Oral delivery of macromolecules: rationale underpinning Gastrointestinal Permeation Enhancement Technology (GIPET).

Oral delivery of macromolecular drugs, particularly peptides and proteins, is the focus of many academic and industrial laboratories. Armed with an increased understanding of the structure and regulation of intestinal epithelial junctional complexes of the paracellular barrier, the development of permeation enhancement technology initially focused on the specific and reversible opening of tight junctions in order to enable oral delivery. Despite intense research, none of these specific tight junction-opening technologies has yet been approved in an oral drug product, likely because of poor efficacy. Less specific enhancer technologies with a long history of safe use in man have additional surfactant-like effects on the transcellular pathway that lead to improved efficacy. These are likely to be the first to market for selected poorly permeable peptides. This review presents a summary of some approaches taken to intestinal permeation enhancement and explores in detail the oral delivery system developed by Merrion Pharmaceuticals, Gastrointestinal Permeation Enhancement Technology (GIPET).

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic.

A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable drugs across the intestinal epithelium. To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository. Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be co-released in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. An advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C(10)), a compound already approved as a food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level as well as in vitro and in vivo efficacy and safety studies. In specific clinical examples, we review how C(10)-based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for antisense oligonucleotides (ISIS Pharmaceuticals, USA).

Oral administration of the GnRH antagonist acyline, in a GIPET-enhanced tablet form, acutely suppresses serum testosterone in normal men: single-dose pharmacokinetics and pharmacodynamics.

PURPOSE: GnRH analogs are useful for the treatment of prostate cancer, but require parenteral administration. The peptide GnRH antagonist acyline potently suppresses luteinizing hormone (LH) and testosterone in man; however, its clinical utility is limited by the requirement for frequent injections. The use of a proprietary enhancer system called GIPET, which is based on medium-chain fatty acids, facilitates the oral bioavailability of peptides. We hypothesized that GIPET enhancement would allow for the safe oral dosing of acyline for the treatment of prostate cancer. METHODS: We enrolled eight healthy young men in a pharmacokinetic and pharmacodynamic study of 10, 20 and 40 mg doses of GIPET-enhanced oral acyline. Blood for measurement of serum LH, FSH, testosterone and acyline was obtained prior to each dose of GIPET-enhanced oral acyline and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48 h after dosing. RESULTS: Serum LH, FSH and serum testosterone were significantly suppressed by all doses of GIPET-enhanced oral acyline after 6 h, with suppression reaching a nadir 12 h after dosing. In addition, the 20 and 40 mg doses demonstrated sustained suppression of testosterone for 12-24 h. All hormone concentrations returned to normal 48 h after administration. There were no treatment-related serious adverse events, and laboratory assessments, including liver function tests and creatinine, were unaffected by treatment. CONCLUSIONS: Oral administration of GIPET-enhanced acyline significantly suppresses testosterone and gonadotropins in normal men without untoward side effects and might have utility in the management of prostate cancer.

Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage forms: GIPET.

One of the most important and challenging goals in drug delivery is overcoming the poor oral absorption of high-value therapeutics that include peptides. Gastrointestinal Permeation Enhancement Technology (GIPET) attempts to address this question by safely delivering drugs across the small intestine in therapeutically relevant concentrations. GIPET is based primarily on promoting drug absorption through the use of medium-chain fatty acids, medium-chain fatty acid derivatives and microemulsion systems based on medium-chain fatty acid glycerides formulated in enteric-coated tablets or capsules. Importantly, these excipients are generally regarded as safe and the systems are formulated in such a way that there is no change in chemical composition of the active ingredient. More than 300 volunteers have been administered GIPET formulations in 16 Phase I studies of 6 separate drugs comprising both single- and repeat-dosing regimes. Oral bioavailability of alendronate, desmopressin and low-molecular-weight heparin in humans was increased using GIPET formulations compared with unformulated controls. GIPET was well tolerated by human subjects. Using fluxes of markers of epithelial permeability, the effects of GIPET on the human intestine were shown to be rapid, short-lived and reversible in vivo. These data suggest that GIPET formulations have genuine potential as a platform technology for safe and effective oral drug delivery of a wide range of poorly permeable drugs.

Relief of hot flushes with new plant-derived 10-component synthetic conjugated estrogens.

OBJECTIVE: A study was conducted to evaluate the safety and efficacy of 3 different doses of synthetic conjugated estrogens B, a new plant-derived 10-component conjugated estrogens product, for the treatment of menopausal vasomotor symptoms. METHODS: This was a randomized, double-blind, placebo-controlled trial. Highly symptomatic menopausal women (N = 281) received 12 weeks of a once-daily oral treatment with 0.3 mg, 0.625 mg, or 1.25 mg of 10-component synthetic conjugated estrogen or placebo. Patients recorded the daily frequency and severity of hot flushes. Statistical analyses compared results at weeks 4, 8, and 12 with baseline values. RESULTS: Statistically significant reductions (P <.05) in the frequency and severity of vasomotor symptoms were observed for all 3 dosage strengths of 10-component synthetic conjugated estrogen compared with placebo. The most commonly reported adverse events in all treatment groups were headaches. No difference in the incidence of treatment-related adverse events was seen between placebo and 10-component synthetic conjugated estrogen groups. CONCLUSION: The 0.3-mg, 0.625-mg and 1.25-mg dose strengths of 10-component synthetic conjugated estrogen significantly reduced the frequency and severity of vasomotor symptoms compared with placebo, and were well tolerated during this 12-week study. LEVEL OF EVIDENCE: I