Therapeutic Peptide Formulations and Oral Delivery

Size: px

Start display at page:

Download "Therapeutic Peptide Formulations and Oral Delivery"

Blake Quinn
6 years ago
Views:

1 Therapeutic Peptide Formulations and Oral Delivery 14 th November, 2016 David Brayden

2 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

3 Why oral peptide delivery is so difficult.. F max = F a. (1 (CL / Q)) Big problem!

4 There are oral peptides most are confined to the GI tract, these four are absorbed but are atypical Aguirre, T. et al (2016) ADDR 2016 Feb 24. doi: /j.addr

5 Formulations with enhancers in clinical trials Phase III TPE Eligen Peptelligence TM Phase II GIPET POD TM IN-105 Axess TM HDV-I Phase I NOD Oshadi Icp Preclinical TrabiOral TM Intravail Microneedles/patches Nanomega nanoparticles Aguirre, T. et al (2016) ADDR 2016 Feb 24. doi: /j.addr

6 Mechanism of action of different PEs Maher et al (2016) ADDR Jun 16. doi: /j.addr

7 Low and variable oral peptide bioavailability with PEs Sturmer et al, (2013) Clin Pharmacokinet. 52: doi: /s

8 SNAC and 1% sct oral bioavailability in man Buclin, T et al (2002). JBMR, 17: /jbmr Sodium N [8 (2 hydroxybenzoyl) Amino] Caprylate

9 Does the gut recover from enhancers? PBS 100mM C 10 min 100mM C 30 min 100mM C 60 min X. Wang et al (2010). Therapeutic Delivery. 1 (1):

10 Clinical experience of the safety of PEs No significant safety issues in the complete response letter to the Mycappsa NDA in April in which C 8 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 C 10 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): e

11 1 phenyl piperazine (PPZ): an efficacious non toxic paracellular PE in Caco 2 Whitehead K, et al. (2008) Pharm Res. (2008) 25: Whitehead K, Mitragotri S. (2008) Pharm Res. 25: Nitrogen containing rings of PPZ

12 PPZ was confirmed as a good permeation enhancer in rat ileal and colonic mucosae in Ussing chambers ileum colon Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:

Odd pharmacology (1): 5 HT 4 antagonists SB 204070 (10 μm) and GR11808 (1 μm) inhibit PPZ induced [

13 Odd pharmacology (1): 5 HT 4 antagonists SB (10 μm) and GR11808 (1 μm) inhibit PPZ induced [ 14 C] mannitol fluxes Caco 2 Rat colon Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:

14 Odd pharmacology of PPZ (2) Caco 2 It elevates intracellular camp Colon It increases Isc Sidedness in colon Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:

15 Histology reveals mucosal damage at 6mM concentrations of PPZ at 2 h Ileum control 0.6mM PPZ in ileum 6mM PPZ in ileum Colon control 0.6mM PPZ in colon 6mM PPZ in colon Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:

16 A complex model for PPZ in intestinal epithelia Basolateral Isc Apical 5HT 4 PPZ Na/K/2Cl + camp + + CFTR + TJ +? Alkaline ph Bzik, V. A. & Brayden, D. J. (2016) Pharm. Res. 33:

17 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

18 Sucrose laurate performs well in Caco 2 monolayers TEER Mannitol flux MTT, 60 min

19 Data confirmed in rat colon in Ussing chambers TEER Mannitol flux Secretory capacity Histology Control 1.5mM 5mM 10mM

20 human insulin studies in normal rats S.C. insulin lowers blood glucose and increases plasma insulin PBS Insulin (I IU/kg) Insulin (I IU/kg) PBS

21 Sucrose laurate enables insulin delivery in rat intra jejunal and colonic instillations Jejunum Jejunum Colon Colon

22 These data are similar to C 10 ad mixed with insulin Jejunum Jejunum Colon Colon

23 Putting the PK together for sucrose laurate and insulin Cmax (mu/l) Tmax (min) AUC ( ) (mu/l.min) Relative %F ( ) 1IU/kg (s.c.) 111±26 20±0 6936±2436 1mM sucrose laurate (i.c.) 179±30 73±13 10mM sucrose laurate (i.c) 241±59 37±13 25mM sucrose laurate (i.c.) 459±52 23±3 50mM sucrose laurate (i.c.) 216±2 33±7 10mM C 10 (i.c.) 293±30 47±0 25mM C 10 (i.c.) 304±52 37±7 50mM sucrose laurate (i.j.) 118±74 20±16 100mM sucrose laurate (i.j.) 156±80 30±13 50mM C 10 (i.j.) 276±54 43±12 100mM C 10 (i.j.) 215±57 43± ± ± ± ± ± ± ± ± ± ± McCartney & Brayden, unpublished Sucrose esters may be more compatible than C10 for emulsion type systems

24 Enhancers built into solid dosage forms Do the best enhancers emerging from admixture studies translate to real dosage forms? Does the instillation model predict outcomes from oral gavage studies in rats?

solid mini spheres Apply an outer controlled release

25 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

26 SmPill process with sct and a range of enhancers for rats CA: citric acid NaTDC: Sodium taurodeoxycholate C10: sodium caprate CG: coco glucoside Aguirre, T.A., et al (2016). J. Controlled Release, 238:

minispheres in the stomach; 1 h: three in the small intestine; 2 h: two in the small intestine;

27 X ray of the GI of a rat showing the movement of three BaSO 4 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:

Surelease /Pectin designed for colonic release Aguirre,

28 X ray of the GI of a rat showing the movement of three BaSO 4 loaded minispheres coated with Opadry white and Surelease /Pectin designed for colonic release Aguirre, T.A., et al (2016). J. Controlled Release, 238:

29 PK for sct from instilled uncoated minispheres in rats Absolute F (0 - Sample C max (ng/ml) T max (min) t 1/2 (min) AUC (0 - ) (min.ng/ml) )* (%) sct (i.j.) 11.7± ± ± ±0.9 SmPill -NaTDC (i.j.) 11.9± ± ± ±1.0* SmPill -CG (i.j.) 12.7± ± ± ±0.8 SmPill -CA (i.j.) 8.2± ± ± ±0.4 sct (i.c.) 26.1± ± ± ±1.5 SmPill -CG (i.c.) 23.0± ± ± ±1.9** SmPill -C 10 (i.c.) 27.2± ± ± ±1.8** Aguirre, T.A., et al (2016). J. Controlled Release, 238:

30 PK for sct from gavaged coated minispheres in rats Sample C max T max t 1/2 AUC (0 - ) Absolute F (0 - ) Oral delivery (ng/ml) (min) (min) (min.ng/ml) (%) sct oral 10.0± ± ±94 0.9±0.1 SmPill -NaTDC (j) 2.5± ± ± ±0.2 SmPill -CG (j) 10.5± ± ± ±0.6* SmPill -CA (j) 7.1± ± ± ±0.4 SmPill -C 10 (c) 7.1± ± ± ±0.5 SmPill - CG (c) 1.7± ± ±69 0.5±0.1 Aguirre, T.A., et al (2016). J. Controlled Release, 238:

31 Summary 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 C 10 in 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

Acknowledgments This work received funding from the European Union Seventh

INT), and also from Science Foundation Ireland SRC/07/B1154 (The Irish Drug

Aversa and Ivan Coulter Thanks also to Dr.

) as part of TRANS-INT The sucrose laurate studies were carried out by Fiona

32 Acknowledgments This work received funding from the European Union Seventh Framework Programme (FP7 / ) under grant agreement n (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

Lipid based DDS for oral delivery of macromolecule JULIEN MEISSONNIER DIRECTOR, R&D PLATFORM

Lipid based DDS for oral delivery of macromolecule JULIEN MEISSONNIER DIRECTOR, R&D PLATFORM Plan Challenges Considerations for oral forms development Permeations enhancers Oral delivery of macromolecules