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Therapeutic Peptide Formulations and Oral Delivery
14th November, 2016
David Brayden
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Topics• Low and variable oral peptide bioavailability‐ clinical examples
• Two recent permeation enhancer stories ‐1 phenyl piperazine‐sucrose laurate ester
• Enhancers built into coated minisphere beads for oral calcitonin delivery
‐emergence of coco‐glucoside
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Why oral peptide delivery is so difficult…..
Big problem!
Fmax = Fa . (1 – (CL / Q))
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Aguirre, T. et al (2016) ADDR 2016 Feb 24. doi: 10.1016/j.addr.2016.02.004
There are oral peptides – most are confined to the GI tract, these four are absorbed but are atypical
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Phase IIIPhase III
Phase IIPhase II
Phase IPhase I
PreclinicalPreclinical
TPE®
Eligen®
PeptelligenceTM
GIPET® PODTM IN-105
AxessTM HDV-I
NOD
Oshadi Icp
TrabiOralTM Intravail®
Microneedles/patches Nanomega nanoparticles
Aguirre, T. et al (2016) ADDR 2016 Feb 24. doi: 10.1016/j.addr.2016.02.004.
Formulations with enhancers in clinical trials
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Mechanism of action of different PEs
Maher et al (2016) ADDR Jun 16. doi: 10.1016/j.addr.2016.06.005.
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Low and variable oral peptide bioavailability ‐ with PEs
Sturmer et al, (2013) Clin Pharmacokinet. 52:995-1004.doi: 10.1007/s40262-013-0083-4.
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SNAC and 1% sCT oral bioavailability in man
Buclin, T et al (2002). JBMR, 17: 1487‐1485. 10.1359/jbmr.2002.17.8.1478
Sodium N‐[8‐(2‐hydroxybenzoyl) Amino] Caprylate
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Does the gut recover from enhancers ? Does the gut recover from enhancers ?
100mM C10@ 10 min
X. Wang et al (2010). Therapeutic Delivery. 1 (1): 75-82.
PBS100mM C10@ 30 min
100mM C10@ 60 min
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Clinical experience of the safety of PEs
• No significant safety issues in the complete response letter to the Mycappsa™ NDA in April in which C8 is a key component
• SNAC is in a marketed product and underwent extensive human safety studies over a 20 year period
• The GIPET® technology based on C10 has been administered to 100s of human subjects in very high doses and toxicity has not been evident
• Chronic repeat dosing is a higher bar and patients with IBD or coeliac disease should not take PEs
McCartney, F., et al (2016). Safety concerns over the use of intestinal permeation enhancers: a mini-review. Tissue Barriers 4(2): e1176822.
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1‐phenyl piperazine (PPZ): an efficacious non‐toxic paracellular PE in Caco‐2
Whitehead K, et al. (2008) Pharm Res. (2008) 25:1782-8.Whitehead K, Mitragotri S. (2008) Pharm Res. 25:1412-9
Nitrogen‐containing rings of PPZ
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ileum
colon
PPZ was confirmed as a good permeation enhancer in rat ileal and colonic mucosae in Ussing chambers
Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:2506-2516.
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Odd pharmacology (1): 5‐HT4 antagonists SB‐204070 (10 μM) and GR11808 (1 μM) inhibit PPZ‐induced [14C]‐mannitol fluxes
Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:2506-2516.
Caco‐2 Rat colon
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Caco‐2
Colon Sidedness in colon
It elevates intracellular cAMP
Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:2506-2516.
It increases Isc
Odd pharmacology of PPZ (2)
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Ileum control 0.6mM PPZ in ileum 6mM PPZ in ileum
Colon control 0.6mM PPZ in colon 6mM PPZ in colon
Histology reveals mucosal damage at 6mM concentrations of PPZ at 2 h
Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:2506-2516.
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cAMP
5HT4
TJ
CFTR
Na/K/2Cl
IscBasolateral Apical
PPZ
++
+
+Alkaline pH
+?
Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:2506-2516.
A complex model for PPZ in intestinal epithelia
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Emergence of sucrose laurate ester as an intestinal PE
• Non‐ionic amphiphilic surfactants
• Fatty acid selection defines HLB
• Esters are approved as food additives ‐ in bread, ice‐cream, instant noodles, chewing gum
• Allowed up to 10g/kg• Allowed in pharmaceutical products (FDA Inactive Ingredients Database)
MCFA
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Sucrose laurate performs well in Caco‐2 monolayers
TEER
Mannitol flux
MTT, 60 min
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Data confirmed in rat colon in Ussing chambers
TEER Mannitol flux
Secretory capacityHistologyControl 1.5mM 5mM 10mM
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human insulin studies in normal rats
PBS
Insulin (I IU/kg)
S.C. insulin lowers blood glucose …and increases plasma insulin
Insulin (I IU/kg)
PBS
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Sucrose laurate enables insulin delivery in rat intra‐jejunal and colonic instillations
Jejunum Jejunum
Colon Colon
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These data are similar to C10ad‐mixed with insulin
Jejunum Jejunum
Colon Colon
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Putting the PK together for sucrose laurate and insulin
Cmax (mU/L) Tmax (min) AUC (0‐120) (mU/L.min) Relative %F (0‐120)
1IU/kg (s.c.) 111±26 20±0 6936±2436 ‐
1mM sucrose laurate (i.c.) 179±3073±13
9382±2400 2.7
10mM sucrose laurate (i.c) 241±5937±13
14679±6068 4.2
25mM sucrose laurate (i.c.) 459±5223±3
30954±4087 8.9
50mM sucrose laurate (i.c.)216±2 33±7
14456±2167 4.2
10mM C10 (i.c.) 293±30 47±021395±6966 6.2
25mM C10 (i.c.) 304±52 37±716138±5476 4.7
50mM sucrose laurate (i.j.)118±74 20±16
4616±1171 1.3
100mM sucrose laurate (i.j.)156±80 30±13
8782±3007 2.5
50mM C10 (i.j.) 276±54 43±1215210±5831 4.4
100mM C10 (i.j.) 215±57 43±1311348±4489 3.3
Sucrose esters may be more compatible than C10 for emulsion‐type systems
McCartney & Brayden, unpublished
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Enhancers built into solid dosage forms
• Do the best enhancers emerging from ad‐mixture studies translate to real dosage forms?
• Does the instillation model predict outcomes from oral gavage studies in rats?
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e.g. SmPill™ technology
• Solid minispheres in capsule for oral delivery• Solubilise as an emulsion• Formulate into solid mini‐spheres• Apply an outer controlled release coating for regional delivery
http://www.sigmoidpharma.com
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SmPill™ process with sCT and a range of enhancers for rats
Aguirre, T.A., et al (2016). J. Controlled Release, 238: 242-252.
CA: citric acidNaTDC: Sodium taurodeoxycholateC10: sodium caprateCG: coco‐glucoside
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X‐ray of the GI of a rat showing the movement of three BaSO4–loaded minispheres coated with Opadry® white and Eudragit®‐L30 D55 designed for jejunal release
30 min after gavage: three minispheres in the stomach; 1 h: three in the small intestine; 2 h: two in the small intestine; 3 h: none detected in the small intestine
Aguirre, T.A., et al (2016). J. Controlled Release, 238: 242-252.
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X‐ray of the GI of a rat showing the movement of three BaSO4–loaded minispherescoated with Opadry® white and Surelease®/Pectin designed for colonic release
Aguirre, T.A., et al (2016). J. Controlled Release, 238: 242-252.
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PK for sCT from instilled uncoated minispheres in rats
SampleCmax
(ng/ml)
Tmax
(min)
t1/2
(min)
AUC(0 - ∞)
(min.ng/ml)
Absolute F(0 -
∞)*
(%)
sCT (i.j.) 11.7±2.8 5 59.5±4.8 732±257 2.6±0.9
SmPill®-NaTDC
(i.j.)11.9±1.1 15 101.4±5.4 1548±268 5.5±1.0*
SmPill®-CG (i.j.) 12.7±2.6 45252.2±20.
01027±211 3.7±0.8
SmPill®-CA (i.j.) 8.2±2.2 45 51.7±6.7 747±101 2.7±0.4
sCT (i.c.) 26.1±5.6 5 42.8±3.2 1974 ±431 7.0±1.5
SmPill®-CG (i.c.) 23.0±1.2 90 38.7±3.5 4878±538 17.3±1.9**
SmPill®-C10 (i.c.) 27.2±2.6 45 79.7±7.3 5131±493 18.2±1.8**
Aguirre, T.A., et al (2016). J. Controlled Release, 238: 242-252.
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PK for sCT from gavaged coated minispheres in rats
Sample
Oral delivery
Cmax
(ng/ml)
Tmax
(min)
t1/2
(min)
AUC(0 - ∞)
(min.ng/ml)
Absolute F(0 - ∞)
(%)
sCT oral 10.0±2.8 20 132.2±6.3 781±94 0.9±0.1
SmPill®-NaTDC (j) 2.5±1.5 180 144.9±9.9 728±207 0.9±0.2
SmPill® -CG (j) 10.5±3.4 150 243.3±13.9 2239±466 2.7±0.6*
SmPill® -CA (j) 7.1±3.1 180 469.8±20.7 1131±308 1.4±0.4
SmPill® -C10 (c) 7.1±2.9 180 172.9±5.6 1389±415 1.7±0.5
SmPill®-CG (c) 1.7±1.4 300 147.9±11.4 374±69 0.5±0.1
Aguirre, T.A., et al (2016). J. Controlled Release, 238: 242-252.
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• Permeation enhancers are in advanced clinical trials with oral peptides in solid dosage forms
• New enhancers like PPZ are risky because they can have complex pharmacology which was only seen in less reductionist models than Caco‐2
• Sucrose laurate, although first explored in the 1980s, looks as good as C10in ad‐mixtures with insulin in rat instillations• A consistent finding is that enhancers work better in colon v jejunum• An alkyl maltoside from the cosmetic industry, coco‐glucoside, emerged from the sCT work as having potential for emulsion‐type formulations
• Rat instillations give a “best case scenario” but unfortunately do not predict rank order for oral gavage for coated solid dosage formulations
Summary
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Acknowledgments• This work received funding from the European Union Seventh Framework
Programme (FP7 / 2007-2013) under grant agreement n° 281035 (TRANS-INT), and also from Science Foundation Ireland SRC/07/B1154 (The Irish Drug Delivery Network)
• Thanks to collaborators at Sigmoid: Drs Monica Rosa, Vincenzo Aversa and Ivan Coulter
• Thanks also to Dr. Didier Bazile and colleagues at Sanofi for the supply of human insulin (Insuman®) as part of TRANS-INT
• The sucrose laurate studies were carried out by Fiona McCartney (UCD, Ph.D. viva pending), the PPZ ones by Victoria Bzik, Ph.D.; and the sCT work by Tanira Aguirre. Ph.D.
Declarations: none