Advanced Polymer Technologies

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


Agenda

• Introduction

• Overview of Drug Delivery Systems

• Design Considerations

• Case Studies

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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.


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.


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.


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)


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.


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


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


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


Mixing Coating Drying Cutting

Packaging SlittingPatch

Patch Production Process (drug in adhesive)


Design Considerations

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Drug Eluting Device Designs

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Matrix Reservoir

= Polymer= API

= Polymer


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


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


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


Regulatory Environment – Inactive Ingredient Database (IID)

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FDA needs to develop a policy on

precedence for ingredients


Case Studies

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• 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.


• 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.


• 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.


Intarcia’s Medici Drug Delivery System on Mad Money

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Video from Mad Money, Intarcia.


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.


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.


Drug-Coated Balloon Mechanism

28 Animation from Medtronic, Inc.


• 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.


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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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,

[email protected]


Thank you!

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Advanced Polymer Technologies

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