therapeutic peptide formulations and oral delivery · 2016-11-10 · phase ii phase i preclinical...

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


Caco‐2 Rat colon

Caco‐2

Colon Sidedness in colon

It elevates intracellular cAMP


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


cAMP

5HT4

TJ

CFTR

Na/K/2Cl

IscBasolateral Apical

PPZ

++

+

+Alkaline pH

+?


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


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


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**


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


• 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

therapeutic peptide formulations and oral delivery · 2016-11-10 · phase ii phase i preclinical...

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