title: Bromocriptine tablet of self-microemulsifying system adsorbed onto porous carrier to stimulate lipoproteins secretion for brain cellular uptake.
abstract: Both low solubility and high hepatic metabolism cause low oral bioavailability of bromocriptine mesylate (BM) leading to very low drug amount in brain. Self-microemulsion (SME) tablets were developed to improve solubility, stimulate lipoprotein synthesis to promote lymphatic transport, avoid hepatic metabolism and target drug to brain. SME liquid containing castor oil, Tween(®) 80 and Cremophor(®) EL was prepared and then adsorbed onto solid carries, Aerosil(®)200, Aeroperl(®)300 or NeusilinUS2(®), yielding SME powders. The optimal ratios of SME liquid to carriers determined from flowability and scanning electron photomicrographs before tableting were 1.5:1, 2:1 and 2.5:1 for Aerosil(®)200, Aeroperl(®)300 and NeusilinUS2(®), respectively. Only Aeroperl(®)300 SME tablet had comparable dissolution to BM commercial tablet. From in vitro study in Caco-2 cells, fluorescein loaded SME tablet showed higher uptake than fluorescein loaded in either oil or surfactant. Although significantly lower amount of drug was permeated from SME tablet than from commercial tablet, higher drug uptake was obviously observed (P<0.05). In addition, higher lipoprotein synthesis expressing as content of apolipoprotein B (apo-B) found in secreted chylomicron resulted in higher drug uptake in co-culture of brain endothelial cells (bEnd.3) and astrocytes (CTX TNA2) from drug loaded SME tablet when compared to commercial tablet (P<0.05) due to binding of apo-B to LDL receptors expressed on the surface of endothelial cells. Therefore, tablet of SME adsorbed onto porous carrier potentially delivered BM to brain via lymphatic transport by increasing the lipoprotein synthesis.
authors.affiliation: Department of Pharmaceuticals and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Sirigul
authors.initials: S
authors.lastname: Thongrangsalit
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand.
authors.forename: Thawatchai
authors.initials: T
authors.lastname: Phaechamud
authors.affiliation: Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Vimolmas
authors.initials: V
authors.lastname: Lipipun
authors.affiliation: Department of Pharmaceuticals and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand. Electronic address: garnpimol.r@chula.ac.th.
authors.forename: Garnpimol C
authors.initials: GC
authors.lastname: Ritthidej
mesh_terms: D000327:Adsorption; D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001971:Bromocriptine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D004655:Emulsions / Q000737:chemistry*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D016062:Porosity; D051381:Rats; D013607:Tablets
chemical_list: D000978:Antiparkinson Agents; D017077:Culture Media, Conditioned; D004337:Drug Carriers; D004655:Emulsions; D008074:Lipoproteins; D013607:Tablets; D001971:Bromocriptine
keywords: Brain cellular uptake; Bromocriptine; Lipoprotein synthesis; Lymphatic transport; Solid self-microemulsion