Therapeutic Peptide Formulations and Oral Delivery
14th November, 2016
David Brayden
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
Why oral peptide delivery is so difficult…..
Big problem!
Fmax = Fa . (1 – (CL / Q))
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
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
Mechanism of action of different PEs
Maher et al (2016) ADDR Jun 16. doi: 10.1016/j.addr.2016.06.005.
Low and variable oral peptide bioavailability ‐ with PEs
Sturmer et al, (2013) Clin Pharmacokinet. 52:995-1004.doi: 10.1007/s40262-013-0083-4.
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
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
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.
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
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.
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
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)
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.
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
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
Sucrose laurate performs well in Caco‐2 monolayers
TEER
Mannitol flux
MTT, 60 min
Data confirmed in rat colon in Ussing chambers
TEER Mannitol flux
Secretory capacityHistologyControl 1.5mM 5mM 10mM
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
Sucrose laurate enables insulin delivery in rat intra‐jejunal and colonic instillations
Jejunum Jejunum
Colon Colon
These data are similar to C10ad‐mixed with insulin
Jejunum Jejunum
Colon Colon
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
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?
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
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
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.
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.
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.
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.
• 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
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