Note: Descriptions are shown in the official language in which they were submitted.
2123481
The present invention relates to microparticles and, in particular, to a
process for
preparing microballs which does not require any solvent or mechanical
treatment of the
active ingredient. It also relates to the microballs thus obtained, which are
characterized
by being substantially spherical and substantially free of active ingredient
on the
external surface.
Microparticles are small pharmaceutical particles comprising a biocompatible
polymer
and an active ingredient. Microparticles are used, for example, as sustained
release
compositions, i.e. the polymer slowly biodegrades or is resorbed by the body,
and as the
polymer biodegrades or resorbs, the active ingredient is released.
One of the problems with microparticles is the "burst effect". The burst
effect is the
phenomenon which occurs when microparticles are first consumed or injected
into the
human or animal being treated. Upon injection, all of the material on the
surface of the
microparticle can be immediately consumed by the body. This means that the
body gets
an excessively large dosage at initial injection. It is advantageous both to
control the
burst effect and to make sure that, throughout the life of the microparticles,
the dosage
available to the body is above the minimum level at which they are efficient.
It has been found that foaming the microparticles so that they are
substantially free of
active ingredient on the surface of the microparticles makes better control of
the burst
effect. One of the advantages of microparticles with substantially no active
ingredient
on the surface is that they have a more easily controlled release profile.
It is to be understood that when it is said that the microparticles have
essentially no
active ingredient on the surface, it is intended to mean that the
microparticles are
uncoated, i.e. they do not have a separate coating on the external surface
thereof. The
microparticles are substantially free of active ingredient at the surface
because of the
manner in which they are formed, not because they have an external coating.
_~12'~481
One way to accomplish this is discussed in the U.S. Patent No. 5 213 812. As
set forth
in that patent, microparticles are prepared with substantially no active
ingredient on the
surface by a process which includes extrusion, tabletting, grinding or other
mechanical
treatment of the particles to be made into microparticles.
While the process of the U.S. Patent No. S 213 812 is a vast improvement over
previous
processes for making microparticles, it has been found that there are further
improvements which can be made. One of the disadvantages of the mechanical
treatment is that it creates irregularly shaped particles which do not give
uniform
release of active ingredient, and which can have uncontrollable burst effect.
Another
disadvantage is that some active ingredients are fragile and are damaged or
destroyed
by the mechanical steps of grinding, tabletting, extrusion, etc. Furthermore,
up to 5 %
of the active ingredient can be lost during the mechanical processing. This is
significant
for two reasons. One is the high cost of many pharmaceutical materials,
notably
peptides, where the loss of up to 5 % active ingredient can be significant.
Furthermore,
since the exact amount of material lost is not ascertainable, the amount of
active
ingredient administered cannot be accurately controlled.
Some processes for producing particles without the need for extruding and/or
grinding
techniques are known. For example, PCT Application W092/21326 discloses a
process
of forming microparticles from a mixture of drug and biocompatible polymers by
heating the combination to an intermediate liquid phase and then pouring the
liquid
phase on a temporary matrix consisting of crystals. The liquid phase is
converted to a
solid phase by cooling and then the matrix is removed from the solid phase by
washing.
The solid phase is thus in a form comprising imprints of the structure of the
temporary
matrix crystals. Consequently, the particles obtained are similar to those
obtained by
mechanical treatment in that they have an irregular external surface and are
non-spheroidal, and do not provide the characteristics required for an
accurate control
of the release.
Another process, called hot-melt encapsulation, is described in E. Mathiowitz
and
R. Linger, Journal of Controlled Release, 5 ( 1987), 13-22. The process
comprises the
mixture of a drug and a melted polymer. The mixture is the suspended solvent
which is
immiscible with the selected polymer and drug. An emulsion is obtained,
stabilized and
then cooled until solidification of the core material. The drawback to this
process is that
the polymer used has a low melting point, e.g. 70-80° C or lower. If it
is desired to use
2123481
a polymer with a higher melting point, the polymer must be combined with a
plasticizer
in order to lower the melting point down to a temperature at which the process
may be
performed. This is because the use of a high processing temperature, which
would be
necessary to use the process with a pure polymer having a high melting point,
leads to
both sticking of the ingredients and degradation of the drug. Thus, it is
impossible to
obtain particles comprising only the drug and a high melting point polymer.
Furthermore, the microparticles obtained have a granulated external surface
and the
disadvantages as previously discussed.
According to the invention there is disclosed a new process for the
preparation of
microballs wherein the drawbacks which exist in the techniques described in
the
previous processes are avoided.
In comparison with the process of the above cited U.S. 5 213 812 patent, the
process of
the present invention is performed without using mechanical formation of the
particles.
In accordance with the present invention, the starting materials may be
limited to the
constituents of the microballs and a supporting phase. The processing
techniques can be
limited to heating, cooling and stirring ; conventional techniques, such as
dry mixture,
extrusion and grinding, are not necessary. Furthermore, the particles of the
present
invention are dry processed without use of any solvents.
The microparticles obtained according to the present invention are also of
substantially
spheroidal form and have substantially no active ingredient on the external
covering.
The process of the invention may be used to obtain microballs with a core
loading of
1 %, 5 %, 10 %, 15 % or above.
The present invention improves on the formation of microparticles by forming
microballs, i.e. substantially spherical microparticles, which have
substantially no
active ingredient on the surface thereof by eliminating the need for
mechanical
treatment of the ingredients making up the microballs. In accordance with the
present
invention, a supporting phase is used for the formation of the microballs. The
supporting phase is immiscihle with the active ingredient and the polymer of
the
microballs to be formed. The supporting phase preferably has a viscosity of
from about
3 000 to about 15 0()0 mPa.s at 25° C.
2123481
The supporting phase is heated to a temperature above the glass transition
temperature
(Tg) of the polymer and below the decomposition temperature of the active
ingredient
or the polymer, whichever is lower. It will be appreciated that if the Tg of a
particular
polymer is above the decomposition temperature of the active ingredient to be
used,
then that particular polymer cannot be used to make microballs with that
particular
active ingredient.
The active ingredient and the polymer can be added to the supporting phase
together or
they can be added separately. Furthermore, each may be added to the supporting
phase
before it is heated, while it is being heated, or after it has reached the
desired
temperature. Still further, the active ingredient and the polymer can he pre-
mixed
before being added to the supporting phase.
After the supporting phase, polymer and active ingredient are at the selected
temperature, they are stirred and the stirring is continued for a time and at
a shear rate
effective to form microballs of the desired size. The amount and rate of
stirring must be
empirically determined for each combination of polymer and active ingredient.
Furthermore, since the microballs can be made of different sizes depending on
the
amount of stirring, the desired size of the particles will also affect the
empirical
determination of the amount of stirring required.
While the ingredients may be combined in any selected order, it is preferred
that the
polymer first be incorporated into the supporting phase and that the
supporting phase be
stirred until microballs of polymer of the desired size are obtained. Then,
while
continuing the stirring at the temperature above the Tg of the polymer, the
active
ingredient is added. The active ingredient may he added in either solid or
liquid form.
Stirring is continued during the addition of the active ingredient until
complete
absorption of the active ingredient by the polymer. Complete absorption must
be
empirically determined for each combination of polymer and active ingredient.
This
particular variation of the process is especially desirable where the active
ingredient has
a comparatively low degree of thermostability. The reason this variation of
the process
is desirable is because the active ingredient is at an elevated temperature
for a relatively
short period of time.
Where the active ingredient is stable at high temperatures, e.g. between
100° C and
200° C, the active ingredient can first be added to the supporting
phase. The supporting
2123481
_5_
phase and active ingredient can then be heated above the Tg of the polymer to
be added,
whereafter the polymer is added and the mixture is stirred until microballs of
the
desired size are obtained.
After the microballs are formed to the required size, the stirring is
discontinued and the
mixture is cooled. An appropriate washing agent, which is a solvent for
neither the
polymer nor the active ingredient, is used to wash the microballs and then the
microballs are recovered by filtration and drying.
After filtration, the microballs can be subjected to a sterilization step.
However, if the
selected temperature to which the mixture of the supporting phase, the
microparticles
and the polymer is high enough, this step can act as the sterilization step
rather than
requiring a separate sterilization step. It is also within the contemplation
of the present
invention to sterilize the active ingredient before it is added to the
supporting phase,
thus eliminating the need for a separate sterilization step or using a
temperature during
the processing which is high enough to act as a sterilization step. In any
case, the
microballs obtained according to the process of the invention may be
sterilized if
desired. Any known technique can be used such as, for instance,
radiosterilization.
The essential characteristics of the supporting phase are that it be
immiscible with the
selected polymer and the active ingredient and that it have a boiling point
which is
above the temperature which is selected to form the microballs. The supporting
phase
may be a homopolymer or a copolymer or a combination of two or more of the
same.
Suitable for use as a supporting phase are liquids such as silicone oil,
sesame oil, peanut
oil, castor oil and the like. Appropriate thickening agents, such as
stearates, may be
added to the supporting phase if desired. The viscosity of the supporting
phase is
suitably from about 3 00() to about 15 000 mPa.s (at 25° C).
Preferably, the viscosity is
of from about 5 000 to about 12 000 mPa.s (at 25° C) and, more
preferably, about
10 000 mPa.s (at 25° C).
The supporting phase may suitably be a hydrophobic or hydrophilic gel. When
the gel
is hydrophobic, the active ingredient is preferably hydrophilic. With a
hydrophobic
supporting phase, the microballs may suitably be recovered by washing the
mixture
with a hydrophobic washing agent, e.g. myristic acid isopropyl ester. When the
supporting phase is hydrophilic, the active ingredient is preferably
hydrophobic ; these
microballs may suitably he recovered by washing the mixture with a hydrophilic
CA 02123481 2003-12-23
-6-
washing agent, e.g_ water or a mixture of water and ethanol. Silicon oil is
the preferred
supporting phase in many instances. The reason is that the hydrophobic or
hydrophilic
nature of the active ingredient is usually not an issue because of the
insolubility of most
active ingredients in silicon oil.
Suitable polymers and active ingredients are well known in the art and are set
forth, for
example, in the prior U.S. Patent No. 5 213 812 .
Suitable polymers include polyanhydrides, polyacetals, polysaccharides,
cellulosic
polymers (e.g_ hydroxymethyl cellulose, hydroxypropylmethyl cellulose),
polyvinylpyrrolidone and polypeptides. The polymer must be biocompatible and
may
also be biodegradable or bioresorbable. Suitable biodegradable polymers
include
homopolymers and copolymers of ~-caprolactone, denatured proteins, polyortho
esters
and polyalkyl-cyanoacrylates. Suitable bioresorbable polymers include
homopolymers
and copolymers of lactic acid and glycolic acid. It will be understood that
other
polymers can be used and that the polymer used may be a homopolymer of any one
of
the foregoing or of any suitable polymer, or a copolymer of any two or more of
the
foregoing or of any two or more other suitable polymers. It is preferred that
the selected
polymer have a Tg between about 25° C and about 200° C and, even
more preferably,
the selected polymer has a Tg between about 35° C and about 150°
C. In addition to the
importance of the Tg, the melting point of the polymer is also important. The
melting
point should be high enough so that the microballs do not melt and stick
together under
normal use conditions. It is preferred that the melting point of the polymer
be at least
about 75° C, more preferred that it be at least about 100° C,
and most preferred that it
be above about 1 SO° C.
The term "active ingredient" is broad and includes any pharmaceutically active
ingredient or a mixture of two or more pharmaceutically active ingredients.
The active
ingredient may be in either liquid or solid form_ Pharmaceutically active
ingredients are
those which can be administered to humans or animals for the purpose of
diagnosis,
cure, mitigation, treatment or prevention of disease. Typical active
ingredients which
can be used in microballs include narcotics, such as morphine ; narcotic
antagonists,
such as naloxone ; antipsychotic agents, such as sodium pentobarbital and
chlorpromazine ; antidepressives, such as imipramine hydrochloride ;
stimulants, such
as methyl phenadate and nikethamide ; hallucinogens ; analgesics, such as
mumorphan
212381
_, _
meperidine ; anorexigenic agents ; antihypertensive agents, such as reserpine
;
antianginal agents, such as papaverine ; drugs for the therapy of pulmonary
disorders,
such as theophylline ethylene diamine salt ; chemotherapeutic agents ;
antiparasitic
agents, such as emetine hydrochloride ; antifungal agents, such as
cyclohexemide ;
anti-neoplastic agents, such as triethylene thiophosphoramide ; agents
affecting
metabolic diseases and endocrine functions, such as prostaglandins ;
athersclerosins,
such as heparin ; steroids and biologically related compounds ; polypeptides,
such as
bacitracin and polymyxin B sulfate ; natural and synthetic hormones, such as
progesterone ; steroid and non-steroidal anti-inflammatory agents, such as
hydrocortisone ; agents affecting thrombosis, such as crystalline trypsin ;
vitamins, such
as vitamin B 12 ; anti-epilepsy agents, such as phenoharbital, and the like.
It should be
understood that the specific drugs mentioned by name are illustrative and not
limitative.
In addition to the active ingredient in the microballs, there can be included
pharmaceutically inert additives such as PvP, mannitol, carbowax, polyethylene
glycols, glycerides and ethyl cellulose. The term "active ingredient" also
includes the
lack of presence of an active ingredient. This can be used, for example, where
it is
desired to have some of the subjects treated with an active ingredient and
other of the
subjects treated with a placebo. In this case, there would be no
pharmaceutically active
ingredient in the placebo, yet the process of the present invention could be
used to make
the microballs used as the placebo. The amount of active ingredient can be
from about 1
to about 99 ~lo of the microballs and the amount of polymer can be from about
99 to
about 1 ~lo of the microballs. Good results have been obtained with 1 part of
active
ingredient per 1()-30 parts of polymer.
As discussed previously, the amount and the shear rate of stiu-ing are largely
dependent
on the size of the particles desired. Stirring can commence when the
supporting phase is
first introduced to the mixing vessel, or stirring can be delayed until the
supporting
phase has been brought up to the selected temperature. In any case, the
stirring must be
at a shear rate high enough to form the microballs. The length of stirring at
that shear
rate will affect the size of the microballs. Stirring of the mixture
comprising the
supporting phase, the polymer, the active ingredient and any other ingredients
at the
selected temperature will generally be for a period of time from about 5
minutes to
about 2 hours, and more typically from about 10 minutes to about 30 minutes.
The size
of the particles of the biocompatible polymer used as a starting material is
not critical
and the size of the particles may be indifferently from about 300 pm to about
5 mm.
2123481
The size of the microballs formed will be reduced to the required size
according to the
amount of stirring and the temperature at which stirring is carried out. For
example,
particles of 5 mm size may be obtained with relatively low stirring in a high
viscosity
supporting phase whereas particles of 3(~ ~tm size will only be obtained with
vigorous
stirring in a relatively low viscosity supporting phase. Stirring may be
carried out in any
conventional manner which gives a shear rate high enough to form microballs,
e.g.
mechanical stirring, use of an ultra-sound generator or a Polytron mixer from
Kinematica GmbH of Luzern, Switzerland. The ultra-sound generator is preferred
since
it also provides heating.
The "selected temperature" is the temperature to which the mixture is heated
to form
the microballs. There are a number of limitations on the selected temperature.
It must
be above the Tg of the selected polymer. However, it cannot be higher than any
of the
following
(a) the temperature at which the polymer degrades or vaporizes ;
(b) the temperature at which the active ingredient degrades or vaporizes ;
(c) the temperature at which the supporting phase degrades or vaporizes.
Obviously, the vaporization temperature will depend on the pressure in the
vessel in
which the mixture is heated which, in turn, will depend on the polymer
employed. As a
general rule, a selected temperature which creates no more than about 2 bars
of pressure
in the reaction vessel is suitable.
The size of the particles produced is a matter of choice and, as previously
indicated, is
highly dependent on the amount of time and shear rate at which the admixture
is stirred
at the selected temperature. It is to be noted that the size of the particles
affects the burst
effect. Larger particles have less burst effect than smaller ones. This means
that the
burst effect can be controlled by controlling the size of the microballs
formed and, in
addition, can be controlled by using a mixture of microballs of different
diameters.
The present invention also includes the microballs obtained using the process
of the
present invention. The microballs are characterized by being substantially
spherical,
having a substantially smooth external surface and having an external surface
which is
substantially free of active ingredient. The microballs preferably have an
average
diameter of from about 10(1 pm to about 5 mm.
2123481
_~,_
The present invention further includes pharmaceutical compositions which
contain the
microballs of the present invention. The microballs of the present invention
may be
administered either orally or parenterally. For parenteral administration, it
is preferred
that the particles have an average diameter which is not greater than about
200 ~tm. For
oral administration, the particles preferably have an average diameter of from
about 0.5
to about 5 mm.
The invention is illustrated by the following examples
EXAMPLE 1
The purpose of this example is to demonstrate that there is substantially no
active
ingredient on the surface of the microballs. The following ingredients were
used
Supporting phase : silicone oil (viscosity, 10 000 mPa.s at 25° C)
Biocompatible polymer : Poly Lactide co Glycolide (PLGA 50/50, weight average
molecular weight range - 40 000 to 50 000)
Active ingredient : blue hydrophilic colorant (Blue Patente V)
To a reactor containing 100 ml of silicone oil, there was added 3 g of the
mixture of
PLGA 50/50. The mixture of PLGA was dispersed for 5 minutes at room
temperature
under stirring. The stirring was discontinued and the mixture was heated to
110° C. The
stirring was resumed and the active ingredient was added. The stirring was
maintained
for 30 minutes at 12S° C to incorporate the active ingredient. The
stirring was stopped
and the mixture was allowed to cool overnight in a freezer at 20° C.
The mixture was
washed with myristic acid isopropyl ester, then filtered and dried to recover
blue
particles. The length of time and shear rate of the stirring formed particles
that had an
average diameter of about 10 pm.
Both the silicone oil and the washing agent were studied, and it was found
that neither
had any blue color. The microballs were then immersed in 20() ml of water and
were
again studied. Once again, no blue coloration of the water was observed.
The microballs were further treated by diluting them in dichloromethane, which
is a
solvent for the polymer. This mixture of particles and dichloromethane was
then added
to water, upon which the water turned blue. This example confirms that there
is
substantially no active ingredient on the surface of the particles.
2123481
_ lo-
In this example, the following ingredients were used
Supporting phase : silicone oil (viscosity, 10 000 mPa.s at 25° C)
Biocompatible polymer : PLGA 50/50, ground to 200 pm
Active ingredient : D-Trp6 LHRH pamoate, particle size 5-10 ~tm
To a reactor containing 500 ml of silicone oil, there was added 5 g of PLGA
50/50
under stirring. Particles of PLGA 50/50 were dispersed in the oil and the
mixture was
heated to 80-100° C. There was then added 0.175 g of particles of
peptide while
continuing the stirring. The progressive incorporation of the peptide
particles in the
polymer was observable. The mixture was stirred for 20 minutes at the same
temperature and then heated to 125° C. At 125° C the stirring
was stopped. The mixture
was cooled to 25° C. It was then diluted with 9 volumes of myristic
acid isopropyl ester
as washing agent after which it was filtered. The length of time and shear
rate of the
stirring formed particles that had an average diameter of 5 to 10 pm. The
yield was
4.5 g.
EXAMPLE 3
In this example, the following ingredients were used
Supporting phase : silicone oil (viscosity, 10 000 mPa.s at 25° C)
Biocompatible polymer : PLGA 50/50, ground to 200 ~m
Active ingredient : D-Tips LHRH acetate, particle size 5-10 pm
To a reactor containing 500 ml of silicone oil, there was added 5 g of PLGA
50/50
under stirring. Particles of PLGA 50/50 were dispersed in the oil and the
mixture was
heated to 80-100° C. There was then added 0.170 g of particles of
peptide while
continuing the stirring. The progressive incorporation of the peptide
particles in the
polymer was observable. The mixture was stirred for 20 minutes at the same
temperature and then heated to 125° C. At 125° C the stirring
was stopped. The mixture
was cooled to 25° C. It was then diluted with ) volumes of myristic
acid isopropyl ester
as washing agent after which it was filtered. The length of time and shear
rate of the
stirring formed particles that had an average diameter of 5 to 10 pm. The
yield was
4.8 g.
-I1-
EXAMPLE 4
In this example, the following ingredients were used
Supporting phase : silicone oil (viscosity, 10 0()() mPa.s at 25°
C)
Biocompatible polymer : PLGA 5()/50, ground to 20() pm
Active ingredient : somatulin pamoate
To a reactor containing 500 ml of silicone oil, there was added 5 g of PLGA
50/50
under stirring. Particles of PLGA 50/50 were dispersed in the oil and the
mixture was
heated to 100-120° C. There was then added 0.9$0 g of particles of
peptide while
continuing the stirring. The progressive incorporation of the peptide
particles in the
polymer was observable. The mixture was stirred for 30 minutes at the same
temperature and then heated to l30° C. At 130° C the stirring
was stopped. The mixture
was cooled to 25° C. It was then diluted with 9 volumes of myristic
acid isopropyl ester
as washing agent after which it was filtered. The length of time and shear
rate of the
stirring formed particles that had an average diameter of 5 to 10 pm. The
yield was
5.1 g.
In this example, the following ingredients were used
Supporting phase : Polyvinylpyrrolidone (PvP) K60 in water (45 %~ w/v ;
viscosity,
10 000 mPa.s at 25° C)
Biocompatible polymer : PLGA 50/50, ground to 200 p.m
Active ingredient : steroids (progesterone), particle size 5-10 pm
To a reactor containing 500 ml of PvP gel, there was added 8 g of PLGA 50/50
under
stirring. Particles of PLGA 50/50 were dispersed in the gel and the mixture
was heated
to 95° C. There was then added 2.44 g of particles of progesterone
while continuing the
stirring. The progressive incorporation of the peptide particles in the
polymer was
observable. The mixture was stirred for 30 minutes at 95° C. The
stirring was stopped
and the mixture was cooled to 25° C. It was then diluted with 10
volumes of water as
washing agent after which it was filtered. The length of time and shear rate
of the
stirring formed particles that had an average diameter of 5 to 10 pm. The
yield was
9.96 g.
212381
- t2 -
In this example, the following ingredients were used
Supporting phase : silicone oil (viscosity, 10 0()0 mPa.s at 25°
C)
Biocompatible polymer : E-caprolactone polymer, ground to 200 ~tm
Active ingredient : D-Trp6 LHRH pamoate, particle size 5-10 pm
To a reactor containing 500 ml of silicone oil, there was added 1 g of polymer
under
stirring. Particles of polymer were dispersed in the oil and the mixture was
heated to
80° C. There was then added 37 mg of particles of peptide while
continuing the stirring.
The progressive incorporation of the peptide particles in the polymer was
observable.
The mixture was stirred for 10 minutes at 110° C. The stirring was
stopped and the
mixture was cooled to 25° C. It was then diluted with 9 volumes of
myristic acid
isopropyl ester as washing agent after which it was filtered. The length of
time and
shear rate of the stirring formed particles that had an average diameter of 5
to 10 Vim.
The yield was 0.952 g.
EXAMPLE 7
In this example, the following ingredients were used
Supporting phase : aluminium stearate in sesame oil (4 % w/v ; viscosity, 12
500 mPa.s
at 25° C)
Biocompatible polymer : PLGA 50/50, ground to 20() ~m
Active ingredient : triptoreline pamoate, particle size 5-10 pm
To a reactor containing 5()0 ml of the supporting phase, there was added 10 g
of
PLGA 50/50 under stirring. Particles of PLGA 50/50 were dispersed in the gel
and the
mixture was heated to 120° C. While continuing the stirring there was
then added
0.638 g of particles of peptide and 100 mg of sorbitane fatty acid ester. The
progressive
incorporation of the peptide particles in the polymer was observable. The
mixture was
stirred for 20 minutes at the same temperature. The stirring was stopped and
the mixture
was cooled to 25° C. It was then diluted with 20 volumes of ethanol as
washing agent
after which it was filtered. The length of time and shear rate of the stirring
formed
particles that had an average diameter of 5 to 10 ~tm. The yield was 9.2 g.
212381
-i3-
In this example, the following ingredients were used
Supporting phase : aluminium stearate in sesame oil (4 % w/v ; viscosity, 12
S00 mPa.s
at 25° C)
Biocompatible polymer : poly E-caprolactone, ground to 200 pm
Active ingredient : triptoreline pamoate, particle size 5-10 ~tm
To a reactor containing 500 ml of the supporting phase, there was added 10 g
of poly
E-caprolactone under stirring. Particles of poly ~-caprolactone were dispersed
in the gel
and the mixture was heated to 120° C. While continuing the stirring
there was then
added 0.638 g of particles of peptide. The progressive incorporation of the
peptide
particles in the polymer was observable. The mixture was stirred for 30
minutes at the
same temperature. The stirring was stopped and the mixture was cooled to
25° C. It was
then diluted with 20 volumes of ethanol as washing agent after which it was
filtered.
The length of time and shear rate of the stirring formed particles that had an
average
diameter of 5 to 10 pm. The yield was 8.7 g.
In this example, the following ingredients were used
Supporting phase : silicone oil (viscosity, 10 ()0() mPa.s at 25°
C)
Biocompatible polymer : PLGA 75/25, ground to 20() ~tm
Active ingredient : tiliquinol (antibacterial), particle size 5-10 ltm
To a reactor containing 500 ml of silicone oil, there was added 8 g of PLGA
75/25 and
1.23 g of particles of tiliquinol under stirring. The mixture was heated to 80-
100° C.
The progressive formation of the microballs and the incorporation of particles
of
tiliquinol in said microballs was ohservable. The mixture was stirred for 30
minutes at
the same temperature. The stirring was stopped and the mixture was cooled to
25° C. It
was then diluted with 9 volumes of myristic acid isopropyl ester as washing
agent after
which it was filtered. The length of time and shear rate of the stirring
formed particles
that had an average diameter of 5 to 10 pm. The yield was 8.25 g.
2~~3~81
In this example, the following ingredients were used
Supporting phase : aluminium stearate in sesame oil (4 % w/v ; viscosity, 12
500 mPa.s
at 25° C)
Biocompatible polymer : PLGA 75/25, ground to 200 p.m
Active ingredient : tiliquinol (antibacterial), particle size 5-10 ftm
To a reactor containing 500 ml of the supporting phase, there was added 2.16 g
of
particles of the tiliquinol under stirring. Particles of tiliquinol were
dispersed in the gel
and the mixture was heated to 120° C. While continuing the stirring
there was then
added 10 g of PLGA 75/25. The progressive formation of the microballs and the
incorporation of particles of tiliquinol in said microballs was observable.
The mixture
was stirred for 25 minutes at the same temperature. The stirring was stopped
and the
mixture was cooled to 25° C. It was then diluted with 20 volumes of
ethanol as washing
agent after which it was filtered. The length of time and shear rate of the
stirring formed
particles that had an average diameter of 5 to 10 Vim. The yield was 11.3 g.
It will be understood that the claims are intended to cover all changes and
modifications
of the preferred embodiments of the invention herein chosen for the purpose of
illustration which do not constitute a departure from the spirit and scope of
the
invention.
