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P12 P52 P76
A NEW MULTI- SIMULATING STRESSFUL NEXT-LEVEL FUTURE
COMPENDIA MODIFIED EMERGENCY-USE SCENARIOS MANUFACTURING FOR
BETA-CYCLODEXTRIN FOR DEVICE USABILITY TESTING MEDICAL TECHNOLOGY
INJECTABLE
DRUG DELIVERY
MAY 13TH 2019 • ISSUE NO 97
Contents
ONdrugDelivery Issue No 97, May 13th, 2019
INJECTABLE DRUG DELIVERY
06 -09 Enabling Subcutaneous Delivery of Biologics
Elektrofi
Company Showcase: Cristal Therapeutics
This edition is one in the ONdrugDelivery series
of publications from Frederick Furness Publishing.
10 - 11 Cristianne Rijcken, Founder and Chief Scientific Officer
Cristal Therapeutics
Each issue focuses on a specific topic within the A New Multi-Compendia Modified Beta-Cyclodextrin,
field of drug delivery, and is supported by industry
leaders in that field. 12 - 15 KLEPTOSE® HPB-LB Parenteral Grade
Elham Blouet, Global Market Manager Injectable, Dialysis and Specialty APIs
Roquette
EDITORIAL CALENDAR Conference Review: 10th Gobal Drug Delivery & Formulation Summit
Jun 2019 Connecting Drug Delivery
Jul Novel Oral Delivery Systems
18 - 19 Josh Lowth, Marketing Director
MA Exhibitions
Aug Industrialising Drug Delivery Systems Skin-Mountable Flexible Needle Patch for
Sep Wearable Injectors Minimally Invasive Controlled Drug Delivery
Oct
Nov
Prefilled Syringes & Injection Devices
Pulmonary & Nasal Drug Delivery
22 - 25 Chi Hwan Lee, Assistant Professor; and
Eun Kwang Lee, Postdoctoral Fellow
Weldon School of Biomedical Engineering, Purdue University
Dec Connecting Drug Delivery
Jan 2020 Ophthalmic Drug Delivery Technology Showcase: Credence MedSystems Multi-Site™ Injection System
Feb Prefilled Syringes & Injection Devices 26 - 27 John Merhige, Chief Commercial Officer
Credence MedSystems
Mar Skin Drug Delivery:
Dermal, Transdermal & Microneedles Microlitre Dosing With Prefillable Syringes – When Does a Device Make Sense?
Bernd Zeiss, Head of Global Technical Support, Gx® Solutions & Syringe Systems
Apr
May
Pulmonary & Nasal Drug Delivery
Injectable Drug Delivery 28 - 31 Gerresheimer
Gautam Shetty, Chief Executive Officer
Congruence Medical Solutions
EDITORIAL:
Altering Patient Treatment: How SC Delivery can
Guy Furness, Proprietor & Publisher
T: +44 1273 47 28 28
E: guy.furness@ondrugdelivery.com
34 - 37 Help Patients Manage Chronic Conditions
Victoria Morgan, Director, Segment Marketing, Biologics
West Pharmaceutical Services
James Arnold, Assistant Editor Patient Tolerability With High-Viscosity, Large-Volume Subcutaneous Infusions
SUBSCRIPTIONS: 40 - 43 Jennifer King, Marketing Manager; and
Matthew Huddleston, Executive Vice-President & Chief Technology Officer
Enable Injections
Audrey Furness, Marketing Executive
E: subscriptions@ondrugdelivery.com A Patient Centric and Pharma Company Centric
11-12 issues of ONdrugDelivery Magazine published
per year, in print, PDF & online.
44 - 46 Prefilled Wearable Bolus Injector
Jesper Roested, Chief Executive Officer
Subcuject
Digital subscription is always completely free.
Print subscription costs £99/year + postage. Training Devices Increase Patient Engagement
ADVERTISING: 47 - 50 and Adherence – Creating Better Outcomes
Erin Miller, Marketing Co-ordinator
Noble
Guy Furness, Proprietor & Publisher
T: +44 1273 47 28 28 Simulating Stressful, Emergency-Use Scenarios
E: guy.furness@ondrugdelivery.com
52 - 56 During Usability Tests of Injection Devices
Allison Strochlic, Research Director – Human Factors Research & Design
Emergo by UL
MAILING ADDRESS:
Frederick Furness Publishing Ltd Multilayer Plastic Vials & Syringes for Biologics
The Candlemakers, West Street, Lewes
East Sussex, BN7 2NZ, United Kingdom
57 - 60 Takuya Minezaki, Research Manager; and
Tomohiro Suzuki, Associate General Manager
Mitsubishi Gas Chemical
ONdrugDelivery Magazine is published by A Re-Usable Connected Autoinjector Customised
Frederick Furness Publishing Ltd for the Credence Companion® Safety Syringe System
Registered in England: No 8348388
VAT Registration No: GB 153 0432 49
62 - 65 Bjarne Sørenson, Director of Front-End Innovation
Phillips-Medisize
John Merhige, Chief Commercial Officer
ISSN 2049-145X print / ISSN 2049-1468 pdf Credence MedSystems
Copyright © 2019 Frederick Furness Publishing Ltd Selecting the Right Primary Container for Injectables in Acute Care
All rights reserved 66 - 69 Alfred Harvey, Associate Director, Health Economics and Outcomes Research
BD Medical – Pharmaceutical Systems
Product Showcase: ZwickRoell Autoinjector Testing Platform
74 Wolfgang Moersch, International Marketing Manager
ZwickRoell
Next-Level Future Manufacturing – Zahoransky’s One-Stop
76 - 78 Solution for Medical Technology
Berthold Schopferer, Business Development Manager – System Technology
Zahoransky
The views and opinions expressed in this issue are those of the authors.
Due care has been used in producing this publication, but the publisher
makes no claim that it is free of error. Nor does the publisher accept
liability for the consequences of any decision or action taken (or not
taken) as a result of any information contained in this publication.
Go for pre-filled
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Elektrofi
ENABLING SUBCUTANEOUS
DELIVERY OF BIOLOGICS
Subcutaneous delivery of monoclonal antibodies is typically limited by viscosity-
associated syringe forces and poor stability. Here, Elektrofi introduces Elektroject™,
a gentle process for the production of ultra-high concentration protein formulations,
that maintains a syringeable format and excellent protein stability, making the switch
from intravenous to subcutaneous delivery viable for numerous biotherapeutics,
including monoclonal antibodies.
Monoclonal antibodies (mAbs) are
expected to reach combined global sales of
US$150 billion (£116 billion) by 2022
“Since their initial
thanks to healthy development pipelines. introduction to the market
In recent years, biosimilars and mAbs in 1986, mAb therapies
with similar drug targets have also
entered the market, creating a highly
have had tremendous
competitive landscape and compelling impact, but have yet to
biopharmaceutical companies to reach their full potential
differentiate their products.1 Since their
initial introduction to the market in 1986,
largely because of hurdles
mAb therapies have had tremendous in drug delivery.”
impact, but have yet to reach their full
potential, largely because of hurdles in
drug delivery. patients, they also offer the opportunity
Solving delivery challenges will be key for self-administration and favourably alter
to enabling mAb therapeutics to reach their the economic landscape: SC mAb drugs
full potential. To achieve optimal therapeutic are much more affordable as they obviate
effect, antibodies often require doses as high the high mark-ups typical of long-duration
as 1 g. These antibodies are conventionally IV infusions.3
administered by high-volume intravenous (IV) This preference for SC delivery is reflected
infusions that can last up to eight hours in the market as an increasing number
under carefully monitored conditions.2 Such of mAb therapeutics have been released
infusions are inconvenient and often financially in an SC form in recent years.3 For many
inaccessible for the patient. Additionally, they mAbs, however, the high concentrations
Elektrofi, Inc
can limit the number of patients that hospitals (>100 mg/mL) needed to reach appropriate
75 Kneeland St, 14th floor
and infusion centers can treat. doses within the volume limit of standard Boston
Subcutaneous (SC) injections of biologics SC injections – 1.0 to 2.25 mL – are MA 02111
are preferable to IV infusions as they typically intractable on account of high United States
decrease the burden on healthcare providers viscosity-associated syringe force or protein
T: +1 617 766 3917
and payers by requiring much less time instability.4 High syringe forces make SC
E: info@elektrofi.com
and offering a lower risk of complications delivery virtually impossible, constraining
(infection, infusion reaction, etc.). For drug manufacturers to either provide IV www.elektrofi.com
6 www.ondrugdelivery.com Copyright © 2019 Frederick Furness Publishing Ltd
Elektrofi
infusions or administer lower doses more Next-Generation
frequently. Elektrofi has overcome these Conventional Delivery
Delivery
delivery challenges (see Table 1).
Delivery Format Intravenous (IV) Subcutaneous (SC) Electroject™ (SC)
ELEKTROJECT™ DIRECTLY
ADDRESSES SC MAB
DELIVERY CHALLENGES
With large-molecule biologics such as mAbs,
protein instability and high viscosities
result from intermolecular interactions in
solution.4 High viscosities make it difficult
to handle and inject the drug. Protein
instability reduces the effective dose as less
of the protein is therapeutically useful and Delivery Time Hours Seconds Seconds
can potentially form aggregates which may
Delivery Frequecy Low frequency High frequency Low frequency
harm the patient.
Strategies for solving these problems Dose Full Low Full
include:
Concentration Low concentration Low concentration High concentration
•
addition of excipients to reduce the
Volume High volume Low volume Low volume
prevalence of intermolecular interactions
• administration using on-body injectors to Table 1: Elektroject™ directly addresses challenges in mAb delivery.
infuse a large volume of low-concentration
drug over a prolonged period procedures (i.e. the addition of hyaluronidase (see Figure 1a). The solid microparticles
•
use of hyaluronidase to enable high- still requires a nurse to keep a needle in the limit the intermolecular interactions
volume SC injections. patient for 5-6 minutes), which preclude responsible for high viscosities and
the potential for self-administration. instabilities in aqueous formulations
However, these methods still have not Elektrofi has developed a next-generation (see Figures 2b and c).
achieved high concentrations without microparticle-based suspension formulation, The particles are suspended in a liquid
compromising on stability and may Elektroject™, which directly addresses carrier vehicle to prevent dissolution until
require relatively complex administration the current challenges of SC mAb delivery injection. This suspension can be filled
by enabling ultra-high concentrations in a prefilled syringe format, eliminating
(>400 mg/mL) of protein, while maintaining the need for complex, error-prone
a syringeable format and excellent reconstitution procedures. The highly
“Compared with aqueous
protein stability. dispersible nature of the microparticles
mAbs, Elektroject™ The Elektroject™ manufacturing enables easy resuspension by gentle shaking,
suspensions achieve much process is inherently scalable and can be allowing for a patient-friendly SC injection.
run aseptically at low temperature. This Within the subcutaneous space, the
lower viscosities at high
novel droplet formation and drying process proteins comprising the microparticles
concentrations.” yields dense, spherical microparticles readily return to their original monomeric
without compromising protein quality state enabling full bioavailability.
(a) (b)
(c)
Figure 1: Elektroject™ microparticle production process (a), microparticles (b), and a cross section of a single microparticle
demonstrating non-porous morphology (c).
Copyright © 2019 Frederick Furness Publishing Ltd www.ondrugdelivery.com 7
Elektrofi
Compared with other microparticle (a)
formation methods, Elektroject™
formulations:
• do not compromise on protein quality
• achieve higher protein loading
•
exhibit tightly controlled particle size
and shape.
Altogether, this allows the mAbs to be
delivered in a prefilled syringe format and
allows SC injection to become the standard
of drug delivery for mAbs.
HIGH-CONCENTRATION,
SYRINGEABLE SUSPENSIONS
Viscosity plays an important role in the
handling and administration of injectable
products. For suspension products, higher
viscosities can prevent settling of the (b)
suspension. But when the viscosity is too
high, it may be too difficult to deliver the
drug through a 27-gauge needle because
it takes much more force to actuate the
syringe. The alternatives, such as using a
wider needle or requiring longer injection
times, reduce patient compliance with their
treatment. Although there is no exact limit
on viscosity, since it depends on the patient
population and the syringe components,
common targets are 20 and 50 cP.
Microparticle size and dispersity also
impact syringeability. Microparticles are
often recommended to be at least 3-10 (c)
times smaller than the inner diameter of
the needle. Even if a small fraction of the
particle population is larger than that, they
may clog the needle and cause the whole
dosage to go to waste.5,6
Compared with aqueous mAbs,
Elektroject™ suspensions achieve much
lower viscosities at high concentrations
(Figure 2a). The tight particle size
distribution control afforded by the
Elektroject™ microparticle production
process allows for the use of smaller
needles without the risk of clogging Figure 2: Elektroject™ enables high concentrations of biologics at low viscosity.
Graph’s x-axis shows protein concentration for aqueous mAb and particle
(Figure 1b).
concentration for Elektroject™ mAb (a). Intermolecular forces drive viscosity and
Compared with other particle protein degradation at high viscosity (b). Elektroject™ formulations physically
production techniques, such as spray reorganise protein solutions into reversible suspensions to reduce viscosity (c).
drying, atmospheric spray freeze drying, or
polymer-based microspheres, Elektroject™ viscosity relationship. The lower the protein maintaining stability of the protein,
can make solid, dense microparticles with loading, the lower the effective protein whereas other microparticle technologies
high protein loading under gentle conditions. concentration, which shifts the suspension require relatively large fractions of
While other particle production techniques curve to the left in Figure 2a. The more stabilisers or protectants.
use high temperatures, which can damage the excipient is loaded into the solid fraction, Elektroject™ microparticles are produced
protein, the Elektroject™ platform operates the higher the viscosity at any given to fit through 27-30-gauge needles without
at low temperatures. Protein loading protein dose. Elektroject™ can achieve needle clogging events. When in a syringe,
plays a role in the effective concentration- protein loadings greater than 90% while the Elektroject™ suspensions take up to
8 www.ondrugdelivery.com Copyright © 2019 Frederick Furness Publishing Ltd
Elektrofi
CONCLUSION
Drug Property Experiment Risk of Error
Patient-friendly products will continue to
Delivery-relevant Viscosity Higher concentrations
define the future of biologics. Although
measurements with lower viscosity
mAb therapeutics already comprise a large
Syringeability Lower syringe forces part of the biopharmaceutical landscape by
at higher concentrations market share, patient accessibility remains
Molecule Size exclusion chromatography Preservation of monomers a problem. Elektrofi’s next-generation
structure and improved storage stability delivery platform, Elektroject™, improves
accessibility by enabling the SC delivery of
Subvisible particle (SvP) analysis Preservation of low SvP count
most protein therapeutics at full dose and
and improved storage stability
without compromise on protein quality.
Cation exchange chromatography Preservation of charge variants
and improved storage stability ABOUT THE COMPANY
Circular dichroism Preservation of secondary
structure and storage stability Elektrofi is a biotechnology company
working on transforming the delivery of
Differential scanning fluorimetry Preservation of melting biologics. It envisions a patient-centric
temperature and storage stability
future where all protein therapeutics can
Molecular Cell-based binding assays Preserved cellular binding be conveniently administered to patients
function activity and storage stability in small-volume syringe injections instead
of large-volume IV infusions or frequent
Cell-based functional assays Preserved functional activity
and storage stability injections. Elektrofi’s gentle platform
technology, Elektroject™, enables the
In vivo function Pharmacokinetic profile Statistically indistinguishable transformation to high-dose SC delivery
without compromise on product quality for
Tumour xenograft efficacy Statistically equivalent efficacy
a wide range of biologics.
Table 2: Summary of Elektroject™ capabilities.
REFERENCES
two hours to sediment and can be easily temperature conditions. Elektroject™
resuspended with gentle shaking. With has demonstrated high preservation of 1. Grilo AL, Mantalaris A,
these suspensions, protein concentrations mAb structure and functional bioactivity “The increasingly human and
of protein concentrations in excess of throughout the manufacturing process. profitable monoclonal antibody
400 mg/mL below 50 cP are possible, Once the suspension mixes with market”. Trends in Biotechnology,
enabling the possibility of SC delivery. aqueous media, complete dissolution occurs 2019, Vol 37(1), pp 9-16.
All this can be done without compromising within seconds to minutes, mitigating any 2. Janssen Biotech, “Darzalex
molecule stability. immunological risks posed by particles (daratumumab) [FDA label]”. 2019.
persisting in the subcutaneous space. 3. Viola M, et al, “Subcutaneous
MAINTAINING MOLECULE STRUCTURE Compared with an equal dose of aqueous delivery of monoclonal antibodies:
mAb, Elektroject™ mAb demonstrated How do we get there?”. J Controlled
Elektroject’s gentle particle formation similar pharmacokinetic profile (AUC, Release, 2018, Vol 286, pp 301-314.
conditions allow for a variety of molecules Cmax, and Tmax) and efficacy (tumour 4. Bussemer T, et al, “Approaches in
to be formed into microparticles, including growth reduction) in an animal model. subcutaneous delivery of monoclonal
fragile molecules such as mAbs and Table 2 contains a list of highlighted antibodies”. Eur Pharm Rev, 2016,
fusion proteins. Unlike other techniques, drug properties comparing Elektroject™ Vol 4, pp 26-31.
Elektroject™ does not require high particles with aqueous drug. 5. Miller M, Engstrom J, Ludher BS,
Johnston KP, “Low Viscosity Highly
Concentrated Injectable Nonaqueous
Suspensions of Lysozyme
“Elektrofi’s next-generation delivery platform, Microparticles”. Langmuir, 2010,
Elektroject™, improves accessibility by enabling the 26(2), pp 1067-1074.
SC delivery of most protein therapeutics at full dose 6. Puthli S, Vavia P, “Stability Studies of
Microparticulate System with Piroxicam
and without compromise on protein quality.” as Model Drug”. AAPS PharmSciTech,
2009, Vol 10(3), pp 872.
In which issue will your company appear?
www.ondrugdelivery.com
Copyright © 2019 Frederick Furness Publishing Ltd www.ondrugdelivery.com 9
Company Showcase
COMPANY SHOWCASE: Cristal Therapeutics
Over the past year, Cristal Therapeutics has therapeutic performance by shielding the those in healthy tissue, allowing very small
transitioned from a research-stage start-up drug from healthy tissues and increasing its particles like CriPec® to escape through the
based on a nanoparticle technology platform, exposure to the target tissue. gaps in the vessel wall and into the tumour
to a fully fledged, clinical-stage business The drug payload is entrapped in the interstitial space.
with a promising pipeline of proprietary core of the CriPec® nanoparticles using Release of the payload from CriPec®
drug candidates. This diverse pipeline proprietary, covalent linkers that prevent nanomedicines is driven purely by chemical
together with the proprietary nanoparticle it from escaping the particles and being hydrolysis. The rate and site of release can
platform, CriPec®, presents a broad range of exposed to healthy cells. The high stability be customised dependent on the needs of the
promising late- and early-stage partnering of CriPec® nanomedicines allows them specific payload to further increase tumour
opportunities for companies active in the to circulate in the bloodstream for much targeting and local sustained exposure. This
oncology space. longer than the native drug molecule can results in a higher ratio of the administered
The CriPec® platform (Figure 1) forms achieve. This long circulation combined drug reaching its target and in turn a
the backbone for the company’s R&D with the small size of CriPec® facilitates lower ratio being exposed to healthy tissue.
efforts. CriPec® is built using tailormade, accumulation in tumour or chronically This drives an enhanced efficacy and safety
proprietary polymers that Cristal inflamed tissue via a phenomenon known profile resulting in a substantially improved
CriPec® Platform to Products
Therapeutics’ expert team of scientists apply as the Enhanced Permeation and Retention therapeutic index.
to create nanomedicines that transiently (EPR) effect. This is the observation that Cristal Therapeutics’ lead CriPec ®
entrap a pharmaceutical payload. The blood vessels in tumours and chronically nanomedicine programme, CPC634,
Unique Tuneability
resulting CriPec® nanomedicines improve inflamed tissues are more “leaky” than employs the taxane docetaxel. Whilst
docetaxel is an essential standard-of-care
treatment across a wide variety of solid
tumours, the native drug suffers significantly
from various toxicities that limit its use and
efficacy in many patients. CriPec® has the
unique ability to address these shortcomings
Dr Cristianne JF Rijcken
Founder and Chief Scientific Officer
T: +31 43 388 5868
E:
cristianne.rijcken@
cristaltherapeutics.com
Cristal Therapeutics
Oxfordlaan 55
6229 EV Maastricht
The Netherlands
Figure 1: Tuneability of CriPec® platform – CriPec® nanomedicines can be fully
www.cristaltherapeutics.com
tweaked dependent on the indication and the API(s), respectively.
10 www.ondrugdelivery.com Copyright © 2019 Frederick Furness Publishing LtdCompany Showcase
whilst further enhancing the efficacy of
docetaxel to provide a vital treatment
option for patients, validating the potential
of this technology.
Cristal Therapeutics also has several
preclinical candidates in its diverse portfolio
utilising multiple therapeutic modalities,
such as oligonucleotides and peptides, and
targeting various tumour types.
CLINICAL EVALUATION
CPC634 was successfully evaluated in a
Phase I clinical trial. The data demonstrated
Figure 2: Clinical visualisation of tumour uptake. The radiolabelled CPC634 carries
that CPC634 is safe and well tolerated at an 89Zr PET label enabling non-invasive imaging by PET/CT scans.
potentially therapeutic doses and has a
significantly better pharmacokinetic profile
compared with conventional docetaxel.
These early-phase results support the basis
“Several of these additional target indications are
of tumour targeting via the EPR effect to especially prevalent in Asia and the emerging market of
provide an improved treatment for patients China. As a result, the company is proactively seeking
with a variety of solid tumours.
An abstract on this study, “A phase I
partners with proven expertise in successful drug
dose-finding and pharmacokinetics study of development and commercialisation in Asia.”
CPC634 (nanoparticle entrapped docetaxel)
in patients with advanced solid tumours”
(poster #3026), will be presented at the nanoparticle entrapped docetaxel (CPC634) PARTNERING WITH
American Society of Clinical Oncology in patients with advanced solid tumours CRISTAL THERAPEUTICS
(ASCO) Annual Meeting (May 31-June 4, using 89Zr-Df-CPC634 positron emission
2019, Chicago, IL, US). tomography / computed tomography Cristal Therapeutics has several ongoing
Based on the promising early signs of (PET/CT)” (poster #3093), will also be collaborations with large pharma and
efficacy in Phase I, CPC634 was advanced presented at ASCO 2019. biotech companies working on a range
to a Phase II trial in October 2018, which of therapeutic modalities and diseases. To
is currently ongoing. The trial is evaluating BROAD APPLICABILITY CRIPEC® capitalise on the full potential of CriPec® the
safety, tolerability and efficacy in a well- company seeks further partners developing
defined patient population with platinum- Utilising docetaxel enables Cristal (immuno-)oncology and other drugs that
resistant ovarian cancer, an indication with Therapeutics to develop its lead candidate in can benefit from CriPec® tumour targeting.
no effective therapies currently, and very an efficient way with an attractive cost and Cristal Therapeutics collaborates by first
poor survival rates. risk profile that simultaneously demonstrates conducting a joint proof-of-concept study
Cristal Therapeutics intends to find a the benefit of CPC634, and validates the to allow partners to test their compounds
partner to expand the CPC634 development potential of the CriPec® platform as a whole, in combination with CriPec®, followed by a
programme to further solid tumours for other therapeutic payloads. licensing deal on the CriPec® platform and
including prostate, breast and lung cancers. CriPec® is an extremely versatile platform mutual further development.
Several of these additional target indications that enables the entrapment of a wide variety Partners will benefit from collaborating
are especially prevalent in Asia and the of therapeutic modalities including small with an experienced company with proven
emerging market of China. As a result, the molecules, peptides and oligonucleotides. expertise in the nanomedicine field, a strong
company is proactively seeking partners Payloads can be entrapped as intellectual property portfolio, and an
with proven expertise in successful drug monotherapies, as is the case for CPC634, established good manufacturing practice
development and commercialisation in Asia. or as synergistic combinations to provide (GMP) site that allows straightforward
In addition to the ongoing Phase II further therapeutic benefit. manufacturing at clinical scale. These
trial, Cristal Therapeutics is developing This broad applicability is driven by foundations make Cristal Therapeutics
a radiolabelled CPC634 to enable non- Cristal Therapeutics’ ability to customise the ideal partner for swift development of
invasive visualisation of the nanomedicine various aspects of the platform to the tumour targeted nanomedicines.
in patients (Figure 2). This radiolabelled specific requirements of particular drugs and Through these collaborations together
CPC634, known as CPC205, is being tested diseases. This can be achieved by tailoring with its own diverse pipeline, Cristal
in a clinical study to demonstrate its tumour the size of the nanoparticles between 30 and Therapeutics is a dynamic, development-
accumulation in patients, and provides the 100 nm, tailoring the linker used to entrap stage enterprise with the expertise to take
basis for the potential future development the drug, or by using targeting ligands on cancer therapies and other treatments to
of a companion diagnostic. An abstract the surface of the particles to provide even the next level by allowing drugs to realise
on this study, “First-in-human imaging of more specific delivery to cancer cells. their full potential.
Copyright © 2019 Frederick Furness Publishing Ltd www.ondrugdelivery.com 11Roquette
A NEW MULTI-COMPENDIA MODIFIED
BETA-CYCLODEXTRIN, KLEPTOSE®
HPB-LB PARENTERAL GRADE
In this article, Elham Blouet, PhD, Global Market Manager Injectable, Dialysis and
Specialty APIs, Roquette, introduces the latest addition to the company’s range of
beta-cyclodextrins, and outlines the benefits it brings.
Roquette, a leader in beta-cyclodextrins ONE SOLUTION FOR
(KLEPTOSE®), recently expanded its range by GLOBAL COMPLIANCE
launching KLEPTOSE® HPB-LB – a new grade
of modified cyclodextrin: hydroxypropyl-beta KLEPTOSE® HPB-LB parenteral grade is
cyclodextrin (HPβCD) as an excipient grade a multi-compendia product that complies
for use in parenteral applications. Meeting with the European Pharmacopoeia (EP) and
the highest global purity standards and US Pharmacopeia (USP) – and has standards
following the principles of GMP, KLEPTOSE® that not only comply with but are even higher
HPB-LB parenteral grade will facilitate the than those of the Chinese pharmacopoeia.
registration of pharmaceutical products in Part of the wider KLEPTOSE® product
multiple target markets. range, KLEPTOSE® HPB-LB supports local
Increased interest in cyclodextrins (CDs) and global pharmaceutical manufacturers
in recent years has led to a strong market in overcoming registration filing challenges
demand, and several new pharmaceutical in China, as well as the rest of the world,
products containing beta-cyclodextrins without the need to develop multiple drug
or their derivatives have reached the solutions. This can accelerate speed to
market successfully. To meet the specific market and provide a competitive advantage.
needs of the pharmaceutical industry,
Roquette now offers a wide range of A VERSATILE EXCIPIENT
KLEPTOSE® products: beta-cyclodextrins
and HPβCDs. Both native and modified CDs have the
ability to form inclusion compounds
through molecular encapsulation with Dr Elham Blouet
a wide range of organic molecules. This Global Market Manager Injectable,
“It is the ability to form ability makes CDs and their derivatives Dialysis and Specialty APIs
valuable as formulation aids. T: +33 32 16 35 128
inclusion compounds E: elham.blouet@roquette.com
They are used to increase the aqueous
through molecular solubility of poorly soluble drugs and so
encapsulation that gives avoid the use of organic solvents. Their Roquette
use is also of great interest for improving Rue de la Haute Loge
HPßCD its interest as a 62136 Lestrem
the physical and chemical stability of drugs
formulation aid.” (protection against light, oxidation, etc.),
France
for enhancing local tolerance of drugs and www.roquette.com
12 www.ondrugdelivery.com Copyright © 2019 Frederick Furness Publishing LtdRoquette
for any other applications where inclusion
compounds would enable innovative
solutions. Oral, parenteral, topical and
ophthalmic preparations containing CDs and
their derivatives are marketed worldwide.
Therefore the new KLEPTOSE® HPB-LB,
parenteral grade is expected to improve
active substance stabilisation against light
and oxidation in parenteral preparations,
and can also be used as a solubility enhancer.
UNIQUE MOLECULAR STRUCTURE
CDs are cyclic oligosaccharides (Figure 1)
obtained from starch by enzymatic
cyclisation using cycloglycosyltransferases. Figure 1: Chemical structure of
They are composed of α-(1.4) linked beta-cyclodextrin.
glucopyranose subunits. The beta-
cyclodextrin, composed of 7 α-(1.4) with its safety profile, it represents an ideal
glucopyranose units, is the most accessible profile for pharmaceutical applications. Figure 2: Chemical structure of
and useful one with significant industrial Thanks to its safety profile, the HPβCD hydroxypropyl-beta-cyclodextrin.
usage. Roquette has branded its beta- is a suitable excipient for parenteral
cyclodextrin as KLEPTOSE®. applications as well as for oral, topical and entraps guest molecules to form so-called
The HPβCD is a CD chemically modified ophthalmic applications. inclusion compounds when in an
by hydroxypropylation. HPβCDs are The HPβCD molecule is a torus-shaped aqueous solution.
purified polydisperse products resulting ring with a polar hydrophilic exterior The secondary OH groups on C-2
from the controlled reaction of propylene and an apolar hydrophobic cavity. This and C-3 are on the opposite edge, which
oxide and native beta-cyclodextrins under structural feature is due to the spatial gives HPβCD its external hydrophilic
base catalysis. distribution of its external hydrophilic properties. The inside of the HPβCD ring
HPβCD has the highest aqueous properties. As a result of this structure is composed of a surface of hydrophobic
solubility (65% at 25°C) and, combined (Figure 2), HPβCD encapsulates or C-3 and C-5 hydrogens as well as glycosidic
ether-like oxygen.
The molar substitution (MS) is the
average number of hydroxypropyl groups
per anhydroglucose unit.
The degree of substitution (DS) is the
number of hydroxypropyl groups per
molecule of HPβCD and is obtained by
multiplying the MS by 7. KLEPTOSE®
HPB-LB is a composite product with
a specific substitution pattern. The
consistency of this substitution pattern is
guaranteed by the manufacturing conditions
applied by Roquette. The MS range of
KLEPTOSE® HPB-LB complies with the
EP/USP requirement (0.40-1.50) and ChP
requirement (0.50-0.71.)
HPßCD INCLUSION COMPLEXES
With HPβCD, the preparation of inclusion
compounds or complexes in aqueous
media is very simple. The general
principle involves the solubilisation of
the predetermined amount of HPβCD.
An instant aqueous solution is obtained.
The active ingredient is added to this
solution and mixed until a clear solution
is formed. Ultimately, the complex can be
Figure 3: Preparation of inclusion complex in aqueous solution. freeze dried or spray dried (Figure 3).
Copyright © 2019 Frederick Furness Publishing Ltd www.ondrugdelivery.com 13Roquette
INCLUSION
“HPßCD is an attractive Kc
excipient in injectable Guest + HPßCD (Guest – HPßCD)
dosage forms as it is highly
Solubilisation RELEASE
water soluble and with
high biological tolerance.” Guest crystal
Figure 4: Inclusion complex equilibrium reaction.
Other more sophisticated techniques
such as supercritical CO2 exist. For initial
trial purposes, and to determine the right
amount of HPβCD to be used, the following
protocol can be applied: add the active
ingredient to a 50% HPβCD solution until
a precipitate is formed.
It is the ability to form inclusion
compounds through molecular
encapsulation that gives HPβCD its
interest as a formulation aid. Molecular
encapsulation between HPβCD and a guest
molecule is an equilibrium reaction (no
covalent bonds) characterised by a binding
Figure 5: Representation of molecular encapsulation possibilities.
constant (Kc) which is specific to each guest
– HPβCD complex (Figure 4). In practical
terms, the higher the binding constant, the
higher the affinity of the guest molecule for “One of the reasons for using the injection route of
the HPβCD. administration is for a systemic fast-acting result,
The ability of a guest molecule to form
which is why the drug must not only be more
a complex with an HPβCD molecule is a
function of two main factors: soluble but also dissolve more quickly.”
• Steric factor (size and shape of the guest
molecule), which explains that a molecule Other factors can influence complex systemic fast-acting result, which is why
can be partially or totally encapsulated formation. Interaction between formulation the drug must not only be more soluble
• Thermodynamic interactions between ingredients is of particular importance and but also dissolve more quickly. There are
the different components. must be evaluated. For instance, thiomersal numerous publications on the solubilising
and benzylic alcohol can be recommended power of HPβCD; the examples given
Molecular encapsulation, like any other as preservatives because they do not here are for illustration only: the effect of
chemical reaction, is ruled by thermodynamic compete with the guest. HPβCD on the solubility of some drugs of
laws. Consequently, the addition of interest in injectable application is shown
formulation additives may influence the PARENTERAL APPLICATIONS in Table 1.
inclusion either positively through the
formation of ternary complexes (e.g. with HPβCD is an attractive excipient in VALUE-ADDED BENEFITS
aqueous soluble polymers, organic hydroxy injectable dosage forms as it is highly water
acids or certain organic bases) or negatively soluble and with high biological tolerance. The new KLEPTOSE® HPB-LB, (HPβCD),
because of competition with the guest The main functionality of HPβCDs are: parenteral grade presents multiple benefits
molecule (e.g. with bile salts). Moreover, an with regards to regulatory compliance,
energy input through temperature increase • Enhancing solubility of poorly soluble physical and chemical properties,
or operations (shear, pressure) can increase active substances to improve their performance, quality systems and enhanced
the complexation efficiency (Figure 5). bioavailability packaging:
The release of the guest molecule from • Stabilising active substances against
the HPβCD complex is driven by two oxidation, hydrolysis, heat degradation • Multi-compendia, enabling access to the
main factors: and light degradation global market
• Reducing irritation at the injection site • High water solubility (ideal for small
• The dilution effect while having low toxicity. volume parenterals)
•
Competition with other molecules • Low viscosity: 20 cP at 20°C, and 40%
which have a higher affinity for HPβCD One of the reasons for using the HPβCD: ideal for injection, especially
complexation. injection route of administration is for a subcutaneous
14 www.ondrugdelivery.com Copyright © 2019 Frederick Furness Publishing LtdRoquette
• Endotoxin controlled, making it suitable
Carbamazepine Danazol Albendazole
for parenteral applications
• Encapsulation process versatility HPβCD Solubility S/SO Solubility S/SO Solubility S/SO
• Encapsulation efficiency of a wide range (mM) mg/mL mg/mL mg/mL mg/mL µg/mL µg/mL
of molecules
• Stability at high temperature allowing 0 0.097 1 1.42 x 10-4 1 1.254 1
terminal steam sterilisation 10 0.788 8 0.193 1362 20.181 16
• Stability at hydrolysis over a wide range
of pH 20 1.45 14 0.34 2396 37.178 29
• Production and quality systems following
30 2.197 22 0.523 3684 46.806 37
GMP principles
• Fibre-free packaging, with tamper-proof 40 3.107 31 0.774 5451 70.376 56
evidence
• Enhanced packaging with recyclable 50 3.927 40 0.94 6623 74.153 59
materials.
100 6.723 69 1.983 13965 146.353 116
ROQUETTE RANGE OF 200 11.805 121 4.239 29854 352.701 281
MODIFIED KLEPTOSE®
SO is the drug solubility in DI water
Roquette has a full range of modified
HPβCD. The key points of each grade of Table 1: Solubility increase as a function of HPßCD molarity.1
KLEPTOSE® HPβCD are listed in Table 2.
needed to develop safe and efficacious ingredients for use in reliable oral and
CONCLUSION pharmaceutical products. parenteral preparations to customers and
As an innovator in the industrial future customers globally.
For more than 40 years, Roquette has development of cyclodextrins with its
made patient safety, improving health and KLEPTOSE® range of beta-cyclodextrins, REFERENCES
ensuring formulation safety among its top Roquette proudly introduces its new
priorities. As a pioneer in pyrogen-free KLEPTOSE® HPB-LB parenteral grade 1. Popescu C et al, “Determination
pharmaceutical ingredients, Roquette has product to the portfolio. As a trusted partner of the Thermodynamic Solubility
set the standard for highly purified and leading integrated supplier offering and the Affinity (Binding) Constants
excipients and APIs – enabling formulation full traceability and supply chain security, of Carbamazepine, Danazol and
with confidence. With multiple your pharmaceutical applications will Albendazole in Hydroxypropyl
manufacturing sites across the world, meet the highest quality and regulatory Beta Cyclodextrin
supported by a vertically integrated supply requirements because Roquette is (KLEPTOSE®HPB) Solutions”.
chain, Roquette provides the confidence committed to securing the purest AAPS Annual Meeting, 2011.
KLEPTOSE® KLEPTOSE® KLEPTOSE® KLEPTOSE® KLEPTOSE® KLEPTOSE®, KLEPTOSE®
HPB, parenteral HP, parenteral HPB , oral grade HP, oral grade HPB, Biopharma HP Biopharma HPB-LB,
grade grade parenteral
grade
Grade Parenteral Parenteral Oral Oral Biopharma Biopharma Parenteral
(low endotoxins) (low endotoxins)
Molar 0.58 – 0.68 0.81 – 0.99 0.58 – 0.68 0.81 – 0.99 0.58 – 0.68 0.81 – 0.99 0.50 – 0.71
Substitution
(MS)
Applications Small molecule Small molecule Small molecule Small molecule Large molecule Large molecule Small molecule
Route of Parenteral, Parenteral, Oral and topical Oral and topical Parenteral Parenteral Parenteral,
administration ophthalmic ophthalmic ophthalmic and
and topical and topical topical
Regulatory EP / USP NF EP / USP NF EP / USP NF EP / USP NF EP / USP NF EP / USP NF EP/ USP NF /
compliance ChP
CEP Yes Yes No No No No No
DMF US DMF US DMF US DMF US DMF US DMF US DMF Chinese DMF
(type II & IV) (type II & IV) (type IV) (type IV) (type IV) (type IV)
Table 2: Key points of the KLEPTOSE® range of hydroxypropyl beta-cyclodextrins (HPßCDs).
Copyright © 2019 Frederick Furness Publishing Ltd www.ondrugdelivery.com 15fo V
r m isit
or the
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in we
fo bs
rm it
at e
io
n!
SMi presents the West Coast’s Leading,
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Assessing Device Development Strategies PASSED
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BENEFITS OF ATTENDING: Aug 1,
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16 www.ondrugdelivery.com Copyright © 2019 Frederick Furness Publishing LtdKLEPTOSE® HPB-LB parenteral grade
DELIVERING
a multi-compendial excipient
for efficient drug delivrey
PATIENT SAFETY
WITH THE RIGHT PARTNER
Roquette’s KLEPTOSE® HPB-LB is a
new grade of hydroxypropyl β-cyclodextrin
(HPBCD) excipient for use in parenteral
applications. Meeting the highest purity
standards across the world and following
the principles of GMP, KLEPTOSE®
HPB-LB parenteral grade facilitates the
registration of pharmaceutical products in
multiple target markets.
For further details, or to learn more about
KLEPTOSE® HPB-LB, please get in touch
with our experts.
pharma@roquette.com
or visit www.roquette.comConference Review
10TH GLOBAL DRUG DELIVERY
& FORMULATION SUMMIT
Berlin, Germany, March 11–13, 2019
By Josh Lowth, Marketing Director,
MA Exhibitions
The second week of March is a key date in
the delivery and formulation event calendar.
This is when the good and the great of
Europe’s pharmaceutical development
community gather in Berlin, Germany, for
the DDF Summit – a high-level scientific
event for industry and academia.
This year, the 10th edition of the
summit, was attended by 400 scientists
and technologists representing, big pharma,
SMEs, solution providers and academia.
The summit is positioned at the intersection
of high science and commercial thinking,
bringing an exciting future
focused angle to the content
and discussions.
The three-day agenda
“The Device Development
is split into four dedicated stream was added last year
streams of sessions: Small to reflect the growing trend
Molecules; Biologics;
Technology & Innovation;
in combination products
and Device Development. and regulatory challenges
This allows attendees to pick around delivery devices.
and choose the specific topics
most interesting to them.
The session in the device
The Device Development room were packed out
stream was added last year from start to finish.”
to reflect the growing trend
in combination products and
regulatory challenges around that high-volume devices are
delivery devices. The sessions in the device going to be important due to the
room were packed out from start to finish. challenges of high concentration
Each day opened and closed with keynote formulations.
sessions, bringing everyone together in the The day ended with another
main room to discuss bigger picture issues biologics-focused keynote, this
and wider themes. Day One started with time given by Alan Harris,
Kerstin Walke, Head of Pharmaceutical Senior Vice-President, Global
Development, Biologicals at Boehringer R&D Lifecycle Management
Ingelheim, discussing how next-generation at Ferring. Dr Harris’s talk
biopharmaceuticals will influence looked at the challenges and
formulation and device development. As opportunities specifically for
formats become more complex there is a oral delivery of peptides. This
growing need for more powerful predictive has been a recurring and popular theme Day Two opened with an excellent talk
tools and high throughput screening systems at recent DDF Summits and 2019 was no by Stefan Bracht, Vice-President, Head
in early stages. She also explained how different. He outlined the importance of of Disruptive Technologies at Bayer. Dr
patient self-administration is playing an taking a patient-centric approach, which Bracht talked through the recent trends
increasingly important role across various was a strong recurring theme throughout and solutions making waves in the field of
indication areas, as well as pointing out the three days in Berlin. drug delivery. We heard about the latest
18 www.ondrugdelivery.com Copyright © 2019 Frederick Furness Publishing LtdConference Review
ideas around patient centricity, specifically
for children and the elderly. As well as the
unmet need in parenteral drug targeting,
with a focus on brain and solid tumours.
Day Two closed with the first panel
session of the summit, which looked at
the impact of the EU Medical Device
Regulation (MDR) as it applies to
combination products. The panel featured
Bjorg Hunter, Regulatory Manager, Devices
at GSK; April Kent, Regulatory Affairs
Manager, Combination Products and IVDs
at Amgen; Louise Place, Head of Regulatory
at Cambridge Design Partnership; James
Mellman, Device Manager at Novartis,
and Torsten Kneuss, Quality Assurance
Manager, Combination Products at Bayer.
The main topic of conversation was Article
117 of the MDR. This has introduced
the need for single
integral medical built into each day, roundtable discussions,
products with a drinks receptions, a poster competition and
device component pre-arranged one-to-one meetings, there are
of class IIa and plenty of ways for attendees to interact.
above to have a After 10 years, there’s a real sense of
Notified Body community at the summit, which gives the
opinion. networking a relaxed and informal feel.
The final day The poster competition was expanded
kicked off with this year with 14 posters displayed around
Beate Bittner, the exhibition hall. The competition is
Senior Portfolio open to all attendees and gives everyone
Strategy Director an opportunity to contribute and display
at Roche, on their work. Attendees can then vote for
formulation and their favourite through the official summit
device lifecycle app. This year’s winner was “Protein-
management. This Protein Interaction and its Influence for
session looked High Concentrated Liquid Formulations”,
at the factors driving the development US FDA and the EMA on patient-focused which was submitted by Josef Hartl of
of devices that allow self-administration. drug development (PFDD), this is becoming Boehringer Ingelheim.
With rising healthcare costs and more mandatory for the pharmaceutical industry. The summit’s resounding success was
complicated combination therapies coming Sven Stegemann, Director of Business reflecting in the attendee survey feedback:
to market, companies are looking to Development at Lonza; Leonie Wagner- 99% of attendees said the summit met,
simplify drug delivery. The talk covered Hatller, Formulation Scientist at Roche; exceeded or greatly exceeded their
how connected devices with features such and Louise Place from Cambridge Design expectations; 96% learned something new
as dosing reminders, adherence trackers and Partnerships, suggested we should take an and useful; 96% would attend again; 98%
patient diaries allow an ongoing dialogue opportunistic view, explaining how PFDD would recommend the summit to a colleague
with healthcare professionals. can help create a competitive advantage by and 84% met somebody who could help
The summit closed with a panel discussion adding real value to patients and payers. with their current challenges.
looking at the regulatory issues surrounding As well as the content, the DDF Summit The DDF Summit returns to Berlin,
patient-centric drug development. With new is very much a networking event. With Germany, on March 9-11, 2020.
guidelines being released by the both the four hours of dedicated networking time www.ddfevent.com
IN WHICH ISSUE SHOULD
YOUR COMPANY APPEAR?
www.ondrugdelivery.com
Copyright © 2019 Frederick Furness Publishing Ltd www.ondrugdelivery.com 19BAVARIAN NORDIC
THE COMPLEX MADE SIMPLE
Market
Production
Vaccines
CDMO SERVICES FOCUSED ON
BRINGING VACCINES TO MARKET
Bavarian Nordic is a globally integrated biotechnology company Based on this in-depth experience we are now entering the
focused on in-house executed research, development, manufac- CDMO market, making the complex simple for you.
turing and marketing of innovative and safer vaccines against As innovators and developers of live virus vaccines, our combi-
cancer and infectious diseases for which the unmet medical need nation of 25 years expertise and state-of-the-art facility, we can
is high and for which we can harness the power of the immune guide and accelerate your biological therapeutics from develop-
system to induce a response. ment to commercial and beyond.
A unique full-service biotech partner for
innovation and manufacturing of GMO2/BSL2
sterile liquid and lyophilized products.
CDMOservices@bavarian-nordic.com
www.cdmo.bavarian-nordic.comFully designed,
developed
and ready for
commercial
supply
A springless passive safety device
for pre-fillable syringes
COST EFFECTIVE
Designed to work with standard,
pre-filled syringes which means
no change to existing primary
container and minimises
USER CONFIDENCE training costs.
Syringe barrel is unobscured,
allowing the user to check the
contents of the syringe, and to
confirm the full dose has
SECURE PLUNGER
been delivered. RELIABILITY
Plunger cannot detach
Prevention of accidental
when removing the RNS.
activation e.g. in transit.
PASSIVE SAFETY
Passive needle
retraction means that SIMPLE 2-STEP
the device is safe as FINAL ASEMBLY COMFORT
soon as the plunger is Final assembly process is Large, ergonomic plunger head
fully depressed. simple and outside of the and a smooth, integrated finger
sterile filling area. flange, resulting in an integrated
look and feel.
REDUCED RISK
No compromise to sterility
in assembly - plunger does
not touch the bung.
Get in touch to discover the full UniSafeTM ecosystem and how it can meet your
differing user’s needs. Visit omdevicesolutions.com for more information.Early Insight
SKIN-MOUNTABLE FLEXIBLE NEEDLE
PATCH FOR MINIMALLY INVASIVE
CONTROLLED DRUG DELIVERY
In this article, Chi Hwan Lee, PhD, Assistant Professor, and Eun Kwang Lee, PhD,
Postdoctoral Fellow, both of Purdue University’s Weldon School of Biomecical
Engineering, introduce a skin-mountable flexible needle patch and discuss its
applications in non-invasive drug delivery applications.
INTRODUCTION: MICRO- required length scale.6 The incorporation of
AND NANO-SCALE NEEDLES nanoscale textures on the surface of needles,
where drug molecules are bonded, can
Minimally invasive injection of increase the drug loading capacity, providing
therapeutics, including biomolecules, into high-throughput delivery.7 Examples of
living cells or tissues is a crucial element of different types of micro/nanoneedles are
various controlled drug delivery systems.1 summarised in Figure 1.8
Research on effective injection methodologies
for biomolecules should consider: S olid
• needles without active
pharmaceutical ingredient (API) are
1)
Ensuring minimal risk to cellular used for skin pre-treatment. The solid
survival and function nanoneedles are applied to the desired
2) Delivery of broad range of biomolecule skin site and removed, leaving micron- Dr Chi Hwan Lee
types with controlled dosage.2 scale holes in the skin. Then ointments Assistant Professor
or medical creams are applied and cross T: +1 765 494 6212
Conventional needle injection penetrates slowly through the pores. E: lee2270@purdue.edu
the stratum corneum, the outermost layer Dissolvable needles made of water-
•
of the skin which acts as a barrier for soluble or biodegradable polymers that
the dermis and epidermis, allowing direct contain drug molecules are used for
delivery of drug molecules into the vascular direct drug delivery. The key benefit of
circulation.3 This method yields a prompt this needle form is that there remain
therapeutic response. However, a challenge no sharp scars after the needles are
remains with the size of commercially completely degraded in the skin.
available hypodermic needles, typically Coated needles are solid needles coated
•
ranging from millimetre to centimetre, with dissolvable polymers that contain
Dr Eun Kwang Lee
which can be difficult for patients to use drug molecules. The stronger physical
Postdoctoral Fellow
themselves, due to pain caused by improper properties of this type of needle enable E: lee3132@purdue.edu
handling or reluctance caused by needle- deeper penetration into the skin.
phobia. Especially in developing countries, Hollow needles are manufactured with
•
spread of bloodborne pathogens by needle empty spaces inside them into which
re-use is also a major issue.4 Hypodermic liquid drug molecules are filled, ready
needles are therefore primarily utilised by for delivery into the skin after injection.
healthcare professionals in a clinical setting Hollow nanoneedles can contain high
or at home by well-trained patients who have molecular weight compounds such as
learned the correct injection method and safe proteins, vaccines and oligonucleotides.
needle disposal.5 Thus, there is an unmet
need for the development of an effective More recently, vertical silicon
Weldon School of
and safe drug delivery system comparable nanoneedles (Si NNs) have been used for
biomedical Engineering
in terms of efficiency with conventional intracellular and intratissue delivery of Purdue University
needle-injection methodologies but without biomolecules, providing further advantages Martin C Jischke Hall
its disadvantages. from their intrinsic bio-dissolvability.7 The 206 S Martin Jischke Drive
For the minimally invasive injection of resultant platform allows the nanoneedles West Lafayette
IN 47907
biomolecules, recent approaches involve the to interact with adjacent cells and tissues
United States
use of micro- or nano-scale needles capable during/after the injection, without inducing
of penetrating the skin or into cells at their toxicity, degradation of cell metabolism www.purdue.edu/BME
22 www.ondrugdelivery.com Copyright © 2019 Frederick Furness Publishing LtdYou can also read
