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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 Allergy and Clinical... Aug 2021Excipients are necessary as a support to the active ingredients in drugs, vaccines, and other products, and they contribute to their stability, preservation,... (Review)
Review
Excipients are necessary as a support to the active ingredients in drugs, vaccines, and other products, and they contribute to their stability, preservation, pharmacokinetics, bioavailability, appearance, and acceptability. For both drugs and vaccines, these are rare reactions; however, for vaccines, they are the primary cause of immediate hypersensitivity. Suspicion for these "hidden dangers" should be high, in particular, when anaphylaxis has occurred in association with multiple chemically distinct drugs. Common excipients implicated include gelatin, carboxymethylcellulose, polyethylene glycols, and products related to polyethylene glycols in immediate hypersensitivity reactions and propylene glycol in delayed hypersensitivity reactions. Complete evaluation of a suspected excipient reaction requires detailed information from the product monograph and package insert to identify all ingredients that are present and to understand the function and structure for these chemicals. This knowledge helps develop a management plan that may include allergy testing to identify the implicated component and to give patients detailed information for future avoidance of relevant foods, drugs, and vaccines. Excipient reactions should be particularly considered for specific classes of drugs where they have been commonly found to be the culprit (eg, corticosteroids, injectable hormones, immunotherapies, monoclonal antibodies, and vaccines). We provide a review of the evidence-based literature outlining epidemiology and mechanisms of excipient reactions and provide strategies for heightened recognition and allergy testing.
Topics: Anaphylaxis; Drug Hypersensitivity; Excipients; Humans; Hypersensitivity; Hypersensitivity, Immediate; Polyethylene Glycols; Vaccines
PubMed: 33737254
DOI: 10.1016/j.jaip.2021.03.002 -
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 -
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 -
Protein Science : a Publication of the... Jul 2015It is well recognized that protein product development is far more challenging than that for small-molecule drugs. The major challenges include inherent sensitivity to... (Review)
Review
It is well recognized that protein product development is far more challenging than that for small-molecule drugs. The major challenges include inherent sensitivity to different types of stresses during the drug product manufacturing process, high rate of physical and chemical degradation during long-term storage, and enhanced aggregation and/or viscosity at high protein concentrations. In the past decade, many novel formulation concepts and technologies have been or are being developed to address these product development challenges for proteins. These concepts and technologies include use of uncommon/combination of formulation stabilizers, conjugation or fusion with potential stabilizers, site-specific mutagenesis, and preparation of nontraditional types of dosage forms-semiaqueous solutions, nonfreeze-dried solid formulations, suspensions, and other emerging concepts. No one technology appears to be mature, ideal, and/or adequate to address all the challenges. These gaps will likely remain in the foreseeable future and need significant efforts for ultimate resolution.
Topics: Animals; Chemistry, Pharmaceutical; Drug Stability; Excipients; Humans; Mutagenesis, Site-Directed; Protein Stability; Proteins
PubMed: 25858529
DOI: 10.1002/pro.2684 -
Therapeutic Innovation & Regulatory... May 2022Manufacture of oligonucleotide active pharmaceutical ingredients (APIs) typically consists of solid-phase synthesis, deprotection and cleavage, purification and... (Review)
Review
Manufacture of oligonucleotide active pharmaceutical ingredients (APIs) typically consists of solid-phase synthesis, deprotection and cleavage, purification and filtration, and isolation from aqueous solutions through lyophilization. In the first step of drug product manufacture, the API is dissolved in water again and excipients are added. While isolation of oligonucleotide APIs can be meaningful in many cases, there may be cases where keeping the API in solution provides benefit, and multiple technical aspects must be taken into account and balanced when determining the appropriate API form. A significant factor is whether an API in solution will contain additional components. While APIs in solution containing additional components (so-called formulated APIs) are well established for biological products, there are regulatory guidelines in place that represent hurdles for industry to using a formulated API approach for oligonucleotide drugs. The present communication outlines conditions where a formulated API approach can be chosen in compliance with existing guidelines. Relevant aspects pertaining to risk management, GMP standards, facility design, control strategies, and regulatory submission content are discussed. In addition, the authors propose that existing guidelines be modernized to enable the use of a formulated API approach for additional reasons than the ones described in the existing regulatory framework. The manuscript aims to promote a dialog with regulators in this field.
Topics: Excipients; Oligonucleotides
PubMed: 35133632
DOI: 10.1007/s43441-022-00384-2 -
International Journal of Molecular... Feb 2022Local drug delivery is an effective strategy for achieving direct and instant therapeutic effects. Current clinical treatments have fallen short and are limited by... (Review)
Review
Local drug delivery is an effective strategy for achieving direct and instant therapeutic effects. Current clinical treatments have fallen short and are limited by traditional technologies. Bioadhesive nanoparticles (NPs), however, may be a promising carrier for optimized local drug delivery, offering prolonged drug retention time and steadily maintained therapeutic concentrations. In addition, the possibility of clinical applications of this platform are abundant, as most polymers used for bioadhesion are both biodegradable and biocompatible. This review highlights the major advances in the investigations of polymer-based bioadhesive nanoparticles and their innumerable applications in local drug delivery.
Topics: Adhesives; Animals; Drug Carriers; Drug Delivery Systems; Excipients; Humans; Nanoparticles; Polymers
PubMed: 35216484
DOI: 10.3390/ijms23042370 -
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... 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