Preformulation studies for the development of a microemulsion formulation from Ambrosia peruviana All, with anti-inflammatory effect

Abstract Natural products are considered an important source of the therapeutic arsenal currently available. Among these alternatives are the seeds of Ambrosia peruviana (altamisa), whose extract has shown an anti-inflammatory effect. The main objective of this work was to perform a preformulation study of Ambrosia peruviana seeds ethanolic extract, where the main factors that affect the physical, chemical, and pharmacological stability of the extract were evaluated, as well as a compatibility study by differential scanning calorimetry (DSC) analysis against different excipients. A dry extract was obtained by rotary evaporation of the seeds macerated with 96% ethanol. The anti-inflammatory activity was determined by measuring its effect on NO production in RAW 264.7 macrophages, stimulated with LPS. The results showed that the dry extract maintained its stability over time when stored at a temperature of 4 and 25ºC, demonstrating its biological activity, the content of phenolic compounds, and its physicochemical parameters remain practically invariable. However, when exposed to high temperatures (60 ºC) it was affected. The thermal analysis revelated that the behavior of most of the selected excipients and the dry extract was maintained, which indicates that it did not present incompatibilities, therefore they can be candidates for formulating a microemulsion.

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.

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.

Effects of polyol excipient stability during storage and use on the quality of biopharmaceutical formulations / 药物分析学报

Biopharmaceuticals are formulated using a variety of excipients to maintain their storage stability.However,some excipients are prone to degradation during repeated use and/or improper storage,and the impurities generated by their degradation are easily overlooked by end users and are usually not strictly monitored,affecting the stability of biopharmaceuticals.In this study,we evaluated the degra-dation profile of polyol excipient glycerol during repeated use and improper storage and identified an unprecedented cyclic ketal impurity using gas chromatography with mass spectrometry(GC-MS).The other polyol excipient,mannitol,was much more stable than glycerol.The effects of degraded glycerol and mannitol on the stability of the model biopharmaceutical pentapeptide,thymopentin,were also evaluated.The thymopentin content was only 66.4％in the thymopentin formulations with degraded glycerol,compared to 95.8％in other formulations after the stress test.Most glycerol impurities(i.e.,aldehydes and ketones)reacted with thymopentin,affecting the stability of thymopentin formulations.In conclusion,this work suggests that more attention should be paid to the quality changes of excipients during repeated use and storage.Additional testing of excipient stability under real or accelerated conditions by manufacturers would help avoid unexpected and painful results.

Characterization of the critical quality attributes for hydroxypropyl methylcellulose with different sources and analysis of the release of sustained-release tablets in vitro / 药学学报

The quality difference of pharmaceutical excipients from different sources affects the molding properties of the powder, resulting in changes in the properties of the final product. In this study, the critical quality attributes of hydroxypropyl methylcellulose (HPMC) with different specifications from two manufacturers (manufacturer A and manufacturer B) were characterized including particle size, physical morphology, viscosity and powder physical quality attributes. Aminophylline, diclofenac sodium, and metformin hydrochloride were utilized as model drugs with different solubility to prepare sustained-release tablets, and the effect of HPMC from different sources on drug release of sustained-release tablets in vitro was investigated. The results showed that HPMC with the same viscosity specification from different sources had outstanding differences in the physicochemical properties (including particle size, physical morphology, viscosity, dimension, compressibility and powder flow), which could change the hardness and friability of the sustained-release tablets. The differences in the physicochemical properties of HPMC had different effects on the dissolution of different sustained-release tablets in vitro. It had no significant effect on the release of easily soluble aminophylline and metformin hydrochloride, but had a greater impact on the release of poorly soluble diclofenac sodium. Compared with manufacturer A, the sustained-release effect of matrix tablets prepared by HPMC from manufacturer B was more excellent. The results of this study will provide a theoretical reference on selecting the appropriate excipients for formulation design.

Compatibility and efficiency of preservatives in emulsive cosmetics containing high surfactant content

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.

Formulation and sterilization assessment of kanamycin sulfate injection based on impurity profiles / 药学学报

The compatibility of kanamycin with sodium citrate for the formulation of kanamycin sulfate injection was determined, including optimization of the amount of sodium citrate in the injection and the sterilization process. An HPLC coupled with an evaporative light scattering detector (ELSD) was used to measure the amount of sodium citrate and the impurity profiles. A validated post-column derivatization HPLC coupled with a fluorescence detector (FLD) was used to determine the correlation between specific impurities in a domestic factory and sodium citrate, and then the formulation was evaluated by HPLC coupled with mass detector (MS) characterization of degradation products. The results show that the amount of sodium citrate in kanamycin sulfate injection from a domestic factory is about 40 times higher than that of the Meiji formulation. Several specific impurities can be detected in solutions heated under simulated sterilization conditions (121 ℃), which were correlated with the amount of sodium citrate. Impurities were characterized by HPLC-MS/MS, and data showed that the identified impurities were interaction products of kanamycin and sodium citrate. These results indicate that greater attention should be directed at formula optimization in domestic factories, as it is crucial to the safety and efficacy of the preparations. Drug-excipient chemical compatibility should also be evaluated in the development of pharmaceutical dosages forms especially when the active pharmaceutical ingredients have a primary amine group.

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.

Yogurt; A Novel Excipient (WITH Its Lysed Bacteria, Amino Acids, Vitamins, Fatty Acids, And Minerals) For “TOPICAL Dermatological Products” And For “SKIN Microbiota”

In recent years various Microbiomes (Skin, Gut Lumen) of the human body have attracted the attention of different research groups. In the meantime it has been shown that the conventional therapy of different diseases by making use of antibiotics and similar antibacterial treatments may disturb the harmony of the Skin Microbiome, resulting in dysbiosis. There are efforts of using “live” or “tyndallized (lysed)” probiotics in order to treat different diseases of the skin. It is also known that amino acids are one of the important key elements of the skin. In this paper, a hypothesis for the utilization of yogurt as an excipient for various topical dermatological products will be proposed. Yogurt contains significant amounts of; Probiotics (starter cultures), Amino Acids, Vitamins, Minerals and various Fatty Acids (saturated, monounsaturated and polyunsaturated). Besides, it has been shown that Antimicrobial Peptides (Bacteriocins) are also present in yogurt. Yogurt could eventually be used as an excipient for the production of various topical dermatological products in order to deliver some of the above-mentioned constituents to the Stratum Corneum (Skin) locally.

Study on traditional processing method of Mongolian medicine and excipient usage based on data mining / 中国中药杂志

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.

Consideration of Excipient Selection in Freeze-dried Injections / 中国药学杂志

OBJECTIVE: To provide reference and consideration for pharmaceutical development by expounding the basic considerations for the selection of freeze-dried injection excipients. METHODS: The excipients in freeze-dried injections approved by FDA in recent years have been listed, and the composition of excipients in the preparations and the maximum amount of excipients contained were summarized. The issues to be considered in the selection of freeze-dried injections were discussed. RESULTS: One quarter of the freeze-dried injections that have been marketed do not use excipients, while the most commonly used excipients are bulking agents, buffering agents and pH adjusters. Other excipients include solubilizing agent, antioxidants, etc.. CONCLUSION: The selection of freeze-dried injection excipients should focus on safety, formulation rationality, functionality-related characteristics and control of excipients.

Research Status of High Functional Co-processed Excipients / 中国药学杂志

Co-processed excipients are enhanced in terms of fluidity, compactness, dilution, and compressibility by restructuring the structure and function of various excipients,which has become an important basis for the high quality and high level development of high quality pharmaceutical preparations, and also an important direction for the future development of excipient industry. This paper mainly summarizes the development history, technological advantages, influencing factors, design principles, preparation methods of co-processed excipients, and summarizes the current situation of industrial development of co-processed excipients, which provides a reference for the in-depth study of composite excipients.

An Introduction to the Standards System and Main Characteristics of Pharmaceutical Excipients in the 2020 Edition of Chinese Pharmacopoeia / 中国药学杂志

OBJECTIVE: To analyze the general situation of pharmaceutical excipients standard in Chinese Pharmacopoeia 2020 edition and understand the standards accurately. METHODSE: This article focuses on the overall information of standard, the changes of working mechanism, the framework of the standard system and the characteristics of all pharmaceutical excipients standards in the 2020 edition of Chinese Pharmacopoeia. RESULTS: It has significantly improved that the number of standards, the standard system and the standard formation mechanism of the 2020 edition of China Pharmacopoeia. CONCLUSION: The Chinese Pharmacopoeia will continue to strengthen the construction of a standard system for pharmaceutical excipients, promote industrial upgrading and improve supervision efficiency.

A Review On Co-Processed Excipients: Current And Future Trend Of Excipient Technology

There is no single-component excipient fulfills all the requisite performance to allow an active pharmaceutical ingredient to be formulated into a specific dosage form. Co-processed excipient has received much more attention in the formulation development of various dosage forms, specially for tablet preparation by direct compression method. The objective of this review is to discuss the emergence of co-processed excipients as a current and future trend of excipient technology in pharmaceutical manufacturing. Co-processing is a novel concept of combining two or more excipients that possess specific advantages that cannot be achieved using a physical admixture of the same combination of excipients. This review article discusses the advantages of co-processing, the need of co-processed excipient, general steps in developing co-processed excipient, limitation of co-processed excipient, technologies used in developing co-processing excipients, co-processed excipients in the literature, marketed products and future trends. With advantages offered by the upcoming newer combination of excipients and newer methods of co-processing, co-processed excipients are for sure going to gain attraction both from academia and pharmaceutical industry. Furthermore, it opens the opportunity for development and use of single multifunctional excipient rather than multiple excipients in the formulation.

Effect of carrier size and surface morphology on the aerosolization of formulation in a capsule-based dry powder inhaler / 药学学报

The size and surface morphology of carrier lactose had influence on the aerosolization performance of dry powder inhalers. In this article, chlorpheniramine maleate was blended with two types of commercial carrier lactose, which were Lactohale 100® and Respitose SV003® (SV003), as formulation model. In vitro experiments were conducted using fast screening impactor at 30 L·min-1 and 60 L·min-1 respectively. Meanwhile, computational fluid dynamics (CFD) coupling with discrete element modelling (DEM) was applied to discuss the movements of those two carrier particles in Handihaler® at the flow rate mentioned above. The dispersion characteristics of two formulations and the dispersion mechanism of Handihaler® were analyzed by establishing the relationship between in vitro experiments and numerical simulation. The results of in vitro experiments and CFD-DEM demonstrated that the aerosolization performance of formulation with SV003 was better. The linear correlation (R2 = 0.940 1) between fine particle dose and total energy loss by carrier collision within the wall of device was found by comparing the in vitro experimental results with CFD-DEM results. It revealed that particle-wall collision in Handihaler® had direct impact on the dispersion results of formulation.

Antitumor mechanism of glycyrrhizic acid and glycyrrhetinic acid and their application as drug delivery carriers / 中草药

Glycyrrhizae Radix et Rhizoma is one of the commonly used Chinese materia medica in clinic. It has the effects of tonifying spleen and replenishing qi, clearing heat and removing toxin, dispelling phlegm, relieving cough, relieving pain, and reconciling various drugs. Its main active ingredients are saponins, flavonoids and polysaccharides. Among them, glycyrrhizic acid and glycyrrhetinic acid not only have inhibitory effects on liver cancer, lung cancer, breast cancer and other cancers, but also can be combined with chemotherapeutic drugs to increase drug efficacy as well. At the same time, they can be developed as drug carrier for drug delivery to solve the problems of low water solubility, low bioavailability, high toxicity and side effects of drugs. It was found that their solubilization may be closely related to their amphiphilic structure, which is expected to further explore the role of their carrier characteristics in drug transmembrane transport. Based on the anti-tumor mechanisms of Glycyrrhizae Radix et Rhizoma, the applications of glycyrrhizic acid and glycyrrhetinic acid in drug delivery systems were systematically summarized in this paper, which could provide reference for the further study of glycyrrhizic acid and glycyrrhetinic acid as excipients of drug delivery systems.

Local Irritation and Cytotoxicity Study of Glycerol as Pharmaceutical Excipient / 中国药学杂志

OBJECTIVE: To study the local irritative response and cytotoxicity of glycerol in vivo and in vitro, and evaluate the safety of glycerol as an excipient in inhaled preparations preliminarily. METHODS: Local irritation test: rats were divided into two groups, the glycerol group received 20% glycerol by intratracheal atomization once a day, followed by 5 d, the control group was given the equal volume of 0.9% sodium chloride solutions in the same way. After administration, the throat, trachea and lung were taken for histopathological examination, and bronchoalveolar lavage was performed in each group, total protein (TP) content (BCA method) and alkaline phosphatase (ALP), lactate dehydrogenase (LDH) activity in the lavage fluid were detected (biochemical instrument). Cytotoxicity test: the toxic effects of glycerol on adenocarcinoma human alveolar epithelial-like cells (A549), human bronchial epithelial cells (16HBE) and rat tracheal epithelial cells (RTE) were studied by MTT assay. RESULTS: Local irritation test:the control group showed mild infiltration of inflammatory cells in the alveolar (1/8), glycerol group showed perivascular inflammation (2/8) and moderate mild to mild infiltration of inflammatory cells in the alveolar (6/8); bronchoalveolar lavage fluid test showed that, compared with the control group, the level of ALP in the glycerol group was elevated significantly (P<0.05). There was a dose-effect relationship between the cytotoxicity on A549, 16HBE and RTE cells with varying volume fraction of glycerol content in the range of 0.25%-10%, r2 values were 0.989, 0.981, 0.964, and IC50 were 4.28%, 4.40%, 4.31% respectively. CONCLUSION: The 20% glycerol has slight irritation to the lung in vivo, and in vitro glycerol has obvious toxic effect on A549 and 16HBE cells when the volume fraction reached 2.0%, when it reached 4.0%, it has significant toxic effect on RTE cells, suggesting that large dose of glycerol may cause mild irritation and toxicity to the lungs.

Review of Excipients Safety in Pediatric Patients / 中国药学杂志

Excipients are essential components of pharmaceutical products for use in adults and children. They are generally considered to be inert ingredients and are therefore rarely concerned due to the growth and development of the body of children and the specificity of the pharmacokinetics of pharmaceutical excipients, it is undeniable that children are facing risks of excipient toxicity. This article summarizes some excipients of defined and potential hazardous risks in the pediatric population, and reviews the current status of pediatric use of excipients in China and other countries, therefore to discuss the safety of excipients in children, and to provide a reference to healthcare professionals including pharmacists, physicians, as well as pharmaceutical manufacturers.

The Key Technologies in Industrialization of Pediatric Preparations / 中国药学杂志

The children aged 0-14 account for about 17% of the total population of China, medicines used by which cost more than 60 billion yuan per year. However, it is difficult for children to swallow medicines and children are more sensitive to taste. In addition, the gastrointestinal, liver and kidney functions are not yet fully developed and the immune function is weak. There are special needs for active pharmaceutical ingredient, dosage form, taste and appearance. However, there is a significant gap between China and Europe and America on pediatric preparations. To promote the breakthrough of key as taste-masking technologies, solubilizing technologies, quantitative dosing devices, technologies in industrialization of pediatric preparations in China, the key technologies, such pediatric excipients and production equipment, are reviewed.

Rheological properties of compound carrageenan / 药学学报

The rheological properties of six compound gels that consists of kappa carrageenan (KC) and another excipient such as konjac gum were explored through comparison of their viscosity measured by the rotation method. The gel fluid type was dependent on the rheological curve fitted by the power-law equation. The effect of concentration on the viscosity of different compound gels was investigated by establishing the linear equation between their viscosity and concentration, the slope of which was used to determine the relation between viscosity and concentration of different compound gels. The viscous flow activation energy (Eη) was calculated by the Arrhenius equation, which was able to investigate the effect of temperature on their viscosity. The interaction between monomer and compound gels was also studied by measuring their viscosity. The results showed that six compound gels were pseudoplastic fluid. Among all compound gels, the KC-xanthan gum (KC-XG) solution exhibited the most obvious shear thinning, the strongest pseudoplasticity, while the smallest Eη, resulting in the best thermal stability of viscosity. Furthermore, the concentration of KC-sodium hyaluronate (KC-HA-Na) solution affected its viscosity significantly. The viscosity of six compound gels was greater than the summation of the two kinds of monomer gels, which suggests that there is a synergistic-viscosity interaction between KC and another excipient.