Extended release polymer systems for complex parenteral ... · 5 Many parenteral depot formulations...

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Extended release polymer

systems for complex

parenteral drug products

Long-Acting Injectables and Implantables Conference

February 7 – 8, 2019

Dr. Andrea Engel

Head of Drug Delivery, Evonik Health Care

[email protected]

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Extended release polymer

systems for complex

parenteral drug products

1.

2.

3.

4.

History of PLG polymer use for extended release

Ultra-low-metal PLGs to enhance API stability

PLG microparticle formulations

PLG particles for nanomedicine

3

1.

Historical insights into the

use of PLG polymers with

extended release drug

products

4

History of PLG Polymers and Parenteral Drug Products

2009

| February 7-8 2019 | Long-Acting Injectables and Implantables Conference | Beerse & Leuven, Belgium

1930s-60s Early patents and publications

1971 Dexon: First synthetic bioabsorbable suture

1973 DuPont: First lactide / glycolide drug delivery patent

1986 Decapeptyl: First injectable extended-release microparticle product

1989 Zoladex®: First implantable extended-release implant product

2002 Eligard®: First injectable extended-release lactide/glycolide in-situ forming product

2001 Atridox®: First local delivery product

2006 SmartShotB12: First injectable microparticle for animals

2007 Genexol® PM: First nanoparticle

2009 Ozurdex®: First product for ocular delivery

2011 Propel®: First drug-eluting device

2011 Revalor®: XS First implantable for animals

2016 Reseligo: First generic implantable

2016 Absorb GT1™: First bioabsorbable drug-eluting cardiovascular stent

2017 ZilrettaTM: First micro-particle product for intra-articular delivery (knee)

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Many parenteral depot formulations are based on PLG polymers

Brand name API Distributor Months OEL

PLG-

Micro-

particles

Bydureon™ Exenatide Astra Zeneca 2 0.1-1

Somatuline® LA Lanreotide acetate Ipsen 0.5 0.1-1

Lupron Depot® & Lutrate Depot® Leuprolide acetate Abbvie 1, 3, 4, 6 0.1-1

Sandostatin LAR® Depot Octreotide acetate Novartis 1 0.1-1

Signifor® LAR Pasireotide Novartis 1* 0.1-1

Decapeptyl® SR Triptorelin acetate Ipsen 1, 3 0.1-1

Trelstar™ Triptorelin pamoate Allergan 1, 3 0.1-1

Suprecur® MP Buserelin acetate Sanofi 1 1-10

Arestin® Minocycline HCl OraPharma 0.5 1-10

Risperdal® Consta Risperidone Johnson & Johnson 0.5 1-10

Vivitrol® Naltrexone Alkermes 1 10-100

SMARTShot B12 Vitamin B12 Virbac 4, 8 100-1000

PLG-

Implants

Revalor®-XS Trenbolone/estradiol Merck 6 < 0.1

Zoladex® Goserelin acetate AstraZeneca 1, 3 0.1-1

Propel™ Mometasone furoate Intersect ENT 1 0.1-1

Scenesse® Afamelanotide Clinuvel 2 1-10

Profact® Depot Buserelin acetate Sanofi 2, 3 1-10

Ozurdex™ Dexamethasone Allergan 1 , 2 1-10

PLG-

In Situ

Forming

Eligard®, Luprogel® Leuprolide acetate Sanofi & MediGene AG 1, 3 0.1-1

Longrange™ Eprinomectin Merial 5 10-100

Atridox® Doxycycline hyclate CollaGenex Ph. 0.25 100-1000

Perseris® Risperidone Indivior 1


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PLG Drug Delivery ActivitiesMarketed and Clinical Pipeline


Pre Clinical42%

Marketed30%

Phase 26%

Phase 16%

Research6%

Undisclosed3%

Approved3%

Phase 32%

Bioequivalency1%

Registration1%

Number of PLG-based injectable products

(marketed & pipeline)

21

11

8

8

4

4

4

2

Cancer

Women's Health,Endocrine/Metabolism,…

Women's Health,Cancer

Endocrine/Metabolism

CNS

Respiratory

Endocrine/Metabolism, Cancer

Women's Health,Endocrine/Metabolism

Marketed, approved and in registration PLG-based

injectable drug products

218

products

in totalTotal # of products: 73

| Source: PharmaCircle data download as of 2018-03-20

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Polymeric Bioabsorbable Complex Parenteral Products


Microparticles

Microparticles Implants

In-situ forming

Major challenges to overcome for local or systemic delivery

Achieving the desired rate of release of a drug after injection

Solubility issues of drugs (cave: precipitation after administration)

Stability limitations of drugs, particularly biopharmaceutical drugs

Potential pain or tissue irritation of the drug and / or its formulation

Nanoparticles

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2.

Ultra-low-metal PLG to

enhance API stability

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RESOMER® Bioresorbable Polymers

100% biodegradable and completely metabolized

API released as polymer resorbed by body

Polymer properties tunable to precisely match release profile

Controlled drug release from days to more than 18 months

Record of safety and performance exceeds 40 years

Modern U.S. and EU production sites for quality and supply security

A broad portfolio of PLG polymers for parenteral controlled release


10 | February 7-8 2019 | Long-Acting Injectables and Implantables Conference | Beerse & Leuven, Belgium

Resorption Times of Lactide/Glycolide Polymers

Resorption of poly(DL-lactide-co-glycolide) microparticles in rats (polymer inherent viscosity of ~ 0.7 dL/g)

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RESOMER® portfolio for parenteral controlled release


RESOMER®

catalog

RESOMER®

Select

RESOMER®

ZeroRESOMER®

Sterile

Highly customizable

options to address

specific requirements

Ultra-low tin content

for APIs sensitive to

impurities

The first sterile PLG to

streamline aseptic

production

More than 20 ready-to-ship

high & low molecular

weight polymers

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RESOMER® Zero


Tin

50 Residual tin content: ≤ 1 ppm

A range of molecular weights and polymer parameters

to protect sensitive APIs from impurities

Suitable for use with all RESOMER® products

Validated to standard GMP processes

3 RESOMER® Zero products in standard catalog

Highly customizable under RESOMER® Select>3

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RESOMER® Zero Study Outcomes


Lactide glycolide copolymerResidual tin amount (ppm)

Lab-scale^ Kilo-scale*

Low IV PLG homopolymer (100:00) 0.64 0.1

High IV 75:25 PLG copolymer 0.03 0.1

Low IV 50:50 PLG copolymer 0.08 0.1

Vacuum Distilled

75:25 PLG

copolymer

Catalyst Purified

75:25 PLG

copolymer

Inherent Viscosity 0.20 dL/g 0.21 dL/g

Molecular Weight 17 kDa 16 kDa

Residual Catalyst 91 ppm < 0.14 ppm

Key Results

Residual tin content ≤ 1 ppm

obtained while critical quality

attributes of products maintained

Robust, repeatable purification

process for various compositions

and inherent viscosities

Purification of catalyst does not

affect quality attributes of polymer

Conclusion

Increased stability of API during

melt processing

Reduced degradation of thermal

and mechanical properties

Image of polymer recovered after

purification at laboratory scale

^ After 4 hours of process time

* Purification of up to 16kg of polymer in single production run

Residual tin amounts measured by inductively coupled plasma mass spectrometry (Thermo Scientific™ iCAP Q)

Inherent viscosity by dilute solution viscometry, molecular weight by GPC, molar composition by NMR spectroscopy

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3.

PLG Microparticle

Formulations

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Microencapsulation Process Commercial Technologies


Phase Separation

Solvent Evaporation

Solvent Extraction Spray Drying

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Evonik Microencapsulation by Continuous Solvent-Extraction


Drug

Polymer

Polymer Solvent

Water

Surfactant

Emulsion

formation

Solvent

extraction

Isolate

and dry

Emulsion

Generator

“Product by Process”

Process conditions

Excipient properties

Drug Properties

Peptides

Small molecules

Critical Process Parameters

Critical Materials Parameters

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FormEZE® ProcessNarrow size distribution and smaller needles

Emulsion

Generator

Dry Microparticles

Smaller needles (27-G to 29-G) for easier injections

Precise microparticle size distribution for smaller needles: 27-29G

compared to 20-23G for marketed products

Smoother, quicker injections: no clogging, no needle change

Smaller injection volumes

Reduced injection volume

30-50% microparticles in injected suspension compared to 10-20%

for marketed products

Lower cost of goods

Typically 20% higher microparticle yields

Fewer microparticle batches to make per year and significant

manufacturing savings


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All classes of drug substances can be formulated but “drug potency counts”


Intramuscular (IM)

(site dependent)Subcutaneous (SC) IM / SC

(pediatrics)

Intra-

vitrealIntra-

dermal

Dose requirements Injection volume limitations

Drug potency

Duration (days to months)

volume = microparticles + vehicle

1-3 mL 1-2 mL 0.5 mL 100 µL 100 µL

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Increasing Drug Loading Hydrophilic Drug Substances

Osmotic pressure

Drug molecular weight

Number of drug molecules

Hydrophilic v. hydrophobic drug

1 wt% loading

Delayed release with

no initial release

10 wt% loading

Extended release with

appropriate initial release

40 wt% loading

Burst release

Polymer strength

Molecular weight

Matrix structure

Amount of polymer


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Peptide and PLG Properties Influence Peptide Release

Polymer matrix pores

Amorphous polymer regions


Peptide

regions

Peptide dissolves

and diffuses out

Water

uptake

Water Uptake Peptide Diffusion Out

Peptide depleted regions

Polymer properties

Lactide/glycolide ratio

End groups (acid/ester)

PEG blocks

PLG hydrolysis

Osmotic pressure (polymer

MW)

Porogens

Aqueous solubility

Charge and charge

distribution

Gel formation of peptide

Particle size of peptide

Peptide loading

Bulk density

Crystallinity

Other salts present (peptide

content)

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Sandostatin® LAR Market Product

Sandostatin® LAR in 6-mL vial

Long acting form of octreotide administered by IM injection every four

weeks for treatment in patients who have responded to and tolerated

immediate release Sandostatin SC injection

Low initial burst and minimal drug release during 3-5 days post

injection, followed by reaching a plateau in serum concentration about

2-3 weeks post injection

Formulation

Sterile extended-release bioabsorbable microparticles containing octreotide acetate

Sandostatin® LAR contains

Octreotide acetate

Star PLG copolymer

Mannitol


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Octreotide Plasma Concentration in RatsComparison of RLD and Evonik Developed Formulations


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4.

PLG particles for

nanomedicine

24

The use of PLG nanoparticles with nanomedicinesOpportunities and challenges


Polymeric Particles PLG-Based Particles Nano-sized PLG particles

Improved stability

Targeted delivery

Extended release

Reduce drug burden and efficacy

100% biodegradable

API released as polymer

resorbed by body

Tunable degradation

Long clinical history for safety

Biocompatibility

Increased suitability for i.v. use

High cellular uptake

Enhanced permeability / retention

Accumulation at inflammation

sites or within tumors

Efficient uptake by immune cells

Illicit strong immune

responses

Key industry challenge obstructing the use of sub-

micron sized PLG-based systems for nanomedicines

GMP-compliant production scale-up

without affecting formulation specifications=

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Technologies for PLG nanoparticle production From Lab to Industrial Scale

Probe sonication High-shear mixing


Polymer concentration

Solvent type

Rotation speed

Total flow-rate

Operti, M. C., et al. (2018). "A comparative assessment of continuous production techniques to generate sub-micron size PLG particles." International Journal of Pharmaceutics 550(1): 140-148.

Microfluidics

Total flow-rate

Aqueous: organic flow ratio

High-pressure homogenization

Process Pressure

Number of process cycles

Lab scale Industrial scale

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Lab-scale technologies


Operti, M. C., et al. (2018).

Particle size and PDI increases

with polymer concentration

EtOAc generates smaller size

particles compared to DCM

More cycle helps decrease

particle size initially, but

may cause instability when

it passes the optimal point

Higher pressure reduces

particle size until reaching

an optimal point

Probe sonication High-pressure homogenization

27 | February 7-8 2019 | Long-Acting Injectables and Implantables Conference | Beerse & Leuven, Belgium

Industrial-scale technologies

Operti, M. C., et al. (2018).

Particle size and PDI are proportional to the

rotation speed, and inversely proportional to

the total flow rate and PLG/PVA flow ratio

High-shear mixing Microfluidics

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Downstream processes for PLG nanoparticles


Significant reduction of residual solvent

(DMSO) and surfactant (PVA) using

continuous tangential flow filtration (TFF)

During lyophilization, a cryoprotecting

agent is needed to prevent agglomeration

98% 87%

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Formulation Complexity


Fredenberg, S., et al., The mechanisms of drug release in poly(lactic-

co-glycolic acid)-based drug delivery systems—A review. International

Journal of Pharmaceutics, 2011. 415(1–2): p. 34-52.

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About Evonik Products, Technologies and Services

Bioresorbable

Polymers

Formulation and

process development

cGMP drug

manufacturing

Drug delivery

technologies

Aseptic

filling

Project support from

feasibility to final

dosage form

RESOMER® portfolio

performance, safety

and flexibility for 40 yrs

A delivery expert for

liposomes, particles and

drug-loaded implants

Clinical and commercial

production at GMP sites

in the U.S. and Canada

Clinical and commercial

filling of powders, liquids

or suspensions in vials


Extended release polymer systems for complex parenteral ... · 5 Many parenteral depot formulations...

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