Note: Descriptions are shown in the official language in which they were submitted.
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S~sTF~l~ FOR RENl)l~l~TNG SUBSl['ANTTA~,T,Y NON-D~[SSOLUBLE
RIo-AFFE~cTING AGI~NTS BIO-AVArl,~Bl,F,
This application is a continuation-in-part of copending application Serial No.
08/524,531, filed on September 7, 1995, the entire disclosure of which is incorporated herein
by reference.
BACKGROUND OF TEIE INVI~ N
The present invention relates to the art of ~-lminicter~ng bio-affecting agents to
bio-systems, and, in particular, for rendering agents, which a.re ~ub~ lially non-dissoluble in
an aqueous environment, available for interaction with a host bio-system, e.g., a human or
animal.
lBio-systems, such as hllm~nc, plants, insects, fish, birds, and m~-nm~lc, are primarily
aqueous systems. In order to effectively ~(1minictçr an bio-affecting agent to such bio-systems,
it is necess~ry to make the agent available for interaction with physiological activity in the
bio-system. This is referred to herein as "bio-availability." ]n the case of bio-affecting agents
which are non-dissoluble in an aqueous environment, as welll as in the case of those which are
only poorly water-soluble, effective ~minictration ofthe bio-affecting agent can be difficult
due to inadequate bio-availability of the agent and consequent low pharmacological activity.
These solubility problems affect many parameters of adll~ Lion, such as the method of
?~dmini.ctration, the rate of a(lmini.ctration, the concentration of ~dmini~ration, etc.
It is known that rate of dissolution of drug particulates can be increased by increasing
the surface area ofthe solid, i.e., decreasing the particle size. Consequently, methods of
making finely divided drugs have been studied and efforts have been made to control the size
and size range of drug particles in pharmaceutical compositions. For example, dry milling
techniques have been used to reduce particle size and thereby infl~l~nce drug absorption.
However, in conventional dry milling, as discussed by T .?l~hm~n et al., The Theory and
Pracfice of Industrial Pharmacy, Chapter 2, "Milling", p. 4~5 (1986), the limit of fin~nçcc is
reached in the region of about 100 ,um (= 100,000 nm), where the milled material begins to
cake onto the surfaces of the milling chamber. Lachman et al. note that wet grinding is
beneficial in further reducing particle size, but that flocculation restricts the lower particle size
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I;mit to applox;~ çly 10,um (= 10,000 nm). There tends to be a bias in the pharm~cel/t
art against wet milling due to concerns associated with co~ AI;on. Co""l~elcial airjet
milling techniques have provided particles ranging in average particle size from as low as
about 1,um to 50 ~m (= 1,000 nm to 50,000 nm).
Other techniques for p,epa,illg pharm~ce~ltical compositions with enhanced aqueous
solubility pl op~l lies include loading drugs into liposomes or polymers, e.g., during emulsion
poly",e, i~alion. However, such techniques have problems and limitations. For example, a
lipid-soluble drug is often required in plepali..g suitable liposomes. Further, unacceptably
large amounts of the liposome or polymer are often required to prepare unit drug doses.
10 Further still, techniques for pl~ lillg such pharm~.;e~tical compositions tend to be co--l~ ,x.
A principal technical difficulty encountered with emulsion polymerization is the removal of
CO..~ i"~ , such as unreacted monomer or h.i~id~or (which can be toxic) at the end ofthe
m~mlf~ct-lring process.
U.S. Patent No. 4,540,602 (Motoyama et al.) discloses a solid drug pulverized in an
15 aqueous solution of a water-soluble high molecular weight substance using a wet grinding
m~chine. However, Motoyama et al. teach that, as a result of such wet grinding, the drug is
formed into finely divided particles ranging from 0.5 ~m (500 nm) to less than 5 ,um
(5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a
20 substance in the form of spherical particles smaller than 500 nm. However, the method
involves a precipitation effected by mixing a solution of the substance and a miscible
non-solvent for the substance, and results in the formation of non-crystalline nanoparticles.
Furthermore, precipitation techniques for pl~ .-hlg particles tend to provide particles
co..~ ed with solvents. Such solvents are often toxic and can be very difficult, if not
25 impossible, to adequately remove to pharmaceutically acceptable levels. Accordingly
pl e.;i~ lion methods are usually impractical.
U.S. Patent No. 4,107,288 describes particles in the size range from 10 to 1,000 nm
co..~ a biologically or pharmacodynamically active material. However, the particles
comprise a crosslinked matrix of macromolecules having the active material supported on or
30 incol~,o,~ted into the matrix.
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U.S. Patent No. 5,145,684 describes a method for providing drug particles having an
effective average particle size of less than about 400 nm. Th,e method includçs wet milling the
drug in the presence of a grinding medium in conjunction with a surface modifier. As in
previous methods, the '684 protocol requires grinding or milling to produce size reduction.
5 The method further requires the use of an additive in the forrrl of a surface modifier.
Moreover, drugs pl ~al c;d by milling, even wet milling such as that described in the
'684 disclosure, are subject to degradation resulting from hea.t as well as physical and chemical
trauma associated with fracture. Grinding also creates "hot spots," i.e., volumes of localized
higher telll~)el ~LIlres which can exceed the melting point or degradation of the drug. The
10 process is also lengthy, requiring attrition exposure over several days. This type of process
effectively exposes the drug to a long "heat history", wherein exposure to elevated
temperatures has been significant, and the purity and potency ofthe drug is rl;",;".~ d to a
significant extent. Furthermore, particles reduced by milling ~re often co..~ ed by the
residue of the grinding operations, especially when ball milling is used and the grinding balls
15 are worn down by abrasion.
It has also been known in the art of drug delivery to improve bio-availability by
aggregating substantially non-dissoluble active ingredients on the surface of soluble sub~ es,
such as water-soluble beads. The active ingredient can be deposited on such substrates by
spraying a solution of the active ingredient over a fl~ ed bed while "flashing off" the solvent
20 used for the active ingredient. This method is highly inefficient in that it requires several hours
to deposit a sufficient amount of active ingredient to prepare a useable delivery system.
Furthermore, an additional ingredient which is unnecessary to the system must be used, i.e.,
the solvent required to dissolve the active ingredient. As previously mentioned, the solvent
must be flashed offduring agglegation. Thus, this system is a long and cumbersome process
25 and does not provide efficiency of dosage delivery.
Solubilization techniques for drugs which have low aqueous solubility require the use
of organic solvents for processing in a solution state. This requires the use of expensive
recove~y systems for solvent h~ntlling capability. When general melt processing techniques are
used to form dispersions, bulk melting and mixing steps often expose the drug to a prolonged
30 heat history.
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It is desirable to provide stable dispersible drug particles in the sub-micrometer size
range which can be readily p~ epal ed in the absence of size reduction by grinding or milling.
Moreover, it ~,vould be highly desirable to provide pharm~ceutical compositions having
Pnh~nced bio-availability.
It is, Il-el erol e, an object of the present invention to overcome the disadvantages
associated with methods for pl epa- ;ng delivery systems for bio-~ g ingredients, especially
those which are subsl~Lially non-dissoluble. As a consequence of o~el co",ing the drawbacks
known in the art, it has been found that other and further objects which enh~nçe the art of
delivery systems have been realized as a result of the present invention.
SUMM~RY OF T~ INVFl~TION
The invention is a composition for delivery of a bio-arr~ g agent to a bio-system,
and a methods of making and using a delivery system which in~ludçs a bio-affecting agent.
The composition and method include the use of:
a solid dispersion of the bio-affecting agent in an increased-energy state in a
water-soluble (or water-dispersible) polymer which is eo-"~alible with the agent and which has
a glass transition te"")e~ re (Tg) in the range of from about 0~C to about 200~C, whereby
the agent is rendered bio-available in an aqueous envholu~w~l.
Preferably, the water-soluble polymer is any polymer which has a glass transition
temperature in the range offrom about 25~C to about 150~C, and more preferably in the
range offrom about 40~C to about 100~C.
Pl ere, l ed water-soluble polymers include polymethacrylic acid polymers. Preferably,
the polymeth~crylic acid polymers have the structure:
----C--CH2--C--CH2--C--CH2--(~--CH2---
Cl=O IC=O ~=0 ~=0 (1)
R2 R4 R2 R4
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wLere;n: Rl, R2, R3, R4 are any substituents provided that the polymer has a glass transition
temperature in desired range. Accordingly, Rl, R2, R3, R4 preferably are independently
hydrogen ~IH) or any alkyl, airyl, alkaryl, aralkyl, alrninoalkyl, a.lkyl-substituted aiminoalkyl,
~..l"onioalkyl, or alkyl-substituted ammonioalkyl group. Still more plere.~bly, R', R2, R3, R4
5 in Structure (1) are independently H, Cl-C6 alkyl, ~mino~likyl, methyl- or dirnethyl-aminoallyl,
or methyl-, di nethyl-, or trimethyl-ammonioalkyl. Yet more ~ f~l~bly, in Structure (1):
Rl is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and
R4 is CH3, C2H5, C3H" C~Hg, CH2CH2N(CH3)3+X-, wherein X~ is any
monovalent anion.
A highly prere" ed water-soluble polymer is a terpolymer of butyl methP~c.rylate,
(2-dimethyl aminoethyl) methacrylate, and methyl methacrylate in relative proportions 1:2:1.
Preferably, the water-soluble polymer is a polymer having pH-ser.sitive solubility in
15 aqueous media. The water-soluble polyirners pl e~ Lially have solubility in aqueous media
having a pH of from about 1 to about 11. More p~c;rel~bly, the water-soluble polymer has
solubi1ity in acidic aqueous media, i.e., having a pH of about 7 or less.
The bio-affecting agent can be any agent known to have an effect in a biologicalsystem. Plerelably, the bio-affechng agent is substantially non-dissoluble in an aqueous
20 envholll"~ L. More preferably, the bio-affecting agent has a solubility which is defined as
practically insoluble or insoluble according to the USP. The bio-affecting agent is preferably
selected from the group consisting of antifungals, anti-infl,.mm~tories, anti-hypertensives,
antimicrobials, steroidal drugs, hormones, prost~gl~n-1in~, interferons, and mixtures thereof.
Moreover, the composition comprising the bio-affect;ng agent and the water-soluble
25 polymer preferably mee$s or exceeds USP dissolution standards for the agent.
The composition of this embodiment can include a solid dispersion provided by
flash-flow processing a feedstock including the bio-affecting agent and the polymer. The
flash-flow processing can be flash heat processing or flash shear processing. The flash heat
processing method is particularly pl erel ~ ~d when processing bio-affecting agents which are
30 heat-sensitive. Alternatively, the solid dispersion can be provided by extrusion mixing for a
time sufficient to form the solid dispersion. Preferably, the t;me of extrusion mixing is less
s
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than about 2 minllt~s, more preferably, less than about 30 seconds. When the solid dispersion
is provided by extrusion mixing, it is highly pl crel I cd that the bio-affecting agent is an
~ntifimg~l, anti-;.,ll;t~ oly, or anti-hypertensive agent.
The composition of the invention incllld~s the bio-affecting agent in an at least
5 s~L~,lially uniform or amorphous solid dispersion. Preferably, the bio-~rc.;lil~g agent is
present in the form of nanoparticles distributed throughout the solid dispersion. More
plcrel~bly, the nano~al licles have an average particle size of less than about 1000 nm. Still
more p~ crcl ~bly, the average particle size of the nanoparticles is less than about 400 nm. The
bio-affecting agent can be dispersed in the water-soluble polymer at the molecular level.
The composition can be prepared as a controlled-release particulate by mççh~nically
red~lcing the solid dispersion. Preferably, the particulate is part of a dosage unit, which is
plcrcl~ly selected from the group consisting of ç~psllle~J tablets, and rapid-dissolve tablets.
Alternatively, the solid dispersion is sized and shaped for fixation in an intravascular (or other
,(JalCnlCI ~1) delivery apl)al~lus. Moreover, the solid dispersion can be provided in the form of
a slow dissolving structures such as a suppository or a lozenge or the like.
The method inr,llldçs .~imlllt~neously l~nsrol.l,ing the bio-~rrcclillg agent to an
increased-energy state and fixing the agent in that state. The method can include
~imlllt~neously ~ n~rull"h~g and fixing by flash-flow processing. This method inr,ludçs use of
flash heat processing or flash shear processing. Heat-sensitive agents are beneficially
processed by flash heat processing. Alternatively, the ~iml~lt~neous L,~n~ro,."i"g and fixing
can be effected by extrusion mixing for a time sufficient to form the solid dispersion,
plercl~bly for a time of less than about 2 minllte~, more preferably less than about 30 seconds.
In the latter approach, the bio-affecting agent is most prcre,~,bly an ~ntifilng~
anti-;..... ....n~ tory, or anti-hypertensive agent.
The method of tran~rol Illhlg the bio-affecting agent into the increased-energy state can
include redllc.ing in the absence of mechanical attrition, the bio-affecting agent to dispersed
nanoparticles having an average particle size of less than about 1000 nm. More preferably, the
mer.h~nical re~ucing yields an average particle size of the nanoparticles of less than about
400 nm. Alternatively, the method can be used to disperse the bio-affecting agent at a
molecular level to provide a solid solution.
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The method can further include mechanically re~u~ing the solid dispersion to
particulates. Thus, the rnethod can further include incorpora!ting the particulates in a dosage
unit, such as a capsule or a rapid-dissolve tablet. Alternativc:ly, the method can further include
sizing and shaping the solid dispersion for fixation in an intra.venous (or other l)a~ tel~l) fluid
5 delivery device. Lozenges, suppositories, and other slow release delivery structures can also
be employed to deliver the bio-affecting agent.
The invention filrther inrl~ldçs method and composition for delivery of a bio-affecting
agent. The composition produced by the method includes:
a) a carrier comprising a water-soluble polymer having a glass transition temperature
10 in the range offrom about 0~C to about 200~C; and
b) a bio-affecting agent microscopically disl,e. ~ed in said water-soluble polymer.
Plt;rel~bly, the water-soluble polymer has pH-sensitive solubility in aqueous media. In
particular, it is pl~rel I ed that the water-soluble polymer be substantially indissoluble in saliva
but soluble in gastric fluid.
The invention is also a method for delivering a composition of a bio-affecting agent, as
described, to a bio-system. The method includes
~ rlmini~tering to the bio-system a solid dispersion cOIlllplisillg the bio-affecting agent
fixed in an increased-energy state in a water-soluble polymer having a glass transition
temperature in the range offrom about 0~C to about 200~C, wherein the solid dispersion
20 renders the bio-affecting agent bio-available to the bio-systern.
The method and composition of the invention possess numerous advantages over theprior art. For example, the method of processing a bio-affecting agent with a water-soluble
polymer to form a solid dispersion according to the invention avoids use of solvents or
mech~nic~l attrition or co.. ~ tion~ which methods have various disadvantages detailed
25 hereinabove. Moreover, the method substantially decreases the heat history of the
bio-a~eling agent, with the advantage that the agent remains substantially less degraded or
decomposed throughout the processing. The method and composition of the invention also
dr~m~tic~lly enhance the bio-availability of bio-affecting agents which are otherwise
substantially non-dissoluble in aqueous environments, thereby enabling delivery of such agents
30 to bio-systems with greater ease and simplicity and through more routes than has heretofore
been possible.
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These and further advantages will be appreciated by those skilled in the art in view of
the following detailed description of the invention and the drawings as set forth below, and the
scope of the invention will be pointed out in the appended claims.
RRTF,F DF.~CI~TPTION OF T~ DR~WINGS
Figure 1 is a graph which shows the effectiveness of the present invention by depicting
the profile of the dissolution characteristics of a solid dispersion prepared by flash heat
procç~ing according to the present invention.
Figure 2 is a graph showing the dissolution profile of bulk niredi~ .c which has not
been prepared for çnh~nced dissolution.
Figure 3 is a graph which shows the effectiveness ofthe present invention by depicting
the profile of the dissolution characteristics of a solid dispersion of niredipine pl epal ed by
extrusion processing according to the present invention.
Figure 4 is a graph which shows the effectiveness of the present invention by depicting
the dissolution profile for solid dispersions of an ~ntifilng~l drug pl~palt;d according to the
present invention as contrasted against the dissolution profile of a known delivery system for
the ~ntifilng~l agent and the dissolution profile ofthe bulk antifilng~l agent which has not been
plepaled for çnh~ncecl dissolution.
Dli'T~n,li'D DF.~C~TPTION OF T~F INV~NTION
The present invention is a composition and method of pl epaling a composition for
delivering a bio-affecting agent and rendering the bio-affecting agent bio-available in an
aqueous environment. The composition of the present invention can be referred to as a solid
dispersion of the bio-affecting agent in a water-soluble polymer.
The present invention is both a composition and method for delivery of a bio-affecting
agent to a s--bslallLially aqueous bio-envilonlllel.l. The present invention renders the
bio-affecting agent more bio-available in the aqueous environment. The method for plepa-i--g
the unique composition of the present invention inçl~ldeo, 1 ) ll ansrc l l-lh~g the bio-affecting
agent to an "increased-energy" state, and 2) fixing the bio-affecting agent in the
"increased-energy" state in a water-soluble polymer. The terrns "increased-energy" or "higher
energy" state refer to the stable dispersion of a bio-affecting agent or drug in a solid matrix,
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such that the bio-affecting agent is either dispersed at a molecular level or is dispersed in
microscopic particulate domains having an average particle size of less than 1000 nm, and
p,t;~.~bly less than about 400 nm. The increased energy state is achieved by modifying
particle formation rather than by size reduction through grinding or attrition. Generally, the
5 invention l~ ~n~r" ~s the bio-affecting agent into solution form or n~op&~ licle form which has
a higher surface energy or free energy than, for example, native crystals which can have an
average size of over 10 ,um.
The composition of the present invention is described herein as a solid dispersion of
the bio-affecting agent in the water-soluble polymer. Upon dissolution of the polymer in the
10 bio-system, the bio-affecting agent is rendered bio-available to the host. "Bio-availability" as
used herein means that the bio-affecting agent is taken up by the host bio-system for
interaction with the bio affecting agent. The me~ ", for being "taken up" in~ludes, but is
not limited to, absorption, adsorption, tran~Çe,~l~ce, cohesion, adhesion, chemical, biological,
and biochemical reactions, etc.
The invention inrlproves the bio-availability of bio-affecting agents, especially those
whose activity is otherwise limited or çlimin~ted because of their relative inability to be
dissolved into aqueous media. The term "substantially non-dissoluble" is applied to materials
which are either substantially insoluble in water or are not w;ater-soluble to any appreciable
degree. Thus, substantially non-dissoluble bio-affecting agellts include those bio-affecting
agents which are either non-soluble or only sparingly soluble in biological fluids, such as
blood, Iymph, gastrointçstin~l fluids, cerebrospinal fluid, plant saps, and the likê. The
bio-affecting agents typically are not enterosoluble as defined hereinbelow.
A material may be said to be "substantially non-dissoluble" if it has a solubility of less
than 10 mg/rnL in water (or other aqueous merlium) having a pH of from about I to about 8.
The solubility of any substance in an aqueous me~ m is a property which is readily
determined by a skilled artisan. In fact, thê solubilities of many substances, including drugs,
are known and published in compendia such as The Merck I~i~dex, 1 2th edition ( 1996). Most
preferably, the bio-affecting agent has a solubility low enough to qualify the agent as
"practically insoluble, or insoluble" as defined by the USP. According to this definition, the
bio-affecting agent is substantially non-dissoluble if it has a solubility requiring at least 10,000
parts of solvent (aqueous medium) for I part of the solute (bio-affecting agent).
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It is believed that all bio-affecting agents can be used in the present invention, bu~ t~e
invention is particularly directed to col"bining a subst~nti~lly non-dissoluble bio-affecting
agent with a water-soluble polymer in a unique manner to render the non-dissoluble agent
bio-available. Substances which would otherwise be capable of being bio-afIe~ g as defined
S herein, but which qualify as substantially non-dissoluble, are pl erel I t;d for delivery accol .lillg
to the invention. It is also contemplated that a subst~nti~lly non-dissoluble bio-affecting agent
can be used in collll~illalion with other substances, incl~ ing other bio-a~eclillg agents, which
are s~sla,llially more soluble in aqueous media.
The polymers which are useful as "water-soluble polyrners" in the present invention
10 include polymers, copolymers, terpolymers, interpolymers, polymeric ~m~lg~m.e, etc., having
molecular weights which range from oligomers to high molecular weight polymeric substances
and polymers having pH dependent solubility characteristics.
"Water-soluble," as used herein, applies to polymers which readily dissolve or disperse
in water and other aqueous media at any or all pH values without the ~Csict~nce of a
15 dissolution-promoting substances such as surf~ct~nte, emulsifiers, etc. The fact that the
polymer does not require an agent to mediate its dissolution in an aqueous envil un~ lll does
not mean, however, that delivery systems pl epal ed in accordance with the present invention
do not include such agents. In order to engineer the apl)l op, iate delivery system, any
additional substances which are required to control, promote, mediate, or modulate the
20 bio-availability of the bio-affecting agent(s) can be used. These substances are referred to
herein as "bio-availability promoters." Furthermore, col,lbillaLions of bio-availability
promoters can be used in the present delivery systems.
By virtue of the present invention the bio-availability of a bio-affecting agent is
çnh~n~ed by altering the physicochemical condition of the bio-affecting agent. This is
25 achieved by processing the bio-affecting agent with a water-soluble polymeric carrier to
produce a solid dispersion of the bio-affecting agent in the polymer. By "solid dispersion" is
meant an appal enlly homogeneous solid substance which consists of a microscopically
heterogenous mixture of the bio-affecting agent and the water-soluble polymer (and other
materials as otherwise defined herein). In conventional terminology, the bio-affecting agent
30 conctitutto.s the "dispersed phase", while the water-soluble polymer con.etitutçc the "dispersion
medium" or"continuous phase."
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1[ he method(s) of the present invention can be used to make solidl dispersion
col,.po~iLions which are either:
a) Solution systems where at least a portion, and pl ere. ~bly all of the bio-affecting
agent is in solution phase with the polymer or dispersed at thle molecular level (i.e., "molecular
dispersions"); or
b) Heterogenous systems where the bio-affecting agent is present in more or lessdiscrete supramolecular domains (nanoparticles), which may be aggregates of molecules,
ulllrul ~ y dispersed within the polymer. Furthermore, as a result of the q~lenchin~ of the
water-soluble polymer in accordance with the present invention, the bio-a~i~in~ agent is
prevented from forming macro-scale distinct phases or large domains in the final product.
As noted, the solid dispersion can include discrete domains of the bio-~ffec~ingsubstance distributed substantially homogeneously throughout the polymeric me~ m When
present, these discrete domains are generally referred to herein as "nanoparticles." In the case
of cryst~lli7~hle bio-affecting agents, the domains of the bio-affecting agent might be
desi~n~ted "nanocrystals." These terms connote the extraordinarily small dimensionality of
the dispersed phase of the solid dispersions of the invention. Specifically, the particles of
dispersed phase in the solid dispersions are typically of the order of nanometers (~I x 10-9 m)
to hundreds of nanometers (~100 x 10-9 m). Thus, the scale of such particles is conveniently
referred to as "nanometer-scale" or "nanoscale." It is believed that this feature of the
proceccin~ method of the invention significantly contributes to increasing the bio-availability of
the bio-affecting agent.
Other solid dispersions according to the invention include the bio-affecting agent
dispersed at the molecular level through the water-soluble polymer. These solid dispersions of
the invention may be characterized as solid solutions, since they meet the criteria
conventionally reserved for solutions. Typically, little or no supramolecular o~gani~alion is
present in such solutions. However, it must be recognized that a solid dispersion according to
the invention can include the bio-affecting agent in a range of physical states ranging from
molecular dispersion to amorphous or pre-crystalline associat.ions of molecules to
nanoparticulate domains.
The solid dispersions of the invention, therefore, refer to intim~te mixtures of two or
more colllpollenLs which form a contin~n-m wherein substantially all domains of the
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bio-* rr~.~ g agent have a higher entropy than the entropy of the agent in its native condition.
As a result of forming the solid dispersions of the present invention, the bio-affecting agent is
fixed or frozen in the solid water-soluble polymer in an increased-energy state."Increased-energy state" as used herein means a physicochemical condition of the bio-affecting
5 agent which has a higher entropy than the bio-affecting agent would have in its native
con-1ition For CA~ C~ the bio-a~e~;ling agent is, in a pl~;relled embodiment, converted to a
s .l,sl~-lially amorphous form and dispersed throughout the water-soluble polymer in the melt
condition such that, when the agent crystallizes (if, in fact, it does crystallize), the average
clystal size will constitute particles of nanoscale dimension, i.e., nanop~ Licles. The
10 bio-~rrec~;.u agent is thereby captured in a highly randomized condition as co---,~a~ed to the
bio-affecting agent in its native form. The increased energy state of the present invention is
sufficient to render the drug more bio-available in an aqueous enviloll---e-". As previously
cl~ssed herein, bio-available means a condition which permits the active ingredient to
interact with, i.e., become available for use in, the target bio-system, i.e., the body of the host
lS animal or human patient.
The composition of the present invention, referred to herein as a solid dispersion, can
be formed by a number ofter.hniqlles In one plere..ed embodiment the solid dispersion is
formed by subjecting a feedstock which includes both the agent and the polymer to flash-flow
processing. Flash-flow processing is defined hereinbelow and incl~ldes both flash-heat
processing and flash-shear processing. Alternatively, it has been found that the solid
dispersion of the present invention can be provided by extrusion mixing the agent and the
polymer for a time sufficient to l- ~n~ro~ ~-- and fix the agent during quenching. In a ~. ~re. . ed
embodiment, the time required to extrusion mix the ingredients is less than about two minutes
(2 min), and is preferably less than about thirty seconds (30 sec).
As a result of the present invention, the bio-affecting agent can be provided as a solid
dosage form which has an ~.nh~nced dissolution rate which can often be ~imlll~ted by in vi~ro
data. It is theorized that the increases in dissolution rate are achieved by a combination of
effects, the most significant being the reduction of particle size to an extent not achieved by
conventional comminution approaches. The smaller size particle (i.e., the nanoparticles of the
invention) appalenlly imparts to the bio-affecting agent a higher surface energy or free energy
than the agent has in its original or native state, providing for enhanced solubility in water,
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generally co~ onding to çnh~nced bio-availability in the bio-system. As previously
mentioned, techniques known to date for producing dispersions in the prior art generally
require either the solubilization or melting of a drug with a freely soluble carrier in a water-like
(low viscosity) state, followed by further processing to p~ ecip~ le or congeal the material into
5 a solid forrn.
The technique and composition of the present invention has inherent advantages in the
production of solid dispersions of bio-aa~ g agents. As a result of the present invention,
the bio-~cl~ agent and the carrier polymer can be combined in a process which mixes,
melts, forms, and solidifies in a continuous process, to provicle the bio-affecting agent in a
10 solid solution or dispersion and having an increased energy clondition as defined hel~i--ab~/e.
The resulting compositions are easily employed to make any of a variety of delivery systems,
inc~ 1in~ tablets, etc., which would otherwise be incapable of effectively delivering the
bio-affecting agent.
Another very important advantage of the invention is that the bio-affecting agent is
15 exposed to a lower heat history during the process of being rendered bio-available. The heat
history required in the inventive process is very short co...pa.ed to conventional teçhniques
used in the formation of congealed materials. Consequently, the process of the invention
induces less degradation or decomposition of the bio-affecting agent, meaning that purity and
potency are improved over prior art systems. This is particu]larly beneficial for those
20 bio-affecting agents which are heat-sensitive.
The systems of the present invention are implemented by the use of bio-affectingagents and water-soluble polymers which are "compatible" v~ith each other. The term
"compatible" is used herein to mean that the polymer has physical characteristics which render
it processable according to the invention. Specifically, the water-soluble polymer must be
25 capable of being processed at ternperatures at or above the melting point (Tm) of the
bio-affecting agent but below the temperature of decomposition (Td) of the bio-affecting agent
and the polyrner. Consequently, it is preferable to use a polymer which is flowable (generally,
thermoplastic) at a temperature which is equal to or above the melting point of the
bio-affecting agent, but below the decomposition temperature of either the agent or the
30 polymer itself.
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Moreover, bio-affecting agents and polymers are said to be "con~paLible" if they ~re
soluble or dispersible in each other in the flowable/non-decomposition stage. For example, if
one were to visualize the bio-affecting agent/water-soluble polymer composition immediately
after soli~ific~tion, in many cases it would appear substantially as a lran,l,a~enl or tr~nclllc~nt
5 glass, i.e., any inhomogeneities are of a scale such that one cannot visually di~tin~ h the
solubilized bio-arrecLi,-g agent from the water-soluble polymer.
Co---palil,ility herein also means that the polymer and bio-affecting agent solidify such
that the bio-affecting agent is captured in an "increased-energy" condition and held stably in
that state following completion of solidification. The bio-a~.;li"g agents may later crystallize,
10 but any crystals which form are of the order of nal opa. Licles, i.e., the crystals will have a
condition of considerably higher entropy than the native crystals of the agent, which have an
average particle size generally in the range of from about 10 ~m to about 50 ,um. If the
polymer and bio-affecting agent solidify at rates which permit the bio-affecting agent to form
domains which es.~enti~lly return the bio-affecting agent to a lower entropy form, e.g., a crystal
15 size which appr xim~tes the agent in its native condition, then the combil-~lion is not
considered col--palil)le as defined herein. More importantly, little or no improvement in
bio-availability is obtained by such incol--palible co...l)inalions. Thus, compatibility further
means that the polymer is capable of being quenched or formed into a solid along with the
bio-affecting agent such that the bio-affecting agent is not permitted to return to a lower
20 energy state, or to a condition of particles having an average size of greater than about
1000 nm.
It is, of course, pl er~- l ed that the polymer have physical characteristics which promote
the formation of solid dispersions described herein. Applicants have unexpecte-lly found that
glass transition temperature (Tg) is a property of polymers which correlates well with the
25 ~ fillness of polymers in the method of the invention. In particular, Applicants have found it
to be pl ere- ~ ed that the polymer has a Tg in the range of from about 0~C to about 200~C.
More preferably, the polymer has a Tg in the range offrom about 25~C to about 150~C. Still
more preferably, the polymer has a Tg in the range offrom about 40~C to about 100~C.
Applicants have found that Tg is related to the flowability or processability of the
30 polymer, with a lower Tg generally correlating with a lower viscosity at a given temperature.
Polymers having a Tg outside of the temperature ranges set forth above are less desirable. On
14
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the one hand, if the T8 is too high, the polymer will tend to be too viscous, making the polymer
difficult to process. On the other hand, if the T,~ is too low, the polymer may not be viscous
enough to effectively capture or freeze the bio-affecting agent in the desired increased-energy
state. Moreover, Applicants have found that the polymers ch~aracterized by the T8 ranges
5 given above tend to have solubilities in aqueous em/i~onlme"L j sufficient to render them
effective for ~nh~n(ing the bio-availability of nor-dissoluble Ibio-a~e~ g agents.
The polymers useful according to the invention generally also meet other
physicochemical characteristics. For example, the polymers useful in this invention generally
have an average molecular weight of above 500 daltons (Da), and p, ert;l,lbly above 1500 Da.
Polymers having molecular weights of 100,000 Da or more mlay be p,~r~"ed for particular
applications. Also, the water-soluble polymers of the presenl; invention preferably have an
intrinsic viscosity of from about 1,000 centipoise (cP) to millions of cP, and a melt viscosity of
from about 50 cP to about 100,000 cP. The viscosity ofthe polymer can be measured by a
Brookfield Viscometer. It is also believed that polymers which do not crystallize are probably
15 preferable to those which do crystallize, but this property is not well understood.
Polymeth~crylic acid polymers (also I~Ç~lled to herein as "polymethacrylates") are
among the water-soluble polymers p-er~ d for use accordimg to the invention. For example,
p,erel-ed polymethacrylates have the general structure:
Rl R3 Rl R3
--CH2~--CH2~--CH2~ CH2---
C=O ~=0 IC=O IC=~O (I)
1~ ~ 1~
R2 R4 R2 R4
20 wherein: R', R2, R3, R4 are independently hydrogen (H) or any alkyl, aryl, alkaryl, aralkyl,
aminoalkyl, alkyl-substituted aminoalkyl, ammonioalkyl, or alkyl-substituted ammonioalkyl
group.
Preferably, Rl, R2, R3, R4 are independently H, Cl-C6 alkyl, amino (Cl-C6)-alkyl,
methyl- or dimethyl-aminoalkyl, or methyl-, dimethyl-, or trirnethyl-amrnonioalkyl.
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More preferably the polymethacrylates of Structure (1) have the following
substit~l~nt~
Rl is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and
R4 is CH3, C2H5, C3H" C4Hg~ CH2CH2N(CH3)3+X-. wherein X~ is any
monovalent anion, preferably Cl~.
Exemplary polymethacrylic acid polymers are described in detail in A.J. Shukla,
"Polymeth~rylates", pp. 362-366 in Handbook of Pharm~( et~fic~ ~cipients, 2d ed., Ainley
Wade and Paul J. Weller, eds. (1994). A large number ofthese polymers are available as
coating materials under the EUDRAGIT trade name from Rohm GmbH. One polymer found
to be particularly effective is a methacrylic acid ester terpolymeric product of butyl
mP.th~rylate, (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate in proportions
1:2:1, sold as EUDRAGIT E.
It is ~l~;rel-ed that the water-soluble polymers be polymers whose solubility ispH-sensitive. Specifically, the polymer is said to be pH-sensitive if its solubility in an aqueous
m~rlillm is affected by pH. Preferably, the water-soluble polymers used in the method and
composition of the invention have higher solubility at pH 1 to pH 10, than at a pH outside this
range. More pre~--ed polymers are those which are subst~nti~lly more soluble at acid pH
than at neutral or basic pH. Thus, the water-soluble polymer is desirably soluble below pH 7.
By sPlectin~ a water-soluble polymer havirig a pH-sensitive solubility, specifically an
acid-sensitive solubility, solubility ofthe solid dispersions ofthe invention can be .~ d
until the material are exposed to acid conditions. Thus, materials can be m~mlfs~ctllred which
are subsla~lLially indissoluble in saliva but soluble in gastric fluid, thereby permitting selective
control over the bio-availability of the bio-affecting agent. (In certain applications, namely
delivering the bio-affecting agent to the intestine, the water-soluble polymer preferably has an
alkali-sensitive solubility.) All such polymers are terrned ~'enterosoluble."
Plerell~d enterosoluble polymers can also be defined according to the comonomersfrom which they are prepared. For example, the copolyrners and terpolymers of methacrylic
acid with methyl acrylate and/or methyl methacrylate are highly pler~ d, having solubilities in
16
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the range offrom about pH 5.5 to about pH 7.2. Such polymers have been described for use
as enteric coatings for tablet plepa,~ion. T ~çhm~nn et al., "New methacrylic acid copolyrners
for improved coating technology," Presentation from AAPS Tenth Annual Meeting (1995),
published by Huls America Inc.
S The EUDRAGIT polymers possess solubilities which are sensitive to pH, meAning that
their solubilities may be higher at certain pHs and lower at otlhers. Depending upon pH, the
solubility of these polymers can vary over an order of mAgnitlJIde or more. Certain of the
polymetllAcryla~es have high aqueous solubility under acidic c,onditions, and have been used to
promote rapid release of active agents in the gastric region of the ga~ e~ tract. The
EUDRAGIT E product has such acid-sensitive solubility, being soluble in gastric fluid and
weakly acidic buffer solutions (i.e., less that about pH ~). Others are p~erere,llially soluble in
mild alkali (e.g., pH 6-7) and therefore are suitable for delivel ing bio-affecting substances to
the i~.le~ e while bypassing the gastric region. However, thlese polymethacrylates have not
been employed as solid solution carrier materials for bio-arre~,ling agents, a new application to
which Applicants have unexpectedly found them to be very v~rell adapted.
Preferably, the bio-affecting agents suitable for use in the method and composition of
the invention are drugs which are potentially bio-affecting to slnim~lc, incl~ltling humans and
other m~mmA1e A non-limiting list ofthese bio-affecting agents in~ludçc, for example:
antitl-e~iives~ Antihi~tAmine~, deconge~L~Ls, alkaloids, mineral supplements, laxatives, vitamins,
AntAritl~, ion f~Y~.h~nge resins, anti-cholesterolemics, anti-lipidl agents, anlia"l,~thrnics,
antipyretics, analgesics, appetite sllpplessal-ls, expectorants, anti-anxiety agents, anti-ulcer
agents, anti-inflAmmAtory substances, coronary dilators, cerebral dilators, peripheral
vasodila~ors, anti-infectives, antifungals, antivirals, psychotropics, A.,l;...Al-ics, sfimulAnt~
gastroin~-estinAl agents, sedatives, antidiarrheal plepa,~Lions, anti-anginal drugs, vasodilators,
25 anti-hypertensive drugs, vasoconstrictors, migraine ll~inlll~ 7 antibiotics, tranquilizers,
anti-psychotics, antitumor drugs, anticoA~ nt~i, antithrombotic drugs, hypnotics,
anti-emetics, anti-nAnc~nt~, anti-convulsants, neuromll~clllAr drugs, hyper- and hypoglycemic
agents, thyroid and anti-thyroid preparations, diuretics, antispasmodics, uterine relaxants,
mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs,
30 anti-A~thmAtics, cough supplessal-ls, mucolytics, anti-uricemic drugs, prostAElAndin~
il.Le,~el-ons, cytokines, steroidal and peptide hormones, ploteii,l-s, and mixtures thereof.
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Other bio-affecting agents for use in the present invention include antidiarrheals such
as IMODIUM AD, ~ntihi~ es, ~ntitllssives, deconpe~ vitamins, and breath
r,c;shelle, ~. Also contemplated for use herein are anxiolytics such as XANAX; antipsychotics
such as CLOZARIL and HALDOL; non-steroidal anti-il.n~.. ~lories (NSAID's) such as
S VOLTAREN and LODINE; antihi~ .;..Fs such as SELDANE, HISMANAL, RELAFEN,
and TAVIST; antiemetics such as KYTRIL and ces~met; bronchodilators such as bentolin,
PROVENTlL; antidel.ressa.,L~ such as PROZAC, ZOLOFT, and PAXIL; anti-migraines such
as imigran; ACE-inhibitors such as VASOTEC, CAPOTEN and ZESTRIL; anti-Alzheimer's
agents such as nicergoline; and CaH-antagonists such as PROCARDIA, ADALAT, and
10 CALAN.
The popular H2-antagonists which can be used include ~imetitlin~ r~niti~ine
hydrochloride, famotidine, ni7~ti~ine, ebrotidine, mifentidine, rox~titline, pi~til1ine and
ace~ l ;(1inP
The invention is especially useful for the following sul,~a"~ially non-dissoluble
15 compounds: vasodilators such as nicergoline; anti-infl~mm~tories, antipyretics, and ~n~lgPcics
such as indometh~in; antiarthritics such as diacerin; progestogens, palliative lle~ P~-t
compounds for breast and endometrial carcinoma, and estrus regulators such as megestrol;
sedatives and hypnotics such as barbitals; ~n~lgesics, anticonvulsants such as ca,ba...~7epine;
antihy~e, lensi~es such as niredi~ e; uricosurics such as probenecid; anti-~ngin~l~ such as
20 felodipine; ~nti~p~modics such as fenalamide; plant fungicides such as fenarimol; and
anti-h~ l.ics such as ferldçn(l~7Qle.
In prere,.ed embodiments the bio-affecting agents include ~ntifi~ng~lc7
anti-;.. n;~.. ~ories, anti-hypertensives, antimicrobials, steroidal drugs, hormones,
prost~gl~ndin~, interferons, and mixtures thereof.
In the case of one pl er~ d embodiment, it has been found that the substantiallynon-dissoluble bio-affecting agents ibuprofen and nifedipine are each coml,d~ible with the acid
soluble polymer known as EUDRAGIT E, a copolymer based on dimethylaminoethyl
mPth~crylate and other neutral methacrylic acid esters, and marketed by Rohm GmbH. This
polymer is available in solvent free granules (EUDRAGIT E 100) and in a 12.5% solution in
propan-2-ol/acetone (60:40) (EUDRAGIT E 12.5). EUDRAGIT E has high aqueous
solubility especially under acidic conditions (below pH 5) and provides for rapid release of the
18
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drug in the gastric region of the gastrointestin~l tract. Although the polymer is principally
amorphous, microcrystalline domains of the polymer can be identified in the virgin polyrner.
Irl a p.ere,-ed embodiment, the process of the present invention can be implem~onted by
flash-flow processing. Flash-flow processing is achieved by subjecting feedstock to
S ~imlllt~neoll~ application of heat and shear sufficient to perrnit L~ rol.llaLion ofthe
morphology of the feedstock. Flash-flow processing creates a. condition of internal flow which
means that the feedstock material is enabled to move and separate at a sub-particle level. In
this embodiment, the feedstock would include a water-soluble polymer and a sub~ ally
non-dissolub1e bio-affecting agent.
Flash-flow processing can be effected by flash-heat processing or flash-shear
processing. In a pl~r~ d embodiment, the present invention collle~ lates flash-flow
processing by the flash-shear method which is described in con~ ol-ly known U.S. Patent No.
5,380,473 to lBogue et al., the contents of which is incorporat~d herein by reference. The
process reported in the Bogue et al. '473 patent is characterized by increasing the temperature
of a non-solubilized feedstock carrier to a point at which it undergoes internal-flow, followed
by forcibly expelling or ejecting a stream of the feedstock and. subjecting the stream to
disruptive fluid shear force which separates the stream into separate masses having
tran~-.--ed morphology.
In an alternative embodiment to the flash-shear method, the components of the present
invention can be mixed and processed in a mix extrusion method without the benefit of
forming disrupted masses as in the flash-shear method. As a rnost pl ~re. . ~d mode of
operation of this alternative embodiment, the feedstock materials e.g., a water-soluble polymer
and a subst~nti~lly non-dissoluble bio-affecting agent (without solubilizing additives) are
subjected to mix extrusion over a very short period of time, ~ erel ~bly not more than about
two min~ltes7 and most preferably not more than about thirty seconds.
Another contemplated embodiment includes processing the co.llponents in a flash-heat
process which creates conditions such as those found in cotton candy m~c.hines. In this
process, the feedstock is introduced to a spinner head in which it is subject to heat and shear
created by centrifugal force from the spinning head. Disclosures which relate to methods and
appal~L~Is suitable for spinning substances include the following: U.S. Pa~ent No. 4,855,326;
19
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U.S. Patent No. 4,873,08S; U.S. Patent No. 5,034,421; U.S. Patent No. 4,997,856; and U.S.
PatentNo. 5,028,632.
Examples in the U.S. patents listed above describe processing feedstock material by
subjecting it to high speed spinning on spinning head in which the feedstock is also subjected
5 to heat provided by a heating element. The change of temperature is quite large, which is
believed to be occasioned by the spinning head quickly and efficiently spreading the feedstock
material against the heating element circu",~ere"Lially disposed around the perimeter of the
spinning head. Thus, extensive surface contact of the feedstock against the heating element is
provided. Nonetheless, the spinning procedure is sufflciently fast that the heat history of the
10 bio-a~-,ling agent is not significantly prolonged.
As previously ~1iccn~ed herein, carriers used in the systems ofthe present invention are
water-soluble polymers which are compalil)le with the bio-affecting agents selected herein.
These carriers have sufficient heat stability for flash-flow processing and can range from low
molecular weight crystalline or amorphous materials to high molecular weight thermoplastic
15 polymers. Thermoplastic polymers, while having no defined melting point, can be processed
in a temperature region above its glass transition temperature, where the polymers elastomeric
properties are sufficient to allow elongation and dissolution of the active ingredient therein.
The present invention includes the co-l-bi,-alion ofthe active ingredient with the
coll")~ le polymer (and other excipients) in a melt form to enable the active ingredient to be
20 captured in an increased-energy condition upon qu~nc.hing Thus, the bio-affecting agent is
solubilized in the substrate or polymer and does not separate into its own crystalline domains.
The drug may form very fine crystals (nanoparticles) in the carrier as a result of being
qu~n~hed in the increased-energy condition, such crystals having significantly enhanced
dissolution and/or dispersibility. In the present invention, the carriers themselves have good
25 aqueous solubility. As a result of the system described herein, the poorly soluble drug is
liberated from the solid solution or dispersion as nanoparticles as the carrier is solubilized. It
is the nanoparticulate dispersion which provides the enh~n~ed bio-availability in vivo.
It is further contemplated that the present invention can be used to provide products
from the compositions resulting herein. Delivery systems can be çngineered to provide the
30 delivery profile which renders the bio-affecting agent available at the rate and intensity
required to treat the host. For example, fibers which are obtained as a result of processing in
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acco~ dallce with the present invention can be ground to proviide small particles of drug-bearing
polyrner. (Note that it is not the grinding of the fibers which provides a sub~lall~ially
homogeneous distribution of the bio-affecting agent in the carrier. Rather, unlike the prior art,
the distribution of the bio-affecting agent has been effected in the ~ntecedent process in which
the fibers were formed.) The drug-bearing particles can then be coated by tech~iques known
in the art. For example, the particles can be coated by means of the method set forth in
commonly-owned copending U.S. Application Serial No. 08t334,729 which was filed on
November 4, 1994, entitled "Delivery of Controlled-Release Systems," tlle disclosure of which
is incorporated herein by reference. The once-coated particles can be used as
controlled-release particles for capsules.
Alternatively, the drug-bearing particles resulting frorn grinding product processed in
accordance with the present invention can be used to make tablets, ~ bly rapidlydissolving tablets, according to known techniques. A 1)l ere, . ed tableting technique is the
method set forth in commonly-owned copending U.S. Application Serial No. 08/259,496, filed
June 14, 1994, and Application Serial No. PCT/US95/07194, filed June 6, 1995, both entitled
"Process and Apparatus for Making Rapidly-Dissolving Dosage Units and Product
Therefrom," the entire disclosures of which are incorporated herein by reference.
The present invention incl~lcles both the controlled-release particles resulting from
grinding the fibers produced in accordance with the present invention and capsules and rapid
dissolved tablets co~ g the controlled-released particles. With respect to these products,
it should be noted that fragile fibers bearing the bio-affecting agent are easily disrupted by
application of physical stress, implying that the bio-affecting ,agent is exposed to minim~l heat
during grinding to produce reducéd particle size of drug bea~ing polymer. This is, indeed, a
vast improvement over grinding raw active ingredients whichl generates significant heat usually
encountered in forced attrition. The heat which is generated by conventional direct grinding of
drugs can be sufficient to cause recryst~lli7~tion, which would work to increase the average
particle size. Thus, using the fragile fibers resulting from the process of the present invention,
the lowest average particle size of the bio-affecting agent can be attained for delivery to the
bio-system, thereby maximi7.ing the bio-availability of the bio-affecting agent.Tablets produced in accordance with the present invention can be processed to provide
yet further desired characteristics. For example, the tablets of the present invention can be
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coated with a semi-permeable membrane to achieve controlled-release of the active.
Furthermore, the tablets of the present invention can be form~ ted to contain tablet
çh~nnçlin~ agents or dissolution agents (bio-availability promoters) to increase or control
breakdown of the tablet. Typical of such bio-availability promoters are cellulosics such as
S h~droxyell,~yl cellulose, hydroxypropylmethyl cellulose, etc.
Moreover, in certain embo-limPnte, the compositions resulting from processing inaccol dance ~,vith the present invention can also be ground or pulverized and subjected to
further procee.eing to make agglomerates which can be tableted. This is especially useful
where additional excipients are required to be added before labl-ling or where the composition
itself is not directly tabletable.
Yet other uses of the present invention include intravascular (e.g., intravenous,
intra-arterial) delivery of drugs. It is known that substantially non-dissoluble agents must be
reduced significantly in size before intravascular delivery. Indeed, some agents cannot be
delivered intravascularly. As a result of the present invention, however, a mass of
drug-bearing water-soluble polymer can be contacted with intravascularly fed fluid for delivery
to the patient. The mass can be placed directly in the stream of flow of the fluid.
Alternatively, the mass can be housed in a compa, ~ ent by which the intravascular fluid passes
in such a manner so that the drug is delivered by the fluid. In the embodiments in which the
bio-affecting agents are used in intravascular applications, a colloid stabilizer is generally used
to keep the particles of bio-affecting agents dispersed.
The composition and method of the present invention is a highly efficient system for
providing a drug delivery system as a commercial product. The compositions of the invention
can be used for intr~m~-~ec~ r injection, parenteral dosage, intranasal, in osmotic pumps,
erodible systems which erode to release the bio-affecting agent, inh~l~nts transdermal patch
systems, subcutaneous injection, vaginal pessary, suppositories, powders, intravenous (IV)
~rlminietration, lozenges or other oral delivery systems, and for topical applications.
Especially p, t;re, I ed uses are those wherein the composition is exposed to a body fluid such as
pe, ~ ion or internal body fluids which solubilize the polymer and release the bio-affecting
agent.
The present invention has been exemplified below in examples in which co-processed
compositions of substantially non-dissoluble bio-affecting agents, e.g., ibuprofen or niredip-ne,
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have been prepared in combination with a commercially obtained water-soluble
polyrnP,th~crylate polymer. The dissolution rate of orally adnninistered drugs which have low
aqueous solubility is quite slow. Low solubility is the result of a low rate of departure of drug
molecules from the undispersed state. In accordance with the present invention, formulation
5 techniqu~ have been provided which produce solid dispersions (or solid solutions) of a
bio-~ffe~in~ agent. The system formed by these forrn~ tionl techniques has been found to be
valuable for making non-dissoluble agents bio-available to host bio-systems.
The examples set forth heteinbelow exemplify the pre sent composition, method, and
duw~ ea-ll products resulting therefrom. The examples ha~e been set forth to satisfy
10 obligations under the statute, but are not in any way intçndecl to limit the scope of protection
provided herein.
FX~MP~
l[buprofell is an excellent non-steroidal anti-infl~mm~lory drug. ~iretli,oh~e is a potent
~nti~ngin~l and antihypertensive drug. Both of these drugs are substantially insoluble in water
1~ and other aqueous media, as defined in the USP. These two compounds were, therefore,
selected as model agents to demonstrate the capability of the present invention.It was discovered that a polymethacrylate aqueous p~lymer used in pharm~ceutical flm
coating, EUDRAGIT E, was miscible with ibuprofen or nife~ipine under melt flow conditions.
The specific polymer used is a copolymer based on dimethylaminoethyl methacrylate and
20 methacrylic acid esters marketed by Rohm GmbH as EUDRAGIT E. This polymer has compendial status in the USP/NF.
FXAMPLE 1 - FLASH-EIEAT P]ROCESS
In this example, the polymethacrylate polymer EUDR AGIT E (EUDRAGIT E 100;
pellet form) obtained from Rohm GmbH, Darmstadt, Germany, was ground to a powder and
25 sized by passing the powder through a 60 mesh screen sieve. Ibuprofen (Product Code
IBlD472, grade 25) obtained from BHC HBMC Advanced Materials Group, Bishop, Texas,
was added to the resulting EUDRAGIT powder and blended together to form a blend
in-.lu(ling 20 wt% ibuprofen in 80 wt% EUDRAGIT polyrner.
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The powder blend was processed in a 5" pharm~ceutiçRl spinning head with 36
heaters. The mRchine parameters included a spinning speed of 3,600 rpm, a power setting of
20.5%, and a m~im-lm temperature of 1 50~C. A fine, clear, and colorless floss was produced
from the flash-heat process.
S Micloscopic ~ Al;on ofthe material in ~im~ ted gastric fluid (no pepsin) revealed
the release of inmlmerable nanoparticles as the polymer solubilized. The size of the
nanoparticles was not measurable by optical means, but was well below 1 ,um. It is believed
that the size ofthe nanoparticles are ofthe order of 100 nm to 600 nm (i.e., 0.1 ,um to
0.6 ~4m).
One gram (1 g) ofthe ibuprofen-co.~ g solid dispersion (= 200 mg of ibuprofen)
was added to 900 mL of 0.1 N HCI and stirred at 100 rpm for 0.5 h. Samples were taken and
ibuprofen collc~llLl ~ion was measured by E~'LC UV. The solid dispersion gave an ibuprofen
concentration of 0.066 ,ug/mL. This corresponds to an increase in solubility of over 100%
compared to the solubility of the raw drug as tested by the same analytical method
(0.030 ~g/rnL).
~ E~AMPL~ 2 - EXTRUSION M~XING
The water-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine
powder and sized by passage through a 60 mesh sieve. The resulting sized powder was mixed
with ibuprofen and blended to form a blend including 20 wt% ibuprofen in 80 wt%
EUDRAGIT polymer.
The resulting powder blend was processed in an APV-Baker MP2015 twin screw
extruder with multiple heater zones and fitted with a 1 cm nozzle. The temperature of each of
the four heating zones was set to 100~C, and the following temperatures were recorded: Zone
1 = 98 ~ C; Zone 2 = 102 ~ C; Zone 3 = 100 ~ C; Zone 4 = 105 ~ C . The speed of the twin screw
was 120 rpm. The extruded product was a solid dispersion of ibuprofen in the
polymethacrylate, having a continuous rod structure.
One gram (1 g) of the ibuprofen-contRining solid dispersion (= 200 mg of ibuprofen)
was added to 900 mL of 0.1 N HCI and stirred at 100 rpm for 0.5 h. Samples were taken and
il)u~ en concentration was measured by HPLC W. The solid dispersion gave an ibuprofen
concentration of 0.067 ~g/mL. This corresponds to an increase in solubility of over 100%
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W O 97/08950 PCTAUS96/14457
co.,.l~al ed to the solubility of the raw drug as tested by the sarne analytical method
(0.030 ~g/mL)
I
~,X ~ M P~,F,3- Fl,~S~-~F,~T PR~O CF,~S
Once again, the water-soluble polymer, EUDRAGIT ]E, 100, was ground from pellet
size to a fine powder and sized by passing the ground powdeî through a 60 mesh sieve.
Nifedipine (Product Code 15620, lot 55, Sanofi) obtained from InterChem Corp., Paramus,
New Jersey, was added to the resulting EUDRAGIT powder ~nd blended together to form a
b1end ins;l~ in~ 20 wt% ~.iredipi~.e in 80 wt% EUDRAGIT polyrner.
The powder blend was processed in a 5" pharm~c.e~ltical spinning head with 36
heaters. The m~chine parameters in~.indçd a spilllling speed a,:f 3,600 rpm, a power setting of
30%, and a maximum temperature of 183 ~C. The spun product was a solid dispersion of
"iredipi~le in the polymethacrylate polymer, in the form of a ylellowish floss.
Dissolution testing of the rnaterial was pe, ~o"l,ed using a sim~ ted gastric fluid (no
pepsin): 900 mL 0.1 N HCI, with 1% TWEEN 20., USP Method II. The sample was ~f,ri
at 37~C, using 50 rpm for 30 min, and then using 200 rpm for 15 min. This solid dispersion
was found to be 78% dissolved in 5 min, and 80% dissolved at 45 mLin. See Figure 1. This
co",paled to a meager 1% dissolution at 5 min, and no more than 16% dissolution at 45 min,
when the bulk (raw) drug was tested. See Figure 2.
F.X~nlp~,F,4- F~xTRuslo N-Ml~yIN G
The water-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine
powder and sized by passage through a 60 mesh sieve. The res-llting sized powder was mixed
with nifedipine and blended to form a blend incl~l~ing 20 wt% nifedipine in 80 wt%
EUDRAGIT polymer.
The r~c--lting powder blend was processed in an APV-Baker MP2015 twin screw
extruder with multiple heater zones and fitted with a 1 cm nozzle. The temperature of each of
the four heating zones was set to 1 75~C, and the following temperatures were recorded: Zone
1 = 172~C; Zone 2 = 1 77~C; Zone 3 = 175 ~C; Zone 4 = 1 80~C. The speed of the twin screw
was 120 rpm. The extruded product was a clear, yellow, solid dispersion of nifedipine in the
polymeth~rylate~ having a discontinuous rod structure.
CA 022310~0 1998-03-03
WO 97/08950 PCTrUS96/14457
Dissolution testing of the extruded material was performed using a ~imnl~ted gastric
fluid (no pepsin): 900 mL 0.1 N HCI, with 1% TWEEN 20, USP Method II. The sample was
~git~tell, at 37~C, using 50 rpm for 30 min, and then using 200 rpm for 15 min. This solid
dispersion was found to be 76% dissolved in 5 min, and 81% dissolved at 45 min. See Figure
3. This co,.~palt;d to a meager 1% dissolution at 5 min, and no more than 16% dissolution at
45 min, when the bu1k (raw) drug was tested. See Figure 2.
~,X~MPI,F 5 - F~ ~SH-~F,~T PROC~ S
In this example, the polymer EUDRAGIT E 100 (in pellet form) was ground to a
powder and sized by passing the powder through a 60 mesh screen sieve. An ~ntifilng~l agent
was added to the r~ ting EUDR~GIT powder and blended together. The two ingredients
were coml)il~ed on a 1: 1 ratio, i.e., the resulting blend had 50% antifungal agent and 50%
EUDRAGIT E polymer by weight.
The powder blend was processed in a spinning head operated at 60 Hz and 50% power
cycling. Thus, the speed ofthe head was approximately 3,500-3,700 rpm and the t~---pe~ re
at the perimeter of the head was m~int~ined at an average of approximately 218~C.
A fine clear floss was produced from the flash-heat process. Mic~oscopic e~ ;on
of the material in sim~ ted gastric fluid (no pepsin) revealed the release of innnmerable
nanoparticles as the polymer solubilized. The size of the nanoparticles was not measurable by
optical means and was well below 1,um. It is believed that the size of the nanoparticles is of
the order of 100 nm to 600 nm.
Dissolution testing ofthe material in sim-ll~ted gastric fluid (no pepsin) 900 mL and
1% TWEEN 20, USP Method II, 100 rpm, gave 88% dissolution in 10 min. This co-llpal~d
to a meager 3.7% dissolution when the bulk drug substance was tested. See Figure 4.
F~AMpl .F 6 - FLASH-S~l~R PROCESS
Once again, the water-soluble polymer, EUDRAGIT E 100, was ground from pellet
size to a fine powder and sized by passing the ground powder through a 60 mesh sieve. The
resulting EUDRAGIT powder was mixed with the ~ntifi~ng~l agent and blended in a grinding
mill. The powder blend was then processed in a flash-shear process using an extruder barrel
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W O 97/08950 PCT~US96/144~7
temperature gradient from 164~C to a 185~CI which a nozzle temperature of 185~C~ and an
ato,l,i~ion air pressure of 10 psi.
The Flash Shear nozzle at the exit end of extruder is of the type described in copending
commonly-owned Application Serial No. 08/269,679, filed September 6, 1994, where the air
was heated to 170~C and was at a pressure of 1.5 psi to 3 psi.
A thick fibrous rnaterial was produced by the process. Microscopic c,~ ion in
.~im~ ted gastric fluid (no pepsin) revealed that a considerable number of nanoparticles were
re1eased from the water-soluble polymer as the polymer became solubilized. The size of the
nanoparticles was well below 1 ~m. It is believed that the si;z:e of the nallop~, licles produced
as a result of the present process is in the range of about 100 nm to about 600 nm. The
material disappeared completely, with a milky dispersion r~ ing thereafter.
Dissolution testing of the material in ~im-ll~ted gastric fluid (no pepsin) of 950 mL and
1% Tween 20, USP Method II, 100 rpm, produced a 77% dissolution in only 10 min. Once
again, this cor"pared to a relatively low 3.7% dissolution when the bulk drug substance was
tested. See Figure 4.
~ MPl ,F 7 - ~XTRUSIO N M ~nNG
The water-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine
powder and sized by passage through a 60 mesh sieve. The resulting sized powder was mixed
with the ~ntifi-ng~l agent at a ratio of 1:1 and blended in a grinding mill.
The res-llting powder blend was processed in a twin screw extruder fitted with a 1 cm
nozzle. A clear extrudate was produced by the process. The appearance of the material
quickly turned to an opaque, hard, and brittle rope. Microsclopic c,~ l ;on of the resulting
extrudate in sim~ ted gastric fluid (no pepsin) revealed the release of a considerable number
of very fine particles, having a size of well below I ,um. The extrudate disappeared completely
with a milky dispersion ~ i"g thereafter.
Dissolution testing of the material in sim~ ted gastric fluid (no pepsin) of 900 rnL and
1% Tween 20, USP Method II, 100 rpm, produced a 94% dissolution in 10 min. This
compared to only 3.7% dissolution when the bulk drug substance was tested. See Figure 4.
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W O 97/08950 PCTAJS96/14457
F,X ~ M P~,F,8- C~PSU~,~,FOR~UT,~TIO N
Ten grams (10 g) ofthe 50/50 ~ntifilng~l/EUDRAGIT E solid dispersion of Example
was ground using a rotary blade, and then sieved through a 20 mesh screen. We were able to
load 400 mg ofthe solid dispersion in a O size capsule, to give a capsule co..l~ g 200 mg of
5 the ~ntifilng~l agent. The material was free flowing, having all of the p~upel Lies of an ideal
material for capsule filling.
FXAMP~ ~ 9 - TAR~ ~T FORMU~ ON
The acid-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine
powder and sized by passage through a U. S. Standard 60 mesh sieve. The resulting powder
10 was mixed with the ~ntifi~ng~l agent at a ratio of 1:1 and blended in a grinding mill.
The powder blend was processed in a twin screw extruder fitted with a 1 cm nozzle.
This extrudate was cooled and the material was ground in a high shear grinding mill to reduce
particle size. Microcrystalline cellulose NF(AVICEL PH101) and croscarmellose sodium NF
were blended with the solid dispersion to provide 15.0% and 3 .00% of the blend, respectively.
15 The antifimg~l agent and EUDRAGIT E each were 41% ofthe blend.
The tablet premix was co---p~essed on a Specac hydraulic press at 13,000 psi using an
11 mm tablet die, to give 236 milligram tablets. These tablets provided a target dose of
100 mg ofthe ~ntifilng~l agent. The tablet had a di~intçgration time of 13 min in sim~ ted
gastric fluid (no pepsin) at 37~C.
EXAMP~,~, 10 - PARTICLE SIZE DISTRIBUTION
A sample of a solid dispersion of the antifungal agent prepared by flash heat processing
according to Example 6 above was subjected to particle sizing. Two hundred milligrams (200
mg) of the solid dispersion was dissolved in 900 mg of 0.1 N HCI. Af[er 9 min. an aliquot was
removed and tested using a standard photon correlation method. Computerized analysis
indicated that the mean particle size in the sample was 196.8 nm, with a monomodal
distribution of particle sizes offrom about 155 nm to about 255 nm. These particles clearly
qualify as "nanoparticles" as described hereinabove.
The compositions of all of the examples can be easily be molded into tablets by using
opposed roller dies or regular dies following the co-processing (flash flow or co-extrusion)
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CA 02231050 1998-03-03
W 097108950 PCT~US96/14457
steps. Experience shows the material is readily compl es~;l,le into tablets of pressures of less
than 80,000 psi and pl ~rel ~bly of pressures of from about 500 psi to about 40,000 psi.
The rOI~goillg examples make it abundantly clear thalt dissolution of the solid
dispersions of the invention in an aqueous envh u~ lc;lll~ is very efficient. Moreover, tablets or
5 capsules made according to the invention provide very convenient delivery of s~ lly
non~ ol~lble bio-a~e~iLing agents. Accordingly, the composition and method of the
invention advantageously improve the bio-availability of substantially non-dissoluble
bio-affecting agents.
Thus, Applicants have described what are pl~selllly believed to be the pl~relled10 embodiments ofthe present invention, and other and further embodimen~s ofthe invention will
be appreciated by those skilled in the art, and it is intenrled to include other modifications and
changes which come within the true scope of the invention as pointed out in the appended
claims.
29
