Abstract
Antihistamines are capable of blocking mediator responses in allergic reactions including allergic rhinitis and dermatological reactions. By incorporating various H1 receptor antagonists into a lipid cubic phase network, these active ingredients can be delivered locally over an extended period of time owing to the mucoadhesive nature of the system. Local delivery can avoid inducing unwanted side effects, often observed after systematic delivery. Lipid-based antihistamine delivery systems are shown here to exhibit prolonged release capabilities. In vitro drug dissolution studies investigated the extent and release rate of two model first-generation and two model second-generation H1 antagonist antihistamine drugs from two monoacyglycerol-derived lipid models. To optimize the formulation approach, the systems were characterized macroscopically and microscopically by small-angle X-ray scattering and polarized light to ascertain the mesophase accessed upon an incorporation of antihistamines of varying solubilities and size. The impact of encapsulating the antihistamine molecules on the degree of mucoadhesivity of the lipid cubic systems was investigated using multiparametric surface plasmon resonance. With the ultimate goal of developing therapies for the treatment of allergic reactions, the ability of the formulations to inhibit mediator release utilizing RBL-2H3 mast cells with the propensity to release histamine upon induction was explored, demonstrating no interference from the lipid excipient on the effectiveness of the antihistamine molecules.
Highlights
Histamine, a biogenic amine whose synthesis in tissue mast cells is driven by the decarboxylation of the free amino acid histidine,[1] is released in mammals in an inflammatory response to tissue injury or allergic reactions through a complex cascade of mediator release and interactions.[1]
Cetirizine dihydrochloride, azelastine hydrochloride, carbinoxamine maleate, and diphenhydramine hydrochloride were purchased from Merck at greater than or equal to 98% purity; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) Thiazolyl Blue Tetrazolium Bromide (M5655), CaCl2, SDS (75746), KCl, CHAPS detergent, ammonia, HCl (320331), hydrogen peroxide, glucose, mucin from bovine submaxillary gland (M3895), Dulbecco’s Modified Eagle’s Medium (D5796), and fetal bovine serum (F7524), were all purchased from Merck
Both host lipids are generally regarded as safe (GRAS) listed digestive products of triglycerides present in the gastrointestinal tract, and they were selected here on account of their biodegradable nature and inherent ability to maintain the cubic phase under physicological conditions.[67,72]
Summary
A biogenic amine whose synthesis in tissue mast cells is driven by the decarboxylation of the free amino acid histidine,[1] is released in mammals in an inflammatory response to tissue injury or allergic reactions through a complex cascade of mediator release and interactions.[1]. The primary course of treatment for managing such allergies is oral dosage forms of antihistamines that target the histamine receptors present on the various cells in the body, of which four have been identified: H1−4. H1 is a receptor present on endothelial and smooth muscle cells that is the target of the majority of marketed and identified antihistamine molecules. More than 45 H1-antihistamines are commercially available[9] and are referred to as inverse agonists,[10] which bind H1 receptors without effecting a response, to inhibit the action of histamine through a competitive or pharmacological antagonism.[11] They have proven their ability to inhibit mast cell activation and subsequent histamine release, likely through the downregulation of calcium ions in the cell, the mechanism is still not fully understood.[9,12−14]
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