# Parental Drug Delivery of Microparticles

PARENTERALD E L I V E R Y

DrugDeliveryTechnology

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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


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.


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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.


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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).


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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.

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# Parental Drug Delivery of Microparticles