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Monica Rosa Ph.D. Sigmoid Pharma

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SmPill - Innovative Solution for Oral Delivery

SmPill - Innovative Solution for Oral Delivery

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  • 1. SmPill™ Innovative Solution for Oral Delivery Mónica Rosa, Ph.D. Bio Pharma Summit, October 31st 2012, Convention Centre Dublin“Innovative Delivery, Delivering Innovation” STRICTLY PRIVATE & CONFIDENTIAL © Sigmoid Pharma Limited 2012 www.sigmoidpharma.com Not to be circulated or copied without prior approval
  • 2. Agenda Introduction to Sigmoid Pharma SmPill™ Overview SmPill™ Poorly Soluble Drugs Oral Delivery SmPill™ Peptide Oral Delivery SmPill™ Vaccines Oral Delivery Conclusion STRICTLY PRIVATE & CONFIDENTIAL 1
  • 3. Sigmoid PharmaLeveraging Drug Delivery for Product DevelopmentIRL Private, development stage, speciality Pharma company Headquarters, development and clinical manufacturing operations in Dublin Founded in 2003 by Dr. Ivan Coulter with ~20 Employees. Over €13 million funding to date Core expertise in SmPillTM has broad applicability Lead product CyColTM has completed Phase IIa clinical trial • Colon-targeted, solubilized cyclosporine • Proof-of-principle achieved in ulcerative colitis Extensive network of clinical, academic and industry collaborations Robust and growing patent portfolio 2 STRICTLY PRIVATE & CONFIDENTIAL
  • 4. Promising Product and Platform Opportunities Program Indication Preclinical Phase I Phase II Phase III Marketed CyColTM Ulcerative - Flexibility in release & PK Cyclosporine opportunity Colitis - Consistent core beads CyCronTM Crohn’s Disease AlloCol™ GI-GvHD CyLow™ Immuno- suppression SmPill™ Broadly applicable across all BCS classes – most advanced product in lateapplicability to manyTechnology platform phase II Oral Preclinical evidence of effect in gastrointestinal enteric pathogenswith broad vaccinemolecules Oral Compelling preclinical data with model peptide, which provides support for peptide applications to other novel peptides * US FDA Orphan Designations granted in 2009 3 STRICTLY PRIVATE & CONFIDENTIAL
  • 5. Agenda Introduction to Sigmoid Pharma SmPill™ Overview SmPill™ Poorly Soluble Drugs Oral Delivery SmPill™ Peptide Oral Delivery SmPill™ Vaccines Oral Delivery Conclusion STRICTLY PRIVATE & CONFIDENTIAL 4
  • 6. Industry Challenges in Drug Delivery Permeability Solubility 50% Drugs Low Permeability 40% Drugs Poor Solubility Drug not absorbed Drug not in free molecular form Require high dose Require high dose Require i.v. Increase side effect risk Increase side effect risk Limits clinical development Limits clinical development Stability Release Profile Effective targeting 30% Drugs Low Stability Target to drug receptor Drug not in active form Target for optimal absorption site Degradation in GI tract Target to treat GI disease Precipitation in solution Require high dose Processing stability Systemic, not local Requires cold-chain Increase side effect risk Limits clinical development Limits clinical development STRICTLY PRIVATE & CONFIDENTIAL 5
  • 7. Industry Approaches Focus on Enhancing DissolutionTraditional approaches use top-down (e.g. particle size reduction) or bottom-up (e.g.controlled crystallization) techniques to increase surface area and enhancedissolution rate. Dissolution/Solubilisation must occur in gastro-intestine from thedosage form. Top-down Crystalline solidParticle size reduction = increased surface area = increased dissolution rate in liquid Bottom-up Crystalline or amorphous solidParticle size control= increased surface area = increased dissolution rate in liquid STRICTLY PRIVATE & CONFIDENTIAL 6
  • 8. SmPill™ - A Solution Not DissolutionSmPill™ pre-solubilises the drug into a solution, encapsulates the liquid solution in a solidoral dosage form and may target delivery of the drug solution within the gastro-intestineCrystalline or amorphous API Drug solubilised in Aqueous –based process; Drug in solution Drug solubilised in mini-spheres in dosage functional excipients added targeted mini-spheres form SmPill™ Integrated Technology Addresses Solubility, Permeability, Stability and Release Collectively STRICTLY PRIVATE & CONFIDENTIAL 7
  • 9. SmPill™ Mini-Spheres Produced Via a Gentle, Modified, Melt-Extrusion-like Process• API Solution uses GRAS excipients• Tailored to unique attributes of drug Heated Pumping System Nozzle &target formulation• Screening may use • Cooling solution is < 0.5 g API gentle and non-toxic • Manufacturing and processing technology compatible with and/or uses conventional systems X-ray Tomography • Uniform spherical shape API Solution Cooling • Smooth surface Solution • Homogenous interior dispersion SmPill™ Process is Highly Scalable and Cost-Comparable to Other Multiparticulate Dosage Forms STRICTLY PRIVATE & CONFIDENTIAL 8
  • 10. SmPill™: Encapsulated Drug Solution in Solid Oral Dosage Form Coating protects inner SmPill ™ mini-sphere from gastro -intestinal contents including stomach acid and digestive enzymes and permits targeting to specific regions of GIDifferent populations ofcoated or un-coatedSmPill ™ mini-spheres canbe combined in one hardgelatine capsule. Suitablefor drug combinations Drug maintained in its fully Solubilised / activeand/or modular release form for optimal pharmacological activity at target site.profiles Solubilised state maintained throughout gastrointestinal transit and release through outer coating SmPill™ Delivers Liquid Drug in an Oral Solid Dosage form which Permits GI Targeting of the Drug in a Stable and Molecularly Active Form STRICTLY PRIVATE & CONFIDENTIAL 9
  • 11. Agenda Introduction to Sigmoid Pharma SmPill™ Overview SmPill™ Poorly Soluble Drugs Oral Delivery SmPill™ Peptide Oral Delivery SmPill™ Vaccines Oral Delivery Conclusion STRICTLY PRIVATE & CONFIDENTIAL 10
  • 12. Cyclosporine Formulated SmPill™ ™ Drug Properties: • Low Solubility (< 5µM in water) •High Permeability (small Intestine) •Cyclic Peptide (11 aa) •Hepatic Metabolism •Intestine Epithelial Metabolism •Indicated for treatment of transplant rejection, rheumatoid arthritis, severe psoriasis •Used off-label to treat severe UC (i.v.) and mild/moderate UC (suppositories/enemas) Objectives: • Cyclosporine formulated with SmPill™ Model Drug: for oral delivery Cyclosporine •Improve solubility •Reduce toxicity •Achieve appropriate pharmacokinetics STRICTLY PRIVATE & CONFIDENTIAL 11
  • 13. Cyclosporine Formulated SmPill™ versus Neoral® ™“Fit-For-Purpose” Bioavailability Human PK 800 Neoral® Mean Whole Blood Concentration (ng/ml) SmPill™ CyA Fast Release 600 Toxic 17 volunteers 400 200 Therapeutic Window1 125-250 µg/L in the first few months post- transplant and can be reduced to 80-150 µg/L thereafter 0 -200 0 2 4 6 8 10 12 14 16 18 20 22 24 Time/Hour Similar BA while reducing toxicity side effects1 Bowers, LD. Therapeutic Monitoring for Cyclosporine: Difficulties in Establishing a Therapeutic Window. Clin Biochem. Vol. 24, 1991, 81-87 STRICTLY PRIVATE & CONFIDENTIAL 12
  • 14. Agenda Introduction to Sigmoid Pharma SmPill™ Overview SmPill™ Poorly Soluble Drugs Oral Delivery SmPill™ Peptide Oral Delivery SmPill™ Vaccines Oral Delivery Conclusion STRICTLY PRIVATE & CONFIDENTIAL 13
  • 15. SmPill™ Is Suitable for Oral Delivery of Peptides Drug Properties: • High Solubility •Low Permeability •Low oral bioavailability •32 amino acid peptide •Hepatic metabolism •Heat sensitivity •sCT available as nasal spray & injection •Indicated for treating postmenopausal osteoporosis, Pagets disease of bone, and hypercalcemia Objectives: •sCT formulated with SmPill™ for oral delivery Model Peptide: •Improve permeability while ensuring safety •Ensure manufacturing stability Salmon Calcitonin •Avoid peptide gut degradation •Select release targeting site STRICTLY PRIVATE & CONFIDENTIAL 14
  • 16. Jejunum Release of sCT Delivers Good Oral Bioavailability Oral Gavage Targeting Jejunum Dissolution in Enteric Media 20 150 A+ SmPill™ E+ SmPill™ % sCT Released 15 [sCT] (ng/ml) F1+ SmPill™ 100 10 50 5 A+ SmPill™ E+ SmPill™ 0 F1+ SmPill™ 0 2 4 6 8 10 0 0 2 4 6 8 10 Time (Hour) Time (Hour) Formulation Permeation F (0- ∞ min) • Published comparative BA benchmarks with enhancer (%) other formulations : A √ 4.8 • 0.5-1.4% demonstrated in Phase I1 • < 2.5% in Phase III2 E √ 10.8 • <1.8% in pre-clinical (rat model) 3 F1 - 4.6 Bioavailability Higher than Benchmarks Formulation E Performs Better but F1 (no PE) still Good1 Buclin et al., J. Bone Mineral Res., vol. 17 (8), 2002, page 1478-1485 STRICTLY PRIVATE & CONFIDENTIAL 152 Karsdal et al., Osteoarthritis & Cartilage, vol. 18 (2), page 150-1593Chen et al., Drug Development and Industrial Pharmacy, 2010; 36(3): 362–370
  • 17. Agenda Introduction to Sigmoid Pharma SmPill™ Overview SmPill™ Poorly Soluble Drugs Oral Delivery SmPill™ Peptide Oral Delivery SmPill™ Vaccines Oral Delivery Conclusion STRICTLY PRIVATE & CONFIDENTIAL 16
  • 18. Oral Vaccination Study Design Female BALB/c mice Oral Gavage Immunisation Blood & Fecal Samples Day 0 Day 13 Day 27 Day 35 Animal Sacrifice Blood samples to determine IgG and IgA antibody titres Fecal pellets to determine mucosal antibody responses Post the final immunization: • saliva was obtained from all mice and subsequently the mice were sacrificed and intestinal washes collected from the small and large intestines • Tissue extracts from the small and large intestines were also obtained for determination of antibody responses locally in the intestine using a modified version of the “PERFEXT” 11 Villavedra et al. Res Immunol 1997 148: 257-266 STRICTLY PRIVATE & CONFIDENTIAL 17
  • 19. SmPill™ Formulated Antigen X Oral Vaccine Protection 100% protection 100 Bacteria Subunit% of mice protected 75 50 25 Thermostable! 0 PBS n n S t) S S tio tio PB D D hi D D C lu lu LE LE P/ so so TA il3 l to T TB O O C lu (D C + so + er TB S100% oral protection in mouse-model using Formulation 2 + D C C D er al LE aG C al l> 70% oral protection in mouse model using Formulation 1 and 3 + aG to TB lu + so C TB + C er C Broadly Applicable al aG + Similar Studies Performed with whole killed cell; strong serum and mucosa immune responses TB C STRICTLY PRIVATE & CONFIDENTIAL 18
  • 20. Agenda Introduction to Sigmoid Pharma SmPill™ Overview SmPill™ Poorly Soluble Drugs Oral Delivery SmPill™ Peptide Oral Delivery SmPill™ Vaccines Oral Delivery Conclusion STRICTLY PRIVATE & CONFIDENTIAL 19
  • 21. Conclusion SmPill™ Successful DD Technology Novel, versatile, scalable drug delivery technology Addresses common drug delivery challenges Addresses unmet oral peptide and vaccine delivery challenges Efficiency of Delivery Supported by Animal/Human Data Applicable across all BCS classifications Modulate Release Capability STRICTLY PRIVATE & CONFIDENTIAL 20