Upload
deesh
View
233
Download
0
Tags:
Embed Size (px)
DESCRIPTION
Drug
Citation preview
PARENTERALD E L I V E R Y
DrugDeliveryTechnology
January2009
Vol9
No1
xx
INTRODUCTION
Throughout the past few years,
several products based on drug-loaded
biodegradable microspheres have
reached the pharmaceutical
marketplace. Well-known examples
are Lupron Depot (Abbott
Laboratories), Trelstar Depot
(Watson Pharmaceuticals), and
Risperdal ConstaTM (Ortho-McNeil-
Janssen Pharmaceuticals). These types
of injectable depot formulations (IM
or SC) can provide sustained and
controlled delivery of the active over a
period of weeks or months and thus
significantly increase patients comfort
and compliance. From the perspective
of the pharmaceutical companies,
microsphere-based depot formulations
of existing compounds offer an
attractive tool in life cycle
management, but most importantly,
offer significant value to patients.
Although microsphere-based drug
delivery is attractive from both the
market and patient perspective,
developers of microsphere
formulations face many challenges in
achieving the desired product
performance and process efficiency.
Many of these challenges are related
to the lack of control over particle size
and uniformity of conventional
microsphere manufacturing methods.
There are a number of techniques in
development designed to overcome
issues regarding size and uniformity.
We believe that a novel manufacturing
process based on MicrosieveTM
emulsification offers the best and most
straightforward opportunity to
overcome these challenges.
KEY FACTORS INDESIGNING SUSTAINED-RELEASE MICROSPHERE
FORMULATIONS
The most important goal in
designing a microsphere formulation
for sustained drug delivery is to
achieve a gradual release of the active
at a constant rate over the desired
period of time. Given a certain
microsphere size, such a zero-order
release profile is typically achieved by
careful selection of the biodegradable
polymer matrix material. Usually, this
is a poly (D,L-lactic-co-glycolic) acid,
PLGA, which is biodegradable,
biocompatible, and equally important,
has been used in many FDA-approved
products. The properties of PLGA can
be tailored to the purpose by changing
the block ratios and the molecular
weight, which have to be chosen such
that the diffusion rate of the active and
the degradation rate of the polymer
match the desired release period. In
addition, the polymer has to be
selected such that the release rate
reduction over time (typical for
diffusion controlled release) is
compensated by the degradation-
related release rate, which increases
over time.
An important parameter for
robust drug formulation, and the focus
of this paper, is the microsphere size.
The chosen microsphere size is
usually a compromise between two
main considerations.
1. The smaller the microspheres,
the better the syringability
(Figure 1) and the smaller the
needle gauge required, which
translates into reduced patient
discomfort. A 27-gauge needle
has an inner diameter of 191
microns. Taking a fair safety
margin of a factor 4, this
suggests an upper limit for the
F I G U R E 1
PLGA microspheres (21 microns) in a 25-gauge needle (240 microns id), showing a highdegree of monodispersity and optimal syringability.
Monodisperse Microspheres for Parenteral Drug DeliveryBy: Gert Veldhuis, PhD, Mriam Girons, PhD, MSc and Debra Bingham
PARENTERALD E L I V E R Y
particle size of about 50 microns
for use with this needle gauge.1
2. The larger the microspheres, the
less risk that the particles will be
cleared from the injection site by
macrophages. It is known from
literature that phagocytosis can
occur up to microsphere sizes of 5
microns.2,3 Therefore, 10 microns
is generally considered to be a safe
lower boundary in order to avoid
particle uptake by macrophages.
Considering the aforementioned, an
average microsphere diameter of about 30
microns seems ideal for depot
applications. In addition to the average
microsphere size, the uniformity of the
microsphere size is very important. A high
fraction of particles much smaller than the
average will significantly reduce the
encapsulation efficiency of the active in
the microspheres and will also cause an
unwanted initial burst of active right after
administration of the microsphere depot.4
Conventional methods for producing
microspheres, such as solvent
evaporation/extraction by high-speed
homogenizers, do not allow for total
control of microsphere size and
uniformity, are very difficult to scale-up,
and often show poor batch-to-batch
reproducibility. Moreover, obtaining an
acceptable size and uniformity requires a
lot of process development. Typically, very
wide particle size distributions with
standard deviations of the mean diameter
of about 30% to 50% (Figure 2) are
achieved. Obtaining narrower size
distributions has to be achieved through
expensive classification steps with high
losses of active in the unwanted size
ranges.
Given the fact that current
manufacturing processes are not capable
of predictably producing uniform sized
particles, and that size uniformity is
important to quality outcome, a
technology that can offer complete control
over size distribution is of great value to
the industry.
TECHNOLOGIES FORMONODISPERSE
MICROSPHERE PRODUCTION
Advances in microengineering and
semiconductor technologies have allowed
the development and production of
precisely designed microfluidic structures
for obtaining monodisperse droplets and
microspheres.4-7One example is given by
flow focusing devices in which a fluid is
injected through a nozzle into a stream of
another fluid, and droplets are detached by
Rayleigh instability. Perfectly
monodisperse particles can be obtained in
the laboratory. However, scaling up this
technology for industrial purposes is
extremely difficult, mainly due to the low
production rate and the need for exact
control over two different fluid streams
(crucial to obtain a certain droplet size).
Thousands of these relatively complex
devices would have to be placed in parallel
with all the exact same supply of two
different fluid streams in order to produce
volumes suitable for pharmaceutical
applications.
Another approach for obtaining
uniform and monodisperse droplets and
particles is offered by membrane
emulsification.8 In membrane
emulsification, a fluid is forced through a
porous membrane. The droplets emerging
on the other side of the membrane surface
are wiped off by the shear forces induced
by a stream of another fluid across the
membrane. The typical membranes used
are similar to those used for filtration
purposes, and processes can be easily
scaled up. Control over droplet size and
F I G U R E 2
Particle size distribution of a microsphere formulation fabricated via Nanomis MicrosieveTM
emulsification (A), with a narrow CV of 5%, and a conventional emulsification with homogenizers (B),with a CV of about 30%. The size limits for phagocytosis and optimal syringability for depot formulationsare also displayed.
DrugDeliveryTechnology
January2009
Vol9
No1
xx
PARENTERALD E L I V E R Y
uniformity is better than for high-shear
homogenizers but inferior to the control
that can be achieved by single microfluidic
devices. In the following section, a new
technology that combines the scaling
advantages of membrane emulsification
with the size control advantages offered by
microfluidics will be discussed.
MICROSIEVETMEMULSIFICATION:
PRINCIPLES & KEY FEATURES
In microsieve emulsification, a
Nanomi proprietary technology,
monodisperse droplets are generated by
dispersing one fluid into a second,
immiscible fluid through a precise
microsieve (Figure 3). Microsieves are
silicon-based membranes fabricated by
proven precise semiconductor technology
in a cleanroom environment. By means of
photolithographic techniques, excellent
uniformity of pore size and shape is
obtained in a highly reproducible way.
Because every pore is the same, every
droplet generated by the membrane is the
same, resulting in highly uniform,
reproducible, and size-controlled droplets
or, after an appropriate solidification step,
particles.
A unique feature of the microsieve
emulsification technology is the
independence of the droplet size to the
specific formulation, the size being solely
determined by the membrane design. This,
and the fact that no cross-flow is needed to
produce droplets, differentiates this
process from other membrane
emulsification systems.
Microsieve emulsification can be
applied in the most common method of
particle fabrication for drug delivery,
solvent evaporation. Basically, the polymer
and the active substance are dissolved in a
volatile solvent and emulsified into an
aqueous surfactant solution. The solvent is
then eliminated by evaporation, resulting
in the formation of solid particles. For
encapsulation of hydrophilic molecules
like peptides or proteins, the W/O/W
emulsion method is used. Here, a primary
W/O emulsion containing an aqueous
solution of the active ingredient dispersed
in the oil phase is emulsified with an
aqueous surfactant solution, forming a
W/O/W double emulsion.
In addition to the solvent evaporation
process, microsieve emulsification can be
used in melt emulsification (eg, for
making lipid microspheres) and is suitable
for the production of O/W, W/O, W/O/W,
S/W/O, and S/O/W emulsions.
Compared to other conventional or
membrane-based droplet and particle
production methods, Nanomis technology
offers the following advantages:
TOTAL CONTROL OF
DROPLET/PARTICLE SIZE - no process
or formulation optimization required to
obtain the desired size and size
distribution of the product (Figure 2,
comparing size distributions achieved with
high-speed homogenizers and microsieve
emulsification).
NO LOSS OF VALUABLE
INGREDIENTS - all generated droplets
and particles have the right size, thus no
post-processing such as fractionation is
required and no valuable ingredients are
lost.
ROBUST, REPRODUCIBLE & STABLE
IN OPERATION - the process is
insensitive to fluid flow and pressure
conditions near the membrane surface and
therefore performs very well in a relatively
simple process configuration.
STRAIGHTFORWARD SCALABILITY -
if the process works for one pore, the
F I G U R E 3
Schematic representation of the microsieveTM emulsification process (A), where a fluid is emulsifiedthrough a silicon microsieveTMmembrane with uniform pores (B). Image of a wafer containingmicrosievesTM (C) fabricated by semiconductor technology.
DrugDeliveryTechnology
January2009
Vol9
No1
xx
PARENTERALD E L I V E R Y
process can easily be scaled to any size by
increasing the number of pores of the
microsieve or by adding more microsieves
to the process.
HIGHLY EFFICIENT
ENCAPSULATION - Because each
droplet is formed individually at negligible
imposed shear and pressure, actives can be
incorporated in the particle very
effectively. Due to the smaller droplet to
pore diameter ratio compared to other
methods, even relatively large
nanoparticles can be encapsulated.
MILD PROCESS CONDITIONS - the
process operates at very low pressures and
shear, and no heat is generated, which
allows processing of sensitive actives, such
as proteins and peptides. On the other
hand, microsieves are very robust and can
resist high temperatures, aggressive
cleaning agents, and autoclaving.
ASEPTIC PROCESSING UNDER GMP
CONDITIONS - the process can be run in
a continuous and closed configuration.
MICROSIEVE EMULSIFICATIONIN THE PRODUCTION OF
MONODISPERSEMICROSPHERES FOR DRUG
DELIVERY
As mentioned previously, particle size
is a crucial parameter that should be
controlled when designing microsphere
drug delivery systems. Therefore, Nanomi
focuses its efforts in developing
monosphere formulations with a specific
size and tight size distribution (often with
a coefficient of variation, CV, under 5%),
which can be chosen for optimal product
performance.
Currently, droplets in the range of 2 to
100 microns and microspheres in the
range 1 to 50 microns are routinely
manufactured with tight size distributions
at a scale in the multiple gram range. Very
recently, the process has successfully been
scaled up to 1 kg/day. Development is
ongoing to drive the minimum particle
size down to the nano range. In addition,
development is in progress to integrate the
process in a GMP-qualified fill and finish
production line.
Nanomi has validated the microsieve
emulsification process for a large number
of biodegradable and biocompatible
polymers, such as PLGA, PCL, PLGA-
PEG, PEG-PBT, PTMC, PEA, and
PMMA. In addition, other materials such
as lipids can also be processed into
microspheres.
Many combinations of (biodegradable
and biocompatible) polymers and active
compounds (water soluble/insoluble) have
been processed by microsieve
emulsification (Figure 4, which displays
some examples of microspheres developed
by Nanomi). Peptides, proteins, small
molecules, antibodies, and other relevant
molecules can be encapsulated with high
efficiency and high loading. Recently
developed PLGA microspheres
(PURASORB PDLG 5004, PURAC
biomaterials) loaded with 10%
progesterone demonstrated a perfect
diffusion-controlled release without burst.
This is in agreement with observations
reported in literature for monodisperse
microsphere formulations fabricated by
another droplet-generating method.4,9
Microsieve emulsification enables the
production of cost-efficient monodisperse
microsphere-based systems for parenteral,
sustained released, drug delivery
applications (IV, IM, SC, Intra-articular,
embolization, etc). Although drug delivery
is the main focus of attention, Nanomi
also provides expertise in the production
of emulsions and microspheres and
nanospheres for diagnostics, molecular
imaging, and research and analysis.
SUMMARY
In summary, the microsieve
emulsification technology is highly
suitable for the production of microsphere-
based drug delivery formulations. It can
provide high predictability and
reproducibility, robustness, scalability, size
control and narrow size distributions.
Moreover, other features like good
syringability, no phagocytosis, high
encapsulation efficiency and no burst can
also be achieved.
F I G U R E 4
Monodisperse PLA microspheres (10 micron-diameter) without (A) and with (B) encapsulatedfluorescent FITC-BSA. Monodisperse 9-micron Polycaprolactone (PCL) microspheres (C) andfluorescent red polymeric markers (D).
DrugDeliveryTechnology
January2009
Vol9
No1
xx
PARENTERALD E L I V E R Y
DrugDeliveryTechnology
January2009
Vol9
No1
xx
New controlled-release technologies
like microsieve emulsification can extend
the life cycle of proprietary drugs that run
out of patent protection and allow for the
delivery of new drugs, among others.
Moreover, Nanomis patent-protected
technology can improve the therapeutic
properties and performance of existing
products, but also enable new products
and therapies, eg, in the field of radio- or
chemo-embolisation, in which extreme
control over microsphere size and
uniformity is a must to achieve a
successful therapy.
REFERENCES
1. Boyd B, Banz K, Rodger J, Carrol S.
Optimizing drug suspension particle
size as a means to reduce the frequency
of intravitreal steroidal injections. Paper
presented at the AAPS Annual meeting
& Exposition in San Diego;2007.
2. Yamamoto N, Fukai F, Ohshima H,
Terada H, Makino K. Dependence of
the phagocytic update of polystyrene
microspheres by differenciated HL60
upon the size and surface properties of
the microspheres, Colloids Surf., B.
2002;25:157.
3. KatareYK, Muthukumaran T, Panda
AK. Influence of particle size, antigen
load, dose and additional adjuvant on
the immuneresponse from antigen
loaded PLA microparticles. Int. J.
Pharm. 2005:301:149-160.
4. Kim K, Pack D. Microspheres for drug
delivery. In: Ferrari M, ed. BIOMEMS
and Biomedical Nanotechnology,
Volume 1: Biological and Biomedical
Nanotechnology Springer; 2007.
5. Utada AS, Lorenceau E, Link DR,
Kaplan PD, Stone HA, Weitz DA.
Monodisperse double emulsions
generated from a microcapillary
device. Science. 2005;308:537.
6. Xu S, Nie Z, Seo M, Lewis P,
Kumacheva E, Stone HA, Garstecki P,
Whitesides GM. Generation of
monodisperse particles by using
microfluidics: control over size, shape,
and composition. Angew. CHem. Int.
Ed. 2005;44:724.
7. Garstecki P, Gitlin I, Diluzio W,
Whitesides GM, Kumacheva E, Stone
HA. Formation of monodisperse
bubbles in a microfluidic flow-focusing
device. App;/ Phys. Lett. 2004;85:2649.
8. Vladisavljevic GT, Williams RA.
Recent developments in manufacturing
emulsions and particulate products
using membranes. Adv. Colloid
Interface Sci.. 2005;113:1.
9. Berkland C, Pollauf E, Raman C,
Silverman R, Kim K, Pack DW.
Macromolecule release from
monodisperse PLG microspheres:
control of release rates and
investigation of release mechanism. J.
Pharm. Sci. 2007;96:1177.
Dr. Gert Veldhuis is Co-Founder and ManagingDirector at Nanomi. Heearned his degree inPhysics and his PhD inMicro Systems Technology(MST) (cum laude) at theUniversity of Twente (TheNetherlands). He authoredmany publications ininternational peer-reviewed
journals and has several patents. Prior tofounding Nanomi in 2004, Dr. Veldhuis wasemployed at Philips Research in Eindhoven andC2V in Enschede (The Netherlands), where hemanaged MST design activities.
Dr. Mriam Girons isSenior DevelopmentEngineer at Nanomi. Sheearned her MSc inChemistry at the Universityof Girona (Spain) and herPhD in Chemical Technologyat the University of Twente(The Netherlands), whereshe studied the fabricationand fouling behavior of
microsieveTM membranes. Her research in thisarea has produced several publications ininternational peer-reviewed journals. Followinga post-doctoral fellowship in TissueEngineering and Biomaterials (University ofTwente), she joined Nanomis team in 2006and has since then been involved in businessdevelopment and the technical supervision ofseveral R&D projects.
Ms. Debra Bingham is aPartner of Valeo Partners, aWashington, DC-based firmthat provides strategicconsulting, businessdevelopment, and M&Aservices to life sciencecompanies in thepharmaceutical,biotechnology, medicaldevice, and drug delivery
markets. Ms. Bingham brings clients over 14years of specialized expertise in thepharmaceutical and drug delivery industries.Her clients include large multinationalpharmaceutical and chemical companies aswell as medium to small specialty pharma anddrug delivery companies. She has workeddirectly with North American, European, andJapanese companies in the area of businessdevelopment strategy and licensing. Heruniquely strong network in Japan, Europe, andNorth America has been an asset to herclients. Ms. Binghams primary focus isdirecting companies in the areas of partnering,business strategy, and growth opportunityassessment.
B I O G R A P H I E S