Nanoparticles containing the R(-)enantiomer of ibuprofen

There is described a composition comprised of nanoparticles of a therapeutic agent having a surface modifier adsorbed on the surface thereof. The present composition is characterized in that the therapeutic agent is ibuprofen or fenoprofen which is substantially enriched in the R(-) enantiomer.

FIELD OF THE INVENTION 
The present invention is directed to nanoparticles including the R(-) 
enantiomer of ibuprofen or fenoprofen as the therapeutic agent. 
Background of Invention 
Bioavailability is the degree to which a therapeutic agent becomes 
available to the target tissue after administration. Many factors can 
affect bioavailability including the dosage form and various properties, 
e.g., dissolution rate of the therapeutic agent. Poor bioavailability is a 
significant problem encountered in the development of pharmaceutical 
compositions, particularly those containing an active ingredient that is 
poorly soluble in water. Poorly water soluble therapeutic agents, i.e., 
those having a solubility less than about 10 mg/ml, tend to be eliminated 
from the gastrointestinal tract before being absorbed into the 
circulation. 
Nanoparticles, described in U.S. Pat. No. 5,145,684, are particles 
consisting of a poorly soluble therapeutic onto which are adsorbed a 
non-crosslinked surface modifier, and which have an average particle size 
of less than about 400 nanometers (nm). These nanoparticles provide for 
increased bioavailability and for improved diagnostic charactistics 
compared to other materials having larger sizes. Nanoparticles also 
provide for more rapid dissolution of the therapeutic agent as compared to 
traditional formulations. 
It is well known that chiral inversion of the R(-) enantiomer of ibuprofen 
to the S(+) form occurs readily and extensively in humans following 
administration. (See J. Pharmacol. 19:669-674). As a result of such 
bioconversion, the effective elimination half life of the S(+) enantiomer 
has been reported to be as much as 50% greater than that following the 
administration of the S(+) form alone. Unfortunately, the R(-) form of 
ibuprofen is characterized by a slower dissolution rate than the S(+) form 
in vitro thus leading one to the conclusion that the R(-) form, if 
administered alone, would have a substantially longer T.sub.max (the time 
to maximum absorption)consistent with a slow rate of absorption. Further, 
if the rate of absorption is too slow, a target analgesic level may never 
be reached with an equivalent dose of the faster dissolving S(+) form. 
Fenoprofen is also reported to have a similar rapid and complete 
conversion. 
If rapid onset were the only criteria, then the pure S(+) form would be the 
most desirable. This is what is claimed in patents such as U.S. Pat. Nos. 
4,851,444 and 4,877,620. However, for some multiple chronic conditions, 
rapid onset is less important than is the duration of the analgesic and 
antiinflamatory effects. Conditions where this may be important for 
example include rheumatoid arthritus and osteoarthritus as well as other 
nonspecific inflamatory or degenerative joint diseases or musculoskeletal 
pain or pain arising from surgical or dental procedures. Even intermediate 
term administration for osteopathic purposes may require long term effect. 
Long term effect is typically achieved with controlled release or 
sustained releas compositions. However, this ads complexity and 
complications which can increase the cost or size of the dosage form. 
SUMMARY OF THE INVENTION 
In accordance with the present invention there is provided a composition 
comprised of nanoparticles of a therapeutic agent having a surface 
modifier adsorbed on the surface thereof, the improvement wherein the 
therapeutic agent is ibuprofen or fenoprofen which is substantially 
enriched in the R(-) enantiomer. 
By "substantially enriched" we mean that the composition contains at least 
about 85% of the R(-) enantiomer and preferrably about 95% or greater.

DESCRIPTION OF PREFERRED EMBODIMENTS 
Ibuprofen is commercially available under the tradenames Motrin.TM., 
Advil.TM. and Nuprin.TM. and has been extensively studied. Reference is 
made to the references cited in U.S. Pat. No. 4,851,444 refered to above. 
Ibuprofen and fenoprofen are members of a class of NSAIDS that are 
propionic acids derivatives Ibuprofen is a-methyl-4-(2-methyl propyl) 
benzene acetic acid and fenoprofen is a-methyl-3-phenoxy benzene acetic 
acid. 
R(-) ibuprofen is commercially available from Catherx Pharmaceuticals, 
Jackson, Miss. The resolution of racemic mixtures can also be accomplished 
by methods known in the art such as described in Kaiser et al, J. Pharm 
Sci, Vol 65, No 2, pgs 269-273 (1976). (While this process is aimed at 
recovering the S(+) form, readily apparent modifications would yield the 
R(-) form.) 
Using the nanoparticle form of R(-) ibuprofen or fenoprofen, two different 
effects can be balanced. With equivalent dosage intervals, the peak to 
trough variation will be reduced compared to administration of the S(+) 
form. The benefit of this is that there is better control of the analgesic 
or antiinflammatory effect. Alternatively, where somewhat greated peak to 
trough variation can be tolerated, a longer dosage interval can be used. 
While this might be achieved using some kind of controlled release system, 
such systems involve additional cost and complexity. 
Surface Modifiers 
The currently preferred surface modifier is hydroxypropyl methylcellulose. 
Suitable surface modifiers can preferably be selected from known organic 
and inorganic pharmaceutical excipeints. Such excipients include various 
polymers, low molecular weight oligomers, natural products and 
surfactants. Preferred surface modifiers include nonionic and ionic 
surfactants. 
Representative examples of surface modifiers include gelatin, casein, 
lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic 
acid, benzalkonium chloride, calcium stearate, glycerol monostearate, 
cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, 
polyotyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 
1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan 
fatty acid esters, e.g., the commercially available Tweens.TM., 
polyethylene glycols, polyoxyethylene stearates, colloidal silicon 
dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose 
calcium, carboxymethylcellulose sodium, methylcellulose, 
hydroxyethylcellulose, hydroxy propylcellulose, 
hydroxypropylmethylcellulose phthlate, noncrystalline cellulose, magnesium 
aluminum silicate, triethanolamine, polyvinyl alcohol, and 
polyvinylpyrrolidone (PVP). Most of these surface modifiers are known 
pharmaceutical excipients and are described in detail in the Handbook of 
Pharmaceutical Excipients, published jointly by the American 
Pharmaceutical Association and The Pharmaceutical Society of Great 
Britain, the Pharmaceutical Press,. 1986. 
Particularly preferred surface modifiers include polyvinylpyrrolidone, 
tyloxapol, poloxamers such as Pluronic.TM. F68 and F108, which are block 
copolymers of ethylene oxide and propylene oxide, and polyxamines such as 
Tetronic.TM. 908 (also known as Poloxamine.TM. 908), which is a 
tetrafunctional block copolymer derived from sequential addition of 
propylene oxide and ethylene oxide to ethylenediamine, available from 
BASF, dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such 
as Aerosol OT.TM., which is a dioctyl ester of sodium sulfosuccinic acid, 
available from American Cyanimid, Duponol.TM. P, which is a sodium lauryl 
sulfate, available from DuPont, Triton.TM. X-200, which is an alkyl aryl 
polyether sulfonate, available from Rohn and Haas, Tween.TM. 20 and 
Tween.TM. 80, which are polyoxyethylene sorbitan fatty acid esters, 
available from ICI Specialty Chemicals; Carbowax.TM. 3550 and 934, which 
are polyethylene glycols available from Union Carbide; Crodesta.TM. F-110, 
which is a mixture of sucrose stearate and sucrose distearate, available 
from Croda Inc., Crodesta.TM. SL-40, which is available from Croda, Inc., 
and SA90HCO, which is C.sub.18 H.sub.37 CH.sub.2 (CON(CH.sub.3)CH.sub.2 
(CHOH).sub.4 CH.sub.2 OH).sub.2. Surface modifiers which have been found 
to be particularly useful include Tetronic.TM. 908, the Tweens.TM., 
Pluronic.TM. F-68 and polyvinylpyrrolidone. Other useful surface modifiers 
include: 
decanoyl-N-methylglucamide; 
n-decyl .beta.-D-glucopyranoside; 
n-decyl .beta.-D-maltopyranoside; 
n-dodecyl .beta.-D-glucopyranoside; 
n-dodecyl .beta.-D-maltoside; 
heptanoyl-N-methylglucamide; 
n-heptyl-.beta.-D-glucopyranoside; 
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside; 
nonanoyl-N-methylglucamide; 
n-noyl .beta.-D-glucopyranoside; 
octanoyl-N-methylglucamide; 
n-octyl-.beta.-D-glucopyranoside; 
octyl .beta.-D-thioglucopyranoside; and the like. 
Another useful surface modifier is tyloxapol (a nonionic liquid polymer of 
the alkyl aryl polyether alcohol type; also known as superinone or 
triton). This surface modifier is commercially available and/or can be 
prepared by techniques known in the art. 
Another preferred surface modifier is p-isononylphenoxypoly(glycidol) also 
known as Olin-10G.TM. or Surfactant 10-G, is commercially available as 
10G.TM. from Olin Chemicals, Stamford, Conn. 
Non-Ionic Surface Modifiers 
Preferred surface modifiers can be selected from known non-ionic 
surfactants, including the poloxamines such as Tetronic.TM. 908 (also 
known as Poloxamine.TM. 908), which is a tetrafunctional block copolymer 
derived from sequential addition of propylene oxide and ethylene oxide to 
ethylenediamine, available from BASF, or Tetronic.TM. 1508 (T-1508), or a 
polymer of the alkyl aryl polyether alcohol type, such as tyloxapol. 
The surface modifiers are commercially available and/or can be prepared by 
techniques known in the art. Two or more surface modifiers can be used in 
combination. 
Tyloxapol 
Tyloxapol (4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide 
and formaldehyde) is a preferred surface modifier and is a nonionic liquid 
polymer of the alkyl aryl polyether alcohol type. Tyloxapol, also known as 
"Superinone", is disclosed as useful as a nonionic surface active agent in 
a lung surfactant composition in U.S. Pat. No. 4,826,821 and as a 
stabilizing agent for 2-dimethylaminoethyl 4-n-butylaminobenzoate in U.S. 
Pat. No. 3,272,700. 
Tyloxapol may be associated with the nanoparticles and may function as a 
surface modifier, as a stabilizer, and/or as a dispersant. Alternatively, 
the tyloxapol may serve other purposes. Tyloxapol may serve all three 
functions. The tyloxapol may serve as a stabilizer and/or a dispersant, 
whereas another compound acts as a surface modifier. 
Auxiliary Surface Modifiers 
Particularly preferred auxiliary surface modifiers are those which impart 
resistance to particle aggregation during sterilization and include 
dioctylsulfosuccinate (DOSS), polyethylene glycol, glycerol, sodium 
dodecyl sulfate, dodecyl trimethyl ammonium bromide and a charged 
phospholipid such as dimyristoyl phophatidyl glycerol. The surface 
modifiers are commercially available and/or can be prepared by techniques 
known in the art. Two or more surface modifiers can be used in 
combination. 
Block Copolymer Surface Modifiers 
One preferred surface modifier is a block copolymers linked to at least one 
anionic group. The polymers contain at least one, and preferably two, 
three, four or more anionic groups per molecule. Preferred anionic groups 
include sulfate, sulfonate, phosphonate, phosphate and carboxylate groups. 
The anionic groups are covalently attached to the nonionic block 
copolymer. The nonionic sulfated polymeric surfactant has a molecular 
weight of 1,000-50,000, preferably 2,000-40,000 and more preferably 
3,000-30,000. In preferred embodiments, the polymer comprises at least 
about 50%, and more preferably, at least about 60% by weight of 
hydrophilic units, e.g., alkylene oxide units. The reason for this is that 
the presence of a major weight proportion of hydrophilic units confers 
aqueous solubility to the polymer. 
A preferred class of block copolymers useful as surface modifiers herein 
includes sulfated block copolymers of ethylene oxide and propylene oxide. 
These block copolymers in an unsulfated form are commercially available as 
Pluronics.TM.. Specific examples of the unsulfated block copolymers 
include F68, F108 and F127. 
Another preferred class of block copolymers useful herein include 
tetrafunctional block copolymers derived from sequential addition of 
ethylene oxide and propylene oxide to ethylene diamine. These polymers, in 
an unsulfated form, are commercially available as Tetronics.TM.. 
Another preferred class of surface modifiers contain at least one 
polyethylene oxide (PEO) block as the hydrophilic portion of the molecule 
and at least one polybutylene oxide (PBO) block as the hydrophobic 
portion. Particularly preferred surface modifiers of this class are 
diblock, triblock, and higher block copolymers of ethylene oxide and 
butylene oxide, such as are represented, for example, by the following 
structural formula: 
.paren open-st.PEO.paren close-st. .paren open-st.PBO.paren close-st.; 
.paren open-st.PEO.paren close-st. .paren open-st.PBO.paren close-st. 
.paren open-st.PEO.paren close-st.; and .paren open-st.PEO.paren close-st. 
.paren open-st.PBO.paren close-st. .paren open-st.PEO.paren close-st. 
.paren open-st.PBO.paren close-st.. 
The block copolymers useful herein are known compounds and/or can be 
readily prepared by techniques well known in the art. 
Highly preferred surface modifiers include triblock copolymers of the 
structure .paren open-st.PEO.paren close-st. .paren open-st.PBO.paren 
close-st. .paren open-st.PEO.paren close-st. having molecular weights of 
3800 and 5000 which are commercially available from Dow Chemical, Midland, 
Mich., and are referred to as B20-3800 and B20-5000. These surface 
modifiers contain about 80% by weight PEO. In a preferred embodiment, the 
surface modifier is a triblock polymer having the structure: 
##STR1## 
Q is an anionic group wherein R is H or a metal cation such as Na.sup.+, 
K.sup.+ and the like, x is 15-700, y is 5-200 and z is 15-700. 
Grinding 
The described particles can be prepared in a method comprising the steps of 
dispersing the R(-) ibuprofen or fenoprofen in a liquid dispersion medium 
and applying mechanical means in the presence of grinding media to reduce 
the particle size of the therapeutic or diagnostic agent to an effective 
average particle size of less than about 400 nm. The particles can be 
reduced in size in the presence of a surface modifier. Alternatively, the 
particles can be contacted with a surface modifier after attrition. 
The R(-) ibuprofen or fenoprofen selected is obtained commercially and/or 
prepared by techniques known in the art in a conventional coarse form. It 
is preferred, but not essential, that the particle size of the coarse R(-) 
ibuprofen or fenoprofen selected be less than about 100 .mu.m as 
determined by sieve analysis. If the coarse particle size of the R(-) 
ibuprofen or fenoprofen is greater than about 100 .mu.m, then it is 
preferred that the particles of the R(-) ibuprofen or fenoprofen be 
reduced in size to less than 100 .mu.m using a conventional milling method 
such as airjet or fragmentation milling. 
The coarse R(-) ibuprofen or fenoprofen selected can then be added to a 
liquid medium in which it is essentially insoluble to form a premix. The 
concentration of the R(-) ibuprofen or fenoprofen in the liquid medium can 
vary from about 0.1-60%, and preferably is from 5-30% (w/w). It is 
preferred, but not essential, that the surface modifier be present in the 
premix. The concentration of the surface modifier can vary from about 0.1 
to about 90%, and preferably is 1-75%, more preferably 20-60%, by weight 
based on the total combined weight of the R(-) ibuprofen or fenoprofen and 
surface modifier. The apparent viscosity of the premix suspension is 
preferably less than about 1000 centipoise. 
The premix can be used directly by subjecting it to mechanical means to 
reduce the average particle size in the dispersion to less than 400 nm. It 
is preferred that the premix be used directly when a ball mill is used for 
attrition. Alternatively, the R(-) ibuprofen or fenoprofen and, 
optionally, the surface modifier, can be dispersed in the liquid medium 
using suitable agitation, e.g., a roller mill or a Cowles type mixer, 
until a homogeneous dispersion is observed in which there are no large 
agglomerates visible to the naked eye. It is preferred that the premix be 
subjected to such a premilling dispersion step when a recirculating media 
mill is used for attrition. 
The mechanical means applied to reduce the particle size of the R(-) 
ibuprofen or fenoprofen conveniently can take the form of a dispersion 
mill. Suitable dispersion mills include a ball mill, an attritor mill, a 
vibratory mill, and media mills such as a sand mill and a bead mill. A 
media mill is preferred due to the relatively shorter milling time 
required to provide the intended result, i.e., the desired reduction in 
particle size. For media milling, the apparent viscosity of the premix 
preferably is from about 100 to about 1000 centipoise. For ball milling, 
the apparent viscosity of the premix preferably is from about 1 up to 
about 100 centipoise. Such ranges tend to afford an optimal balance 
between efficient particle fragmentation and media erosion. 
Preparation Conditions 
Ibuprofen or fenoprofen should be milled under acidic conditions since 
under alkaline conditions, the particles will grow over time. The milling 
vehicle can be acidified or buffered using common pharmaceutically 
acceptable acids and buffers. One useful milling vehicle is dilute 
hydrochloric acid. The target pH should be less than the pKa of ibuprofen 
or fenoprofen, e.g. less than about 3.5. 
The attrition time can vary widely and depends primarily upon the 
particular mechanical means and processing conditions selected. For ball 
mills, processing times of up to five days or longer may be required. On 
the other hand, processing times of less than 1 day (residence times of 
one minute up to several hours) have provided the desired results using a 
high shear media mill. The particles must be reduced in size at a 
temperature which does not significantly degrade the R(-) ibuprofen or 
fenoprofen. Processing temperatures of less than about 
30.degree.-40.degree. C. are ordinarily preferred. If desired, the 
processing equipment can be cooled with conventional cooling equipment. 
The method is conveniently carried out under conditions of ambient 
temperature and at processing pressures which are safe and effective for 
the milling process. For example, ambient processing pressures are typical 
of ball mills, attritor mills and vibratory mills. Control of the 
temperature, e.g., by jacketing or immersion of the milling chamber in ice 
water are contemplated. Processing pressures from about 1 psi (0.07 
kg/cm.sup.2) up to about 50 psi (3.5 kg/cm.sup.2) are contemplated. 
Processing pressures from about 10 psi (0.7 kg/cm.sup.2) to about 20 psi 
(1.4 kg/cm.sup.2) are typical. 
The surface modifier, if it was not present in the premix, must be added to 
the dispersion after attrition in an amount as described for the premix 
above. Thereafter, the dispersion can be mixed, e.g., by shaking 
vigorously. Optionally, the dispersion can be subjected to a sonication 
step, e.g., using an ultrasonic power supply. For example, the dispersion 
can be subjected to ultrasonic energy having a frequency of 20-80 kHz for 
a time of about 1 to 120 seconds. 
After attrition is completed, the grinding media is separated from the 
milled particulate product (in either a dry or liquid dispersion form) 
using conventional separation techniques, such as by filtration, sieving 
through a mesh screen, and the like. 
Grinding Media 
The grinding media for the particle size reduction step can be selected 
from rigid media preferably spherical or particulate in form having an 
average size less than about 3 mm and, more preferably, less than about 1 
mm. Such media desirably can provide the particles with shorter processing 
times and impart less wear to the milling equipment. The selection of 
material for the grinding media is not believed to be critical. We have 
found that zirconium oxide, such as 95% ZrO.sub.2 stabilized with 
magnesia, zirconium silicate, and glass grinding media provide particles 
having levels of contamination which are believed to be acceptable for the 
preparation of pharmaceutical compositions. However, other media, such as 
stainless steel, titania, alumina, and 95% ZrO.sub.2 stabilized with 
yttrium, are expected to be useful. Preferred media have a density greater 
than about 3 g/cm.sup.3. 
Polymeric Grinding Media 
The grinding media can comprise particles, preferably substantially 
spherical in shape, e.g., beads, consisting essentially of polymeric 
resin. Alternatively, the grinding media can comprise particles comprising 
a core having a coating of the polymeric resin adhered thereon. 
In general, polymeric resins suitable for use herein are chemically and 
physically inert, substantially free of metals, solvent and monomers, and 
of sufficient hardness and friability to enable them to avoid being 
chipped or crushed during grinding. Suitable polymeric resins include 
crosslinked polystyrenes, such as polystyrene crosslinked with 
divinylbenzene, styrene copolymers, polycarbonates, polyacetals, such as 
Delrin.TM., vinyl chloride polymers and copolymers, polyurethanes, 
polyamides, poly(tetrafluoroethylenes), e.g., Teflon.TM., and other 
fluoropolymers, high density polyethylenes, polypropylenes, cellulose 
ethers and esters such as cellulose acetate, polyhydroxymethacrylate, 
polyhydroxyethyl acrylate, silicone containing polymers such as 
polysiloxanes and the like. The polymer can be biodegradable. Exemplary 
biodegradable polymers include poly(lactides), poly(glycolide) copolymers 
of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), 
poly(imino carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl 
hydroxyproline) esters, ethylene-vinyl acetate copolymers, 
poly(orthoesters), poly(caprolactones), and poly(phosphazenes). In the 
case of biodegradable polymers, contamination from the media itself 
advantageously can metabolize in vivo into biologically acceptable 
products which can be eliminated from the body. 
The polymeric resin can have a density from 0.8 to 3.0 g/cm.sup.3. Higher 
density resins are preferred inasmuch as it is believed that these provide 
more efficient particle size reduction. 
The media can range in size from about 0.1 to 3 mm. For fine grinding, the 
particles preferably are from 0.2 to 2 mm, more preferably, 0.25 to 1 mm 
in size. 
In a particularly preferred method, the R(-) ibuprofen or fenoprofen is 
prepared in the form of submicron particles by grinding the agent in the 
presence of a grinding media having a mean particle size of less than 
about 75 microns. 
The core material of the grinding media preferably can be selected from 
materials known to be useful as grinding media when fabricated as spheres 
or particles. Suitable core materials include zirconium oxides (such as 
95% zirconium oxide stabilized with magnesia or yttrium), zirconium 
silicate, glass, stainless steel, titania, alumina, ferrite and the like. 
Preferred core materials have a density greater than about 2.5 g/cm.sup.3. 
The selection of high density core materials is believed to facilitate 
efficient particle size reduction. 
Useful thicknesses of the polymer coating on the core are believed to range 
from about 1 to about 500 microns, although other thicknesses outside this 
range may be useful in some applications. The thickness of the polymer 
coating preferably is less than the diameter of the core. 
The cores can be coated with the polymeric resin by techniques known in the 
art. Suitable techniques include spray coating, fluidized bed coating, and 
melt coating. Adhesion promoting or tie layers can optionally be provided 
to improve the adhesion between the core material and the resin coating. 
The adhesion of the polymer coating to the core material can be enhanced 
by treating the core material to adhesion promoting procedures, such as 
roughening of the core surface, corona discharge treatment, and the like. 
Continuous Grinding 
In a preferred grinding process, the particles are made continuously rather 
than in a batch mode. The continuous method comprises the steps of 
continuously introducing the R(-) ibuprofen or fenoprofen and rigid 
grinding media into a milling chamber, contacting the ibuprofen or 
fenoprofen with the grinding media while in the chamber to reduce the 
particle size of the agent, continuously removing the ibuprofen or 
fenoprofen and the grinding media from the milling chamber, and thereafter 
separating the ibuprofen or fenoprofen from the grinding media. 
The R(-) ibuprofen or fenoprofen and the grinding media are continuously 
removed from the milling chamber. Thereafter, the grinding media is 
separated from the milled particulate ibuprofen or fenoprofen (in either a 
dry or liquid dispersion form) using conventional separation techniques, 
in a secondary process such as by simple filtration, sieving through a 
mesh filter or screen, and the like. Other separation techniques such as 
centrifugation may also be employed. 
In a preferred embodiment, the ibuprofen or fenoprofen and grinding media 
are recirculated through the milling chamber. Examples of suitable means 
to effect such recirculation include conventional pumps such as 
peristaltic pumps, diaphragm pumps, piston pumps, centrifugal pumps and 
other positive displacement pumps which do not use sufficiently close 
tolerances to damage the grinding media. Peristaltic pumps are generally 
preferred. 
Another variation of the continuous process includes the use of mixed media 
sizes. For example, larger media may be employed in a conventional manner 
where such media is restricted to the milling chamber. Smaller grinding 
media may be continuously recirculated through the system and permitted to 
pass through the agitated bed of larger grinding media. In this 
embodiment, the smaller media is preferably between about 1 and 300 mm in 
mean particle size and the larger grinding media is between about 300 and 
1000 mm in mean particle size. 
Precipitation Method 
Another method of forming the desired nanoparticle dispersion is by 
microprecipitation. This is a method of preparing stable dispersions of 
R(-) ibuprofen or fenoprofen in the presence of a surface modifying and 
colloid stability enhancing surface active agent free of trace of any 
toxic solvents or solubilized heavy metal inpurities by the following 
procedural steps: 
1. Dissolving the R(-) ibuprofen or fenoprofen in aqueous base with 
stirring, 
2. Adding above #1 formulation with stirring to a surface active surfactant 
(or surface modifiers) solution to form a clear solution, and, 
3. Neutralizing above formulation #2 with stirring with an appropriate acid 
solution. The procedure can be followed by: 
4. Removal of formed salt by dialysis or diafiltration and 
5. Concentration of dispersion by conventional means. 
This microprecipitation process produces dispersion of R(-) ibuprofen or 
fenoprofen with Z-average particle diameter less than 400 nm (as measured 
by photon correlation spectroscopy) that are stable in particle size upon 
keeping under room temperature or refrigerated conditions. Such 
dispersions also demonstrate limited particle size growth upon 
autoclave-decontamination conditions used for standard blood-pool 
pharmaceutical agents. 
Step 3 can be carried out in semicontinuous, continuous batch, or 
continuous methods at constant flow rates of the reacting components in 
computer-controlled reactors or in tubular reactors where reaction pH can 
be kept constant using pH-stat systems. Advantages of such modifications 
are that they provide cheaper manufacturing procedures for large-scale 
production of nanoparticulate dispersion systems. 
Additional surface modifier may be added to the dispersion after 
precipitation. Thereafter, the dispersion can be mixed, e.g., by shaking 
vigorously. Optionally, the dispersion can be subjected to a sonication 
step, e.g., using an ultrasonic power supply. For example, the dispersion 
can be subjected to ultrasonic energy having a frequency of 20-80 kHz for 
a time of about 1 to 120 seconds. 
In a preferred embodiment, the above procedure is followed with step 4 
which comprises removing the formed salts by diafiltration or dialysis. 
This is done in the case of dialysis by standard dialysis equipment and by 
diafiltration using standard diafiltration equipment known in the art. 
Preferably, the final step is concentration to a desired concentration of 
the agent dispersion. This is done either by diafiltration or evaporation 
using standard equipment known in this art. 
An advantage of microprecipitation is that unlike milled dispersion, the 
final product is free of heavy metal contaminants arising from the milling 
media that must be removed due to their toxicity before product is 
formulated. 
A further advantage of the microprecipitation method is that unlike solvent 
precipitation, the final product is free of any trace of trace solvents 
that may be toxic and must be removed by expensive treatments prior to 
final product formulation. 
In another preferred embodiment of the microprecipitation process, a 
crystal growth modifier is used. A crystal growth modifier is defined as a 
compound that in the co-precipitation process incorporates into the 
crystal structure of the microprecipitated crystals of the pharmaceutical 
agent, thereby hindering growth or enlargement of the microcrystalline 
precipitate, by the so called Ostwald ripening process. A crystal growth 
modifier (or a CGM) is a chemical that is at least 75% identical in 
chemical structure to the pharmaceuticl agent. By "identical" is meant 
that the structures are identical atom for atom and their connectivity. 
Structural identity is charactarized as having 75% of the chemical 
structure, on a molecular weight basis, identical to the therapeutic or 
diagnostic agent. The remaining 25% of the structure may be absent or 
replaced by different chemical structure in the CGM. The crystal growth 
modifier is dissolved in step #1 with the therapeutic or diagnostic agent. 
Particle Size 
AS used herein, particle size refers to a number average particle size as 
measured by conventional particle size measuring techniques well known to 
those skilled in the art, such as sedimentation field flow fractionation, 
photon correlation spectroscopy, or disk centrifugation. When photon 
correlation spectroscopy (PCS) is used as the method of particle sizing 
the average particle diameter is the Z-average particle diameter known to 
those skilled in the art. By "an effective average particle size of less 
than about 400 nm" it is meant that at least 90% of the particles have a 
weight average particle size of less than about 400 nm when measured by 
the above-noted techniques. In preferred embodiments, the effective 
average particle size is less than about 300 nm and more preferrably less 
than about 250 nm. In some embodiments, an effective average particle size 
of less than about 100 nm has been achieved. With reference to the 
effective average particle size, it is preferred that at least 95% and, 
more preferably, at least 99% of the particles have a particle size less 
than the effective average, e.g., 400 nm. In particularly preferred 
embodiments, essentially all of the particles have a size less than 400 
nm. In some embodiments, essentially all of the particles have a size less 
than 250 nm. 
Dosage Forms 
The resulting dispersion is stable and consists of the liquid dispersion 
medium and the described particles. The dispersion of surface modified 
R(-) ibuprofen or fenoprofen containing nanoparticles can be spray coated 
onto sugar spheres or onto a pharmaceutical excipient in a fluid-bed spray 
coater by techniques well known in the art. 
Solid Forms 
Solid dosage forms for oral administration include capsules, tablets, 
pills, powders and granules. In such solid dosage forms, the active 
compound is admixed with at least one inert customary excipient (or 
carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or 
extenders, as for example, starches, lactose, sucrose, glucose, mannitol 
and silicic acid, (b) binders, as for example, carboxymethylcellulose, 
alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) 
humectants, as for example, glycerol, (d) disintegrating agents, as for 
example, agar-agar, calcium carbonate, potato or tapioca starch, alginic 
acid, certain complex silicates and sodium carbonate, (e) solution 
retarders, as for example paraffin, (f) absorption accelerators, as for 
example, quaternary ammonium compounds, (g) wetting agents, as for 
example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for 
example, kaolin and bentonite, and (i) lubricants, as for example, talc, 
calcium stearate, magnesium stearate, solid polyethylene glycols, sodium 
lauryl sulfate or mixtures thereof. In the case of capsules, tablets and 
pills, the dosage forms may also comprise buffering agents. 
Solid compositions of a similar type may also be employed as fillers in 
soft and hard-filled gelatin capsules using such excipients as lactose or 
milk sugar as well as high molecular weight polyethyleneglycols, and the 
like. 
Solid dosage forms such as tablets, dragees, capsules, pills and granules 
can be prepared with coatings and shells, such as enteric coatings and 
others well known in the art. They may contain opacifying agents, and can 
also be of such composition that they release the active compound or 
compounds in a certain part of the intestinal tract in a delayed manner. 
Examples of embedding compositions which can be used are polymeric 
substances and waxes. 
The active compounds can also be in micro-encapsulated form, if 
appropriate, with one or more of the above-mentioned excipients. 
Liquid Forms 
Liquid dosage forms for oral administration include pharmaceutically 
acceptable emulsions, solutions, suspensions, syrups and elixirs. In 
addition to the active compounds, the liquid dosage forms may contain 
inert diluents commonly used in the art, such as water or other solvents, 
solubilizing agents and emulsifiers, as for example, ethyl alcohol, 
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl 
benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in 
particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, 
castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, 
polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these 
substances, and the like. 
Dosage Levels 
Actual dosage levels of active ingredients in the compositions may be 
varied so as to obtain an amount of active ingredient that is effective to 
obtain a desired therapeutic or diagnostic response for a particular 
composition and method of administration. The selected dosage level 
therefore depends upon the desired therapeutic or diagnostic effect, on 
the route of administration, on the desired duration of treatment and 
other factors. 
The total daily dose administered to a host in single or divided dose may 
be in amounts, for example, of from about 1 nanomol to about 5 micromoles 
per kilogram of body weight. Dosage unit compositions may contain such 
amounts of such submultiples thereof as may be used to make up the daily 
dose. It will be understood, however, that the specific dose level for any 
particular patient will depend upon a variety of factors including the 
body weight, general health, sex, diet, time and route of administration, 
rates of absorption and excretion, combination with other therapeutic 
agents and the severity of the particular disease being treated. 
Ratios 
The relative amount of R(-) ibuprofen or fenoprofen and surface modifier 
can vary widely and the optimal amount of the surface modifier can depend, 
for example, upon the particular R(-) ibuprofen or fenoprofen and surface 
modifier selected, the critical micelle concentration of the surface 
modifier if it forms micelles, the hydrophilic lipophilic balance (HLB) of 
the stabilizer, the melting point of the stabilizer, its water solubility, 
the surface tension of water solutions of the stabilizer, etc. The surface 
modifier preferably is present in an amount of about 0.1-10 mg per square 
meter surface area of the therapeutic or diagnostic agent. The surface 
modifier can be present in an amount of 0.1-90%, preferably 20-60% by 
weight based on the total weight of the dry particle. 
Additives 
Besides such inert diluents, the composition can also include adjuvants, 
such as wetting agents, emulsifying and suspending agents, sweetening, 
flavoring and perfuming agents. 
Suspensions, in addition to the active compounds, may contain suspending 
agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene 
sorbitol and sorbitan esters, microcrystalline cellulose, aluminum 
metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these 
substances, and the like. 
These compositions may also contain adjuvants such as preserving, wetting, 
emulsifying, and dispensing agents. Prevention of the action of 
microorganisms can be ensured by various antibacterial and antifungal 
agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the 
like. It may also be desirable to include isotonic agents, for example 
sugars, sodium chloride and the like. Prolonged absorption of the 
injectable pharmaceutical form can be brought about by the use of agents 
delaying absorption, for example, aluminum monostearate and gelatin. 
Method of Treating 
A method of treating or diagnosing a mammal comprises the step of 
administering to the mammal in need of treatment an effective amount of 
the above-described R(-) ibuprofen or fenoprofen composition. The selected 
dosage level of the R(-) ibuprofen or fenoprofen for treatment is 
effective to obtain a desired therapeutic response for a particular 
composition and method of administration. 
Examples 
Simulated pharmacokinetic profiles were generated using Scientist software 
available from MicroMath Scientific Software Inc., Salt Lake City Utah. 
This software includes a library of pharmacokinetic models that can be 
manipulated based on specific parameters that the operator selects. For 
the sumulations presentd here, a one compartment (biexponential) model 
with first order input and first order elimination was employed. Values of 
absorption (Ka) and elimination (Ke) rate constants as well as fraction 
abosorbed (Fd) and volume of distribution were obtained from the 
literature for ibuprofen. 
FIGS. 1 and 2 (FIG. 1 illustrating the invention and FIG. 2 illustrating 
S(+) administration) represent plasma concentration vs. time profiles 
following a single 600 mg dose. FIGS. 3 and 4 (FIG. 3 illustrating the 
invention and FIG. 4 illustrating S(+) administration) represents the 
arrival of steady state conditions following multiple 600 mg doses at 8 
hour intervals. 
The invention has been described with particular reference to preferred 
embodiments thereof, but it will be understood that variations and 
modifications can be effected within the spirit and scope of the 
invention.