United ' States Patent [19]
`Liversidge et a].
`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`5,145,684
`Sep. 8, 1992
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`US005145684A
`[11] Patent Number:
`[45] Date of Patent:
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`[54]
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`[75]
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`[73]
`[21]
`[22]
`I51]
`[52]
`[58]
`[56]
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`SURFACE MODIFIED DRUG
`NANOPARTICLES
`Inventors: Gary G. Liversidge, West Chester;
`Kenneth C. Cundy, Pottstown, both
`of Pa.; John F. Bishop, Rochester;
`David A. Czekai, Honeoye Falls,
`both of NY.
`Assignee: Sterling Drug Inc., New York, NY.
`Appl. No.: 647,105
`Filed:
`Jan. 25, 1991
`
`Int. Cl.5 .............................................. .. A61K 9/14
`U.S. Cl. .................................. .. 424/489; 424/495;
`424/499
`Field of Search ...................... .. 424/495, 489, 499
`References Cited
`U.S. PATENT DOCUMENTS
`
`2,671,750 3/1954 Macek ............................... .. 514/179
`4,107,288 8/1978 Oppenheim
`. 424/499
`4,540,602 9/1985 Motoyama
`424/495
`4,826,689 5/1989 Violanto ...... ..
`424/489
`4,851,421 7/1989 Iwasaki et a1. .................... .. 514/352
`
`FOREIGN PATENT DOCUMENTS
`
`411629 2/1991 European Pat. Off. .
`
`2282330 11/1990 Japan .
`2185397 7/1987 United Kingdom .
`2200048 7/1988 United Kingdom .
`
`OTHER PUBLICATIONS
`Lachman et al., “the Theory and Practice of Industrial
`Pharmacy”, Chapter 2, Milling (1986).
`Remington’s Pharmaceutical Sciences 17th Edition,
`Chapter 20, Schott, H., “Colloidal Dispersions”.
`Primary Examiner—-Thurman K. Page
`Assistant Examiner-William E. Benston, Jr.
`Attorney, Agent, or Firm—Arthur H. Rosenstein;
`William J. Davis '
`
`ABSTRACT
`[57]
`Dispersible particles ‘consisting essentially of a crystal
`line drug substance having a surface modi?er adsorbed
`on the surface thereof in an amount sufficient to main
`tain an effective average particle size of less than about
`400 nm, methods for the preparation of such particles
`and dispersions containing the particles. Pharmaceutical
`compositions containing the particles exhibit unex
`pected bioavailability and are useful in methods of treat
`ing mammals.
`
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`SURFACE MODIFIED DRUG NANOPARTICLES
`
`FIELD OF THE INVENTION
`This invention relates to drug particles, methods for
`the preparation thereof and dispersions containing the
`particles. This invention further relates to the use of
`such particles in pharmaceutical compositions and
`methods of treating mammals.
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`?nely divided particles ranging from 0.5 pm (500 nm)
`or less to 5 pm (5,000 nm) in diameter.
`EPO 275,796 describes the production of colloidally
`dispersible systems comprising a 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 nanoparticle. Furthermore, precipitation
`techniques for preparing particles tend to provide parti
`cles contaminated with solvents. Such solvents are
`often toxic and can be very dif?cult, if not impossible, to
`adequately remove to pharmaceutically acceptable lev
`els to be practical.
`US Pat. No. 4,107,288 describes particles in the size
`range from 10 to 1,000 nm containing a biologically or
`pharmacodynamically active material. However, the
`particles comprise a crosslinked matrix of macromole
`cules having the active material supported on or incor
`porated into the matrix.
`It would be desirable to provide stable dispersible
`drug particles in the submicron size range which can be
`readily prepared and which do not appreciably ?occu
`late or agglomerate due to interparticle attractive forces
`and do not require the presence of a crosslinked matrix.
`Moreover, it would be highly desirable to provide phar
`maceutical compositions having enhanced bioavailabil
`ity.
`
`BACKGROUND OF THE INVENTION
`Bioavailability is the degree to which a drug 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
`drug. Poor bioavailability is a signi?cant problem en
`countered in the development of pharmaceutical com
`positions, particularly those containing an active ingre
`dient that is poorly soluble in water. Poorly water solu
`ble drugs, i.e., those having a solubility less than about
`10 mg/ml, tend to be eliminated from the gastrointesti
`nal tract before being absorbed into the circulation.
`Moreover, poorly water soluble drugs tend to be unsafe
`for intravenous administration techniques, which are
`used primarily in conjunction with fully soluble drug
`substances.
`It is known that the rate of dissolution of a particulate
`drug can increase with increasing surface area, i.e.,
`decreasing particle size. Consequently, methods of mak
`ing ?nely 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 re
`duce particle size and hence in?uence drug absorption.
`However, in conventional dry milling, as discussed by
`Lachman, et al., The Theory and Practice of Industrial
`Pharmacy, Chapter 2, “Milling”, p. 45, (1986), the limit
`of ?neness is reached in the region of 100 microns
`(100,000 nm) when material cakes on the milling cham
`ber. Lachman, et al. note that wet grinding is bene?cial
`in further reducing particle size, but that ?occulation
`restricts the lower particle size limit to approximately
`10 microns (10,000 nm). However, there tends to be a
`bias in the pharmaceutical art against wet milling due to
`concerns associated with contamination. Commercial
`airjet milling techniques have provided particles rang
`ing in average particle size from as low as about 1 to 50 _
`pm (l,O00-50,000 nm).
`Other techniques for preparing pharmaceutical com
`positions include loading drugs into liposomes or poly
`mers, e.g., during emulsion polymerization. However,
`such techniques have problems and limitations. For
`example, a lipid soluble drug is often required in prepar
`ing suitable liposomes. Further, unacceptably large
`amounts of the liposome or polymer are often required
`to prepare unit drug doses. Further still, techniques for
`preparing such pharmaceutical compositions tend to be
`complex. A principal technical difficulty encountered
`with emulsion polymerization is the removal of contam
`inants, such as unreacted monomer or initiator, which
`can be toxic, at the end of the manufacturing process.
`U.S. Pat. No. 4,540,602 (Motoyama et al.) discloses a
`solid drug pulverized in an aqueous solution of a water
`soluble high molecular substance using a wet grinding
`machine. However, Motoyama et a1. teach that as a
`result of such wet grinding, the drug is formed into
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`SUMMARY OF THE INVENTION
`We have discovered stable, dispersible drug nanopar
`ticles and a method for preparing such particles by wet
`milling in the presence of grinding media in conjunction
`with a surface modi?er. The particles can be formulated
`into pharmaceutical compositions exhibiting remark
`ably high bioavailability.
`More speci?cally, in accordance with this invention,
`there are provided particles consisting essentially of a
`crystalline drug substance having a surface modi?er
`adsorbed on the surface thereof in an amount sufficient
`to maintain an effective average particle size of less than
`about 400 nm.
`This invention also provides a stable dispersion con
`sisting essentially of a liquid dispersion medium and the
`above—described particles dispersed therein.
`In another embodiment of the invention, there is
`provided a method of preparing the above-described
`particles comprising the steps of dispersing a drug sub
`stance in a liquid dispersion medium and applying me
`chanical means in the presence of grinding media to
`reduce the particle size of the drug substance 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 modi?er. Alternatively, the particles can be
`‘contacted with a surface modi?er after attrition.
`In a particularly valuable and important embodiment
`of the invention, there is provided a pharmaceutical '
`composition comprising the above~described particles
`and a pharmaceutically acceptable carrier therefor.
`Such pharmaceutical composition is useful in a method
`of treating mammals.
`'
`It is an advantageous feature that a wide variety of
`surface modi?ed drug nanoparticles free of unaccept
`able contamination can be prepared in accordance with
`this invention.
`It is another advantageous feature of this invention
`that there is provided a simple and convenient method
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`parasympathomimetics, parathyroid calcitonin and bi
`for preparing drug nanoparticles by wet milling in con
`phosphonates, prostaglandins, radio-pharmaceuticals,
`junction with a surface modi?er.
`Another particularly advantageous feature of this
`sex hormones (including steroids), anti-allergic agents,
`stimulants and anoretics, sympathomimetics, thyroid
`invention is that pharmaceutical compositions are pro
`vided exhibiting unexpectedly high bioavailability.
`agents, vasodilators and xanthines. Preferred drug sub
`Still another advantageous feature of this invention is
`stances include those intended for oral administration
`that pharmaceutical compositions containing poorly
`and intravenous administration. A description of these
`classes of drugs and a listing of species within each class
`water soluble drug substances are provided which are
`suitable for intravenous administration techniques.
`can be found in Martindale, The Extra Pharmacopoeia,
`Other advantageous features will become readily
`Twenty-ninth Edition, The Pharmaceutical Press, Lon
`don, 1989, the disclosure of which is hereby incorpo
`apparent upon reference to the following Description of
`rated by reference in its entirety. The drug substances
`Preferred Embodiments.
`are commercially available and/or can be prepared by
`techniques known in the art.
`Representative illustrative species of drug substances
`useful in the practice of this invention include:
`l7-a-pregno-2,4-dien-20-yno-[2,3-d]-isoxazol-17-01
`(Danazol);
`5a,l7a,-l'-(methylsulfonyl)-l'H-pregn-20-yno[3,2-c]
`pyrazol-l7-ol (Steroid A);
`piposulfam;
`-
`piposulfan;
`camptothecin; and
`ethyl-3,5-diacetoamido-2,4,6-triiodobenzoate
`In particularly preferred embodiments of the inven
`tion, the drug substance is a steriod such as danazol or
`Steroid A or an antiviral agent.
`The particles of this invention contain a discrete
`phase of a drug substance as described above having a
`surface modi?er adsorbed on the surface thereof. Useful
`surface modi?ers are believed to include those which
`physically adhere to the surface of therdrug substance
`but do not chemically bond to the drug.
`Suitable surface modi?ers can preferably be selected
`from known organic and inorganic pharmaceutical ex
`cipients. Such excipients include various polymers, low
`molecular weight oligomers, natural products and sur
`factants. Preferred surface modi?ers include nonionic
`and anionic surfactants. Representative examples of
`excipients include gelatin, casein, lecithin (phospha
`tides), gum acacia, cholesterol, tragacanth, stearic acid,
`benzalkonium chloride, calcium stearate, glyceryl mon
`ostearate, cetostearl alcohol, cetomacrogol emulsifying
`wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g.,
`macrogol ethers such as cetomacrogol 1000, polyoxy
`ethylene castor oil derivatives, polyoxyethylene sorbi
`tan fatty acid esters, e.g., the commercially available
`Tweens, polyethylene glycols, polyoxyethylene stea
`rates, colloidol silicon dioxide, phosphates, sodium
`dodecylsulfate, carboxymethylcellulose calcium, car
`boxymethylcellulose sodium, methylcellulose, hydrox
`yethylcellulose,
`hydroxypropylcellulose, hydroxy
`propylmethycellulose phthalate, noncrystalline cellu
`lose, magnesium aluminum silicate, triethanolamine,
`polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
`Most of these excipients 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, the disclosure of which is
`hereby incorporated by reference in its entirety. The
`surface modi?ers are commercially available and/or
`can be prepared by techniques known in the art.
`Particularly preferred surface modi?ers include poly
`vinyl pyrrolidone, Pluronic F68 and F108, which are
`block copolymers of ethylene oxide and propylene ox
`ide, Tetronic 908, which is a tetrafunctional block co
`polymer derived from sequential addition of ethylene
`
`DESCRIPTION OF PREFERRED
`EMBODIMENTS
`This invention is based partly on the discovery that
`drug particles having an extremely small effective aver
`age particle size can be prepared by wet milling in the
`presence of grinding media in conjunction with a sur
`face modi?er, and that such particles are stable and do
`not appreciably flocculate or agglomerate due to inter
`particle attractive forces and can be formulated into
`pharmaceutical compositions exhibiting unexpectedly
`high bioavailability. While the invention is described
`herein primarily in connection with its preferred utility,
`i.e., with respect to nanoparticulate drug substances for
`use in pharmaceutical compositions, it is also believed to
`be useful in other applications such as the formulation of
`particulate cosmetic compositions and the preparation
`of particulate dispersions for use in image and magnetic
`recording elements.
`The particles of this invention comprise a drug sub
`stance. _The drug substance exists as a discrete, crystal
`line phase. The crystalline phase differs from a non
`crystalline or amorphous phase which results from pre
`cipitation techniques, such as described in EPO 275,796
`cited above.
`The invention can be practiced with a wide variety of
`drug substances. The drug substance preferably is pres
`ent in an essentially pure form. The drug substance must
`be poorly soluble and dispersible in at least one liquid
`medium. By “poorly soluble” it is meant that the drug
`substance has a solubility in the liquid dispersion me
`dium of less than about 10 mg/ml, and preferably of less
`than about 1 mg/ml. A preferred liquid dispersion me
`dium is water. However, the invention can be practiced
`with other liquid media in which a drug substance is
`poorly soluble and dispersible including, for example,
`aqueous salt solutions, safflower oil and solvents such as
`ethanol, t-butanol, hexane and glycol. The pH of the
`aqueous dispersion media can be adjusted by techniques
`known in the art.
`Suitable drug substances can be selected from a vari
`ety of known classes of drugs including, for example,
`analgesics, anti-in?ammatory agents, anthelmintics,
`anti-arrhythmic agents, antibiotics (including penicil
`lins),
`anticoagulants, antidepressants,
`antidiabetic
`agents, antiepileptics, antihistamines, antihypertensive
`agents, antimuscarinic agents, antimycobacterial agents,
`antineoplastic agents, immunosuppressants, antithyroid
`agents, antiviral agents, anxiolytic sedatives (hypnotics
`and neuroleptics), astringents, beta-adrenoceptor block
`ing agents, blood products and substitutes, cardiac ino
`tropic agents, contrast media, corticosteroids, cough
`suppressants (expectorants and mucolytics), diagnostic
`agents, diagnostic imaging agents, diuretics, dopaminer
`gics (antiparkinsonian agents), haemostatics, immurio
`logical agents, lipid regulating agents, muscle relaxants,
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`oxide and propylene oxide to ethylenediamine, dextran,
`vary from about 0.1 to about 90%, and preferably is
`lecithin, Aerosol 0T, which is a dioctyl ester of sodium
`l-75%, more preferably 20-60%, by weight based on
`sulfosuccinic acid, available from American Cyanamid,
`the total combined weight of the drug substance and
`Duponol P, which is a sodium lauryl sulfate, available
`surface modi?er. The apparent viscosity of the premix
`from DuPont, Triton X-200, which is an alkyl aryl
`suspension is preferably less than about 1000 centipoise
`polyether sulfonate, available from Rohm and Haas,
`The premix can be used directly by subjecting it to
`Tween 80, which is a polyoxyethylene sorbitan fatty
`mechanical means to reduce the average particle size in
`acid ester, available from ICI Specialty Chemicals, and
`the dispersion to less than 400 nm. It is preferred that
`Carbowax 3350 and 934, which are polyethylene gly
`the premix be used directly when a ball mill is used for
`attrition. Alternatively, the drug substance and, option
`cols available from Union Carbide. Surface modi?ers
`which have found to be particularly useful include poly
`ally, the surface modi?er, can be dispersed in the liquid
`vinylpyrrolidone, Pluronic F-68, and lecithin.
`medium using suitable agitation, e.g., a roller mill or a
`The surface modi?er is adsorbed on the surface of the
`Cowles type mixer, until a homogeneous dispersion is
`drug substance in an amount suf?cient to maintain an
`observed in which there are no large agglomerates
`effective average particle size of less than about 400 nm.
`visible to the naked eye. It is preferred that the premix
`The surface modi?er does not chemically react with the
`be subjected to such a premilling dispersion step when a
`drug substance or itself. Furthermore, the individually
`recirculating media mill is used for attrition.
`adsorbed molecules of the surface modi?er are essen
`The mechanical means applied to reduce the particle
`tially free of intermolecular crosslinkages.
`size of the drug substance conveniently can take the
`As used herein, particle size refers to a number aver
`form of a dispersion mill. Suitable dispersion mills in
`age particle size as measured by conventional particle
`clude a ball mill, an attritor mill, a vibratory mill, and
`size measuring techniques well known to those skilled
`media mills such as a sand mill and a bead mill. A media
`mill is preferred due to the relatively shorter milling
`in the art, such as sedimentation ?eld ?ow fractionation,
`photon correlation spectroscopy, or disk centrifugation.
`time required to provide the intended result, i.e., the
`By “an effective average particle size of less than about
`desired reduction in particle size. For media milling, the
`apparent viscosity of the premix preferably is from
`400 nm” it is meant that at least 90% of the particles
`have a weight average particle size of less than about
`about 100 to about 1000 centipoise. For ball milling, the
`400 nm when measured by the above-noted techniques.
`apparent viscosity of the premix preferably is from
`In preferred embodiments of the invention, the effective
`about 1 up to about 100 centipoise. Such ranges tend to
`average particle size is less than about 250 nm. In some
`afford an optimal balance between efficient particle
`fragmentation and media erosion.
`embodiments of the invention, an effective average
`particle size of less than about 100 nm has been
`The grinding media for the particle size reduction
`achieved. With reference to the effective average parti
`step can be selected from rigid media preferably spheri
`cle size, it is preferred that at least 95% and, more pref
`cal or particulate in form having an average size less
`erably, at least 99% of the particles have a particle size
`than about 3 mm and, more preferably, less than about
`less than the effective average, e. g., 400 nm. In particu
`1 mm. Such media desirably can provide the particles of
`larly preferred embodiments, essentially all of the parti
`the invention with shorter processing times and impart
`less wear to the milling equipment. The selection of
`cles have a size less than 400 nm. In some embodiments,
`essentially all of the particles have a size less than 250
`material for the grinding media is not believed to be
`critical. We have found that zirconium oxide, such as
`40
`nm.
`The particles of this invention can be prepared in a
`95% ZrO stabilized with magnesia, zirconium silicate,
`method comprising the steps of dispersing a drug sub
`and glass grinding media provide particles having levels
`stance in a liquid dispersion medium and applying me
`of contamination which are believed to be acceptable
`for the preparation of pharmaceutical compositions.
`chanical means in the presence of grinding media to
`reduce the particle size of the drug substance to an
`However, other media, such as stainless steel, titania,
`effective average particle size of less than about 400 nm.
`alumina, and 95% ZrO stabilized with yttrium, are ex
`The particles can be reduced in size in the presence of a
`pected to be useful. Preferred media have a density
`surface modi?er. Alternatively, the particles can be
`greater than about 3 g/cm3.
`contacted with a surface modi?er after attrition.
`The attrition time can vary widely and depends pri- ‘
`A general procedure for preparing the particles of
`marily upon the particular mechanical means and pro
`50
`this invention is set forth below. The drug substance
`cessing conditions selected. For ball mills, processing
`selected is obtained commercially and/or prepared by
`times of up to ?ve days or longer may be required. On
`techniques known in the art in a conventional coarse
`the other hand, processing times of less than 1 day (resi
`form. It is preferred, but not essential, that the particle
`dence times of one minute up to several hours) have
`size of the coarse drug substance selected be less than
`provided the desired results using a high shear media
`about 100 pm as determined by sieve analysis. If the
`mill.
`coarse particle size of the drug substance is greater than
`The particles must be reduced in size at a temperature
`about 100 pm, then it is preferred that the particles of
`, which does not signi?cantly degrade the drug sub- '
`the drug substance be reduced in size to less than 100
`stance. Processing temperatures of less than about
`pm using a conventional milling method such as airjet
`30°—40° C. are ordinarily preferred. If desired, the pro
`or fragmentation milling.
`cessing equipment can be cooled with conventional
`cooling equipment. The method is conveniently carried
`The coarse drug substance selected can then be added
`to a liquid medium in which it is essentially insoluble to
`out under conditions of ambient temperature and at
`form a premix. The concentration of the drug substance
`processing pressures which are safe and effective for the
`milling process. For example, ambient processing pres
`in the liquid medium can vary from about 0.1-60%, and
`preferably is from 5—30% (w/w). It is preferred, but not
`sures are typical of ball mills, attritor mills and vibratory
`essential, that the surface modi?er be present in the
`mills. Processing pressures up to about 20 psi (1.4
`kg/cm2) are typical of media milling.
`premix. The concentration of the surface modi?er can
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`The surface modi?er, 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. Thereaf
`ter, the dispersion can be mixed, e. g., by shaking vigor
`ously. 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 ultra
`sonic energy having a frequency of 20-80 kHz for a
`time of about 1 to 120 seconds.
`The relative amount of drug substance and surface
`modi?er can vary widely and the optimal amount of the
`surface modi?er can depend, for example, upon the
`particular drug substance and surface modi?er selected,
`the critical micelle concentration of the surface modi
`?er if it forms micelles, etc. The surface modi?er prefer
`ably is present in an amount of about 0.l—l0 mg per
`square meter surface area of the drug substance. The
`surface modi?er can be present in an amount of
`01-90%, preferably 20-60% by weight based on the
`total weight of the dry particle.
`As indicated by the following examples, not every
`combination of surface modi?er and drug substance
`provides the desired results. Consequently, the appli
`cants have developed a simple screening process
`whereby compatible surface modi?ers and drug sub
`stances can be selected which provide stable dispersions
`of the desired particles. First, coarse particles of a se
`lected drug substance of interest are dispersed in a liquid
`in which the drug is essentially insoluble, e.g., water at
`5% (w/w) and milled for 60 minutes in a DYNO-MILL
`30
`under the standard milling conditions which are set
`forth in Example 1 which follows. The milled material
`is then divided into aliquots and surface modi?ers are
`added at concentrations of 2, l0 and 50% by weight
`based on the total combined weight of the drug sub
`stance and surface modi?er. The dispersions are then
`sonicated (1 minute, 20 kHz) to disperse agglomerates
`and subjected to particle size analysis by examination
`under an optical microscope (1000 >< magni?cation). If a
`stable dispersion is observed, then the process for pre
`paring the particular drug substance surface modi?er
`combination can be optimized in accordance with the
`teachings above. By stable it is meant that the dispersion
`exhibits no flocculation or particle agglomeration visi
`ble to the naked eye at least 15 minutes, and preferably,
`at least two days or longer after preparation.
`The resulting dispersion of this invention is stable and
`consists of the liquid dispersion medium and the above
`described particles. The dispersion of surface modi?ed
`drug nanoparticles can be spray coated onto sugar
`spheres or onto a pharmaceutical excipient in a ?uid
`bed spray coater by techniques well known in the art.
`Pharmaceutical compositions according to this inven
`tion include the particles described above and a pharma
`ceutically acceptable carrier therefor. Suitable pharma
`ceutically acceptable carriers are well known to those
`skilled in the art. These include non-toxic physiologi
`cally acceptable carriers, adjuvants or vehicles for par
`enteral injection, for oral administration in solid or liq
`uid form, for rectal administration, and the like. A
`method of treating a mammal in accordance with this
`invention comprises the step of administering to the
`mammal in need of treatment an effective amount of the
`above-described pharmaceutical composition. The se
`lected dosage level of the drug substance for treatment
`is effective to obtain a desired therapeutic response for
`a particular composition and method of administration.
`The selected dosage level therefore, depends upon the
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`particular drug substance, the desired therapeutic ef
`feet, on the route of administration, on the desired dura
`tion of treatment and other factors. As noted, it is a
`particularly advantageous feature that the pharmaceuti
`cal compositions of this invention exhibit unexpectedly
`high bioavailability as illustrated in the examples which
`follow. Furthermore, it is contemplated that the drug
`particles of this invention provide more rapid onset of
`drug action and decreased gastrointestinal irritancy.
`It is contemplated that the pharmaceutical composi
`tions of this invention will be particularly useful in oral
`and parenteral, including intravenous, administration
`applications. It is expected that poorly water soluble
`drug substances, which prior to this invention, could
`not have been administered intravenously, may be ad
`ministered safely in accordance with this invention.
`Additionally, drug substances which could not have
`been administered orally due to poor bioavailability
`may be effectively administered in accordance with this
`invention.
`While applicants do not wish to be bound by theoreti
`cal mechanisms, it is believed that the surface modi?er
`hinders the ?occulation and/or agglomeration of the
`particles by functioning as a mechanical or steric barrier
`between the particles, minimizing the close, interparti
`cle approach necessary for agglomeration and ?occula
`tion. Alternatively, if the surface modi?er has ionic
`groups, stabilization by electrostatic repulsion may re
`sult. It was surprising that stable drug particles of such
`a small effective average particle size and free of unac
`ceptable contamination could be prepared by the
`method of this invention.
`The following examples further illustrate the inven
`tion.
`
`20
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`25
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`35
`
`EXAMPLE 1
`PVP Modi?ed Danazol Particles Prepared in a Ball
`Mill
`A nanoparticulate dispersion of Danazol was pre
`pared using a DYNO-MILL (Model KDL, manufac
`tured by Willy A. Bachoffen AG Maschinenfabrik).
`The following ingredients were added to a glass vessel
`and agitated on a roller for 24 hours to dissolve the
`polyvinylpyrrolidone‘ surface modi?er.
`Polyvinylpyrrolidone K-15 (made by GAF)--98 g _
`High purity water-664 g
`Subsequently, 327 grams of dry powdered Danazol
`was added to the above solution and rolled for one
`week. This step aided in evenly dispersing the Danazol
`in the surface modi?er solution, thereby reducing the
`treatment time required in the media mill. The Danazol
`was purchased in a micronized form (average particle
`size of about 10 microns) from Sterling Drug Inc. The
`particles had been prepared by a conventional airjet
`milling technique. This premix was added to a holding
`vessel and agitated with a conventional propeller mixer
`at low'speed to maintain a homogeneous mixturefor the ‘
`media milling event. The media mill was prepared ac
`cordingly for the media milling process. The mill grind
`ing chamber was partially ?lled with silica glass spheres
`and the premix was continuously recirculated through
`the media mill operating at the following conditions:
`Grinding vessel: water jacketed stainless steel cham
`ber
`Premix flow rate: 250 ml per minute
`Available volume of grinding vessel: 555 ml
`Media volume: 472 ml of glass beads
`
`Actavis - IPR2017-01100, Ex. 1028, p. 5 of 10
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`5,145,684
`9
`10
`Media type: size range of 05-075 mm silica glass
`The relative bioavailability of Danazol from the nano
`beads, unleaded (distributed by Glen Mills, Inc.)
`particulate dispersion was 15.9 fold higher than from
`Recirculation time: 240 min
`the Danazol suspension containing Danazol particles
`Residence time: 60 min
`having an average particle size of about 10 microns
`Impeller speed: 3000 RPM, tangential speed 1952
`prepared by conventional airjet milling. Comparison of
`ft/min (595 m/min)
`oral plasma levels with dose corrected plasma levels
`Grinding vessel coolant: water
`following intravenous administration of Danazol gave a
`Coolant temperature: 50° F. (10° C.)
`mean absolute bioavailability (iSEM) of 82.3i-10.l%
`After recirculating the slurry for 240 minutes, a sam
`for the nanoparticulate dispersion and 5.1i 1.9% for the
`ple of the dispersion was removed and evaluated for
`unmilled material.
`particle size distribution using a sedimentation ?eld
`?ow fractionator (made by DuPont). The particles
`were determined to have a number average diameter of
`77.5 nm and a weight average diameter of 139.6 nm.
`The particle size of the dispersion ranged in size from
`3-320 nm.
`
`5
`
`15
`
`EXAMPLE 3
`PVP Modi?ed Danazol Particles Prepared in a Ball
`Mill at High Solids
`A nanoparticle dispersion of Danazol was prepared
`using 1 mm diameter glass grinding media (0.85-1.18
`mm from Potters Industries). A cylindrical glass vessel
`having a diameter of 2.75 inches (7.0 cm) with a volume
`of 400 ml was charged with 212 ml of unleaded glass
`grinding media. The following ingredients were added
`to this vessel:
`30.4 g of micronized Danazol
`9.12 g of Polyvinylpyrrolidone K-lS
`112.48 g of high purity water
`This vessel was rotated horizontally on its axis at a
`controlled rotational speed of 80.4 revolutions per min
`ute (50% of critical speed) for 5 days. The slurry was
`immediately separated from the grinding media and
`evaluated for particle size and grinding media attrition
`using inductively coupled plasma emissions (ICP). The
`particle size measured with a sedimentation ?eld ?ow
`fractionator yielded a number average diameter of 112.7
`nm and a weight average diameter of 179.3 n