Enteral delivery of MIF-1peptide using ArisCrown technology
Anthony Padfield†, Sylvie Tchertchian‡, Roger Causon†, Doriane Theurillat‡, Tim Luker†, Martin Quibell†,
Timothy Schulz-Utermoehl†, Fraser Murray†, Andrew Parker† and Paolo Botti‡
† Exploratory Projects, Shire Pharmaceuticals, Unity Place, Hampshire International Business Park, Basingstoke,
Hampshire RG24 8EP, UK,
‡ ArisGen SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland
ABSTRACT
We evaluated the efficiency of ArisCrown technology to deliver the bioactive peptide L-prolyl-L-leucyl-glycinamide (MIF-1) orally in rats. Oral delivery
of therapeutic peptides is significantly restricted by the digestive system which is designed to cleave peptide backbones and prevent permeation. MIF-1 is
a polar tri peptide exerting a variety of pharmacological effects in the CNS, with therapeutic potential in depression and Parkinson’s disease, and an
orally bio available formulation would be highly desirable.
Methods: Male Sprague Dawley rats 175 – 250 g were used. For oral administration, peptide was administered via surgically implanted intraduodenal
cannulae. Quantitative bioanalysis of MIF-1 was performed by liquid chromatography – tandem mass spectrometry (UPLC-MS/MS). The
pharmacokinetic parameters of MIF-1 peptide following ID administration in proprietary formulations were determined and compared to exposure
following ID, intraperitoneal, oral and intravenous dosing of peptide in standard vehicles. The brain exposure was also determined in the same animals.
ARISCROWN STRATEGY
Table I. Plasma pharmacokinetic parameters of MIF-1 in the rat following intraduodenal dosing at 25 mg/kg,
Figure 1. Example of crown compound structure and illustration of its interaction with
a model peptide basic side-chain
RESULTS
The ArisCrown formulations led to greatly enhanced bioavailability
(F = 25 to 51% compared to <1%) at different MIF-1 peptide
concentrations (2, 6, 15 and 20 mg/ml) and doses (1, 3, 10 and 25
mg/kg) as compared to standard vehicles.
CONCLUSION
The ArisCrown formulation of MIF-1 led to a significantly improved
bioavailability in rats dosed ID when compared to unformulated MIF-1
leading to therapeutically effective plasma concentrations. This
demonstrates the potential of the ArisCrown formulation to facilitate
oral delivery of therapeutic peptides especially for neurodegenerative
diseases, where invasive delivery methods are undesirable and lead to
poor patient compliance.
Poster 90 x 110 cm.indd 1
Formulation
Dose
(mg/kg)
Route
Cmax
(ng/mL)
Tmax (Hours)
AUClast
(ng.h/mL)
AUCinf
(ng.h/mL)
Half life
(Hours)
T>50%Cmax Bioavailability
(Hours)
(%)§
Water
25
ID
133
0.25
109
109
0.51
0.66
0.8
ArisCrown
20 mg/ml MIF-1
25
ID
7150
0.25
6733
6736
0.68
0.57
51
Saline
5*
IP
3060
0.25
1812
1812
0.22
0.42
69
Water
50*
PO
203
0.25
166
167
0.32
0.54
0.63
ArisCrown
2 mg/ml MIF-1
1
ID
320
0.083
141
141
0.22
0.31
27
ArisCrown
6 mg/ml MIF-1
3
ID
795
0.083
508
508
0.3
0.43
32
ArisCrown
20 mg/ml MIF-1
10*
ID
2670
0.083
1310
1310
0.2
0.3
25
*composite sampling, § calculated relative to AUCiv 0-t = 5266 ng*h/ml, dose = 10 mg/kg.
REFERENCES
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4(12), 1527-31.
[2] Albrecht HP, Hofman HP, Klebe G, Kreiskott H., 1991. L-dopa potentiating
analogs of Pro-Leu-Gly-NH2 with oral efficacy.Bull Chim Farm. Feb 130(2) pp 55-9
[3] Barbeau A. 1975. Potentiation of levodopa effect by intravenous L-prolyl-Lleucyl-glycine amide in man. Lancet Oct 11;2 pp 683-4.
[4] Bernkop-Schnürch, A., Schmitz, T., 2007, Presystemic metabolism of orally
administered peptide drugs and strategies to overcome it, Curr. Drug Metab., 8(5), pp
509-17.
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