Inhibition of intestinal metabolism of the antiviral ester prodrug bis(POC)-PMPA by nature-identical fruit extracts as a strategy to enhance its oral absorption: an in vitro study.

Purpose: To explore the usefulness of fruit extracts as enhancers of the oral absorption of esterase-sensitive prodrugs.

Methods: Inhibition of esterase-mediated degradation by nature-identical fruit extracts was evaluated using 1) p-nitrophenylacetate (model substrate for esterase-activity) in rat intestinal homogenates and 2) bis(isopropyloxycarbonyloxymethyl)-(R)-9-[(2-phosphonomethoxy++ +)propyl]adenine [bis(POC)-PMPA] (esterase-sensitive prodrug of the antiviral agent PMPA) in Caco-2 cell homogenates and in intestinal homogenates from rat, pig and man. Subsequently, transport of the ester prodrug was studied across Caco-2 monolayers in the presence or absence of fruit extracts.

In vitro biodegradation study of acetyl and methyl inulins by Bifidobacteria and inulinase.

The purpose of this study was to investigate if acetylated and methylated inulins can be degraded by inulinase from Aspergillus niger and by Bifidobacteria, in order to determine their potential in colonic drug delivery. Methyl and acetyl inulins were synthesized by the reaction of inulin (Raftiline HP) with methyl sulfate and acetic anhydride, respectively. The degree of substitution (DS) and the structure of the reaction products were confirmed by 13C-NMR.

Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits.

Lyophilized polyacrylic acid powder formulations loaded with apomorphine HCl were prepared and the influence of drug loading on in vitro release and in vivo absorption studied after intranasal administration in rabbits. These formulations prepared with Carbopol 971P, Carbopol 974P and polycarbophil sustained apomorphine release both in vitro and in vivo. The in vitro release rate and mechanism were both influenced by the drug loading.

Inulin hydrogels as carriers for colonic drug targeting. Rheological characterization of the hydrogel formation and the hydrogel network.

Free radical polymerization converts aqueous solutions of methacrylated inulin into cross-linked hydrogels. The purpose of this work was to study the hydrogel formation and to characterize the fully cured hydrogels. The gelation process of aqueous solutions of methacrylated inulin was monitored as a function of time by means of linear oscillatory shear measurements, at a fixed frequency and amplitude.

Colonic drug targeting.

Specific targeting of drugs to the colon is recognized to have several therapeutic advantages. Drugs which are destroyed by the stomach acid and/or metabolized by pancreatic enzymes are slightly affected in the colon, and sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Treatment of colonic diseases such as ulcerative colitis, colorectal cancer and Crohn's disease is more effective with direct delivery of drugs to the affected area.

Carrier mechanisms involved in the transepithelial transport of bis(POM)-PMEA and its metabolites across Caco-2 monolayers.

Purpose: To investigate the role of carrier mechanisms in: [1] the polarized transport of the bis(pivaloyloxymethyl)- [bis(POM)-] ester prodrug of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA] and [2] the directional secretion of its metabolites.

Methods: Caco-2 monolayers were used to study the modulation effect of carriers on the transport of bis(POM)-PMEA and the efflux of intracellularly formed metabolites mono(POM)-PMEA and PMEA from the cells. The interaction of bis(POM)-PMEA and its metabolites with the efflux mechanisms present in Caco-2 monolayers was investigated by testing the effect of various concentrations of verapamil (30, 100, 300, microns) or indomethacin (10-500 microns) on transport and efflux.

Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine in mice.

To overcome the low oral bioavailability of the highly potent and selective antiretroviral agent (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA), a new lipophilic ester derivative, i.e., the bis(isopropyloxycarbonyloxymethyl)-ester [bis(POC)-PMPA], was prepared.

Comparison of the disposition of ester prodrugs of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA] in Caco-2 monolayers.

Purpose: To evaluate the potential of several bis-ester prodrugs of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir) to enhance the oral absorption of PMEA.

Methods: Caco-2 monolayers were used to estimate intestinal transport and metabolism of the bis(pivaloyloxymethyl)-ester [bis(POM)-] and a series of bis(S-acyl-2-thioethyl)-esters [bis(SATE)-] of PMEA. An LC-MS method was used for the identification of unknown metabolites which were formed from the SATE-esters.

Inulin hydrogels as carriers for colonic drug targeting: I. Synthesis and characterization of methacrylated inulin and hydrogel formation.

Purpose: Vinyl groups were introduced in inulin chains in order to form hydrogels of this sugar polymer by free radical polymerization.

Methods: Inulin was reacted with glycidyl methacrylate in N,N-dimethylformamide in the presence of 4-dimethylaminopyridine as catalyst. 1H and 13C NMR spectroscopy were used for the characterization of the obtained reaction product.

In vivo evaluation of a colon-specific drug delivery system: an absorption study of theophylline from capsules coated with azo polymers in rats.

Azo polymers based upon 2-hydroxyethyl methacrylate, methyl methacrylate, and methacrylic acid, and containing N,N'-bis [(methacryloyloxyethyl)oxy(carbonylamino)]azobenzene as azo aromatic agent were evaluated in vivo as coating for colon-specific drug delivery. The gastrointestinal absorption of theophylline from capsules coated with the azo polymers was examined in the proximal part of the small intestine and the cecum of male Wistar rats. The capsules were surgically inserted in the region of interest.

The relation between swelling properties and enzymatic degradation of azo polymers designed for colon-specific drug delivery.

Copolymers of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA), and terpolymers of HEMA, MMA, and methacrylic acid (MA) were synthesized in the presence of N,N'-bis(methacryloyloxyethyloxycarbonylamino)azobenzene (B(MOEOCA)AB) and evaluated as coating materials for colonic targeting. The release of ibuprofen, a model drug, from capsules coated with the azo polymers was investigated in vitro. The release medium was made up of sonicated rat cecal content, benzyl viologen, glucose-6-phosphate, glucose-6-phosphate dehydrogenase, and nicotine amide dinucleotide phosphate (NADP) in phosphate buffer (pH 6.