Hydrophilic absorption enhancement

Sakai, M., Noach, A.B., Blom-Roosemalen, M.C., de Boer, A.G., and Breimer, D.D., Absorption enhancement of hydrophilic compounds by Verapamil in Caco-2 cell monolayers, Biochem. Pharmacol., 48,1199,1994. 

Noach, A.B., M.C. Blom-Roosemalen, A.G. de Boer, and D.D. Breimer. 1995. Absorption enhancement of a hydrophilic model compound by verapamil after rectal administration to rats. J Pharm Pharmacol 47 466. 

In the past two decades, many studies have tested adjuvants that act by either permeabilizing the rectal mucosa or inhibiting drug degradation. Oral and rectal routes of drug administration are unsuitable for adequate absorption of various compounds with a peptide or protein structure and of several hydrophilic antibiotics. The use of absorption enhancers, e.g., salicylates, enamines, surfactants, and straight-chain fatty acids, has gained wide interest... 

The factors that hinder the absorption of peptides through the intestinal epithelium, namely high molecular weight, charge, and hydrophilicity also affect their absorption through the oral mucosa. Combinations of mucoadhesive systems, absorption enhancers, and enzyme inhibitors have enabled better absorption. 

Chitosan as Absorption Enhancer of Hydrophilic Macromolecular Drugs... 

Chitosan and its derivatives have been applied to enhance the absorption of proteins (e.g., insulin) and polypeptides (e.g., buserelin). /V-Trimethyl chitosan chloride exhibits opening of the tight junctions of the intranasal and intestinal epithelial cells so that the transport of hydrophilic compounds is increased through the para-cellular transport pathway. The absorption-enhancing effect was concentration dependent and reversible and dependent on the integrity of the intercellular cell contact zone. 

At all mucosal sites, the coadministration of absorption enhancers is normally necessary to achieve therapeutic relevant plasma levels of (large) hydrophilic molecules such as peptides or proteins. Table 1 gives an overview of the most used and researched absorption enhancers and their possible mechanism of action. 

Finally, it should be noted that during the last decade both weakly crosslinked poly(acrylic acid) derivatives and chitosan derivatives were described as safe penetration enhancers for hydrophilic compounds especially as they can trigger mechanisms of tight junction opening of mucosal tissues and did not show acute toxicity. Poly(acrylic acid) derivatives were shown to have excellent mucoadhesive properties and can inhibit the activity of gut enzymes, such as trypsin, chymo-trypsin, and carboxypepsidases. Chitosan salts and Ni-trimethylchitosan chloride revealed to be potential absorption enhancers for nasal absorption of calcitonin and insulin and for the intestinal absorption of buserilin.f ... 

Although the objective of most absorption enhancers is to avoid direct interaction with the mucosal membrane, cell permeation enhancers use this as a means to increase drug absorption. One form of enhancer currently of interest consists of glycosylated molecules, or facial amphiphiles. It is claimed that these compounds temporarily increase membrane permeability. Molecules are designed to self-assemble in membranes to form transient pores that permit hydrophilic com-poimds to cross the membrane. This technology has considerable potential for absorption enhancement. No adverse effects have been reported to date. ... 

Mucus also appears to be a barrier to the permeation enhancing effect of polymeric or monomeric absorption enhancers. In the aforementioned TMC studies, the enhancement effect (enhancement ratio = permeation rate of the drug in the presence of polymer vs. permeation rate of the drug alone) was higher in vitro (Caco-2 cells no mucus secretion) than the absorption enhancement in vivo. Meaney and O Driscoll studied the effect of mucus on the permeation properties of a micellar system consisting of sodium taurocholate in a coculture of Caco-2 and Ht29GlucH (mucin-secreting) cells. They found that the effect of bile salts on the permeation of hydrophilic paracellular markers was increased in the cocultures that were pretreated with the mucolytic compound A/-acetylcysteine. 

Some hydrophilic drugs such as antibiotics and peptide drugs are not easily absorbed from the rectum and absorption enhancers are required. 

Intemasal delivery of peptide and protein drugs is severely restricted by pre-systemic elimination due to enz5miatic degradation or mucociliary clearance and by the limited extent of mucosal membrane permeability. a-CyD has been shown to remove some fatty acids from nasal mucosa and to enhance the nasal absorption of leuprolide acetate in rats and dogs. The utility of chemically modified CyDs as absorption enhancers for peptide drugs in rats has been demonstrated. For example, DM-P-CyD was shown to be a potent enhancer of insulin absorption in rats, and a minimal effective concentration of DM-(3-CyD for absorption enhancement exerted only a mild effect on the in vitro ciliary movement.The scope of interaction of insulin with CyDs is limited, because CyDs can only partially include the hydrophobic amino acid residues in peptides with small stability constants. Under in vivo conditions, these complexes will readily dissociate into separate components, and hence the displacement by membrane lipids may further destabilize the complexes. The direct interaction of peptides with CyDs is therefore of minor importance in the enhancement of nasal absorption. Of the hydrophilic CyDs tested, DM- 3-CyD had the most prominent inhibitory effect on the enzymatic degradation of both BLA and insulin in rat nasal tissue homogenates. Because of the limited interaction between peptides and CyDs,... 

The permeability of drugs that are poorly absorbed because of their hydrophilic character can be influenced by manipulating either the drug or the imembrane. Therefore, most strategies for absorption enhancement either change the permeability properties of the epithelial cells or alter the physicochemical properties cf the compound itself. Currently, three general strategies can be employed to increase the transport of a solute across an epithelial membrane ... 

Everted gut sacs are used mainly to quantily paracellular transport of hydrophilic molecules and to estimate the effects, including toxicity (release of intracellular enzymes, histological characterization), of potent absorption enhancers. They have also been exploited for studying transport of macromolecules and liposomes [22, 56, 58]. The transport of paracellular markers (e.g., mannitol) shows the same apparent permeability as has been reported for low molecular weight hydrophilic compounds in human perfusion studies. This similarity also applies to highly permeable molecules that cross the epithelium by a transcellular route. 

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