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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 -
International Journal of Molecular... Sep 2022Hyaluronic acid (HA) fillers have become the most popular material for facial volume augmentation and wrinkle correction. Several filler brands are currently on the... (Review)
Review
Hyaluronic acid (HA) fillers have become the most popular material for facial volume augmentation and wrinkle correction. Several filler brands are currently on the market all around the world and their features are extremely variable; for this reason, most users are unaware of their differences. The study of filler rheology has become a wellspring of knowledge, differentiating HA fillers, although these properties are not described thoroughly by the manufacturers. The authors of this review describe the more useful rheological properties that can help clinicians understand filler characteristics and the likely correlation of these features with clinical outcomes.
Topics: Cosmetic Techniques; Dermal Fillers; Excipients; Hyaluronic Acid; Rheology; Skin Aging
PubMed: 36142430
DOI: 10.3390/ijms231810518 -
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 -
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 -
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 -
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... 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 -
Journal of Controlled Release :... Nov 2022Among the various dosage forms, oral medicine has extensive benefits including ease of administration and patients' compliance, over injectable, suppositories, ocular... (Review)
Review Comparative Study
Among the various dosage forms, oral medicine has extensive benefits including ease of administration and patients' compliance, over injectable, suppositories, ocular and nasal. Despite of extensive demand and emerging advantages, over 50% of therapeutic molecules are not available in oral form due to their physicochemical properties. More importantly, most of the biologics, proteins, peptide, and large molecular drugs are mostly available in injectable form. Conventional oral drug delivery system has limitation such as degradation and lack of stability within stomach due to presence of highly acidic gastric fluid, hinders their therapeutic efficacy and demand more frequent and higher dosing. Hence, formulation for controlled, sustained, and targeted drug delivery, need to be designed with feasibility to target the specific region of gastrointestinal (GI) tract such as stomach, small intestine, intestine lymphatic, and colon is challenging. Among various oral delivery approaches, mucoadhesive vehicles are promising and has potential for improving oral drug retention and controlled absorption to treat local diseases within the GI tract, as well systemic diseases. This review provides the overview about the challenges and opportunities to design mucoadhesive formulation for oral delivery of therapeutics in a way to target the specific region of the GI tract. Finally, we have concluded with future perspective and potential of mucoadhesive formulations for oral local and systemic delivery.
Topics: Humans; Drug Delivery Systems; Excipients; Colon; Gastrointestinal Tract; Administration, Oral; Drug Carriers
PubMed: 36116580
DOI: 10.1016/j.jconrel.2022.09.024