`Lupin v. iCeutica
`US Patent No. 8,999,387
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`Methods For The Preparation Of Biologically Active Compounds
`
`In
`
`-1-
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`Nanoparticulate Form
`
`Field of the Invention
`
`The present invention relates to methods for the preparation of biologically active
`
`compounds in nanoparticulate form. The invention also relates to biologically
`
`active compounds in nanoparticulate form produced by said methods,
`
`to
`
`compositions comprising such compounds, to medicaments produced using said
`biologically active compounds in nanoparticulate form and/or compositions, and to
`
`methods of treatment of an animal,
`
`including man, using a therapeutically
`
`effective amount of said biologically active compounds administered by way of
`
`said medicaments.
`
`Background
`
`Poor bioavailability is a significant problem encountered in the development of
`
`therapeutic compositions, particularly those compounds containing a biologically
`
`active compound that is poorly soluble in water at physiological pH. An active
`
`compound’s bioavailability is the degree to which the active compound becomes
`
`available to the target tissue in the body after systemic administration through, for
`
`example, oral or intravenous means. Many factors affect bioavailability, including
`
`the form of dosage and the solubility and dissolution rate of the active compound.
`
`Poorly and slowly water-soluble compounds tend to be eliminated from the
`
`. gastrointestinal tract before being absorbed into the circulation.
`
`In addition, poorly
`
`soluble active agents tend to be disfavored or even unsafe for intravenous
`
`administration~'due to the risk of particles of agent blocking blood flow through
`
`capillaries.
`
`It is known that the rate of dissolution of a particulate drug will increase with
`
`increasing surface area. One way of increasing surface area is decreasing
`
`particle size. Consequently, methods of making finely divided or sized drugs have
`been studied with a view to controlling the size and size range of drug particles for
`
`pharmaceutical compositions.
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`For example, dry milling techniques have been used to reduce particle size and
`
`hence influence drug absorption. However, in conventional dry milling the limit of
`
`fineness is reached generally in the region of about 100 microns (100,000 nm), at
`
`which point material cakes on the milling chamber and prevents any further
`
`diminution of particle size. Alternatively, wet grinding may be employed to reduce
`
`particle size, but flocculation restricts the lower particle size limit to approximately
`
`10 microns (10,000 nm).
`
`The wet milling process, however,
`
`is prone to
`
`contamination, thereby leading to a bias in the pharmaceutical art against wet
`
`milling. Another alternative milling technique, commercial airjet milling, has
`
`provided particles ranging in average size from as low as about 1 to about 50
`
`microns (1 ,000—50,000 nm).
`
`There are several approaches currently used to formulate poorly soluble active
`
`agents. One approach is to prepare the active agent as a soluble salt. Where
`
`this approach cannot be employed, alternate (usually physical) approaches are
`
`employed to improve the solubility of the active agent. Alternate approaches
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`generally subject the active agent to physical conditions that change the agent’s
`
`physical and or chemical properties to improve its solubility. These include
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`process technologies
`
`such as micro-ionisation, modification of crystal or
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`polymorphic structure, development of oil based solutions, use of co-solvents,
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`surface stabilizers or complexing agents, micro-emulsions, super critical fluid and
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`production of solid dispersions or solutions. More than one of these processes
`
`may be used in combination to improve formulation of a particular therapeutic
`
`compound.
`
`These techniques for preparing such pharmaceutical compositions tend to be
`
`complex. By way of example, a principal
`
`technical difficulty encountered with
`
`emulsion polymerization is the removal of contaminants, such as unreacted
`
`monomers or initiators (which may have undesirable levels of toxicity), at the end
`
`of the manufacturing process.
`
`Another method of providing reduced particle size
`
`is
`
`the formation of
`
`pharmaceutical drug microcapsules, which techniques
`
`include micronizing,
`
`polymerisation and co-dispersion. However,
`
`these techniques suffer from a
`
`number of disadvantages including at least the inability to produce sufficiently
`
`small particles such as those obtained by milling, and the presence of co-solvents
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`and/or contaminants such as toxic monomers which are difficult
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`to remove,
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`leading to expensive manufacturing processes.
`
`Over the last decade,
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`intense scientific investigation has been carried out to
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`improving the solubility of active agents by converting the agents to ultra fine
`
`powders by methods such as milling and grinding. These techniques may be
`
`used to increase the dissolution rate of a particulate solid by increasing the overall
`
`surface area and decreasing the average particle size.
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`US Patent 6,634,576 discloses examples of wet-milling a solid substrate, such as
`
`a phannaceutically active compound, to produce a “synergetic co-mixture”.
`
`'
`
`l nternational
`
`Patent
`
`Application
`
`PCT/AU2005/001977
`
`(Nanoparticle
`
`Composition(s) and Method for Synthesis Thereof) describes, inter alia, a method
`
`comprising the step of contacting a precursor compound with a co-reactant under
`
`mechanochemical synthesis conditions wherein a solid-state chemical reaction
`
`between the precursor compound and the co—reactant produces therapeutically
`
`active nanoparticles dispersed in a carrier matrix. Mechanochemical synthesis,
`
`as discussed in International Patent Application PCT/AU2005/001977, refers to
`
`the use of mechanical energy to activate, initiate or promote a chemical reaction,
`
`a crystal structure transformation or a phase change in a material or a mixture of
`
`materials, for example by agitating a reaction mixture in the presence of a milling
`
`media to transfer mechanical energy to the reaction mixture, and includes without
`
`limitation
`
`"mechanochemical
`
`activation",
`
`"mechanochemical
`
`processing",
`
`"reactive milling", and related processes.
`
`The present invention provides methods for the preparation of biologically active
`
`compounds in nanoparticulate form, which ameliorate some of the problems
`
`attendant with prior technologies, or provides an alternative thereto.
`
`As an example of
`
`the need for such novel compounds and methods for
`
`synthesizing them, consider osteoporosis. Osteoporosis describes a group of
`
`diseases which arises from diverse etiologies, but which are characterized by the
`
`net loss of bone mass per unit volume. The consequence of this loss of bone
`
`mass and resulting bone fracture is the failure of the skeleton to provide adequate
`support for the body. One of
`the most common types of osteoporosis is
`
`associated with menopause. Most women lose from about 20% to about 60% of
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`the bone mass in the trabecular compartment of the bone within 3 to 6 years after
`
`the cessation of menses. This rapid loss is generally associated with an increase
`
`of bone resorption and formation. However,
`
`the resorptive cycle is more
`
`dominant and the result is a net loss of bone mass. Osteoporosis is a common
`
`and serious disease among postmenopausal women.
`
`The most generally accepted method for the treatment of postmenopausal
`
`osteoporosis is estrogen replacement therapy. Although therapy is generally
`
`successful, patient compliance with the therapy is low, primarily because estrogen
`
`treatment frequently produces undesirable side effects. An additional method of
`
`treatment would be the administration of a bisphosphonate compound, such as,
`
`for example, Fosamaxm (Merck & Co., lnc.).
`
`Throughout premenopausal
`
`time, most women have
`
`less
`
`incidence
`
`of
`
`cardiovascular disease than men of the same age.
`
`Following menopause,
`
`however, the rate of cardiovascular disease in women slowly increases to match
`
`the rate seen in men. This loss of protection has been linked to the loss of
`
`estrogen and, in particular, to the loss of estrogen's ability to regulate the levels of
`
`serum lipids. The nature of estrogen's ability to regulate serum lipids is not well
`
`understood, but evidence to date indicates that estrogen can up regulate the low
`
`density lipid
`
`(LDL)
`
`receptors
`
`in the liver
`
`to remove excess cholesterol.
`
`Additionally, estrogen appears to have some effect on the biosynthesis of
`
`cholesterol, and other beneficial effects on cardiovascular health.
`
`It has been reported in the literature that serum lipid levels in postmenopausal
`
`women having estrogen replacement therapy return to concentrations found in the
`
`premenopausal state. Thus, estrogen would appear to be a reasonable treatment
`
`for this condition. However, the side effects of estrogen replacement therapy are
`
`not acceptable to many women, thus limiting the use of this therapy. An ideal
`
`therapy for this condition would be an agent which regulates serum lipid levels in
`
`a manner analogous to estrogen, but which is devoid of the side effects and risks
`
`associated with estrogen therapy.
`
`A number of structurally unrelated compounds are capable of interacting with the
`
`estrogen receptor and producing unique in vivo profiles. Compounds with in‘vivo
`
`profiles typical of a "pure" antagonist (for example, ICI 164,384) or of a relatively
`"pure" agonist (for example, 17[3—estradio|) represent opposite ends of a spectrum
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`in this classification. Between these t\No extremes lie the SERMs ("selective
`
`estrogen receptor modu|ator"), characterized by clinical and/or preclinical
`
`selectivity as full or partial agonists in certain desired tissues (for example, bone),
`
`and antagonists or minimal agonists in reproductive tissues. Within this
`
`pharmacologic class,
`
`individual SERMs may be further differentiated based on
`
`profiles of activity in reproductive tissues.
`
`Raloxifene, a second generation SERM, displays potentially useful selectivity in
`
`uterine tissue with apparent advantages over triphenylethylene-based estrogen
`
`receptor ligands. As such, raloxifene appears to be well—suited at least for the
`
`treatment
`
`of postmenopausal
`
`complications,
`
`including
`
`osteoporosis
`
`and
`
`cardiovascular disease.
`
`It is anticipated that, as further advances are made in the
`
`pharmacology and molecular biology of estrogen receptor active agents, further
`
`subclassifications of SERMS may evolve in the future along with an increased
`
`understanding of the therapeutic utility of these novel classes of estrogenic
`
`compounds.
`
`The
`
`advancement
`
`of
`
`raloxifene has been
`
`hampered
`
`by
`
`its
`
`physical
`
`characteristics,
`
`particularly
`
`low solubility, which
`
`affects
`
`bioavailability.
`
`Accordingly, any improvement in the physical characteristics of raloxifene would
`
`potentially offer more beneficial therapies.
`
`In particular, it would be a significant
`
`contribution to the art
`
`to provide forms of raloxifene which have increased
`
`solubility, methods of preparation of such forms, pharmaceutical formulations
`
`comprising such forms, and methods of use of such formulations.
`
`Although the background to the present invention is discussed in the context of
`improving the bioavailability of compounds that are poorly‘or slowly water soluble,
`
`the applications of the methods of the present invention are not limited to such, as
`
`is evident from the following description of the invention.
`
`Further, although the background to the present invention is largely discussed in
`
`the context of improving the bioavailability of therapeutic or pharmaceutical
`
`compounds, the applications of the methods of the present invention are clearly
`
`not limited to such. For example, as is evident from the following description,
`
`applications of the methods of the present invention include but are not limited to:
`
`veterinary therapeutic applications and agricultural chemical applications, such as
`
`pesticide and herbicide applications.
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`Summary of the invention
`
`The present invention is directed to the unexpected discovery that biologically
`
`active compounds in nanoparticulate form can be produced by dry milling solid
`
`biologically active compound together with a millable grinding compound, such
`
`that the resulting nanoparticulate biologically active compound dispersed in milled
`
`grinding compound resists reagglomeration.
`
`Thus, in one aspect, the present invention comprises a method for producing a
`
`biologically active compound in nanoparticulate form, the method comprising the
`
`step of:
`
`dry milling a mixture of a solid biologically active compound and a millable
`
`grinding Compound,
`
`in a mill comprising a plurality of milling bodies,
`
`to
`
`produce a solid dispersion or solution comprising nanoparticulate biologically
`
`active compound dispersed in at least partially milled grinding compound.
`
`The term millable means that
`
`the grinding compound is capable of being
`
`physically degraded under the dry milling conditions of the method of the
`
`invention.
`
`in one embodiment of the invention, the milled grinding compound is of
`
`a comparable particle size to the nanoparticulate biologically active compound.
`
`Without wishing to be bound by theory, it is believed that the physical degradation
`
`of the millable grinding compound affords the advantage of the invention by acting
`
`as a more effective diluent than grinding compounds of a larger particle size.
`
`in a highly preferred form, the grinding compound is harder than the biologically
`
`active compound, and is thus capable of physically degrading such under the dry
`
`milling conditions of the invention. Again without wishing to be bound by theory,
`
`under these circumstances it
`
`is believed that the millable grinding compound
`
`affords the advantage of the present invention through a second route, with the
`
`smaller particles of grinding compound produced under the dry milling conditions
`
`enabling the production of smaller particles of biologically active compound.
`
`The solid dispersion or solution may then be separated from the milling bodies
`
`and removed from the mill.
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`In a preferred aspect, the grinding compound is separated from the dispersion or
`
`solution.
`
`In one aspect, where the grinding compound is not fully milled, the
`
`unmilled grinding compound is separated from the nanoparticulate biologically
`
`active compound.
`
`In a further aspect, at least a portion of the milled grinding
`
`compound is separated from the nanoparticulate biologically active compound.
`
`The milling bodies are essentially resistant to fracture and erosion in the dry
`
`milling process.
`
`The quantity of the grinding compound relative to the quantity of biologically active
`
`compound in nanoparticulate form, and the extent of physical degradation of the
`
`grinding compound,
`
`is sufficient
`
`to inhibit reagglomeration of the biologically
`
`active compound in nanoparticulate form.
`
`The grinding compound is not
`
`chemically reactive with the pharmaceutical compound under
`
`the milling
`
`conditions of the invention.
`
`In additional aspects,
`
`the present invention also relates to biologically active
`
`compounds in nanoparticulate form produced by said methods, to compositions
`
`comprising said compounds,
`
`to medicaments produced using said biologically
`
`active compounds in nanoparticulate form and/or said compositions, and to
`
`methods of treatment of an animal,
`
`including man, using a therapeutically
`
`effective amount of said biologically active compounds administered by way of
`
`said medicaments.
`
`Medicaments of
`
`the invention may comprise only the biologically active
`
`compounds in nanoparticulate form or, more preferably, the biologically active
`
`compounds in nanoparticulate form may be combined with one or more
`
`pharmaceutically acceptable carriers, as well as any desired excipients or other
`
`like agents commonly used in the preparation of medicaments.
`
`While the method of the present
`
`invention has particular application in the
`
`preparation
`
`of
`
`poorly water-soluble
`
`biologically
`
`active
`
`compounds
`
`in
`
`nanoparticulate form,
`
`the scope of the invention is not
`
`limited thereto.
`
`For
`
`example, the method of the present invention enables production of highly water-
`
`soluble biologically active compounds in nanoparticulate form. Such compounds
`
`may exhibit advantages over conventional compounds by way of, for example,
`
`more rapid therapeutic action or lower dose.
`
`In contrast, wet grinding techniques
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`utilizing water (or other comparably polar solvents) are incapable of being applied
`
`to such compounds, as the particles dissolve appreciably in the solvent.
`
`As will be described subsequently, selection of an appropriate grinding compound
`
`affords particular highly advantageous applications of the method of the present
`
`invention. Some grinding compounds appropriate for use in the invention are
`
`readily separable from the biologically active compound in nanoparticulate form
`
`by methods not dependent on particle size (such methods being inappropriate
`
`due to the degradation of the grinding compound). For example, selecting an
`
`appropriate grinding compound that also possesses solubility properties different
`
`from the biologically active compound in nanoparticulate form allows separation of
`
`the two by relatively straightfon/vard selective dissolution techniques. Examples of
`
`such grinding compounds are provided in the detailed description of the invention.
`
`Thus, a particularly advantageous application of the method of the invention is the
`
`use of a water-soluble salt as a grinding compound in conjunction with a poorly
`
`water-soluble biologically active compound.
`
`Again, as will be described subsequently, a highly advantageous aspect of the
`
`present invention is that certain grinding compounds appropriate for use in the
`
`method of the invention are also appropriate for use in a medicament. The
`
`present invention encompasses methods for the production of a medicament
`
`incorporating both the biologically active compound in nanoparticulate form and at
`
`least a portion of the grinding compound, medicaments so produced, and
`
`methods of treatment of an animal,
`
`including man, using a therapeutically
`
`effective amount of said biologically active compounds by way of said
`
`medicaments.
`
`Analogously, as will be described subsequently, a highly advantageous aspect of
`
`the present invention is that certain grinding compounds appropriate for use in the
`
`method of the invention are also appropriate for use in a carrier for an agricultural
`
`chemical, such as a pesticide or a herbicide. The present invention encompasses
`
`methods for the production of an agricultural chemical composition incorporating
`
`both the biologically active compound in nanoparticulate form and at least a
`
`portion of the grinding compound, and agricultural chemical compositions so
`
`produced.
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`The agricultural chemical compound may include only the biologically active
`
`compound in nanoparticulate form together with the milled grinding compound or,
`
`more preferably, the biologically active compounds in nanoparticulate form and
`
`milled grinding compound may be combined with one or more pharmaceutically
`
`acceptable carriers, as well as any desired excipients or other like agents
`
`commonly used in the preparation of medicaments.
`
`Analogously,
`
`the agricultural chemical composition may include only the
`
`biologically active compound in nanoparticulate form together with the milled
`
`grinding compound or, more preferably, the biologically active compounds in
`
`nanoparticulate form and milled grinding compound may be combined with one or
`
`more carriers, as well as any desired excipients or other like agents commonly
`
`used in the preparation of agricultural chemical compositions.
`
`In one particular form of the invention, the grinding compound is both appropriate
`
`for use in a medicament and readily separable from the biologically active
`
`compound in nanoparticulate form by methods not dependent on particle size.
`
`Such grinding compounds are described in the following detailed description of
`
`the invention. Such grinding compounds are highly advantageous in that they
`
`afford significant flexibility in the extent to which the grinding compound may be
`
`incorporated with the biologically active compound in nanoparticulate form into a
`
`medicament.
`
`In one aspect, the invention provides novel formulations of raloxifene. Raloxifene
`
`is
`
`[6—hydroxy-2-(4-hyd roxyphenyl)benzol[b]thien—3-yl][4~[2-(1 —
`
`piperidinyl)ethoxy]phenyl-, and is also known as 6—hydroxy—2-(4-hydrophenyl)-3-
`
`[4-(2—piperidinoethoxy)—benzoy|]benzo-[b]—thiophene. Other names for raloxifene
`
`may also be found in the literature. The structural formula for raloxifene is
`
`illustrated below:
`
` HO
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`This invention provides raloxifene, or a pharmaceutically acceptable salt or
`
`solvate thereof, in particulate form having a mean particle size of between about
`
`10 nm and about 500nm.
`
`The invention further provides methods for producing said particulate raloxifene,
`
`pharmaceutically acceptable salt or solvate thereof.
`
`The
`
`invention
`
`also provides pharmaceutical
`
`compositions
`
`comprising or
`
`formulated using the said particulate raloxifene, or pharmaceutically acceptable
`
`salt or solvate thereof.
`
`The present invention further provides the use of the said particulate raloxifene, or
`
`pharmaceutically acceptable salt or solvate thereof,
`
`in the manufacture of a
`
`pharmaceutical
`
`composition for
`
`alleviating
`
`human
`
`pathologies,
`
`including
`
`osteoporosis, serum lipid lowering, and inhibiting endometriosis, uterine fibrosis,
`
`and breast cancer.
`
`The present invention further provides the use of such compositions comprising or
`
`formulated using the said raloxifene, or pharmaceutically acceptable salt or
`
`solvate thereof, for alleviating human pathologies, including osteoporosis, serum
`
`lipid lowering, and inhibiting endometriosis, uterine fibrosis, and breast cancer.
`
`in one aspect, then, the invention provides a method for producing a composition
`
`comprising nanoparticles of a biologically active
`
`compound,
`
`the method
`
`comprising the step of:
`
`dry milling a solid biologically active compound and a millable grinding
`
`compound in a mill comprising a plurality of milling bodies, for a time period
`
`sufficient to produce a solid dispersion comprising nanoparticles of the biologically
`
`active compound dispersed in at least partially milled grinding compound. A
`
`pharmaceutically acceptable carrier may also be combined with such composition
`
`to produce a pharmaceutical composition, or a medicament.
`
`In another aspect, the nanoparticles have an average size less than 1000nm, less
`
`than 500nm, less than 350nm, less than 200nm, less than 100nm, less than 75
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`nm, less than 50 nm, or less than 40 nm. The particle size of at least 50%, or
`
`75%, of the nanoparticles may be within the average size range.
`
`The time period for the milling operation is preferably between 5 minutes and 8
`
`hours, more preferably between 5 minutes and 2 hours, more preferably between
`
`5 minutes and 4 hours, preferably between 5 and 45 minutes, more preferably
`
`between 5 and 30 minutes, most preferably between 10 and 25 minutes.
`
`In another aspect of this invention, the milling medium is selected from the group
`
`consisting of ceramics, glasses, polymers, ferromagnetics, and metals, such as
`
`steel balls, which may have a diameter of between 1 and 20 mm, preferably
`
`between 2 and 15 mm, more preferably between 3 and 10mm.
`
`The method of the invention is suitable for milling biologically active compounds,-
`
`such as biologics, amino acids, proteins, peptides, nucleotides, nucleic acids, and
`
`analogs homologs and first order derivatives thereof. Many drugs are amenable
`
`to the methods of the invention, including but not limited to diclofenac, olanzapine,
`
`sildenafil, raloxifene, and others.
`
`In another aspect, the method further comprises the step of removing at least a
`
`portion of the at least partially milled grinding compound.
`
`The invention also provides a nanoparticle composition comprising nanoparticles
`
`of a biologically active compound, formed by the process of dry milling a solid
`
`biologically active compound and a millable grinding compound in a mill
`
`comprising a plurality of milling bodies, for a time period sufficient to produce a
`
`solid dispersion comprising nanoparticies of the biologically active compound
`
`dispersed in at
`
`least partially milled grinding compound.
`
`Such nanoparticle
`
`compositions may have the same particle size ranges as aforementioned.
`
`Likewise, the process may further comprise removing at least a portion of the at
`
`least partially milled grinding compound.
`
`In another aspect, the invention provides a method of treating a human in need of
`
`such treatment comprising the step of administering to such human a
`
`pharmaceutically
`
`effective
`
`amount
`
`of
`
`a
`
`nanoparticle
`
`composition,
`
`a
`
`pharmaceutical composition, or a medicament as described above.
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`Other aspects and advantages of the invention will become apparent to those
`
`skilled in the art from a review of the ensuing description.
`
`Brief Description of the Drawings
`
`Figure 1 shows that with decreasing volume percentage of diclofenac acid in NaCl
`
`grinding compound, the surface area of the diclofenac nanoparticles increases
`
`(nanoparticles after removal of grinding compound by washing);
`
`Figure 2 illustrates diclofenac acid nanoparticles obtained by dry milling a 15 vol%
`
`diclofenac acid in NaCl grinding medium, and separated from the grinding
`
`medium by washing with 0.01 M HCI and 1 mM CTAB solution. Larger particles,
`
`as can be seen in the intensity distribution on (b), were largely removed by
`
`centrifugation for 1 min at 3,000 g to achieve a narrow size distribution of 160 130
`
`nm, which is number weighted 100% (a). The amount of nanoparticles after
`
`removal of aggregates or larger particles by centrifugation in the dispersion or
`
`solution is greater than 80 weight %, as determined by the intensity weighted size
`
`distribution (a);
`
`Figure 3 comprises SEM images of olanzapine milled with NaCl grinding
`
`compound
`
`for
`
`180 minutes,
`
`showing
`
`(a)
`
`agglomerate morphology of
`
`olanzapine/grinding
`
`compound mixture
`
`at
`
`10000 magnification,
`
`and (b)
`
`nanoparticulate morphology of olanzapine/grinding compound mixture at 100000
`
`magnification;
`
`Figure 4 comprises high resolution SEM and TEM images of washed diclofenac
`
`acid nanoparticles of 5, 10, 15, 30 and 50 wt°/o diclofenac acid to grinding
`
`compound ratio;
`
`Figure 5 is a TEM image of diclofenac acid milled with NH4C| and washed with 0.1
`
`M HCl and 1 mM CTAB, and dried on a TEM grid.;
`
`Figure 6 plots heat flow against temperature for diclofenac acid dry milled with
`
`NH4Cl grinding compound, with the peak at 177 °C showing the presence of
`
`diclofenac acid, and the peak at 194 °C being due to the NH4Cl grinding
`
`compound;
`
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`_13_
`
`. Figure 7 illustrates the effect of increasing milling time of diclofenac acid with
`
`NaCl grinding compound, 15 vol%), showing that the melting point shifts to lower
`
`temperatures,
`
`likely due to a decrease of the diameter of the particles of
`
`diclofenac acid;
`
`Figure 8 is a comparison of the dissolution profiles of particulate raloxifene
`
`hydrochloride of an embodiment of the invention and commercial raloxifene
`
`hydrochloride in simulated gastric fluid and in simulated intestinal fluid;
`
`Figures 9a through 9d are scanning electron micrographs comparing particulate
`
`raloxifene hydrochloride of an embodiment of the invention and commercial
`
`raloxifene hydrochloride;
`
`Figure 10 illustrates a size distribution of particulate raloxifene hydrochloride of an
`
`embodiment of the invention determined by dynamic light scatter (DLS);
`
`Figure 11 compares melting points of particulate raloxifene hydrochloride of an
`
`embodiment of the invention and commercial raloxifene hydrochloride;
`
`Figure 12 compares XRD-spectra for particulate raloxifene hydrochloride of an
`
`embodiment of the invention and commercial raloxifene hydrochloride;
`
`Figure 13 is a solution 1H—NMR spectrum for particulate raloxifene hydrochloride
`
`of an embodiment of the invention;
`
`Figure 14 compares the FT-IR spectra of particulate raloxifene hydrochloride of
`
`an embodiment of the invention with commercial raloxifene hydrochloride;
`
`Figure 15 compares XRD spectra of raloxifene hydrochloride at various stages of
`
`processing according to a method of the present invention;
`
`Figure
`
`16
`
`is
`
`a
`
`scanning electron micrograph of particulate
`
`raloxifene
`
`hydrochloride according to an embodiment of the invention;
`
`Figure 17 compares FT—lR spectra of raloxifene hydrochloride at various stages of
`
`processing according to an embodiment of the method of the present invention;
`
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`-14-
`
`Figure 18 is a scanning electron micrograph of raloxifene (free base) as obtained
`
`(a and b) and after processing by milling with sodium chloride (c and d).
`
`Figure 19 shows the structures of ionic surfactants utilized in some embodiments
`
`of the method of the invention;
`
`Figure 20 is a scanning electron micrograph of particulate raloxifene (free base)
`
`according to an embodiment of the invention;
`
`Figure 21 compares XRD spectra of raloxifene (free base) at various stages of
`
`processing according to a method of the present invention;
`
`Figure 22 compares FT-IR spectra of raloxifene hydrochloride at various stages of
`
`processing according to an embodiment of the method of the present invention;
`
`Figure 23 provides concentration v time data for animal experiments comparing
`
`particulate raloxifene hydrochloride of an embodiment of the invention and
`
`commercial raloxifene hydrochloride;
`
`Figure 24 provides the data of Figure 16 in graphical and tabular form;
`
`Figure 25 provides mean pharmacokinetic data in tabular form; and
`
`Figure 26 provides an additional comparison of Cmax and AUCo_t results.
`
`Figure 27 comprises high resolution SEM images showing washed particulate
`
`fenofibrate produced by milling in an attrition mill for 30, 45 and 60 minutes.
`
`Figure 28 comprises a high resolution SEM micrograph of raloxifene HCI in a
`
`lactose grinding compound;
`
`Figure 29 compares in vitro dissolution of raloxifene HCI API with raloxifene milled
`
`with both sodium chloride and lactose as grinding compound and without removal
`
`of the grinding compound; and
`
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`-15-
`
`Figure 30 comprises SEM micrographs showing that olanzapine free base can be
`
`ground with lactose to a fine powder with some larger agglomerates (Figure 30a)
`
`and very fine particles of about 50-100 nm (Figure 30b).
`
`Detailed Description of the Invention
`
`General
`
`Those skilled in the art will appreciate that the invention described herein is
`
`susceptible to variations and modifications other than those specifically described.
`
`It
`
`is to be understood that
`
`the invention includes all such variations and
`
`modifications. The invention also includes all of the steps, features, compositions
`
`and compounds referred to or indicated in the specification,
`
`individually or
`
`collectively and any and all combinations or any two or more of the steps or
`
`features.
`
`The present invention is not to be limited in scope by the specific embodiments
`
`described herein, which are intended for the purpose of exemplification only.
`
`Functionally equivalent products, compositions and methods are clearly within the
`
`scope of the invention as described herein.
`
`The invention described herein may include one or more ranges of values (e.g.
`
`size, concentration etc). A range of values will be understood to include all values
`
`within the range, including the values defining the range, and values adjacent to
`
`the range that lead to the same or substantially the same outcome as the values
`
`immediately adjacent to that value which defines the boundary to the range.
`
`The entire disclosures of all publications (including patents, patent applications,
`
`journal articles, laboratory manuals, books, or other documents) cited herein are
`
`hereby incorporated by reference.
`
`Inclusion does not constitute a