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Development of Ophthalmic Formulations
Published in Sandeep Nema, John D. Ludwig, Parenteral Medications, 2019
Paramita Sarkar, Martin Coffey, Mohannad Shawer
The cornea offers the major site of drug diffusing into the anterior chamber of the eye, especially for small molecules. Drug penetration through the cornea can be by passive diffusion or by active transport mechanisms. The two main factors influencing the passive diffusion are lipophilicity and molecular size. Small lipophilic compounds generally penetrate through the epithelium via the intracellular route, while small hydrophilic compounds are limited to the paracellular route (partitioning of small lipophilic compounds into the cornea causes it to act as a depot). Large hydrophilic compounds (>5,000 Da) are generally excluded by the epithelium tight junctions [30]. The fraction of a lipophilic compound penetrating through the cornea is 20 times more than a hydrophilic molecule of similar molecular size [31]. A logD value of 2–3 for beta-blockers was reported to provide optimal corneal permeation [32]. Molecular size is also an important factor for small hydrophilic and lipophilic compounds. Increasing the molecular size from 0.35 to 0.95 nm reduces the permeability through the cornea, and conjunctiva, significantly [31].
Biological Fate of Nanoparticles
Published in C. Anandharamakrishnan, S. Parthasarathi, Food Nanotechnology, 2019
S. Parthasarathi, C. Anandharamakrishnan
On the other hand, a wide range of drugs including genes need to enter the cells to function properly; however, cell membranes are not permeable to them. So understanding these biological barriers is necessary for fabricating engineered nanoparticles with the ability to bypass these barriers and reach the target cells. Two main mechanisms are involved in the crossing of internal barriers: (1) passive and active transport, and (2) endocytosis. In passive diffusion, concentration gradient across the barrier and solute governs the passage of solutes between cells (i.e. paracellular) or across cells (i.e. transcellular). In the case of passive facilitated diffusion, transport is facilitated by influx transporters and the passage through the barrier depends on size, concentration gradient, hydrophobicity, polarity, and protein binding. In the case of active transport, the passage is mediated by influx transporters and it takes place against concentration gradient with energy expenditure. Endocytosis is another mechanism followed by nanoparticles for crossing internal barriers. Endocytosis of nanoparticles involves engulfment in membrane invagination and subsequent inclusion into the cytoplasm of the cell (Pietroiusti et al., 2013).
Nanobased Cns Delivery Systems
Published in Anil K. Sharma, Raj K. Keservani, Rajesh K. Kesharwani, Nanobiomaterials, 2018
Rahimeh Rasouli, Mahmood Alaei-Beirami, Farzaneh Zaaeri
Movement of solute across membrane driven by the physicochemical concentration gradient (from high concentration to low concentration) without consumption of (chemical) energy until omission of gradient is termed passive diffusion. Rate of passive diffusion depends on the membrane permeability, solute lipophilicity and molecular weight. Solutes with molecular weight less than 400 Dalton pass BBB using passive diffusion. Most of small molecules are not able to pass BBB considering high molecular weight or preset water solubility (Camenisch et al., 1998; Cohen and Bangham, 1972; van de Waterbeemd et al., 1998). Then it could be concluded that, low concentration, big size and preset water solubility (more hydrogen binding donors) prevent transporting BBB. Because of ATP-Binding caste proteins in BBB which efflux agents to blood, most of agent could not reach effective dose in CNS despite employing passive diffusion. Diffusions could be transcellular (lipophilic agents like ethanol) and paracellular (like cellular Sucrose that limited because of tight junctions).
Significant biopolymers and their applications in buccal mediated drug delivery
Published in Journal of Biomaterials Science, Polymer Edition, 2021
Drug absorption in the buccal cavity occurs by passive diffusion of the nonionized species (a process governed primarily by a concentration gradient) through the intercellular spaces of the epithelium. The passive transport (primary transport mechanism) of non-ionic species takes place across the lipid membrane of the buccal cavity. The buccal mucosa has a lipoidal barrier for the passage of drugs therefore the more lipophilic the drug molecule, the more readily it is absorbed through mucosal membranes. The dynamics of buccal absorption of drugs could be adequately described by the first-order rate process [4]. In the buccal route of drug delivery, the absorption of the drug takes place by two pathways. One pathway is intracellular (transcellular) and another is intercellular (paracellular). A larger molecule undergoes the intercellular pathway, where there is the penetration of layers, resulting in the modification of the intercellular substances in the upper surface layer. The lipid layer plays a vital role in the intercellular pathway, in case the lipids and peptides are hydrophilic and having higher molecular weight. The absorption of the drug via the buccal route is found to be affected by the pH. With an increase in the pH, the absorption of the drug decreases and vice versa. Most of the drug absorption via the intercellular pathway occurs by passive diffusion. Previous studies have reported that using mucoadhesive biopolymers, drugs can be safely and effectively delivered through the buccal route for better treatment [8, 9].
Improved skin-permeated diclofenac-loaded lyotropic liquid crystal nanoparticles: QbD-driven industrial feasible process and assessment of skin deposition
Published in Liquid Crystals, 2021
Tejashree Waghule, Shalini Patil, Vamshi Krishna Rapalli, Vishal Girdhar, Srividya Gorantla, Sunil Kumar Dubey, Ranendra Narayan Saha, Gautam Singhvi
DDE is a low molecular weight compound (369.3 g/mol) which is amphiphilic. It has high protein binding thus more affinity towards albumin which gets accumulated in high concentrations in the surrounding region of the inflamed tissue and joints. DDE exhibits pKa of 4.0, thus remain un-ionised at acidic pH around inflamed tissues, cross the membrane barriers efficiently and accumulate in the neutral intracellular space where COX-2 enzymes are present. Due to these reasons, DDE is considered as a suitable candidate for topical delivery in pain management [3,4]. Topical NSAIDs act on the peripheral pain receptors (nociceptors) which are present in abundant quantities in the articular tissues with relatively less central effects. The topical treatment of pain requires improved concentration of drug in the synovial tissue and muscles as compared to the plasma concentrations. Thus, for the topical DDE to show effect, the drug first has to overcome the outermost stratum corneum barrier of the skin, then diffuse/permeate into the deeper skin layers (epidermis, dermis, muscle/synovial tissue) and reach the site of action in therapeutic concentrations to inhibit the COX-2 enzyme. The movement of drugs through the skin follows Fick’s law of diffusion through the intracellular pathway. Drug transport follows the passive diffusion process followed by partitioning into tissues. Although improved permeation can cause some drug to enter into the systemic circulation (present in the dermis), the plasma levels fall 0.2–8% as compared to after oral administration. Thus, the systemic exposure can be reduced significantly [3,5].
Fatigue: Is it all neurochemistry?
Published in European Journal of Sport Science, 2018
One big advantage of animal research is the ability to use in vivo brain microdialysis. This technique is based on the kinetic dialysis principle. A small microdialysis catheter or probe is inserted in the area of interest. This probe functions as a blood capillary and is connected to inlet and outlet tubing. Its membrane, permeable to water and small solutes, separates two fluid compartments. The membrane is continuously being flushed on one side (inlet) with a solution that lacks the substances of interest, whereas the other side (outlet) is in contact with the extracellular space. This creates a concentration gradient which in turn causes passive diffusion to take place. Brain microdialysis allows to have direct analysis of extracellular neurotransmitters and metabolites from the brain of resting or active animals with only limited tissue trauma (Meeusen & De Meirleir, 1995; Meeusen et al., 2006). Two studies by Hattori, Li, Matsui, and Nishino (1993) and Hattori, Naoi, and Nishino (1994) – using in vivo brain microdialysis – showed that only 20 min of running on a treadmill significantly increased DA concentration in the rat striatum. Hasegawa, Yazawa, Yasumatsu, Otokawa, and Aihara (2000) measured the neurotransmitter concentrations in the preoptic area and anterior hypothalamus (PO/AH) – the thermoregulatory centre of the brain – in exercising rats, using an in vivo microdialysis technique. They reported that the extracellular level of DOPAC and HVA, both DA metabolites, in the PO/AH increased during treadmill exercise, whereas the levels of serotonin and 5-HIAA were left unchanged. Hasegawa et al. (2000) concluded that DA is the prime candidate for thermoregulatory substances working in the PO/AH.