Note: Descriptions are shown in the official language in which they were submitted.
f
' t331343
TUN-090
A M W ANT-ENHANCED SUSTAINED RELEASE COMPOSITION
AND METHOD FOR MAKING
ACKGROUND OF ~ INVENTIO~
This invention pertains to novel microparti-
culate material, the particles of which are sometimes ::
referred to as microcapsules, and to a method for `::
making such material. More specifically, thi~ inven-
tion pertains to an improved microparticulate
material, formed by the addition of one or more ad-
juvants, wherein said improved microparticle~ may act -~
as a carrier for diffusable reactants, such as chemi- ~:
:
. ~ . ,, . . , ,, . -
~`
1331343
TUN-090 -2-
cals and pharmaceuticals, in order to ~erve as sus-
ta~ned or controlled release '~icroencapsulated~
delivery forms.
Microencapsulation is a technique of enclo-
sing core materials within a polymeric membrane to
produce microparticles. The encapsulated material may
be released over a period of time by diffusion or
immediately by crushing or by digesting the shell-like
wall of the microparticle. These types of microparti-
cles are used extensively in the dye industry and in
the food and cosmetic industries.
In the pharmaceutical industry, c~nsiderable ~-
interest has been generated by the use of microparti-
cles as sustained release drug delivery formulations.
However, many microparticle formulations are of
limited utility because of their relatively large
particle size. A particle size of greater than that
of an erythrocyte (about 7 microns) is not suitable to
be injected intravenously.
Further problems with known prior art micro-
particulate material arise from the fact that gene-
rally such material tends to agglomerate, thus delete-
riously affecting certain important properties of the
materials such as dispersibility. Additionally, mi-
croparticulate material which is of suitable size for
injection may be captured by the reticulo-endothelial
- 1 33 1 343
TUN-090 -3-
system, which could have deleterious effects on blood
clearance of the microparticle shell material and
tissue distribution of the encapsulated core material~
A specific type of microparticulate material
and a method of making such material is disclo~ed in
U. S. Patent No. 3,989,457 (of common inventorship and
assignment herewith). This material is comprised of
the reaction product produced at the inter-phase
boundary of a finely dispersed emulsion, compri~ing:
I) a water immiscible solution of an organic
polyfunctional Lewis base in a low boiling point,
slightly polar, organic solvent; and
II) an aqueous solution of a partially hy-
drophilic, partially lipophilic, polyfunctional Lewis
acid.
Microparticles of this type comprise a
multiplicity of closed structures formed of lattice-
l$ke high molecul~r weight salt molecules of the Lewis
acid and Lewis base, through which an encapsulated
core material diffuses. The rate of diffusion i8
controlled by both the particle or molecular size of
the encapsulated compound and by the openness of the
lattice or networ~ of molecules comprising the parti-
cle walls. The degree of openness of the lattice is
controlled by the spacing of reactive sites on the
,
1 33 1 343
--4--
high molecular weight polyfunctional Lewis acids and by
the thickness of the particle walls.
In Lewis acid-Lewis base salt microparticles,
of the type referred to above, the degree to which
diffusibility can be controlled is somewhat limited.
There are also some limitations on the type and number of
compounds which these microparticles can encapsulate, or
which are soluble and stable in polar organic solvents of
the type typically used in making these microparticles.
According to one aspect of the invention, there
is provided microparticulate material, consisting essen-
tially of the reaction product of an emulsion of: a) a `
partially hydrophilic, partially lipophilic, polyfunct-
ional Lewis acid in an aqueous solution, said solution
comprising a continuous phase; and b) a polyfunctional
Lewis base dissolved in a slightly polar non-aqueous
solvent, and a core material dispersed therein, said non-
aqueous solvent comprising a discontinuous droplet phase,
said continuous aqueous phase surrounding the droplets of
said discontinuous phase, wherein, said Lewis acid and
said Lewis base and said non-aqueous solvent are adapted
by reaction of said Lewis acid and said Lewis base at the
phase interface on the surface of said droplets to form
enclosed cellular structures comprising a microparticu-
late material containing said core material in said
closed structures, in a manner to permit controlled
release of the core material through the microparticle
wall, said emulsion further including at least one
adjuvant selected from the group consisting of
poloxamers, which function as part of said core material,
and tetronomers, which function as at least part of said
Lewis base, said tetronomers and said poloxamers, if
present, being disposed in said non-aqueous phase, said
non-aqueous phase also including, if poloxamer is
present, a basic wall-forming reactant having a pKa of at
least 9.
,~,. .. . .
Z'' '
,, ' , , ~ ,
-4a- 1 331 343
According to another aspect of the invention, there
is provided in a method of producing microparticulate
material comprising: a) making a mixture of an aqueous
solution of a partially hydrophilic, partially
lipophilic, polyfunctional Lewis acid, with a water
immiscible solution of a polyfunctional Lewis base in a
slightly polar solvent, said water immiscible solution
containing a core material; b) agitating said mixture to
form an emulsion of water immiscible solution droplets
surrounded by a continuous phase of said aqueous
solution, wherein said Lewis acid and said Le~is base are
adapted to react with one another at the common phase
interface of said droplet surfaces to form microparticu-
late material comprising a multiplicity of closed
cellular structures containing said core material; c)
separating and washing and removing residual solvent from
said microparticulate material, the improvement consist-
ing of including in said mixture at least one adjuvant
selected from the group consisting of poloxamers, which
function as part of said core material, and tetronomers,
which function as at least part of said Lewis base, said
tetronomers and said poloxamers, if present, being
disposed in said water immiscible phase, said water
immiscible phase also including, if poloxamer is present
a basic wall-forming reactant having a pKa of at least 9.
According to a further aspect of the invention,
there is provided microparticulate material, consisting
essentially of the reaction product of an emulsion of:
a) a partially hydrophilic, partially lipophilic,
polyfunctional Lewis acid in an aqueous solution, said
solution comprising a continuous phase; and b) a
polyfunctional Lewis base dissolved in a slightly polar
non-aqueous solvent, and a core material dispersed
therein, said non-aqueous solvent comprising a
discontinuous droplet phase, said continuous aqueous
phase surrounding the droplets of said discontinuous
~ ; :'
.
-4b- 1 3 3 1 3 4 3
phase, wherein, said Lewis acid an~ said Lewis base and
said non-aqueous solvent are adapted by reaction of said
Lewis acid and said Lewis base at the phase interface on
the surfaces of said droplets to form enclosed cellular
structures comprising a microparticulate material
containing said core material in said closed structures,
in a manner to permit controlled release of the core
material through the microparticle wall, said emulsion
including at least one adjuvant selected from the group
consisting of: (i) a polyether linkage-containing basic
wall-forming reactant dissolved in said slightly polar
non-aqueous solvent and having a pKa of at least 9, and
(ii) an extremely weak basic, but essentially neutral
core-forming reactant, having a pKa of 5-7, disposed in
said slightly polar non-aqueous solvent phase, said
solvent phase also including, if (ii) is present, a basic
wall-forming reactant having a pKa of at least 9.
According to yet another aspect of the invention,
there is provided in a method of producing microparticu-
late material comprising: a) making a mixture of an
aqueous solution of a partially hydrophilic, partially
lipophilic, polyfunctional Lewis acid, with a water
immiscible solution of a polyfunctional Lewis base in a
slightly polar solvent, said water immiscible solution
containing a core material; b) agitating said mixture to
form an emulsion of water immiscible solution droplets
surrounded by a continuous phase of said aqueous
solution, wherein said Lewis acid and said Lewis base are
adapted to react with one another at the common phase
interface of said droplet surfaces to form microparticu-
late material comprising a multiplicity of closed
cellular structures containing said core materials;
c) separating and washing and removing residual solvent
from said microparticulate material, the improvement
consisting of including in said emulsion at least one
adjuvant selected from the group consisting of: (i) a
polyether linkage-containing basic wall-forming reactant
1 33 1 3~3
-4c-
dissolved in said water immiscible solution and having a
pKa of at least 9, and (ii) an extremely weak basic, but
essentially neutral core-forming reactant, having a pKa
of 5-7, disposed in said water immiscible solution, said
water immiscible solution also including, if (ii) is
present, a basic wall-forming reactant having a pXa of at
least 9.
This invention comprises Lewis acid-Lewis base salt
microparticulate materials of the type referred to above
which include at least one additional constituent, known
as an "adjuvant". The adjuvant may be a carbomer, such
as high molecular weight polymers of acrylic acid cross-
linked with a polyalkenyl polyether, or a polyoxamer,
such as a polyoxyethylene-polyoxypropylene copolymer, or
a tetronomer, such as a polyoxyethylene adduct of
ethylenediamine.
As used herein, the term "adjuvant," refers to a
class of compounds which provide some advantageous
characteristics to the microcapsule. An adjuvant may
assist in solubilizing a core material in the
k~ ~
' ' ' ' ' ' '' ' '' ' ' , , ;
' . ':
~" ' : ' ` ', -
1 33 1 343
TUN-090 5
non-aqueous solvent or may assist in the formation of
the microparticle wall or may assist both of these
functions.
Furthermore, the adjuvant may provide addi-
tional advantageous characteristics to the micropart$-
cle such as further controlling the susta$ned release
of the encapsulated core material, or it may asist in
the manufacture of the m~croparticulate material by
accelerating the phase separation of the aqueous and
non-aqueous solutions.
In some instances, certain adjuvants having
acidic or basic functions may be used in place of the `
Lewis acids or Lewis bases of U. S. Patent 3,959,437.
J Descript~on Q~ the Invention
Generally, microparticles of the type to
which this invention is directed are made as follows~
A non-aqueous solution of a Lewis base in a
slightly polar solvent is added to an aqueous ~olution
of a Lewis acid, such as acacia gum, or arabic acid,
or carboxymethylcellulose. The Lewis base may be, for -~
example, piperazine, or triethylenediamine, or ethy-
lenediamine. These solutions are combined with rapid
stirring to produce a finely dispersed emulsion of
organic phase droplets in a continuous aqueous phase.
1331343
TUN-090 -6-
Included in the non-aqueous solven~ is a core material
such a~ a drug. For purposes of sustained release of
the core material, it must be of such molecular ~ize
that it will be able to diffuse out of the individual
microparticulate material.
In the organic phase droplets of the finely
dispersed emul~ion of the aqueous and non-aqueous
solutions, the polyfunctional Lewis base is drawn to
the surface of the droplet by the polar attraction of
the surrounding aqueous phase. In the aqueous phase,
the partially hydrophilic, partially lipophilic, poly- `
functional Lewis acid is drawn, due to its partially
lipophilic characteristic towards the interface be-
tween the organic droplet and the surrounding aqueous
phase where it reacts, presumably through dipole
and/or ionic bonding, with the polyfunctional Lewis
base concentrated on the outer surfaces of the organ$c
phase droplets adjacent the interface, to produce a
shell-like insoluble particle generally coxrespondlng
in shape and size to the organic droplets. Each of
these shell-like particles is thought tc consist of an
open network, or lattice, of molecules of a dipole
and/or ionic salt.
The reaction of the polyfunctional Lewls
acid and the polyfunctional Lewis base is thought to
be essentially a two-step reaction sequence re~ulting
in the formation of anisotropic salt films in ~mall
, ~ , , . . .. . . . .... " . ., , .. , . . . . -., ; ; ,
~33~343
TUN-090 -7-
spherical or sphere-like shapes sometimes referred to
as microcapsules. The general$zed reaction sequence
is more clearly set out in U.S. Patent 3,959,457.
In accordance with the present invention,
also included in the emulsion is at least one adju-
vant, which may be dissolved in the aqueous solution
or in the non-aqueous solYent or both, prior to com-
bining the aqueous and non-aqueous solutions. Selec-
ted adjuvants must, of course, be substantially non-
reactive with other components in the reaction medium
and must al80 be substantially soluble in the appro-
priate solvent phase.
1~ Adjuvants are of two types, wall-formin~ and
core-forming. Core-forming adjuvants are understood
to be entirely within the core of the finished micro-
capsule. Core-forming adjuvants are typically poly-
oxyethylene-polyoxypropylene copolymers or block co-
polymers thereof. They are referred to herein as
~poloxomers" and are added to the non-aqueous, ~-
slightly polar organic phase before the emulsification ~-
~tep~
Wall-forming ad~uvants contribute to both
wall and core fonmation. They combine in their mole- ~-
cular structures either acidic or basic functions
together with polyether chains of varying length ;
Wall-forming adjuvants which combine acidic functional ~
1 331 343
TUN-O90 -8- ;
groups with ether chains are exemplified by high mole-
cular weight polymers of acrylic acid cross-linked
with a polyalkenyl polyether; such adjuvants are re-
ferred to herein as "carbomersn. Wall-forming adju-
vants which combine basic functional groups with
polyether chains are exemplified by ethylene oxlde
adducts of ethylenediamine, and are referred to herein
as "tetronomers~.
Both carbomers and tetronomers react with
ionizable species at the inter-phase boundary during
the wall-forming process to form salts which become
integral components of the ionic salt wall structure
of the microcapsule. The polyether chains of carbo-
mers and tetronomers are thought to project inwardly
from the inner surface of the microcapsule wall for
short distances, into what might otherwise be thought
of as a core space.
In practice/ carbomers are dissolved in the
aqueous phase of the manufacturing system. Tetrono-
mers are dissolved in the non-aqueous, slightly polar
organic phase. Tetronomerfi and carbomers fulfill a
primary function as wall-forming materials and al80
act as adjuvants.
~ a
1 331 343
TUN-O90 -9-
5en~ral Pr~çedures ~Q~ Forminq Miçrocapsules
In all instances where an aqueous solutlon
is utilized as the continuous phase for the dispersion
or emulsification of a second solution of materials
dissolved in an organic solvent, it is preferred, but
not essential, that the organic solvent be slowly and
~teadily added to the aqueous 801 ution over a period
of approximately 30 seconds. In all instances, solu-
tîons are prepared and reactions take place a~ room
temperature, unless otherwise stated. Any of several
means to disperse or emulsify the organic solution in
the aqueous medium may be employed including:
~ vigorously stirring the solution with a
magnetically driven stirring bar at a nominal shear
rate, generally 700 or more cm/s;
b. vigorously mixing the solution with a
multi-orifice axial turbine lsuch as a Brinkmann homo-
genizer PTlOJ35 and generator PST/10, Brinkmann
Instruments, Westbury, ~Y.) at a nominal setting of
5; or ~-
c. vigorously agitating the solution~ with ~
an ultrasonic probe (such a Heat Systems model ~ ~-
W185D, Ultrasonics, Inc., Plainview, N.Y.) at a nomi-
nal output o~f 100 watts.
-
1331343
TUN-090 -10-
Gençr~l Example ~ Method Q~ Makina ~lus~eE~l~
Products ~on~i mn~ ~Q~-Formina ~LhlY~ Materials
An aqueous solution of arabic acid was pre-
pared by adding to one gram of arabic acid, enough
water to make 10 mL Typically, the arabic acid is
first wetted with a small amount o$ alcohol to assist
in solubilizing the otherwise slowly solubilized Lew~s
acid. A non-aqueous solution was also prepared
by adding anhydrous pipe~azine (in a~.amount stoichio-
me~rically equivalent to the arabic acid), 1.0 g of a
core material (acetanilide), and 1.0 g of poloxamer
(polyoxyethelene-polyoxypropylene block copolymer;
such as Pluronic F68, a product of BASF-Wyandotte
Corp., Wyandotte, Illinois), to enough dichloromethane
to make 10 mL of solution.
The aqueous and non-aqueous solutions were
then combined in a container and continuously agitated
for approximately one minute, to produce an emulsion
of organic droplets, approximately 5 microns in dia-
meter, dispersed in and surrounded by continuous phase
aqueous ~olution.
Upon standing after agitation, the non-
aqueous organic phase was allowed to separate from the
aqueous phase. The essentially-clear, non-aqueous
organic phase was then removed from the aqueous phase
r
1 331 343
TUN-090 -11-
containing the microcapsules. The milk-like
suspension of newly formed microcapsul es settl ed to
the bottom of the container. Unreacted or excess
reaction components were then removed by adding an
equal amount of water to the microcapsules and
subsequent removal of the added water. Re~idual
dichloromethane was removed b~ evaporation upon
exposure of the microcapsules to the atmosphere. The - !
suspension of dichloromethane-free microcapsules wae
centrifuged to produce a flowable concentrate of
microparticulate material comprised of microcapsules
consisting of shell-like films surrounding the core
material (acetanilide) and the adjuvant.
General Example Q~ Method Qf Ma~ina Microca~sule
Products CQntainina ~ Formina Adjuvant ~QIj
Microparticulate material prepared by the
process of the present invention can ~e prepared by
omitting either the conventional Lewis acids or the
conventional Lewis bases. In these products, polymers
of acrylic acid (providing an acidic moiety) cros~-
linked polyalkenyl polyethers (providing an adjuvant
moiety) may perform the function of the Lewis aci~
The Lewi~ bases may also be substituted for by the use
of polyoxyethylene adducts (the adjuvant moiety~ of
ethylenediamine (the Lewis base moiety).
In both ca~es the polyether part of the
,
1 331 343
- -12-
Lewis acid or Lewis base molecule functions as an
adjuvant in accordance with the present invention.
For example, an aqueous solution of a carbomer was
prepared by addin~ to 0.1 g of finely divided poly-
acrylic acid cross-linked with polyalkenyl polyethers
such as Carbomer-68, (a product of Rohm and Haas
Company, Philadelphia, PA) enough water to make 10 mL.
A non-aqueous solution was also prepared by adding a
stoichiometric amount of anhydrous piperazine and 1.0
g of a core material (acetanilide) to enough dichloro-
methane to make lO mL.
The aqueous and non-aqueous solutions were
then combined in a container and continuously agitated
lS for approximately l minute to produce an emulsion of
organic droplets of approximately 5 microns in di-
ameter in continuous phase comprising the aqueous
solution.
The resulting product was handled as pre-
viously described, yielding a flowable microparticle
material comprised of microcapsules consisting of
shell-like films surrounding the core material.
Alternatively, for example, an aqueous solu-
tion of arabic acid was prepared by adding to l.0 g of
arabic acid enough water to make 10 mL. A non-aqueous
solution was also prepared by adding l.0 9 of core
* TRADE-MARK ~;
, ~
,, " , , ~ ,
~33~3~3
material (acetanilide) and 1.0 g of a poly-oxyethylene
adduct of ethylenediamine tsuch as Tetronic 702, a
product of BASF-Wyandotte Corp., Wyandotte, Illinois),
to enough dichloromethane to make 10 mL.
The aqueous and non-aqueous solutions were
then combined in a container and continuously agitated
for a minute to produce an emulsion of organic drop-
lets, approximately 5 microns in diameter, in an
aqueous continuous phase. The resulting product was
handled as previously described/ to yield a flowable
microparticulate material consisting of shell-like
films surrounding the core material.
Adjuvant-containing microparticles of the
present invention are physically more robust and are
able to withstand greater mechanical and thermal
stress than non-adjuvant containinq microparticles.
For example, when warmed in a water suspension of
approximately 40'C, the non-adjuvant containing micro-
particles of U. S~ Patent 3,959,347 will readily dis-
solve. Conversely, adjuvant containing microparticles
of the present invention, comprised of essentially the
same Lewis acid-Lewis base combinations, are stable
under these conditions and only begin to dissolve at
temperatures near 80'C. Similarly, continued agita- `
tion of non-adjuvant containing microparticles can
result in their rupture while adjuvant containing
microparticles are able to withstand vigorous shaking
: .
* TRADE-MARK
1 33 1 343
-14-
for extended periods.
Furthermore, adjuvant-modified micropar-
ticles may facilitate encapsulation of a wider range
and/or greater amount of core materials. Many
substances are more readily and more extensively solu-
ble in adjuvant-containing, non-aqueous manufacturing
solvents, than in those same solvents without the
adjuvant. For example, piperazine arabate walled
microcapsules containing mineral oil as a core ~-
material may be seen to begin to coalesce within
minutes after manufacture and may be seen to degrade
extensively and to separate into aqueous and oily
layers, free of capsular material, within hours after
manufacture. However, the addition of a core-forming
adjuvant (such as the polyoxyethylene-polyoxypropylene
block copolymer, Pluronic F68~ to the organic phase
before the emulsification step results in producing
piperazine arabate walled microcapsules of mineral oil
which remain stable for months. The microencapsula-
tion of mineral oil, through the use of an adjuvant,
demonstrates the encapsulation of a wider range of
core materials than had been possible without the use
of an adjuvant.
Furthermore, the use of a core-forming adju-
vant enables greater concentrations of relatively
polar core materials, such as acetanilide, to be dis-
solved in the dichloromethane phase. Thus more core
* TRADE-MARK
1 331 343
TUN-090 -15-
material can be encapsulated than is possible without
the adjuvant.
Additionally, acidic drugs, such as certain
non-steroidial anti-inflammatory agents, exemplified
by salicylic acid and ibuprofen, which interfere wlth
wall formation in non-adjuvant containing microparti-
cles, may successfully be encased in adjuvant con-
taining microparticles.
:'
Release of core materials (e.g., a drug)
from the adjuvant-containing microparticles of the
present invention can be more extensively controlled
than can release from non-adjuvant containing micro-
particles made according to the teachings of U. S.
Patent 3,959,457. For example, in the absence of an
adjuvant, a quite water soluble substance, such as the
model drug acetanilide, may be released from micro-
capsules into surrounding aqueous medium essentially
completely within the space of an hour. However, the
addition of a small amount of a core-forming adjuvant
can increa~e the duration of the period of release by
at least a factor of 10. In effect, the core-forming ~-
adjuvant modifies the release properties of the micro-
capsular system so that, while it retains the diffu-
sional barrier provided by the capsular wall, release
of the drug from the adjuvant-containing system i~
influenced by the partitioning equilibrium between the ~ ;
adjuvant and the small volume of water which diffuses
,
~ . -
1331343
TUN-090 -16-
into the capsule. Thus/ the proportion of adjuvant to
active cvre material (e.g., acetanilid~) in the micro-
capsule formulation and the rate of release of active
core material are inversely proportional, all other
factors being held constant.
Not only may the ratio of core-forming adju-
vant to active core material be modified, but the wide
range of compositions of core-forming adjuvants with
markedly different partitioning characteristics for
the same substance allow a second means of controlling
rates of release of the active core component.
Independently, the wall-forming adjuvants,
by virtue of the differences in ionic lattice spacing
of the microcapsules they provide, afford yet another
means of controlling rates of release of active core
components. It is these three variables, the ratio of
core-forming adjuvant to active core component, the
range of partitioning coefficient of the active core
component between core-forming adjuvants and water,
and the lattice structure variation available from
wall-forming adjuvants which provide extensive control f
of the release rate for encapsulated substances. `~
Thus, the improved controlled release
characteristics of adjuvant-modified microparticles,
coupled with the improved capacity of such microparti~
cles, allow formulation of microparticles capable of
.
1 33 1 343
TUN-090 -17-
uniform sustained release of core components over a
greatly extended period of time.
While this invention has been described with
reference to specific, and particularly, preferred
embodiments thereof, it is not limited thereto and the
appended cl aLms are intended to be con~trued to encom-
pa~s not only the 6pecific f orms and variants of the
invention shown but to such other fonms and variantæ
as may be devised by those skilled in the art without
departing from the true spirit and scope of this
invention.
