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Journal of Pharmaceutical Sciences Jul 2021This review identified 126 commercially available antibodies approved globally between 1986 and February 2021 including 10 antibody drug conjugates, 16 biosimilars, and... (Review)
Review
This review identified 126 commercially available antibodies approved globally between 1986 and February 2021 including 10 antibody drug conjugates, 16 biosimilars, and 3 antibody fragments. Prior to 2014 there were ≤ 5 approved each year, but after 2014 there have been ≥ 7 approved each year with the years 2017, 2019 and 2020 having the most at 17 each. A total of 136 products were identified of which 36 are lyophilized powders and 100 are solutions. The routes of administration are mainly subcutaneous or intravenous infusion with three intravenous bolus, two intravitreal, and one intramuscular. The subcutaneous products are ready-to-use solutions or reconstituted lyophilized powders that do not require dilution while most intravenous products are concentrates that require dilution into saline or another intravenous fluid prior to infusion. Most are packaged in single-dose units and the exception of multi-use is Herceptin® and its biosimilars. The package configurations are vials, prefilled autoinjectors, or prefilled syringes. A typical antibody formulation contains an antibody, an excipient to adjust tonicity or osmolality for solutions or a lyoprotectant for lyophilized powders, a buffer, and a surfactant. The ionic tonicity-adjusting excipient is mainly sodium chloride and the non-ionic osmolality-adjusting excipients include sucrose, trehalose, mannitol, maltose, and sorbitol. The lyoprotectants are trehalose and sucrose. The pH range is 4.8-8.0 and the buffers or pH-modifying agents include histidine, citrate, succinate, acetate, phosphate, glutamate, adipic acid, aspartic acid, lactic acid, tromethamine, and 2-(N-morpholino)-ethanesulfonic acid. The surfactants include mostly polysorbate 20 or polysorbate 80, with four containing poloxamer 188, and one that does not contain a surfactant but contains PEG 3350. One product does not contain a buffer, and 12 do not contain a surfactant. The viscosity-lowering excipients are sodium chloride and the amino acids arginine, glycine, proline, and lysine. Arginine may also function to adjust ionic strength and minimize aggregation. Human serum albumin is used in 2 products for intravenous infusion. Other excipients include methionine as an anti-oxidant, and EDTA or DTPA as chelating agents. The maximum volume of subcutaneous injection is 15 mL administered over 3-5 minutes, but the typically volume is 0.5-2 mL. Five fixed-dose combinations have recently been approved and four contain hyaluronidase to assist the large volume subcutaneous injection of up to 15 mL, while one is a fixed-dose combination for intravenous with three antibodies. Prefilled autoinjectors and syringes are becoming more common and many come affixed with a needle of 27-gauge or 29-gauge, while a few have a 26-gauge or a 30-gauge needle. Recent advancements include hyaluronidase to assist the large subcutaneous injection volume of 5-15 mL, fixed-dose combinations, buffer-free formulation, and smaller subcutaneous injection volume (0.1 mL).
Topics: Biosimilar Pharmaceuticals; Excipients; Humans; Polysorbates; Surface-Active Agents; Trastuzumab
PubMed: 33789155
DOI: 10.1016/j.xphs.2021.03.017 -
Therapeutic Delivery Jul 2023The effectiveness of pharmaceutical drugs depends not only on their active components and manufacturing processes, but also on the role played by pharmaceutical... (Review)
Review
The effectiveness of pharmaceutical drugs depends not only on their active components and manufacturing processes, but also on the role played by pharmaceutical excipients. The traditional definition of excipients as inactive and cost-effective substances has evolved significantly. They are now recognized as essential elements of drug formulations, constituting 80-90% of the final product. The rapid advancements in delivery systems, along with scientific, regulatory, financial and technological developments in biopharmaceutics, have generated renewed interest in the use and functionality of excipients, especially in solid dosage forms. This review focuses on the categorization of excipients according to the International Pharmaceutical Excipient Council (IPEC) and the establishment of guidelines for evaluating the safety of a new proposed excipient.
Topics: Excipients; Chemistry, Pharmaceutical; Drug Compounding; Biopharmaceutics; Pharmaceutical Preparations
PubMed: 37464784
DOI: 10.4155/tde-2023-0026 -
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 -
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 -
Pharmaceutical Nanotechnology 2020Self-emulsifying drug delivery system (SEDDS) is a kind of solid or liquid formulation composed of drugs, oil, surfactant and cosurfactant. It could form a fine emulsion... (Review)
Review
Self-emulsifying drug delivery system (SEDDS) is a kind of solid or liquid formulation composed of drugs, oil, surfactant and cosurfactant. It could form a fine emulsion (micro/nano) in the gastrointestinal tract after oral administration. Later on, the formed emulsion is absorbed through the lymphatic pathway. The oral bioavailability of drugs in SEDDS would be improved for bypassing the first-pass effect of the liver. Therefore, SEDDS has become a vital strategy to increase the oral bioavailability of poor watersoluble drugs. In addition, there is no aqueous phase in SEDDS, thus SEDDS is a homogeneous system, consequently being suitable for large-scale production and more stable than conventional emulsion. However, the role of formulation aspects in the biological property of SEDDS is not fully clear. In order to prepare the satisfying SEDDS to improve oral drug bioavailability, we need to fully understand the various factors that affect the in vivo behavior of SEDDS. In this review, we would explore the role of ingredient (drugs, oils, surfactant and cosurfactant) of SEDDS in increasing oral drug bioavailability. We would also discuss the effect of physicochemical property (particle size and zeta potential) of SEDDS on the oral drug bioavailability enhancement. This review would provide an approach to develop a rational SEDDS to improving oral drug bioavailability. Lay Summary: Self-emulsifying drug-delivery system (SEDDS) has been proven to be promising in ameliorating the oral bioavailability of poor water-soluble drugs. This review highlighted the influence of excipients and physicochemical property of SEDDS on the formation of emulsion and the oral absorption of drugs in the body.
Topics: Administration, Oral; Animals; Biological Availability; Drug Carriers; Drug Compounding; Emulsions; Excipients; Humans; Particle Size; Pharmaceutical Preparations; Technology, Pharmaceutical
PubMed: 32781978
DOI: 10.2174/2211738508666200811104240 -
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 -
International Journal of Pharmaceutical... 2023Pharmaceutical excipients are substances formulated with an active ingredient in a medication. This article has provided a brief discussion on excipients, the...
Pharmaceutical excipients are substances formulated with an active ingredient in a medication. This article has provided a brief discussion on excipients, the purpose of excipients, the selection of appropriate excipients, the use of excipients in formulation development by compounding pharmacists/manufacturers, excipient examples and usage, the numerous incompatibilities that should be considered when choosing an excipient, and a list of adverse effects related to excipients.
Topics: Excipients; Drug Compounding
PubMed: 37816181
DOI: No ID Found -
PDA Journal of Pharmaceutical Science... 2020It is important to identify, assess, and address current barriers to implementation of post-approval changes that are intended to ensure continued (uninterrupted)... (Review)
Review
It is important to identify, assess, and address current barriers to implementation of post-approval changes that are intended to ensure continued (uninterrupted) operations and drive innovation and continual improvement in a maximally efficient, agile, and flexible pharmaceutical manufacturing sector. Leveraging the International Conference for Harmonisation Quality Guideline Q10 provides regulatory relief when it comes to addressing changes related to excipients, specifically excipient supplier's name and address changes, which will ensure a sustainable, reliable global supply and the availability of high quality product to patients through the entire commercial lifecycle of a product without extensive regulatory oversight.
Topics: Chemistry, Pharmaceutical; Drug Industry; Equipment and Supplies Utilization; Excipients; Humans; Quality Control
PubMed: 32179712
DOI: 10.5731/pdajpst.2019.011239 -
Journal of Controlled Release :... Aug 2020Hydroxypropylmethylcellulose (HPMC), also known as Hypromellose, is a traditional pharmaceutical excipient widely exploited in oral sustained drug release matrix... (Review)
Review
Hydroxypropylmethylcellulose (HPMC), also known as Hypromellose, is a traditional pharmaceutical excipient widely exploited in oral sustained drug release matrix systems. The choice of numerous viscosity grades and molecular weights available from different manufacturers provides a great variability in its physical-chemical properties and is a basis for its broad successful application in pharmaceutical research, development, and manufacturing. The excellent mucoadhesive properties of HPMC predetermine its use in oromucosal delivery systems including mucoadhesive tablets and films. HPMC also possesses desirable properties for formulating amorphous solid dispersions increasing the oral bioavailability of poorly soluble drugs. Printability and electrospinnability of HPMC are promising features for its application in 3D printed drug products and nanofiber-based drug delivery systems. Nanoparticle-based formulations are extensively explored as antigen and protein carriers for the formulation of oral vaccines, and oral delivery of biologicals including insulin, respectively. HPMC, being a traditional pharmaceutical excipient, has an irreplaceable role in the development of new pharmaceutical technologies, and new drug products leading to continuous manufacturing processes, and personalized medicine. This review firstly provides information on the physical-chemical properties of HPMC and a comprehensive overview of its application in traditional oral drug formulations. Secondly, this review focuses on the application of HPMC in modern pharmaceutical technologies including spray drying, hot-melt extrusion, 3D printing, nanoprecipitation and electrospinning leading to the formulation of printlets, nanoparticle-, microparticle-, and nanofiber-based delivery systems for oral and oromucosal application. Hypromellose is an excellent excipient for formulation of classical dosage forms and advanced drug delivery systems. New methods of hypromellose processing include spray draying, hot-melt extrusion, 3D printing, and electrospinning.
Topics: Drug Compounding; Drug Liberation; Excipients; Hypromellose Derivatives; Solubility; Tablets; Technology, Pharmaceutical; Viscosity
PubMed: 32479845
DOI: 10.1016/j.jconrel.2020.05.045