Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings

Schellekens, Reinout C. A.; Stellaard, Frans; Mitrovic, Dragana; Stuurman, Frederik E.; Kosterink, Jos G. W.; Frijlink, Henderik W.

doi:10.1016/j.jconrel.2008.08.008

Cited by 77 publications

(43 citation statements)

References 36 publications

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“…Having been demonstrated with rodents, this will next be evaluated with nonhuman primate challenge models to determine its contribution to immune protection. Should these results support the concept of a mucosal vaccine, an effort will be made to formulate an Ad vector for delivery to the ileum in humans, since the sitespecific delivery technology to deliver drugs and vaccines to the ileum has been developed with partial success so far (14,16,27,36). The use of rAd5 vaccines in populations with moderate to high neutralizing antibodies to Ad5 based on the STEP trial (3a) results is a concern.…”

Section: Discussionmentioning

confidence: 99%

Delivery of Human Immunodeficiency Virus Vaccine Vectors to the Intestine Induces Enhanced Mucosal Cellular Immunity

Wang

Cheng

et al. 2009

J Virol

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Effective vaccines for human immunodeficiency virus type 1 (HIV-1) will likely need to stimulate protective immunity in the intestinal mucosa, where HIV-1 infection causes severe CD4 ؉ T-cell depletion. While replication-competent recombinant adenovirus (rAd) vectors can stimulate adenovirus-specific mucosal immunity after replication, oral delivery of replication-defective rAd vectors encoding specific immunogens has proven challenging. In this study, we have systematically identified barriers to effective gut delivery of rAd vectors and identified sites and strategies to induce potent cellular and humoral immunity. Vector-mediated gene transfer by rAd5 was susceptible to low-pH buffer, gastric and pancreatic proteases, and extracellular mucins. Using ex vivo organ explants, we found that transduction with rAd5 was highest in the ileum and colon among all intestinal segments. Transgene expression was 100-fold higher after direct surgical introduction into the ileum than after oral gavage, with rAd5 showing greater potency than the rAd35 or the rAd41 vector. A single immunization of rAd5 encoding HIV-1 gp140B to the ileum stimulated potent CD8؉ T-cell responses in the intestinal and systemic compartments, and these responses were further enhanced by intramuscular rAd5 boosting. These studies suggest that induction of primary immune responses by rAd5 gut immunization and subsequent systemic boosting elicits potent antigen-specific gut mucosal responses.

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Section: Discussionmentioning

confidence: 99%

Delivery of Human Immunodeficiency Virus Vaccine Vectors to the Intestine Induces Enhanced Mucosal Cellular Immunity

Wang

Cheng

et al. 2009

J Virol

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“…Stable isotope technology has been used to assess oral colon drug delivery systems in a few cases. To this end, 13 C-glucose [50,51] and 13 C-urea [52,53] have so far been used as marker substances. Both marker substances signal their arrival in bacteria-rich intestinal segments.…”

Section: Figurementioning

confidence: 99%

Applications of stable isotopes in clinical pharmacology

Schellekens

Stellaard

Woerdenbag

et al. 2011

Brit J Clinical Pharma

105

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This review aims to present an overview of the application of stable isotope technology in clinical pharmacology. Three main categories of stable isotope technology can be distinguished in clinical pharmacology. Firstly, it is applied in the assessment of drug pharmacology to determine the pharmacokinetic profile or mode of action of a drug substance. Secondly, stable isotopes may be used for the assessment of drug products or drug delivery systems by determination of parameters such as the bioavailability or the release profile. Thirdly, patients may be assessed in relation to patient-specific drug treatment; this concept is often called personalized medicine. In this article, the application of stable isotope technology in the aforementioned three areas is reviewed, with emphasis on developments over the past 25 years. The applications are illustrated with examples from clinical studies in humans.

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“…This system is based on the non-percolating incorporation of disintegrants in a coating which consists further of a continuous matrix of pH-responsive polymer (Eudragit S). Extensive in vitro release studies performed by Schellekens et al (2008) involved coatings with different concentrations and disintegrants and comparing it with non-disintegrant containing coatings. In vitro data showed that the incorporation of swelling agents in a Eudragit S coating still allows delayed release in the simulated terminal ileum.…”

Section: Chemical Stimuli Induced Systemmentioning

confidence: 99%