Biopharmaceutics Aspects of Dermally Applied Drug Delivery Systems
Tapash K. Ghosh in Dermal Drug Delivery, 2020
In the absence of quantifiable systemic level, traditional IVIVC from topical dosage forms for local therapy is not feasible. For TDS (be it matrix, reservoir or semisolid type), establishment of an IVIVC may be possible. Transdermal dosage forms are designed for extended release; however, the drug release and permeability mechanism from these systems are more complicated than oral extended release dosage forms. Transdermal IVIVC generally uses drug permeability data whereas oral drug IVIVC uses dissolution data. In order to obtain in vitro permeability data, excised human skin or animal skin are used to conduct an in vitro test using a diffusion cell. Some studies used artificial membrane to conduct permeability tests. A few studies employed USP apparatus, including the use of Apparatus 5 (Paddle over Disk Method), Apparatus 6 (Rotating Cylinder Method) and Apparatus 7 (Reciprocating Holder Method) as described in USP General Chapter <724> describing Drug Release for transdermal systems (TDS) and other dosage forms to obtain drug release data from TDS [5]. However, drug release data might not be appropriate to be used to simulate the process of in vivo drug penetration through the skin.
Performance Testing
Marc B. Brown, Adrian C. Williams in The Art and Science of Dermal Formulation Development, 2019
A relatively recent development is the Strat-M™ synthetic membrane which is described as being constructed of two layers of polyethersulfone (PES, more resistant to diffusion) on top of one layer of polyolefin (more open and permeable). These polymeric layers create a porous structure with a gradient across the membrane in terms of pore size and diffusivity. The porous structure is impregnated with a proprietary blend of synthetic lipids, imparting additional skin-like properties to the synthetic membrane. The manufacturers claim that permeation through Strat-M correlates closely to human skin. It should be noted that most of the data to support this correlation was conducted with approved topical drugs with ideal physiochemical properties rather than novel agents or formulations.
Stimulus-Secretion Coupling: Exocytosis
Stephen W. Carmichael, Susan L. Stoddard in The Adrenal Medulla 1986 - 1988, 2017
Kolchinskaya, Chaika and Kravets (1988) examined the interaction of chromaffin cell membrane fragments with artificial phospholipid membranes. Membrane fragments obtained from bovine adrenal medulla were shown to bind tritiated nitrendipine. The interaction of these fragments with an artificial phospholipid bilayer induced preferable conductance for calcium and barium ions. This effect was blocked by cadmium and stimulated by a calcium channel agonist, BAY K 8644. Kolchinskaya et al. (1988) suggested that fragments of chromaffin cell membrane containing functional calcium channels can be incorporated into an artificial membrane.
Recent advancements to measure membrane mechanical and transport properties
Published in Journal of Liposome Research, 2022
Since the structure and chemical composition of liposomes can be finely tuned and controlled by simply varying their precursors during the preparation, a broad range of various physical properties shared by their biological counterparts may be mimicked. The major benefits of synthetic membrane vesicles being flexible and easy to handle, help the researchers to characterize the physical properties of cell membranes in a better way (Evans and Needham 1987, Lasic 1993, Phapal et al.2017). Besides the use of liposomes as a model for biological membranes (Lasic 1993), they are widely used in the controlled and targeted release of both hydrophilic and lipophilic drugs in vivo (Storm et al.1987, McCalden 1990). The size of liposomes plays a crucial role in drug delivery and model membranes. According to their size and the number of bilayers (i.e. lamellarity), liposomes are generally classified into small unilamellar vesicles (SUVs) (<100 nm), large unilamellar vesicles (LUVs) (>100 nm), giant unilamellar vesicles (GUVs) (>1000 nm), oligolamellar vesicles (OLVs) (100–1000 nm), multilamellar vesicles (MLVs) (>500 nm), and multivesicular vesicles (MVVs) (>1000 nm) (Lasic 1993, Has and Sunthar 2020). Although liposomes can be formulated in the size ranging from a few nanometres to several micrometres, it is suggested that the vesicles of 50–200 nm size are optimal for drug delivery applications (Dhand et al.2014, Has et al.2018). GUVs, on the other hand, are easy to employ as models for cell membranes because of their large size that can be visualized and manipulated directly using microscopy techniques (Dimova et al.2006).
How can we better realize the potential of immobilized artificial membrane chromatography in drug discovery and development?
Published in Expert Opinion on Drug Discovery, 2020
Biological membranes are essential for drug efficacy, triggering research in the field of artificial membrane technology in the aim to face impediments in the early drug discovery phase. The development of IAM chromatography, by immobilizing crucial phospholipids on silica support, has been a key advancement toward this direction, providing an intermediate step between in silico and more complex in vitro assays. Initially, IAM Chromatography was intended to meet the criticism toward the octanol-water system and to provide an alternative to traditional lipophilicity. However, understanding of the molecular factors, involved in IAM retention, which define it as a border case between passive diffusion and binding, highlights many other applications. Thus, one measurement on an IAM column provides information for more issues relevant to multi-objective drug discovery, while it offers the possibility to determine more than one index, allowing the medicinal chemist to choose the most appropriate for his/her purpose. Isocratic retention factors logkw, their gradient elution alternative CHI, as well as their discrete polar component Δlogkw have been so far successfully used to model ADME properties, in particular permeability through essential biological barriers, such as human intestinal and blood–brain barrier. The binding component in IAM retention permits rapid estimation of complex pharmacokinetic properties that involve nonspecific binding, while increased IAM retention may be an indication for phospholipidosis [20], extending its use to drug safety. Moreover, IAM retention may be associated with drug intracellular concentration, cell accumulation, or retention [17].
Elucidation of clearance mechanism of TP0463518, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor: does a species difference in excretion routes exist between humans and animals?
Published in Xenobiotica, 2022
Hiroki Takano, Akiko Mizuno-Yasuhira, Jun-ichi Yamaguchi, Hiromi Endo
The membrane or cell permeability of TP0463518 was evaluated using PAMPA, LLC-PK1 cells, and MDCKII cells. The artificial membrane permeability of TP0463518 across a PAMPA membrane was 7.7 × 10−6 cm/s (pH7.4). The cell permeabilities of TP0463518 across control LLC-PK1 cell monolayers and control MDCKII cell monolayers were 1.17–1.32 × 10−6 and 1.16–1.79 × 10−6 cm/s, respectively, as shown in Tables 1 and 2. TP0463518 exhibited a low permeability across an artificial membrane and cell monolayers.
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