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Ethylene-vinyl acetate polymers for long-acting dosage forms
Jeff Haley, Product Specialist Medical & Pharma
© 2020 Celanese Corporation
Outline
2
• Overview of EVA in pharmaceutical products
• EVA drug release mechanisms
• Releasing high molecular weight APIs
External
© 2020 Celanese Corporation
VitalDose® EVA Excipients in drug-eluting devices
3
EVA is a low-melting thermoplastic,nonresorbable, and water insolublematerial that can be processed withactive ingredients and formed intoshape
EVA is compatible with a widevariety of establishedmanufacturing processes anddrug molecules.
Active ingredients diffuseout of device after insertion,implantation or application
Ph
oto
Co
urte
sy of Le
istritz
Hot-melt (co)extrusion
Injection molding
Film & tube extrusion
Solution casting & coating
External
© 2020 Celanese Corporation
History of EVA in FDA approved devices & drug products
EVA is used in parenteral drug products approved by US FDA and EMA
4
Subcutaneous implant (rod) E.g. Buprenorphine release for addiction therapy; Etonogestrelrelease for contraception
Intravaginal ringE.g. Etonogestrel & Ethinylestradiol release for contraception
Ophthalmic insert/Ocular implantE.g. Pilocarpine release for glaucoma; Ganciclovir for CMV retinitis
Dental implantE.g. Tetracycline release for Periodontitis
Intrauterine deviceE.g. Progesterone release for contraception
Transdermal filmE.g. Estradiol for contraception, Nicotine for addiction therapy, Nitroglycerin for heart disease
External
© 2020 Celanese Corporation
Benefits of long-acting implantable dosage forms
Parenteral delivery may enable delivery of drugs with narrow therapeutic window, extensive first-pass metabolism, severe side effects, poor water solubility
External 5
More reliable drug dosing: no dose dumping or food effects [Croxatto 2000; Shell 1984]
Reduced risk of side effects due to continuous dosing [Langer 1998; Shell 1984; Dash 1998; Legha 1982]
Delivery of drugs with short in vivo half-life [Langer 1998; Shell 1984]
Local, site-specific drug delivery [Byrne 2016]
Increased patient compliance & comfort [Croxatto 2000; Adams 2009; Shell 1984]
Advanced abuse-deterrence for delivery of opioids & stimulants [Itzoe 2017; Simon 2015; US FDA 2015]
May offer lower overall costs compared to oral application [Lipetz 2009; Espey 2011]
© 2020 Celanese Corporation
Tradeoffs between bioresorbable and bioinert materials
External
Advantages Disadvantages
Bioresorbablepolymers(ex. PLGA)
• Suitable for a wide range of dosage forms, including microspheres, in situ gels, and implants
• Microspheres and in situ gels can be self administered
• No need to remove device when treatment is complete
• Tuning release rate can be challenging as multiple mechanisms can contribute
• Extended release of more than one year seems difficult to achieve with some resorbable chemistry
• Can be difficult or impossible to remove implanted device if needed
• Not well-suited for IVRs
Bioinertpolymers (ex. EVA)
• Suitable for implants and intravaginal devices
• A variety of strategies to tune release rate and control the release of a wide range of active ingredients
• Multiple years of treatment possible with a single implant
• Microsphere or gel will not bioresorband would be difficult to explant
• Material typically removed after treatment
6
© 2020 Celanese Corporation
Understanding ethylene / vinyl acetate comonomer ratio effect on crystallinity
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Crystallinity decreases with increasing VA content.
Polyethylene EVA
Ethylene segments pack into crystals
during solidification
Vinyl acetate limits the size and
quantity of crystals
Ethylene Vinyl Acetate (VA)
Changing the ratio of ethylene and vinyl acetate in the polymer controls crystallinity
0
10
20
30
40
50
60
0 10 20 30 40
Cry
stal
linit
y %
Vinly Acetate %
External
© 2020 Celanese Corporation
The effect of vinyl acetate content on release rate
8
In the solid state, EVA is a mix of crystallites and amorphous regions. When more vinyl acetate is incorporated in the polymer, it increases the amorphous fraction of the material.
Diffusion of a dissolved API only takes place in amorphous regions of the material.
The consequence of this is that release rate is often a strong function of the vinyl acetate content of the polymer.
External
© 2020 Celanese Corporation
Different scenarios for EVA controlled release – working with actives of varying solubility
9
Soluble API in EVA matrix
Soluble API in EVA matrix with rate-limiting outer layer
Partially soluble API in EVA matrix
Co-continuous dispersion of API in EVA
Release rate influenced by diffusivity and device geometry
Release rate influenced by diffusivity and outer layer thickness
Release rate influenced by diffusivity, solubility, drug morphology, and device geometry
Release rate influenced by morphology and egress of material through channels
R. Langer, Chem. Eng. Commun. 6 (1980) 1–48
External
© 2020 Celanese Corporation
Release scenarios with partially soluble API
10
Time
Rel
ease
Rat
e
Increasing D Csoluble Co
Time
Rel
eas
e R
ate Increasing Dskin Csoluble
Act
ive
Co
nc
PositionSurfaceCenter
Csoluble
Act
ive
Co
nc
PositionSurfaceCenter
Csoluble
Higuchi model: release rate ~ t-1/2L
L T
External
© 2020 Celanese Corporation
Experiments conform to Higuchi mechanism
11
M ~ t1/2
𝑀 𝑡 ≈ 𝐴 2𝐷𝐶𝑠𝐶𝑜𝑡
1-D Higuchi model: Cartesian coordinates
• Results conform to Higuchi model.
• In many practical cases, release from a monolithic system conforms to this model
External
© 2020 Celanese Corporation
Moving from monolithic to multi-layer systems
► Long-term drug-delivery implant for contraception
► Commercial implant releases therapeutic amounts of etonogestrel (ENG) for 3 years
► One of the most reliable hormonal contraceptive methods
► Multilayer subcutaneous zero order release implant
► EVA core / EVA rate control membrane
► 68 mg ENG per implant (75 wt.-% ENG in core)
► 25 – 40µg ENG released per day
► Manufacturing in a HME process: co-extrusion
► Product launched 1999, still on market
12
C. Schneider, R. Langer, D. Hair, D. Loveday, Journal of Controlled Release 262 (2017) 284–295
Etenogestrel324 g/mol
External
© 2020 Celanese Corporation
Moving to higher molecular weight APIs
EVA used to elute wide range of molecular and biological entities in solid parenteral dosage forms
13
MOLECUAR MASS (KDA)1 10 100
Etenogestrel
325
Buprenorphine
468
Leuprolide
1,209
Cyclosporin
1,203
TAFs
50,000
Fibroblast GF4
21,000
Epidermal GF
6,000
mABs
100,000+
GF: growth factor; TAFs: tumor angiogenesis factors; mAbs: monoclonal AntibodiesBioactive model biologics released from EVA matrices
Monoclonal IgG
150,000Ferritin
450,000
Thrombospondin
420,000
Anti-horseradish
peroxidase
44,000
Trypsin
23,000
Nerve GF
27,000
Heparin
5,000
DNA
RNA
Plasmids
Polysaccharides
Protein structure & data source: www.rcsb.orgC. Schneider, R. Langer, D. Hair, D. Loveday, Journal of Controlled Release 262 (2017) 284–295
External
© 2020 Celanese Corporation
Cyclosporin A release from EVA
Celanese Studies to Illustrate CR of Cyclosporin A
► Cyclosporine A compounded with 18 and 28% VA copolymers at two loading levels (0.28 and 1.4%, by weight)
► Injection molded rings were made
► In-vitro elution into aqueous buffers with some surfactant
► Monitored daily for 28 days with daily replacement of buffer
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y = 1195*(time in days)0.5
R² = 0.9992
y = 535*(time in days)0.5
R² = 0.9991
y = 266*(time in days)0.5
R² = 0.9956
y = 162*(time in days)0.5
R² = 0.99540
1000
2000
3000
4000
5000
6000
7000
0 5 10 15 20 25 30
Re
lea
se
(μ
g)
Time/Days
Loading: 25mg Cyclosporine in 28% VA
Loading: 25mg Cyclosporine in 18% VA
Loading: 5mg Cyclosporine in 28% VA
Loading: 5mg Cyclosporine in 18% VA
Data generated in collaboration with Particle Sciences, Inc. (2010)
Solubility (wt%)
Diffusion Coefficient (cm2/sec)
In 18% VA EVA: 0.14 2.5 x 10-10
In 28% VA EVA: 0.2 1.0 x 10-9
Parameters estimated using Higuchi cylinder model
MW = 1203 g/mol
External
© 2020 Celanese CorporationExternal 15
25 mm
3 mm
Tunable membrane
Polymer reservoir with dispersed model protein particles
Bro
me
lain re
lease
Monolithic release
New system
Value Elements• zero-order release without burst effect
demonstrated in disc geometry • simple mechanism to adjust rate
Cu
mu
lati
ve r
elea
se (
% o
f to
tal l
oad
ing) Bromelain used as a high
molecular weight model protein
Tunable, steady release of a model protein
© 2020 Celanese Corporation
EVA as potential new, differentiated oral excipient
► Different property profile when compared with common oral excipients‒ Insoluble in water and alcohol
‒ Semi-crystalline, thermoplastic copolymer
‒ Low glass transition (Tg < -30°C) and melting temperatures (as low as 45 – 50°C)
‒ High impact resistance
‒ Tunable drug permeability & elution1
► Reported technical value propositions for EVA copolymers in oral dosage forms
‒ Tablets with tamper-resistant properties (resistance against milling, crushing, hot-water extraction & dose dumping):
‒ Patent application US2015/0017250 describes tamper resistant oral formulations of Tramadol HCl based on EVA and different swelling agents, manufactured by HME
‒ Prolonged/extended release tablet without pH effect:
‒ Al-Nimry et al., J. Appl. Pol. Sci. 2013, 4138-4149; Follonier et al., J. Controlled Release 1995, 36(3), 243-250; Almeida et al. Eur. J. Pharm. Biopharm. 2012, 82(3), 526-533
► EVA not listed for oral use on FDA IIDB, but evaluations are ongoing
External 16
1: Follonier, Drug Dev. Ind. Pharm. 1994, 20(8), 1323-1339
© 2020 Celanese Corporation
Summary
17External
►Low-melting thermoplastic, non-resorbable, and water insoluble material that can be processed with active ingredients and formed into shape
►Long track record of use in drug delivery applications
►Used in a variety of approved parenteral drug products, with many other products in active development
►Flexible chemistry provides a highly tunable and adjustable release profile for a variety of APIs in different form factors
►Capable of eluting a diverse set of active ingredients, ranging from low molecular weight actives to macromolecules
© 2020 Celanese Corporation
Disclaimer
This publication was produced based on Celanese’s present state of knowledge, and Celanese undertakes no obligation to update it. Because conditions of product use are outside Celanese’s control, Celanese makes no warranties, express or implied, and assumes no liability in connection with any use of this information. Nothing herein is intended as a license to operate under or a recommendation to infringe any patents.
Copyright © 2020 Celanese or its affiliates. All rights reserved.
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