KET enantiomers in rats shows substantial differences, as the plasma levels of S-KET were higher than those of R-KET. Plasma levels of enantiomers from the R-KET microspheres had similar stereoselectivity as rac-KET microspheres. The S/R ratio of rac-KET microspheres was significantly lower than that of rac-KET suspension (regular-release formulation) (p<.05), and the differences is 3-5 fold. Besides, rates of R-KET converted to S-KET exhibited differences between rac-KET microspheres and suspension. Similar results were also found between R-KET microspheres and suspension. All investigations suggest that the chitosan interacting preferentially with S-KET to R-KET significantly affect the stereoselective pharmacokinetics of rac-KET from chitosan microspheres in rats.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Chitosan/administration & dosage , Drug Delivery Systems/methods , Ketoprofen/administration & dosage , Microspheres , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Chitosan/chemistry , Chitosan/metabolism , Drug Evaluation, Preclinical/methods , Female , Ketoprofen/chemistry , Ketoprofen/metabolism , Male , Molecular Docking Simulation/methods , Rats , Rats, Sprague-Dawley , StereoisomerismABSTRACT
In the pharmaceutical process, raw material (including APIs and excipients) variability can be delivered to the final product, and lead to batch-to-batch and lot-to-lot variances in its quality, finally impacting the efficacy of the drug. In this paper, the Panax notoginseng saponins (PNS) sustained-release matrix tablet was taken as the model formulation. Hydroxypropyl methylcellulose with the viscosity of 4000 mPa·s (HPMCK4M) from different vendors and batches were collected and their physical properties were characterized by the SeDeM methodology. The in-vitro dissolution profiles of active pharmaceutical ingredients (APIs) from matrix tablets made up of different batches HPMC K4M displayed significant variations. Multi-block partial least squares (MB-PLS) modeling results further demonstrated that physical properties of excipients played dominant roles in the drug release. In order to achieve the target drug release profile with respect to those far from the criteria, the optimal selection method of incoming materials from the available was established and validated. This study provided novel insights into the control of the input variability of the process and amplified the application of the SeDeM expert system, emphasizing the importance of the physical information of the raw materials in the drug manufacturing process.