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International Journal of Molecular... Nov 2020Conclusions from previously reported articles have revealed that many commonly used pharmaceutical excipients, known to be pharmacologically inert, show effects on drug... (Review)
Review
Conclusions from previously reported articles have revealed that many commonly used pharmaceutical excipients, known to be pharmacologically inert, show effects on drug transporters and/or metabolic enzymes. Thus, the pharmacokinetics (absorption, distribution, metabolism and elimination) of active pharmaceutical ingredients are possibly altered because of their transport and metabolism modulation from the incorporated excipients. The aim of this review is to present studies on the interaction of various commonly-used excipients on pre-systemic metabolism by CYP450 enzymes. Excipients such as surfactants, polymers, fatty acids and solvents are discussed. Based on all the reported outcomes, the most potent inhibitors were found to be surfactants and the least effective were organic solvents. However, there are many factors that can influence the inhibition of CYP450, for instance type of excipient, concentration of excipient, type of CYP450 isoenzyme, incubation condition, etc. Such evidence will be very useful in dosage form design, so that the right formulation can be designed to maximize drug bioavailability, especially for poorly bioavailable drugs.
Topics: ATP-Binding Cassette Transporters; Animals; Cytochrome P-450 Enzyme System; Excipients; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Pharmaceutical Preparations
PubMed: 33153099
DOI: 10.3390/ijms21218224 -
The Journal of Clinical Psychiatry Sep 2015Generic drugs are bioequivalent to the original brand; this is a prerequisite for marketing approval. It is theoretically possible that one generic drug may overestimate...
Generic drugs are bioequivalent to the original brand; this is a prerequisite for marketing approval. It is theoretically possible that one generic drug may overestimate the pharmacokinetic (PK) parameters of the original and another generic may underestimate these PK parameters; in consequence, these 2 generics may not be bioequivalent between themselves. The result could be loss of efficacy or development of drug-related adverse effects if these generics are interchanged in stable patients. In a recent study involving 292 indirect comparisons of generic formulations of 9 different drugs, mathematical modeling showed that in most cases (87.0% for maximum concentration, 90.1% for area under the curve, and 80.5% for both) generic drugs are bioequivalent to each other. These reassuring findings notwithstanding, prudence dictates that, in stable patients, generic drugs should be interchanged only if there is a good reason for it. This is because bioequivalent brands of drugs may differ in their excipient content, and this can result in variations in safety profiles.
Topics: Drugs, Generic; Excipients; Humans; Therapeutic Equivalency
PubMed: 26455677
DOI: 10.4088/JCP.15f10300 -
Journal of Pharmaceutical Sciences Jun 2023N-Nitrosamine risk assessment and control have become an integral part of pharmaceutical drug product development and quality evaluation. Initial reports of nitrosamine...
N-Nitrosamine risk assessment and control have become an integral part of pharmaceutical drug product development and quality evaluation. Initial reports of nitrosamine contamination were linked with the drug substance and its manufacturing process. Subsequently, the drug product and aspects of the formulation process have shown to be relevant. Regarding specific formulation contributions to nitrosamine content in a product, one risk lies in possible interactions between nitrosating agents, derived from nitrite in excipients, and vulnerable amines, either present as moieties of the active molecule or as impurities / degradants. However, the limited validated information on nitrite levels in excipients available until now, has been an obstacle for scientists to assess the risk of nitrosamine formation in pharmaceutical products. This has driven the creation of a database to store and share such validated information. The database, maintained by Lhasa Limited, constitutes a central platform to hold the data donated by the pharmaceutical company members on the nitrite concentrations in common excipients measured with validated analytical procedures. The goal of this data sharing initiative is to provide a common framework to contextualize and estimate the risk posed by presence of nitrites to contribute to the formation of nitrosamines in drug products. The major findings from the database analyses are: (1) average nitrite content and batch to batch variance differ among excipients, (2) for solid dosage forms, the nitrite contribution is dominated by the highest formula % excipients, e.g., the fillers (diluents), which are typically used in larger proportion, and are characterized by low nitrite levels and low variability, leading to an average value of 1 µg/g nitrite in a typical formulation, (3) substantial differences in average nitrite content in batches from different excipient vendors potentially reflecting differences in source materials or processing methods for excipient manufacturing. That final point suggests that future selection of raw materials or processing by excipient manufacturers may help reduce nitrite levels in finished drug product formulations, and thus the overall risk of nitrosamine formation in cases where the product contains vulnerable amines.
Topics: Nitrites; Nitrosamines; Excipients; Chemistry, Pharmaceutical; Amines; Risk Assessment
PubMed: 35500671
DOI: 10.1016/j.xphs.2022.04.016 -
International Journal of Pharmaceutics Jun 2020This review presents the early history, the motivation, the research and some of the backstories behind the discovery and development of sulfobutylether-β-cyclodextrin... (Review)
Review
This review presents the early history, the motivation, the research and some of the backstories behind the discovery and development of sulfobutylether-β-cyclodextrin as a novel parenterally safe solubilizer and stabilizer. A specific sulfobutylether-β-cyclodextrin with an average degree of 6.5 sulfobutyl-groups variably substituted on the 2-, 3- and 6-hydroxyls of the seven glucopyranose (dextrose) units of β-cyclodextrin, is known by its commercial name, Captisol®. Today it is in 13 FDA approved injectables and numerous clinical candidates. It is also an example of a novel product discovered and initially preclinically developed at an academic institution.
Topics: Drug Stability; Excipients; History, 20th Century; History, 21st Century; Humans; Injections; Pharmaceutical Preparations; Solubility; beta-Cyclodextrins
PubMed: 32376442
DOI: 10.1016/j.ijpharm.2020.119396 -
International Journal of Molecular... Sep 2020The development of medicines designed for children can be challenging since this distinct patient population requires specific needs. A formulation designed for...
The development of medicines designed for children can be challenging since this distinct patient population requires specific needs. A formulation designed for paediatric patients must consider the following aspects: patient population variability; dose flexibility; route of administration; patient compliance; drug and excipient tolerability. The purpose of this Special Issue entitled "Paediatric Formulation: Design and Development" is to provide an update on both state-of-the-art methodology and operational challenges in the design and development of paediatric formulations. It aims at re-evaluating what is needed for more progress in the design and development of age-appropriate treatments for paediatric diseases, focusing on: formulation development; drug delivery design; efficacy, safety, and tolerability of drugs and excipients. This editorial, briefly, summarizes the objects of nine original research and review papers published in this Special Issue.
Topics: Chemistry, Pharmaceutical; Child; Drug Compounding; Drug Delivery Systems; Drug Development; Excipients; Humans; Periodicals as Topic
PubMed: 32992469
DOI: 10.3390/ijms21197118 -
AAPS PharmSciTech Mar 2010Drying is one of the standard unit operations in the pharmaceutical industry and it is important to become aware of the circumstances that dominate during the process....
Drying is one of the standard unit operations in the pharmaceutical industry and it is important to become aware of the circumstances that dominate during the process. The purpose of this study was to test microcapsulated thermochromic pigments as heat indicators in a fluid bed drying process. The indicator powders were manually granulated with alpha-lactose monohydrate resulting in three particle-size groups. Also, pellets were coated with the indicator powders. The granules and pellets were fluidized in fluid bed dryer to observe the progress of the heat flow in the material and to study the heat indicator properties of the indicator materials. A tristimulus colorimeter was used to measure CIELAB color values. Color indicator for heat detection can be utilized to test if the heat-sensitive API would go through physical changes during the pharmaceutical drying process. Both the prepared granules and pellets can be used as heat indicator in fluid bed drying process. The colored heat indicators give an opportunity to learn new aspects of the process at real time and could be exploded, for example, for scaling-up studies.
Topics: Color; Desiccation; Excipients; Hot Temperature; Indicators and Reagents; Particle Size; Powders
PubMed: 20039220
DOI: 10.1208/s12249-009-9351-x -
Molecules (Basel, Switzerland) Jan 2021Amorphous solid dispersion drug delivery systems (ASD DDS) were proved to be efficient for the enhancement of solubility and bioavailability of poorly water-soluble... (Review)
Review
Amorphous solid dispersion drug delivery systems (ASD DDS) were proved to be efficient for the enhancement of solubility and bioavailability of poorly water-soluble drugs. One of the major keys for successful preparation of ASD is the selection of appropriate excipients, mostly polymers, which have a crucial role in improving drug solubility and its physical stability. Even though, excipients should be chemically inert, there is some evidence that polymers can affect the thermal stability of active pharmaceutical ingredients (API). The thermal stability of a drug is closely related to the shelf-life of pharmaceutical products and therefore it is a matter of high pharmaceutical relevance. An overview of thermal stability of amorphous solids is provided in this paper. Evaluation of thermal stability of amorphous solid dispersion is perceived from the physicochemical perspective, from a kinetic (motions) and thermodynamic (energy) point of view, focusing on activation energy and fragility, as well all other relevant parameters for ASD design, with a glance on computational kinetic analysis of solid-state decomposition.
Topics: Chemistry, Pharmaceutical; Drug Stability; Excipients; Pharmaceutical Preparations; Polymers; Temperature; Thermodynamics
PubMed: 33466393
DOI: 10.3390/molecules26010238 -
International Journal of Molecular... May 2023This review focuses on the methods of preparation and biological, physiochemical, and theoretical analysis of the inclusion complexes formed between estrogens and... (Review)
Review
This review focuses on the methods of preparation and biological, physiochemical, and theoretical analysis of the inclusion complexes formed between estrogens and cyclodextrins (CDs). Because estrogens have a low polarity, they can interact with some cyclodextrins' hydrophobic cavities to create inclusion complexes, if their geometric properties are compatible. For the last forty years, estrogen-CD complexes have been widely applied in several fields for various objectives. For example, CDs have been used as estrogen solubilizers and absorption boosters in pharmaceutical formulations, as well as in chromatographic and electrophoretic procedures for their separation and quantification. Other applications include the removal of the endocrine disruptors from environmental materials, the preparation of the samples for mass spectrometric analysis, or solid-phase extractions based on complex formation with CDs. The aim of this review is to gather the most important outcomes from the works related to this topic, presenting the results of synthesis, in silico, in vitro, and in vivo analysis.
Topics: Cyclodextrins; Chemical Phenomena; Drug Compounding; Excipients; Hydrophobic and Hydrophilic Interactions; Solubility
PubMed: 37240133
DOI: 10.3390/ijms24108780 -
European Journal of Pharmaceutical... May 2022Drug administration by inhalation is a well-established approach to treat respiratory and systemic diseases. To deliver a drug into the lung dry powder inhalation (DPI)... (Review)
Review
Drug administration by inhalation is a well-established approach to treat respiratory and systemic diseases. To deliver a drug into the lung dry powder inhalation (DPI) is an advantageous, but yet challenging option. A variety of strategies is available for developing DPI formulations. These formulation strategies should address the present disadvantage of insufficient drug delivery and enable therapies in general or to reach new targets (e.g. mucosal vaccination). To increase therapy safety and efficacy scientists challenge the limits of technical feasibility to engineer respiratory medicines. In this review, we provide a concise overview of particle engineering as enabling formulation technique or as an optimisation approach for existing strategies in pulmonary drug delivery. It comprehensively describes different techniques for particle engineering in carrier-based blends for inhalation. This covers considerations on which attributes are beneficial for carriers, followed by methods to modify such attributes or directly manufacture the desired carriers. Furthermore, this work comprises the current state of knowledge on nanocrystal and nanoparticle production as well as other carrier-free technologies and their applications. This review is completed by a glance in the future of carrier engineering using additive manufacturing.
Topics: Administration, Inhalation; Aerosols; Drug Delivery Systems; Dry Powder Inhalers; Excipients; Lung; Particle Size; Powders
PubMed: 35248734
DOI: 10.1016/j.ejps.2022.106158 -
International Journal of Molecular... Sep 2018Nanocarriers encapsulating multiple chemotherapeutics are a promising strategy to achieve combinational chemotherapy for cancer therapy; however, they generally use... (Review)
Review
Nanocarriers encapsulating multiple chemotherapeutics are a promising strategy to achieve combinational chemotherapy for cancer therapy; however, they generally use exotic new carriers without therapeutic effect, which usually suffer from carrier-related toxicity issues, as well as having to pass extensive clinical trials to be drug excipients before any clinical applications. Cargo-free nanomedicines, which are fabricated by drugs themselves without new excipients and possess nanoscale characteristics to realize favorable pharmacokinetics and intracellular delivery, have been rapidly developed and drawn much attention to cancer treatment. Herein, we discuss recent advances of cargo-free nanomedicines for cancer treatment. After a brief introduction to the major types of carrier-free nanomedicine, some representative applications of these cargo-free nanomedicines are discussed, including combination therapy, immunotherapy, as well as self-monitoring of drug release. More importantly, this review draws a brief conclusion and discusses the future challenges of cargo-free nanomedicines from our perspective.
Topics: Drug Delivery Systems; Drug Liberation; Excipients; Humans; Immunotherapy; Nanomedicine; Neoplasms
PubMed: 30274177
DOI: 10.3390/ijms19102963