Decrease of genital organ weights and plasma testosterone levels in rats following oral administration of leuprolide microemulsion

Zheng, Jack; Fulu, Mou-ying

doi:10.1016/j.ijpharm.2005.10.007

Cited by 24 publications

(6 citation statements)

References 17 publications

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“…As the formulation was a water-in-oil-in-water (w/o/w) emulsion, however, protection towards peptidases was likely provided resulting in a significantly improved oral bioavailability of this therapeutic peptide. The release of leuprolide out of this emulsion and the impact of lipase on it, however, was not investigated (Zheng and Fulu, 2006).…”

Section: Discussionmentioning

confidence: 99%

Oral self-nanoemulsifying peptide drug delivery systems: impact of lipase on drug release

Mahjub

Dorkoosh

Rafiee-Tehrani

et al. 2015

Journal of Microencapsulation

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It was the aim of this study to evaluate the impact of lipases on the release behaviour of a peptide drug from oral self-nanoemulsifying drug delivery systems. Octreotide was ion paired with the anionic surfactants deoxycholate, decanoate, oleate and dodecylsulphate. The lipophilic character of these complexes was characterised by determining the n-octanol/buffer pH 7.4 partition coefficient. In the following the most hydrophilic complex was incorporated in a likely lipase degradable self-nanoemulsifying drug delivery systems (SNEDDS) formulation containing a triglyceride (olive oil; Pharm.Eur.) and in a likely not lipase degradable SNEDDS containing lipids and surfactants without any ester bonds. After 1:100 dilutions in artificial intestinal fluid (AIF), the lipid droplets were characterised regarding size distribution. With these SNEDDS, drug release studies were performed in AIF with and without lipase. Results showed that the most hydrophobic complex can be formed with deoxycholate in an octreotide:anionic surfactant ratio of 1:5. Even 73.1 ± 8.1% of it could be quantified in the n-octanol phase. SNEDDS containing octreotide | olive oil | cremophor EL | propylene glycol (2|57|38|3) and octreotide | liquid paraffin | Brij 35 | propylene glycol | ethanol (2|66.5|25|5|1.5) showed after dilution in AIF, a mean droplet size of 232 ± 53 nm and 235 ± 50 nm, respectively. Drug release studies showed a sustained release of octreotide out of these formulations for at least 24 h, whereas > 80% of the drug was released within 2 h in the presence of lipase in the case of the triglyceride containing SNEEDS. In contrast the release profile from ester-free SNEDDS was not significantly altered (p < 0.05) due to the addition of lipase providing evidence for the stability of this formulation towards lipases. According to these results, SNEDDS could be identified as a useful tool for sustained oral peptide delivery taking an enzymatic degradation by intestinal lipases into considerations.

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Section: Discussionmentioning

confidence: 99%

Oral self-nanoemulsifying peptide drug delivery systems: impact of lipase on drug release

Mahjub

Dorkoosh

Rafiee-Tehrani

et al. 2015

Journal of Microencapsulation

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“…, 1986; Ward et al. , 1989; Zheng and Fulu, 2006). However, the effects of acute administration of GnRH are less characterized.…”

Section: Methodsmentioning

confidence: 99%

Kisspeptin‐54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms

Thompson

Amber

Stamp

et al. 2009

British J Pharmacology

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Background and purpose:The kisspeptins are critical regulators of reproduction and a therapeutic target for reproductive disease. Intracerebroventricular (i.c.v.) or peripheral injection of kisspeptin potently stimulates the hypothalamic-pituitary gonadal (HPG) axis via gonadotrophin-releasing hormone (GnRH). However, little is known regarding the effects of kisspeptin administration on testicular function. We investigated the mechanism(s) of kisspeptin-induced testicular degeneration in the rat. Experimental approach: Kisspeptin-54 (50 nmol·day -1 ) was continuously administered subcutaneously (6 h to 3 days) to male Wistar rats and reproductive hormones and testicular histology analysed. We also investigated the effects of a single subcutaneous injection of 0.5, 5 or 50 nmol kisspeptin-54. In order to determine whether the testicular degeneration observed is peripherally or centrally mediated, we investigated effects of i.c.v. injections of 5 nmol kisspeptin-54 and pre-administered a GnRH-receptor antagonist (cetrorelix) to rats peripherally treated with kisspeptin-54. Key results: Continuous subcutaneous administration of kisspeptin-54 caused testicular degeneration after only 12 h, when gonadotrophins were still markedly raised, suggesting that the degeneration is independent of the desensitization of the HPG axis to kisspeptin-54. Furthermore, a single subcutaneous injection of kisspeptin-54 caused dose-dependent testicular degeneration. Continuous kisspeptin-54 administration is thus not required to cause testicular degeneration. Pretreatment with cetrorelix blocked kisspeptin-induced testicular degeneration, and a single i.c.v. injection of kisspeptin-54 caused testicular degeneration, suggesting it is GnRH-mediated. Conclusions and implications: Kisspeptin-induced testicular degeneration appears to be centrally mediated, and result from acute hyper-stimulation of the HPG axis. Doses must be carefully considered if kisspeptin is to be used therapeutically.

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“…Intragastric delivery of insulin in this microemulsion to rats marginally improved bioavailability compared with insulin solution [27]. Other peptides that have been formulated in w/o microemulsions include leuprolide acetate [207] and N-acetylglucosaminyl-N-acetylmuramyl dipeptide [208]. Soligenix Inc. (USA) (formerly DorBiopharma Inc.) has designed reverse micelle formulations to orally deliver peptides [209].…”

Section: Microemulsion Micelle and Liquid Dispersion Approachesmentioning

confidence: 99%

Formulation Strategies to Improve Oral Peptide Delivery

et al. 2014

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Delivery of peptides by the oral route greatly appeals due to commercial, patient convenience and scientific arguments. While there are over 60 injectable peptides marketed worldwide, and many more in development, most delivery strategies do not yet adequately overcome the barriers to oral delivery. Peptides are sensitive to chemical and enzymatic degradation in the intestine, and are poorly permeable across the intestinal epithelium due to sub-optimal physicochemical properties. A successful oral peptide delivery technology should protect potent peptides from presystemic degradation and improve epithelial permeation to achieve a target oral bioavailability with acceptable intra-subject variability. This review provides a comprehensive up-to-date overview of the current status of oral peptide delivery with an emphasis on patented formulations that are yielding promising clinical data.

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Decrease of genital organ weights and plasma testosterone levels in rats following oral administration of leuprolide microemulsion

Cited by 24 publications

References 17 publications

Oral self-nanoemulsifying peptide drug delivery systems: impact of lipase on drug release

Oral self-nanoemulsifying peptide drug delivery systems: impact of lipase on drug release

Kisspeptin‐54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms

Formulation Strategies to Improve Oral Peptide Delivery

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