advanced polymer technologies
TRANSCRIPT
Advanced Polymer TechnologiesNew Frontiers in Drug Delivery Systems
©2016 The Lubrizol Corporation, all rights reserved.2
Presented by
Meera RaghuramDirector, Regulatory Strategy and PolicyLubrizol Advanced Materials Inc.
©2016 The Lubrizol Corporation, all rights reserved.
Polymers. Formulation. Manufacturing.
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FORMULATION: advanced drug delivery solutions, including, among others, sterile and particulate drug products and drug-eluting devices
POLYMERS: comprehensive, customizable, application-specific medical and pharmaceutical grade materials
MANUFACTURING: contract manufacturing for medical device and components and cGMP drug product manufacturing for the pharmaceutical industry
Service offerings along the value chain – Simplification of supply chain
©2016 The Lubrizol Corporation, all rights reserved.
Agenda
• Introduction
• Overview of Drug Delivery Systems
• Design Considerations
• Case Studies
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©2016 The Lubrizol Corporation, all rights reserved.
Introduction
• Life cycle management of drugs is driving invention of new formulations for already approved drugs
• Extension of patents
• Protection of intellectual property
• Regulatory schemes that allow modest changes to approved drugs
• Site specific drug administration
• Sustained release of a therapeutic agent
• Patient compliance
• Bypass first-pass metabolism
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Photo from WebMD.
©2016 The Lubrizol Corporation, all rights reserved.
Advanced Polymeric Drug Delivery Systems
• Drug-Eluting Devices – Pharmaceutical • Devices that are placed within the body to control release of drugs over a given
period of time
• Drug delivery is primary purpose
• Drug-Eluting Devices – Medical • Devices such as antimicrobial catheters or drug-eluting stents which are
improved by the incorporation of an API, typically through a polymer coating
• Drug delivery is secondary benefit
• Reduced side-effects of device
• Less hospital acquired infections
• Transdermal Drug Delivery Systems• Devices such as patches which deliver drugs systemically through the skin
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Photo from Cook Group, Inc.
Photo from The Lubrizol Corporation.
Photo from The Lubrizol Corporation.
©2016 The Lubrizol Corporation, all rights reserved.
Drug-Eluting Devices (Examples)
• Intravaginal Rings
• Vaginal Pessaries
• Subcutaneous Implants
• Bladder Implants
• Ocular Implants
• Osmotic Pumps
• Sensor Devices
• Nano/Microparticle Formulations
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Photo from ViroPan, Inc. Photo from AxxiaPharmaceuticals, LLC.
• Drug-Eluting Stents & Drug-Coated Balloons
• Orthopedic Implants & Screws
• Antimicrobial Catheters
• Pacing Devices
• Implantable Drug Pumps
Photo from Drexel University.
©2016 The Lubrizol Corporation, all rights reserved.
Common Polymers in Drug-Eluting Devices
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Biodegradable Non-biodegradable
Polylactic acid (PLA) Thermoplastic polyurethane (TPU)
Polyglycolic acid (PGA) Silicone
PLGA Ethylene vinyl acetate (EVA)
Polycaprolactone (PCL) Polymethylmethacrylate (PMMA)
Polyanhydrides Polyvinyl chloride (PVC)
Polytetrafluoroethylene (PTFE)
Ultra-high-molecular-weight polyethylene (UHMWPE)
©2016 The Lubrizol Corporation, all rights reserved.
Considerations for Device Material in Combination Drug Delivery Systems
• Biocompatibility
• Interaction with drug constituents
• Impact of leachables/extractables of device materials into the drug or final
combination product
• Changes in stability of the drug constituent
• Drug adhesion/absorption to the device materials that could impact delivered dose
• Ability to control release of API
• Presence of inactive breakdown products or manufacturing residues
• Processability at relatively low temperatures
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How are Drugs Incorporated Into Polymeric Devices?
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Compounding / Blending
Coating / Impregnation
• Tube filling• Sealing
• Fold• Weld
• Antimicrobial• Anti-thrombogenic• Anti-inflammatory• Lubricious
Component Manufacturing
Hollow-Core Reservoir
Filling
Terminal Sterilization / Packaging
Base Materials
Secondary Operations
• Assembly• Polymers
• TPU, PE, Silicone, PLGA, others
• Metals• Ceramics
• Molding• Extrusion• Dip Molding
Photos from Hamilton Plastics Equipment, LLC, CardionovumGmbH, Medtronic, Inc.
©2016 The Lubrizol Corporation, all rights reserved.
Transdermal Drug Delivery Systems
• Pain management • Lidocaine
• Fentanyl
• Buprenorphine
• Hormonal patches• Estrogen (menopause, hormone replacement therapy)
• Estradiol (contraceptive)
• Testosterone (low T)
• Others• Rivastigmine (Alzheimer’s)
• Scopolamine (motion sickness)
• Clonidine (anti-hypertensive)
• Nicotine
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Photo from Novartis Pharmaceuticals
Photo from Endo Pharmaceuticals
©2016 The Lubrizol Corporation, all rights reserved.
Where Polymers are Used in Transdermal Systems
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1. Backing Layer Film: Occlusive films of varied composition and/or thickness
2. Adhesive or Reservoir: A layer that incorporates the API
3. Release Liner: Removable coated film or polymer based protective layer
(Optional) Rate-Controlling Membrane: Inert polymer film with or without pores that modulates the diffusion of API
Photo from Mylan Pharmaceuticals
©2016 The Lubrizol Corporation, all rights reserved.
Common Polymers in Transdermal Systems
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Component Polymer
Matrix Formers Polyethylene glycol (PEG)Acrylic acidEthyl cellulose
Adhesive PolyacrylatesPolyisobutyleneSilicones
Rate-Controlling Membrane EVASiliconePolyurethane
Backing PolyurethaneEVAPolyethylenePET
Release Liner FluoropolymersSiliconized PET or polypropylene
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Mixing Coating Drying Cutting
Packaging SlittingPatch
Patch Production Process (drug in adhesive)
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Design Considerations
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Drug Eluting Device Designs
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Matrix Reservoir
= Polymer= API
= Polymer
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Subcutaneous Osmotic Pump
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Water pick up rate Drug release
Fixed
Fixed
Fixed Drug loading - FixedSemi-permeable Membrane -
Outer Shell - Titanium
Semi-permeable Membrane -
Salt Osmotic EnginePiston - HDPE Diffusion ModeratorAPI
Figure and Information from IntarciaTherapeutics. Inc
©2016 The Lubrizol Corporation, all rights reserved.
Transdermal Drug Delivery System Technology
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Matrix Patch 1 Matrix Patch 2
Drug-in-Adhesive Patch Reservoir Patch
Iontophoresis
Active DeliveryPassive Delivery
Sonophoresis
Microneedles
Diffusion
©2016 The Lubrizol Corporation, all rights reserved.
Regulatory Environment – Office of Combination Products (OCP)
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Eluting Drug-Eluting Med
Devices*Medical Devices (Non-DE)
Medical Devices
Complex Formulations Traditional
Pharmaceutical Products
ImplantableDrug Eluting
Devices
Nano- & Micro-
Particulate
Tablets, Liquids and Ointments
Vaginal Rings
Transdermal Patches
Intra-ocular
Sub-cutaneous
Drug-Eluting Rx Devices*
Center for Devices & Radiological Health Center for Drug Evaluation and Research
Office of Combo ProductsOffice of Combo Products
Reg
ulat
ory
Pat
h
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Regulatory Environment – Inactive Ingredient Database (IID)
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FDA needs to develop a policy on
precedence for ingredients
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Case Studies
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©2016 The Lubrizol Corporation, all rights reserved.22
• First ring for HIV prevention in women
• Previous were for contraception (NuvaRing) and postmenopausal changes (Estring, Femring)
• Acts against: HIV-1
• Formulation: Silicone matrix vaginal ring
• Active ingredient: Dapivirine
• Length of action: One month, with a three-month ring in development
Intravaginal Rings: International Partnership for Microbiocides - HIV Ring
Feb. & July 2016: Phase III clinical trial showed reduced HIV rates and long-term safetyToday: Two open-label extension studies are currently underway
Photos from of International Partnership for Microbiocides.
©2016 The Lubrizol Corporation, all rights reserved.23
• 3D-printed antimicrobial resin that can serve as a replacement tooth
• Acts against: Oral infection & bacterial disease
• Formulation: Methacrylate-based polymer-drug matrix
• Active ingredient: Ammonium salts
• Length of action: TBD
Dental Implants: University of Groningen –3D-Printed Antimicrobial Teeth
Oct. 2015: Successful in vitro antimicrobial tests, killing >99% of Streptococcus mutans bacteria
Photo from University of Groningen.
©2016 The Lubrizol Corporation, all rights reserved.24
• Subcutaneous osmotic pump with potential to treat wide range of conditions
• Acts against: Diabetes, obesity (future)
• Formulation: Polymer-enabled osmotic mini-pump
within titanium tube
• Active ingredient: Exenatide (for diabetes)
• Length of action: Six months to one year
Subcutaneous Implants: Intarcia - Medici Drug Delivery System™
Aug. 2016: Phase III clinical trial showed improved glucose control over oral pillsNov. 2016: Submitted NDA for treatment of type 2 diabetes
Feb. 2017: FDA filing acceptance of NDA
Photo from Intarcia.
©2016 The Lubrizol Corporation, all rights reserved.
Intarcia’s Medici Drug Delivery System on Mad Money
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Video from Mad Money, Intarcia.
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Ocular Implants: pSivida - Retisert®, Illuvien®, & Durasert™
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Retisert Iluvien Durasert
Polymer Type Biodurable Biodurable Biodegradable
Acts Against Uveitis (inflammation) Diabetic macular edema Ocular hypertension(glaucoma, AMD)
Formulation Reservoir sutured to eye Polymer-drug matrix Polymer-drug matrix
Active Ingredient Fluocinolone acetonide Fluocinolone acetonide Latanoprost
Length of Action 2.5 years 3 years ??
Status 2005: FDA approval,marketed by Basuch & Lomb
2014: FDA approval, marketed by Alimera Sciences
Phase I/II trial underway, partnership with Pfizer
Photos from pSivida.
©2016 The Lubrizol Corporation, all rights reserved.
Drug-Eluting Medical Devices: Abbott and Medtronic - Vascular Device Coatings
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Xience drug-eluting stent
Absorb™ bioresorbablestent
IN.PACT Admiral drug-coated balloon
Acts against Stenosis Stenosis Restenosis
Formulation Polymer-drug matrix Polymer-drug matrix Polymer-drug matrix
Active ingredient Everolimus Everolimus Paclitaxel
Length of action N/A 3 years 180 days
Status 2008: FDA approval July 2016: FDA approval Sept. 2016: FDA approval
Photos from Abbott Laboratories, Medtronic, Inc.
©2016 The Lubrizol Corporation, all rights reserved.
Drug-Coated Balloon Mechanism
28 Animation from Medtronic, Inc.
©2016 The Lubrizol Corporation, all rights reserved.29
• Hollow or solid microneedles that allow for tunable delivery of wide range of drugs
• Potentially acts against: Blood clots, diabetes
• Formulation: Polymer-drug matrix
• Potential active ingredients: Heparin, cancer drugs, insulin
• Length of action: TBD
Transdermal Systems: NC State University & UNC – Microneedle Patch
July 2015: Insulin delivery patch developed March 2016: Cancer immunotherapy patch developed
Nov. 2016: Heparin delivery patch developed
Photos from North Carolina State University.
©2016 The Lubrizol Corporation, all rights reserved.
Key Takeaways
• The drug delivery systems will continue to evolve with new innovative technologies
• Excipient and medical polymers play a critical role in this space
• Regulations for combination products are a “work in progress”.
• It is imperative for organizations like IPEC to lead and engage with regulators
• A pan segment approach including players from medical device, drug and excipients industry is needed to develop and implement best practices
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©2016 The Lubrizol Corporation, all rights reserved.
Contact Us
• If you have any additional questions, please contact the Lubrizol LifeSciences Drug Delivery Team:
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Joey GlasscoGlobal Market Manager,
Drug-Eluting [email protected]
Eric RohrGlobal Market Manager,
Dermal [email protected]
Nick DiFrancoMarketing Specialist,
©2016 The Lubrizol Corporation, all rights reserved.
Thank you!
Questions?