Biomedical subjects

Stanley S Davis

Publications and source records attributed to Stanley S Davis.

9 recordsLinked to original sources

PubMed2006

The use of soluble polymers and polymer microparticles to provide improved vaccine responses after parenteral and mucosal delivery.

It is important when developing new vaccine systems to give proper attention to the question of delivery. In some cases the judicious choice of a delivery system can provide a greatly enhanced immune response and avoid the need to use a vaccine adjuvant. Delivery systems that have been developed originally for the administration of challenging drug can be used with success for vaccines. Polymer microspheres and lamellar particle based on the biodegradable materials polylactide and polylactide co-glycolide can be employed for the improved parenteral and mucosal administration of antigens. Likewise soluble biopolymers such as chitosan can be used for the improved nasal delivery of various antigens as well as DNA. Results from animal studies and recent clinical trials are provided.

Absorbable Implants↗

PubMed2006

Advances in the use of tocols as drug delivery vehicles.

There has been increasing interest in recent years in the drug delivery applications of tocols and their derivatives. Their biocompatibility and potential to deliver both poorly soluble and water-soluble drugs make tocols attractive as drug delivery vehicles. This review article will focus primarily on topical, oral, and parenteral drug administration using tocols, although other routes of delivery such as pulmonary and nasal will also be discussed. After an overview of the tocol structures, physicochemical properties with emphasis on their solvent properties, functions, and metabolism, specific case studies will be discussed where tocols have been successfully used in topical, oral, and parenteral drug formulations and marketed drug products. Case studies will be extended to those where tocol-based formulations were administered pulmonarily and nasally. As more clinical data and marketed drug products emerge, the utility and therapeutic value of tocols will certainly increase.

Animals↗

PubMed2005

Formulation strategies for absorption windows.

Absorption windows in the proximal gut can limit the bioavailability of orally administered compounds and can be a major obstacle to the development of controlled release formulations for important drugs. Methods to increase the residence of drug formulations at or above the absorption window are discussed in this review. Two main approaches are presently being explored: (i) bioadhesive microspheres that have a slow intestinal transit; and (ii) the gastroretentive dosage system, which is based on multiparticulates or large single unit systems. A good understanding of gastrointestinal transit in humans and the effect of factors such as food can be helpful in the design of rational systems that will have clinical benefit.

Administration, Oral↗

PubMed2004

LEAPT: lectin-directed enzyme-activated prodrug therapy.

Targeted drug delivery to selected sites allows reduced toxicity, enhanced efficiency and interchangeable target potential [Langer, R. (2001) Science 293, 58-59 and Molema, G. & Meijer, D. K. F., eds. (2001) Drug Targeting (Wiley-VCH, Weinheim, Germany)]. We describe a bipartite drug-delivery system that exploits (I) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (II) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an alpha-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of alpha-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzyme-activated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model.

Animals↗

PubMed2004

Design and evaluation of an emulsion vehicle for paclitaxel. I. Physicochemical properties and plasma stability.

PURPOSE: The current formulation of paclitaxel contains ethanol and Cremophor EL and has been reported to cause serious adverse reactions. The purpose of the present work was to develop an improved emulsion vehicle for paclitaxel and to study the physicochemical properties of such a system. METHODS: Emulsions were prepared by either microfluidization or sonication method and the droplet size characterized by dynamic light scattering and light microscopy. RESULTS: Stable emulsions could be made using mixtures of lecithin/sodium deoxycholate as the emulsifiers. The formulation was further improved by using a combination of free acid and the sodium salt. Paclitaxel could be loaded into the emulsions at 2.5 mg/ml without the formation of drug crystals. While these emulsions were stable on storage, they flocculated when mixed with plasma. Steric stabilization of the emulsion droplets with poloxamer 188 increased the stability of the emulsions in plasma but promoted the crystallization of paclitaxel. The crystallization tendency could be reduced by using PEG5000PE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[poly (ethylene glycol) 5000]), a less water-soluble stabilizer. CONCLUSIONS: Emulsions with good stability characteristics containing 2.5 mg/ml paclitaxel could be made using bile salt/acid and lecithin, and the excellent stability of these emulsions in plasma was achieved by steric stabilization using PEG5000PE.

Animals↗

PubMed2003

Absorption enhancers for nasal drug delivery.

This paper describes the basic concepts for the transmucosal delivery of drugs, and in particular the use of the nasal route for delivery of challenging drugs such as polar low-molecular-weight drugs and peptides and proteins. Strategies for the exploitation of absorption enhancers for the improvement of nasal delivery are discussed, including consideration of mechanisms of action and the correlation between toxic effect and absorption enhancement. Selected enhancer systems, such as cyclodextrins, phospholipids, bioadhesive powder systems and chitosan, are discussed in detail. Examples of the use of these enhancers in preclinical and clinical studies are given. Methods for assessing irritancy and damage to the nasal membrane from the use of absorption enhancers are also described. Finally, the mucosal use of absorption enhancers (chitosan) for the improved nasal delivery of vaccines is reported with reference to recent phase I/II clinical studies.

Absorption↗

PubMed2002

Parenteral polymers.

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Drug Delivery Systems↗

PubMed2002

The effect of ileal brake activators on the oral bioavailability of atenolol in man.

A study was carried out in human volunteers to investigate whether ileal brake activators could alter the bioavailability of atenolol from the small intestine by slowing intestinal transit and thereby increasing the time available for absorption. Oleic acid and a monoglyceride were formulated into modified release capsules that were targeted to the small intestine. Atenolol was either dosed separately or incorporated into one of the capsules. Radiolabelled non-disintegrating tablets were dosed at the same time in order to determine the small intestinal transit time (SITT). Plasma concentrations of atenolol were determined by HPLC. The results showed that in some volunteers an increase in SITT did lead to an increase in the quantity of drug absorbed. However, drug absorption was related not only to the total time spent by the drug in the small intestine but other factors such as the proportion of such time spent at the ileocaecal junction. The study highlights the complexities of exploiting natural gastrointestinal processes to enhance the oral bioavailability of drugs.

Administration, Oral↗

PubMed2002

Development of multicomponent DNA delivery systems based upon poly(amidoamine)-PEG co-polymers.

PEGylated polyamidoamine (PAA) polymers were investigated for the production of sterically stabilised DNA delivery systems. Comparison of a PEGylated polymer (NG47) with a non-PEGylated polymer (NG49) showed similar binding of co-polymer to DNA by displacement of ethidium bromide (EB) and DNA melting studies. Gel electrophoresis, turbidimetric analysis and PCS demonstrated differences in the colloidal properties of the complexes, which were attributable to the formation of soluble complexes by the PEGylated co-polymer. However, transmission electron microscopy (TEM) showed that the resulting complexes containing poly(ethylene glycol) (PEG) were not well condensed, susceptible to degradation by nucleases, and thus not suited for in vivo delivery. The poor properties of the PEGylated co-polymer were attributed to an excess of PEG. However, polymer blends of NG47 and NG49 at defined ratios of polymer to co-polymer and total repeating units (RUs) to nucleotide, spontaneously formed complexes with a range of desirable properties. These included small size and polydispersity, high particle density, low surface charge and resistance to nuclease degradation. Complexes made with PEGylated polymer alone, and the polymer blends both suffered from a reduced polyfection activity. This was attributed to a low surface charge on the complex, which reduced interactions with the cell membrane and consequent uptake of the particles into the cell.

Animals↗