Contemporary Formulation Development for Inhaled Pharmaceuticals

Sou, Tomás; Bergström, Christel A S

doi:10.1016/j.xphs.2020.09.006

Cited by 29 publications

(17 citation statements)

References 258 publications

(157 reference statements)

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“…Simulations of lipid bilayers containing products of lipid oxidations have found a decrease in permeability for the case of oxysterols [550] and tail oxidized phosphatidylcholine [481]. From the standpoint of pharmaceutical research, the most interesting are studies of membranes that form a boundary with an extracellular environment, including bacterial membranes [415,[610][611][612][613][614][615][616], the stratum corneum, i.e., the most external layer of the skin [617][618][619][620][621][622][623][624][625][626], membranes present in the eyes [557,[627][628][629][630][631], and the ocular mucous membrane [632], or lung surfactant monolayers [263,558,[633][634][635][636][637][638]. Specifically, MD simulations have been used in studies of enhancer effects on the permeability of the stratum corneum (e.g., [544]).…”

Section: Translocation Through the Membranementioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: Translocation Through the Membranementioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“…The particle size distribution was characterized by the D[0.1] (10% of the volume distribution is below this value), D[0.5] (the volume median diameter is the diameter where 50% of the distribution is above and 50% is below), and D[0.9] (90% of the volume distribution is below this value) values. The size distribution Span was calculated according to Equation (1). A high Span value denotes a broad particle size distribution.…”

Section: Determination Of Particle Size and Distributionmentioning

confidence: 99%

“…The main advantages of pulmonary delivery are the result of the huge surface area of the lung (100 m 2 ) with a thin absorption layer (0.1-0.2 µm), as well as low metabolic activity. Targeted delivery of the drug could provide benefits such as achieving a greater local concentration at the target site with a reduced dose, resulting in reduced systemic side effects and adverse events [1]. Local delivery is especially effective in patients with serious pulmonary diseases such as asthma, cystic fibrosis (CF), chronic obstructive pulmonary (COPD) disease, and lung cancer [2].…”

Section: Introductionmentioning

confidence: 99%

Formulation and In Vitro and In Silico Characterization of “Nano-in-Micro” Dry Powder Inhalers Containing Meloxicam

et al. 2021

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Pulmonary delivery has high bioavailability, a large surface area for absorption, and limited drug degradation. Particle engineering is important to develop inhalable formulations to improve the therapeutic effect. In our work, the poorly water-soluble meloxicam (MX) was used as an active ingredient, which could be useful for the treatment of non-small cell lung cancer, cystic fibrosis, and chronic obstructive pulmonary disease. We aimed to produce inhalable “nano-in-micro” dry powder inhalers (DPIs) containing MX and additives (poly-vinyl-alcohol, leucine). We targeted the respiratory zone with the microcomposites and reached a higher drug concentration with the nanonized active ingredient. We did the following investigations: particle size analysis, morphology, density, interparticular interactions, crystallinity, in vitro dissolution, in vitro permeability, in vitro aerodynamics (Andersen cascade impactor), and in silico aerodynamics (stochastic lung model). We worked out a preparation method by combining wet milling and spray-drying. We produced spherical, 3–4 µm sized particles built up by MX nanoparticles. The increased surface area and amorphization improved the dissolution and diffusion of the MX. The formulations showed appropriate aerodynamical properties: 1.5–2.4 µm MMAD and 72–76% fine particle fraction (FPF) values. The in silico measurements proved the deposition in the deeper airways. The samples were suitable for the treatment of local lung diseases.

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“…Based on the importance that the development of giBCS has for the regulatory and development aspects of oral bioequivalent drugs [ 135 ], it is normal to consider the full development of the iBCS as a useful tool in the bioequivalence of inhaled drugs. Furthermore, various are the authors that mention the projections of the iBCS in decision making on how to better address the bioequivalence of OIDPs, both from the regulatory point of view and its analysis and development [ 136 , 137 , 138 ].…”

Section: Future Of Bioequivalence For Inhaled Drugs: Biopharmaceutical Classification System For Inhaled Medicines (Ibcs)mentioning

confidence: 99%

Innovating on Inhaled Bioequivalence: A Critical Analysis of the Current Limitations, Potential Solutions and Stakeholders of the Process

Gallegos-Catalán

Warnken²,

Bahamondez-Canas

et al. 2021

Pharmaceutics

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Orally inhaled drug products (OIDPs) are an important group of medicines traditionally used to treat pulmonary diseases. Over the past decade, this trend has broadened, increasing their use in other conditions such as diabetes, expanding the interest in this administration route. Thus, the bioequivalence of OIDPs is more important than ever, aiming to increase access to affordable, safe and effective medicines, which translates into better public health policies. However, regulatory agencies leading the bioequivalence process are still deciding the best approach for ensuring a proposed inhalable product is bioequivalent. This lack of agreement translates into less cost-effective strategies to determine bioequivalence, discouraging innovation in this field. The Next-Generation Impactor (NGI) is an example of the slow pace at which the inhalation field evolves. The NGI was officially implemented in 2003, being the last equipment innovation for OIDP characterization. Even though it was a breakthrough in the field, it did not solve other deficiencies of the BE process such as dissolution rate analysis on physiologically relevant conditions, being the last attempt of transferring technology into the field. This review aims to reveal the steps required for innovation in the regulations defining the bioequivalence of OIDPs, elucidating the pitfalls of implementing new technologies in the current standards. To do so, we collected the opinion of experts from the literature to explain these trends, showing, for the first time, the stakeholders of the OIDP market. This review analyzes the stakeholders involved in the development, improvement and implementation of methodologies that can help assess bioequivalence between OIDPs. Additionally, it presents a list of methods potentially useful to overcome some of the current limitations of the bioequivalence standard methodologies. Finally, we review one of the most revolutionary approaches, the inhaled Biopharmaceutical Classification System (IBCs), which can help establish priorities and order in both the innovation process and in regulations for OIDPs.

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Contemporary Formulation Development for Inhaled Pharmaceuticals

Cited by 29 publications

References 258 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Formulation and In Vitro and In Silico Characterization of “Nano-in-Micro” Dry Powder Inhalers Containing Meloxicam

Innovating on Inhaled Bioequivalence: A Critical Analysis of the Current Limitations, Potential Solutions and Stakeholders of the Process

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