Shimon Amselem

Improved Oral Delivery of Desmopressin via a Novel Vehicle: Mucoadhesive Submicron Emulsion

AbstractPurpose. Desmopressin acetate (DDAVP) is used parenterally and intranasally in the control of several diseases. Oral administration of DDAVP, while most desirable, is not practical presently due to low bioavailability. The objective of the present study was to explore the feasibility for employing oil-in-water MucoAdhesive SubMicron Emulsion (MA-SME), a novel mucoadhesive vehicle with polymer-coated droplets, for enhanced oral delivery of DDAVP. Methods. We used a modified pharmacopeal method, based on measurement of the antidiuretic activity, for the assessment of oral delivery of DDAVP in rats. DDAVP formulated in two MA-SME preparations, in non-mucoadhesive SME (plain-SME), in saline and in other control solutions was administered orally to rats via a stomach tube at a dose of 0.5 units/kg. At various times following DDAVP administration, water was given via a stomach tube. Excretion times for 30% and 60% of the total water load were measured. Results. Excretion times for DDAVP in MA-SME formulations were always longer (up to 2-fold) than those following DDAVP in saline. By contrast, excretion times for DDAVP in plain-SME and in non-SME Carbopol (a Mucoadhesive polymer) solution were virtually identical to those for DDAVP in saline. Conclusions. Formulations of MA-SME were shown to generate substantial enhancement (up to 12-fold) of the rat oral bioavailability of DDAVP with regard to simple saline solution of the drug. From the results it is also evident that MA-SME, but not plain-SME or non-SME Carbopol solution, is responsible for the enhancement of oral delivery of DDAVP in rats.

The role of molecular physicochemical properties and apolipoproteins in association of drugs with triglyceride‐rich lipoproteins: in‐silico prediction of uptake by chylomicrons

Objectives The uptake of drugs by chylomicrons is a key element in both intestinal lymphatic transport and postprandial alterations in the disposition profile of lipophilic drugs. The aim of this article was to elucidate the factors that affect this phenomenon.

Formulation development for a zidovudine chemical delivery system 1. Parenteral dosage forms

Abstract A chemical delivery system for zidovudine (AZT-CDS) has been shown to increase brain levels of the parent antiretroviral agent while at the same time reducing blood concentrations. Such selectivity may improve the therapeutic index for AZT. Unfortunately, the AZT-CDS is lipophilic and labile to oxidative and hydrolytic degradation thereby complicating the development of a convenient formulation. The configuration of several potentially acceptable parenteral dosage forms using cyclodextrin-based systems are described herein. A prototype formulation was developed using the AZT-CDS potassium salt in an aqueous matrix of 2-hydroxypropyl-β-cyclodextrin (HPβCD) (15% w/v) and Na 3 PO 4 (0.005 M). While alkaline, the formulation was associated with a low buffering capacity and was not irritating in a rat tail model of extravasation. Systemic administration of this dosage form provided for, in addition to improved brain levels of AZT and an increased brain to blood ratio, improved bioavailability compared to a dimethyl sulfoxide (DMSO) vehicle.

Formulation development for a zidovudine chemical delivery system 2. Towards oral and non-parenteral dosage forms

Steps toward the development of an oral dosage form for a dihydronicotinate chemical delivery system for zidovudine (AZT-CDS) were examined. Administration of the AZT-CDS by gavage to rats indicated poor bioavailability consistent with the acid lability of the CDS. Furthermore, administration of the AZT-CDS in dimethyl sulfoxide (DMSO) intraintestinally did not result in therapeutically relevant brain or blood levels of the AZT-CDS or its metabolites. Use of a liposome formulation, however, did provide for significant uptake with administration to the jejunum more effective than AZT-CDS administration to the ileum or colo-caecum. Invasive administration of AZT-CDS complexed with various chemically modified cyclodextrins to the intestine also resulted in good bioavailability. Perfusion of a section of jejunum with a solution of AZT-CDS in 2-hydroxypropyl-β-cyclodextrin (HPβCD) resulted in demonstrable AZT-CDS uptake and pre-liver/post-liver blood concentration ratio of approx. 0.5. These results suggest that an enterically coated AZT-CDS tablet may provide for pharmacologically useful oral bioavailability. A second route of administration considered was rectal dosing. AZT was significantly bioavailable from prototype suppositories in the rat and although AZT-CDS could be detected after AZT-CDS treatment, the absolute bioavailability for AZT after such treatment was low.

Effect of abdominal surgery on the intestinal absorption of lipophilic drugs: possible role of the lymphatic transport

Although abdominal surgery is a routine procedure in clinical practice and in preclinical investigation, little is known regarding its effect on the intestinal absorption of drugs. The aim of this study was to investigate the effect of abdominal surgery on the intestinal absorption of highly lipophilic compounds with different absorption mechanisms following oral administration. The 2 compounds that were tested were biopharmaceutical classification system (BCS) class 2 model lipophilic cannabinoid derivatives, dexanabinol and PRS-211,220. Although dexanabinol is mostly absorbed via passive diffusion to the portal blood, PRS-211,220 is absorbed mostly via lymphatic transport. In this work, we compared the absorption of these compounds after abdominal surgery in rat with the absorption data obtained from naïve animals. The outcomes of this investigation showed that the abdominal surgery mostly affected the absorption process on the preenterocyte level, as indicated by the 2-fold increase in the extent of intestinal absorption of dexanabinol, which is a compound with a low degree of intestinal lymphatic transport. However, the lymphatic transport was not affected by the surgical procedure as evident by the absence of change in the extent of absorption of PRS-211,220, which is transported to the systemic circulation mainly by intestinal lymphatics. In conclusion, abdominal surgery can significantly affect the intestinal absorption of lipophilic drugs; however, intestinal lymphatic transport seems to be less affected by the abdominal surgery.