US20150164802A1 - Methods for the preparation of biologically active compounds in nanoparticulate form - Google Patents

Methods for the preparation of biologically active compounds in nanoparticulate form Download PDF

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US20150164802A1
US20150164802A1 US14/461,594 US201414461594A US2015164802A1 US 20150164802 A1 US20150164802 A1 US 20150164802A1 US 201414461594 A US201414461594 A US 201414461594A US 2015164802 A1 US2015164802 A1 US 2015164802A1
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Prior art keywords
milling
biologically active
compound
raloxifene
grinding
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Raffaele Cammarano
Felix Meiser
Almar Postma
Frank Caruso
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Iceutica Pty Ltd
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Iceutica Pty Ltd
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Priority claimed from AU2006903527A external-priority patent/AU2006903527A0/en
Application filed by Iceutica Pty Ltd filed Critical Iceutica Pty Ltd
Priority to US14/461,594 priority Critical patent/US20150164802A1/en
Assigned to ICEUTICA PTY LTD. reassignment ICEUTICA PTY LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CARUSO, FRANK, CAMMARANO, RAFFAELE, POSTMA, ALMAR, MEISER, FELIX
Publication of US20150164802A1 publication Critical patent/US20150164802A1/en
Priority to US16/016,443 priority patent/US11103456B2/en
Priority to US17/461,713 priority patent/US20220054418A1/en
Priority to US18/399,546 priority patent/US20240122855A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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    • A61P9/12—Antihypertensives

Definitions

  • 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.
  • 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.
  • dry milling techniques have been used to reduce particle size and hence influence drug absorption.
  • 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.
  • 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 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).
  • Another method of providing reduced particle size is the formation of pharmaceutical drug microcapsules, which techniques include micronizing, polymerisation and co-dispersion.
  • 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 and/or contaminants such as toxic monomers which are difficult to remove, leading to expensive manufacturing processes.
  • U.S. Pat. No. 6,634,576 discloses examples of wet-milling a solid substrate, such as a pharmaceutically active compound, to produce a “synergetic co-mixture”.
  • Mechanochemical synthesis 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.
  • 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 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.
  • estrogen replacement therapy 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, FosamaxTM (Merck & Co., Inc.).
  • SERMs selective estrogen receptor modulator
  • desired tissues for example, bone
  • 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
  • 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.
  • 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.
  • applications of the methods of the present invention are clearly not limited to such.
  • 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.
  • 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.
  • the present invention comprises a method for producing a biologically active compound in nanoparticulate form, the method comprising the step of:
  • millable means that the grinding compound is capable of being physically degraded under the dry milling conditions of the method of the invention.
  • the milled grinding compound is of a comparable particle size to the nanoparticulate biologically active compound.
  • 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.
  • 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.
  • 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.
  • the grinding compound is separated from the dispersion or solution.
  • the unmilled grinding compound is separated from the nanoparticulate biologically active compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • wet grinding techniques utilizing water (or other comparably polar solvents) are incapable of being applied to such compounds, as the particles dissolve appreciably in the solvent.
  • 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).
  • 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 straightforward selective dissolution techniques. Examples of such grinding compounds are provided in the detailed description of the invention.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the invention provides novel formulations of raloxifene.
  • Raloxifene is [6-hydroxy-2-(4-hydroxyphenyl)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)-benzoyl]benzo-[b]-thiophene.
  • Other names for raloxifene may also be found in the literature. The structural formula for raloxifene is illustrated below:
  • 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 500 nm.
  • 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.
  • the invention provides a method for producing a composition comprising nanoparticles of a biologically active compound, the method comprising the step of:
  • the nanoparticles have an average size less than 1000 nm, less than 500 nm, less than 350 nm, less than 200 nm, less than 100 nm, less than 75 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 minutes and 4 hours, preferably between 5 and 45 minutes, more preferably between 5 and 30 minutes, most preferably between 10 and 25 minutes.
  • 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 10 mm.
  • 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.
  • biologically active compounds such as biologics, amino acids, proteins, peptides, nucleotides, nucleic acids, and analogs homologs and first order derivatives thereof.
  • drugs are amenable to the methods of the invention, including but not limited to diclofenac, olanzapine, sildenafil, raloxifene, and others.
  • 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 nanoparticles 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.
  • the process may further comprise removing at least a portion of the at least partially milled grinding compound.
  • 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.
  • FIG. 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);
  • FIG. 2A and FIG. 2B 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 HCl 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 ⁇ 30 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);
  • FIG. 3A and FIG. 3B 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;
  • FIG. 4 comprises high resolution SEM and TEM images of washed diclofenac acid nanoparticles of 5, 10, 15, 30 and 50 wt % diclofenac acid to grinding compound ratio;
  • FIG. 5 is a TEM image of diclofenac acid milled with NH 4 Cl and washed with 0.1 M HCl and 1 mM CTAB, and dried on a TEM grid;
  • FIG. 6 plots heat flow against temperature for diclofenac acid dry milled with NH 4 Cl grinding compound, with the peak at 177° C. showing the presence of diclofenac acid, and the peak at 194° C. being due to the NH 4 Cl grinding compound;
  • FIG. 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;
  • FIG. 8A and FIG. 8B 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;
  • FIGS. 9 a through 9 d are scanning electron micrographs comparing particulate raloxifene hydrochloride of an embodiment of the invention and commercial raloxifene hydrochloride;
  • FIG. 10 illustrates a size distribution of particulate raloxifene hydrochloride of an embodiment of the invention determined by dynamic light scatter (DLS);
  • DLS dynamic light scatter
  • FIG. 11 compares melting points of particulate raloxifene hydrochloride of an embodiment of the invention and commercial raloxifene hydrochloride;
  • FIG. 12 compares XRD-spectra for particulate raloxifene hydrochloride of an embodiment of the invention and commercial raloxifene hydrochloride;
  • FIG. 13 is a solution 1 H-NMR spectrum for particulate raloxifene hydrochloride of an embodiment of the invention.
  • FIG. 14 compares the FT-IR spectra of particulate raloxifene hydrochloride of an embodiment of the invention with commercial raloxifene hydrochloride;
  • FIG. 15 compares XRD spectra of raloxifene hydrochloride at various stages of processing according to a method of the present invention
  • FIG. 16 is a scanning electron micrograph of particulate raloxifene hydrochloride according to an embodiment of the invention.
  • FIG. 17 compares FT-IR spectra of raloxifene hydrochloride at various stages of processing according to an embodiment of the method of the present invention
  • FIG. 18A through 18D 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).
  • FIG. 19 shows the structures of ionic surfactants utilized in some embodiments of the method of the invention.
  • FIG. 20A and FIG. 20B is a scanning electron micrograph of particulate raloxifene (free base) according to an embodiment of the invention.
  • FIG. 21 compares XRD spectra of raloxifene (free base) at various stages of processing according to a method of the present invention
  • FIG. 22 compares FT-IR spectra of raloxifene hydrochloride at various stages of processing according to an embodiment of the method of the present invention
  • FIG. 23A through 23D provides concentration v time data for animal experiments comparing particulate raloxifene hydrochloride of an embodiment of the invention and commercial raloxifene hydrochloride;
  • FIG. 24A and FIG. 24B provides the data of FIG. 16 in graphical and tabular form
  • FIG. 25 provides mean pharmacokinetic data in tabular form
  • FIG. 26A through 26C provides an additional comparison of C max and AUC 0-t results.
  • FIG. 27 comprises high resolution SEM images showing washed particulate fenofibrate produced by milling in an attrition mill for 30, 45 and 60 minutes.
  • FIG. 28A and FIG. 28B comprises a high resolution SEM micrograph of raloxifene HCl in a lactose grinding compound
  • FIG. 29 compares in vitro dissolution of raloxifene HCl API with raloxifene milled with both sodium chloride and lactose as grinding compound and without removal of the grinding compound;
  • FIG. 30A and FIG. 30B comprises SEM micrographs showing that olanzapine free base can be ground with lactose to a fine powder with some larger agglomerates ( FIG. 30 a ) and very fine particles of about 50-100 nm ( FIG. 30 b ).
  • 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.
  • “Therapeutically effective amount” as used herein with respect to methods of treatment and in particular drug dosage shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that “therapeutically effective amount,” administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a “therapeutically effective amount” by those skilled in the art. It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.
  • inhibitor is defined to include its generally accepted meaning which includes prohibiting, preventing, restraining, and lowering, stopping, or reversing progression or severity, and such action on a resultant symptom.
  • the present invention includes both medical therapeutic and prophylactic administration, as appropriate.
  • mean particle size is defined as equivalent spherical diameter as determined by laser light diffraction scattering.
  • the particles in the raw state as well as after milling or other particle size reduction techniques are irregular in shape, it is necessary to characterize them not by measurement of an actual size such as thickness or length, but by measurement of a property of the particles which is related to the sample property possessed by a theoretical spherical particle.
  • the particles are thus allocated an “equivalent spherical diameter”.
  • the values found from characterizing a large number of “unknown” particles can be plotted frequency vs. diameter or in other methods weight vs. diameter, usually adopting percentage undersize values for frequency or weight. This gives a characteristic curve representing size distribution of the sample, i.e., cumulative percentage undersize distribution curve. Values from this can be read off directly or plotted on log-probability paper to give an appropriate straight line.
  • the mean equivalent spherical volume diameter is the 50% undersize value.
  • 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.
  • an effective average particle size of less than about 400 nm it is meant that at least 90% of the particles have a number average particle size of less than about 400 nm when measured by the above-noted techniques.
  • the term “effective mean particle diameter” is defined as the mean diameter of the smallest circular hole through which a particle can pass freely.
  • the effective mean particle diameter of a spherical particle corresponds to the mean particle diameter
  • the effective mean particle diameter of an ellipsoidal particle corresponds to the mean length of the longest minor axis.
  • solvate is used to describe an aggregate that comprises one or more molecules of the solute, such as raloxifene, with one or more molecules of solvent.
  • the term “pharmaceutically acceptable salt” refers to either acid or base addition salts which are known to be non-toxic and are commonly used in the pharmaceutical literature.
  • the pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.
  • the compounds used in the methods of this invention primarily form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids, and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
  • the pharmaceutically acceptable acid addition salts are typically formed by reacting raloxifene with an equimolar or excess amount of acid.
  • the reactants are generally combined in a mutual solvent such as diethyl ether or ethyl acetate.
  • the salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration, or the solvent can be stripped off by conventional means.
  • dry mill or variations, such as “dry milling”, should be understood to refer to milling in at least the substantial absence of liquids. If liquids are present, they are present in such amounts that the contents of the mill retain the characteristics of a paste or, preferably, a dry powder.
  • Flowable means a powder having physical characteristics rendering it suitable for an automatic or semi-automatic manufacturing process as, for example, would be used for the manufacture of pharmaceutical compositions and formulations.
  • nanoparticulate form includes nanoparticle compositions, wherein the composition comprises at least nanoparticles having an average particle size smaller than 1000 nm.
  • Non-nanoparticulate active agents have an effective average particle size of greater than about 2 microns, meaning that at least 50% of the active agent particles have a size greater than about 2 microns.
  • a “solid solution” consists of one phase only, irrespective of the number of differing components present.
  • a solid solution may be classified as continuous, discontinuous, substitutional, interstitial or amorphous.
  • Typical solid solutions have a crystalline structure, in which the solute molecules can either substitute for solvent molecules in the crystal lattice or fit into the interstices between the solvent molecules.
  • Interstitial crystalline solid solutions occur when the dissolved molecules occupy the interstitial spaces between the solvent molecules in the crystal lattice.
  • Amorphous solid solutions occur when the solute molecules are dispersed molecularly but irregularly within the amorphous solvent.
  • a solid dispersion in general means a system in solid state comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components.
  • the present invention is directed to a method for producing for the preparation of a biologically active compound in nanoparticulate form, the method comprising the step of:
  • the solid dispersion or solution may then be separated from the milling bodies and removed from the mill.
  • 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 milling of the grinding compound, is sufficient to inhibit reagglomeration of the biologically active compound in nanoparticulate form.
  • the grinding compound is neither chemically nor mechanically reactive with the pharmaceutical compound under the conditions present in the process of the invention.
  • the present invention also relates to biologically active compounds in nanoparticulate form produced by said methods, to medicaments produced using said biologically active compounds in nanoparticulate form 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.
  • the method of the present invention requires the grinding compound to be milled with the pharmaceutical compound; that is, the grinding compound will physically degrade under the dry milling conditions of the invention to facilitate the formation and retention of the biologically active compound in nanoparticulate form.
  • the precise extent of degradation required will depend on certain properties of the grinding compound and the biologically active compound (for example, any charge distribution or surface effects causing the grinding compound to have a greater or lesser affinity for the biologically active compound), the ratio of biologically active compound to grinding compound, and the desired particle size and particle size distribution of the nanoparticles comprising the biologically active compound in nanoparticulate form.
  • the milled grinding compound is of a comparable particle size to the nanoparticulate biologically active compound.
  • the physical properties of the grinding compound necessary to achieve the requisite degradation are dependant on the precise milling conditions. For example a harder grinding compound may degrade to a sufficient extent provided under more vigorous dry milling conditions.
  • Physical properties of the grinding compound relevant to the extent that the agent will degrade under dry milling conditions include hardness, friability, as measured by indicia such as fracture toughness and brittleness index.
  • a low hardness (typically a Mohs Hardness less than 7) of the biologically active compound is desirable to ensure fracture of the particles during processing, so that nanocomposite microstructures develop during milling.
  • the grinding compound is of low abrasivity.
  • Low abrasivity is desirable to minimise contamination of the dispersion or solution of the biologically active compound in nanoparticulate form in the grinding compound by the milling bodies and/or the milling chamber of the media mill.
  • An indirect indication of the abrasivity can be obtained by measuring the level of milling-based contaminants.
  • the grinding compound has a low tendency to agglomerate during dry milling. While it is difficult to objectively quantify the tendency to agglomerate during milling, it is possible to obtain a subjective measure by observing the level of “caking” of the grinding compound on the milling bodies and the milling chamber of the media mill as dry milling progresses.
  • the grinding compound may be an inorganic or organic compound.
  • the grinding compound is selected from the following: sodium hydrogen sulfate, sodium hydrogen carbonate, sodium hydroxide, or succinic acid; crystalline organic acids, for example (but not limited to) fumaric acid, maleic acid, tartaric acid, citric acid); alternatively ammonium salts (or salts of volatile amines), for example (but not limited to) ammonium chloride, methylamine hydrochloride, ammonium bromide, crystalline hydroxides, hydrogen carbonates, hydrogen carbonates of pharmaceutical acceptable alkali metals, such as but not limited by, sodium, potassium, lithium, calcium, and barium, sodium sulphate, sodium chloride, sodium metabisulphite, sodium thiosulphate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulphate, magnesium sulphate, potash alum, potassium chloride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate.
  • the grinding compound is a compound that is considered GRAS (generally regarded as safe) by persons skilled in the pharmaceutical arts.
  • the quantity of the grinding compound relative to the quantity of biologically active compound in nanoparticulate form and the extent of degradation of the grinding compound determine whether reagglomeration of the biologically active compound in nanoparticulate form is at least inhibited.
  • the extent of degradation of the grinding compound under the dry milling conditions of the invention may affect the quantity of grinding compound required to produce the biologically active compound in nanoparticulate form, such that grinding compounds that degrade to a greater extent are required in smaller relative quantities.
  • the volume fraction of the nanoparticles comprising the biologically active compound in nanoparticulate form may be greater than the theoretical percolation threshold, which, for 3-dimensional random dispersions of spherical particles, is around 15 vol %.
  • the volume fraction of the nanoparticles comprising the biologically active compound in nanoparticulate form is less than about 25 vol %. More preferably, the volume fraction of the nanoparticles comprising the biologically active compound in nanoparticulate form is less than about 20 vol %. In a highly preferred form of the invention, the volume fraction of the nanoparticles comprising the biologically active compound in nanoparticulate form is less than about 15 vol %.
  • the milling bodies are preferably chemically inert and rigid.
  • chemically-inert means that the milling bodies do not react chemically with the biologically active compound or the grinding compound.
  • the milling bodies are essentially resistant to fracture and erosion in the milling process.
  • the milling bodies are desirably provided in the form of bodies which may have any of a variety of smooth, regular shapes, flat or curved surfaces, and lacking sharp or raised edges.
  • suitable milling bodies can be in the form of bodies having ellipsoidal, ovoid, spherical or right cylindrical shapes.
  • the milling bodies are provided in the form of one or more of beads, balls, spheres, rods, right cylinders, drums or radius-end right cylinders (i.e., right cylinders having hemispherical bases with the same radius as the cylinder).
  • the milling media bodies desirably have an effective mean particle diameter (i.e. “particle size”) between about 0.1 and 30 mm, more preferably between about 1 and about 15 mm, still more preferably between about 3 and 10 mm.
  • the milling bodies may comprise various materials such as ceramic, glass, metal or polymeric compositions, in a particulate form.
  • Suitable metal milling bodies are typically spherical and generally have good hardness (i.e. RHC 60-70), roundness, high wear resistance, and narrow size distribution and can include, for example, balls fabricated from type 52100 chrome steel, type 316 or 440C stainless steel or type 1065 high carbon steel.
  • Preferred ceramic materials can be selected from a wide array of ceramics desirably having sufficient hardness and resistance to fracture to enable them to avoid being chipped or crushed during milling and also having sufficiently high density. Suitable densities for milling media can range from about 1 to 15 g/cm 3 .
  • Preferred ceramic materials can be selected from steatite, aluminum oxide, zirconium oxide, zirconia-silica, yttria-stabilized zirconium oxide, magnesia-stabilized zirconium oxide, silicon nitride, silicon carbide, cobalt-stabilized tungsten carbide, and the like, as well as mixtures thereof.
  • Preferred glass milling media are spherical (e.g. beads), have a narrow size distribution, are durable, and include, for example, lead-free soda lime glass and borosilicate glass.
  • Polymeric milling media are preferably substantially spherical and can be selected from a wide array of polymeric resins having sufficient hardness and friability to enable them to avoid being chipped or crushed during milling, abrasion-resistance to minimize attrition resulting in contamination of the product, and freedom from impurities such as metals, solvents, and residual monomers.
  • Preferred polymeric resins can be selected from crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethylmethacrylate, polycarbonates, polyacetals, vinyl chloride polymers and copolymers, polyurethanes, polyamides, high density polyethylenes, polypropylenes, and the like.
  • crosslinked polystyrenes such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethylmethacrylate, polycarbonates, polyacetals, vinyl chloride polymers and copolymers, polyurethanes, polyamides, high density polyethylenes, polypropylenes, and the like.
  • Polymeric resins typically can have densities ranging from about 0.8 to 3.0 g/cm 3 . Higher density polymeric resins are preferred.
  • the milling media can be composite particles comprising dense core particles having a polymeric resin adhered thereon. Core particles can be selected from materials known to be useful as milling media, for example, glass, alumina, zirconia silica, zirconium oxide, stainless steel, and the like. Preferred core materials have densities greater than about 2.5 g/cm 3 .
  • the milling media are formed from a ferromagnetic material, thereby facilitating removal of contaminants arising from wear of the milling media by the use of magnetic separation techniques.
  • metals have the highest specific gravities, which increase grinding efficiency due to increased impact energy.
  • Metal costs range from low to high, but metal contamination of final product can be an issue.
  • Glasses are advantageous from the standpoint of low cost and the availability of small bead sizes as low as 0.004 mm.
  • specific gravity of glasses is lower than other media and significantly more milling time is required.
  • ceramics are advantageous from the standpoint of low wear and contamination, ease of cleaning, and high hardness.
  • the biologically active compound substrate and grinding compound in the form of crystals, powders, or the like, are combined in suitable proportions with the plurality of milling bodies in a milling chamber that is mechanically agitated (i.e., with or without stirring) for a predetermined period of time at a predetermined intensity of agitation.
  • a milling apparatus is used to impart motion to the milling bodies by the external application of agitation, whereby various translational, rotational or inversion motions or combinations thereof are applied to the milling chamber and its contents, or by the internal application of agitation through a rotating shaft terminating in a blade, propeller, impeller or paddle or by a combination of both actions.
  • the nature and intensity of the forces applied by the milling bodies to the biologically active compound and the grinding compound is influenced by a wide variety of processing parameters including: the type of milling apparatus; the intensity of the forces generated, the kinematic aspects of the process; the size, density, shape, and composition of the milling bodies; the weight ratio of the biologically active compound and grinding compound mixture to the milling bodies; the duration of milling; the physical properties of both the biologically active compound and the grinding compound; the atmosphere present during activation; and others.
  • the media mill is capable of repeatedly or continuously applying mechanical compressive forces and shear stress to the biologically active compound substrate and the grinding compound.
  • Suitable media mills include but are not limited to the following: high-energy ball, sand, bead or pearl mills, basket mill, planetary mill, vibratory action ball mill, multi-axial shaker/mixer, stirred ball mill, horizontal small media mill, multi-ring pulverizing mill, and the like, including small milling media.
  • the milling apparatus also can contain one or more rotating shafts.
  • the dry milling is effected a ball mill.
  • dry milling being carried out by way of a ball mill.
  • examples of this type of mill are attritor mills, nutating mills, tower mills, planetary mills, vibratory mills and gravity-dependent-type ball mills.
  • dry milling in accordance with the method of the invention may also be achieved by any suitable means other than ball milling.
  • dry milling may also be achieved using jet mills, rod mills, roller mills or crusher mills.
  • the biologically active compound includes therapeutically active compounds, including compounds for veterinary and human use, and agricultural compounds such as pesticides, herbicides and fungicides, germinating agents and the like.
  • the biologically active compound is an organic compound.
  • the biologically active compound is an organic, therapeutically active compounds for veterinary or human use.
  • the biologically active compound is an organic, therapeutically active compounds for human use.
  • the biologically active compound substrate is ordinarily a compound for which one of skill in the art desires improved properties arising from smaller particle sizes.
  • the biologically active compound substrate may be a conventional active agent or drug, although the process of the invention may be employed on formulations or agents that already have reduced particle size compared to their conventional form.
  • Biologically active compounds suitable for use in the invention include biologics, amino acids, proteins, peptides, nucleotides, nucleic acids, and analogs, homologs and first order derivatives thereof.
  • the biologically active compound can be selected from a variety of known classes of drugs, including, but not limited to: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics,
  • biologically active compounds include, but are not limited to: haloperidol (dopamine antagonist), DL isoproterenol hydrochloride ( ⁇ -adrenergic agonist), terfenadine (H1-antagonist), propranolol hydrochloride ( ⁇ -adrenergic antagonist), desipramine hydrochloride (antidepressant), salmeterol (b2-selective adrenergic agonist), sildenafil citrate, tadalafil and vardenafil.
  • Minor analgesics cyclooxygenase inhibitors
  • fenamic acids Piroxicam
  • Cox-2 inhibitors and Naproxen, and others, may all benefit from being prepared in a nanoparticulate form.
  • biologically active compounds that are poorly water soluble at physiological pH will particularly benefit from being prepared in nanoparticulate form, and the method of the present invention is particularly advantageously applied to compounds that are poorly water soluble at physiological pH.
  • Such compounds include, but are not limited to: albendazole, albendazole sulfoxide, alfaxalone, acetyl digoxin, acyclovir analogs, alprostadil, aminofostin, anipamil, antithrombin III, atenolol, azidothymidine, beclobrate, beclomethasone, belomycin, benzocaine and derivatives, beta carotene, beta endorphin, beta interferon, bezafibrate, binovum, biperiden, bromazepam, bromocryptine, bucindolol, buflomedil, bupivacaine, busulfan, cadralazine, camptothesin, canthaxanthin, captopril, carbamazepine, carboprost, cefalexin, cefalotin, cefamandole, cefazedone, cefluoroxime, cefinenoxime, cefopera
  • biologically active compounds may have the benefit of absorption through the skin if presented in a nanoparticle formulation.
  • biologically active compounds include, but are not limited to, Voltaren (diclofenac), rofecoxib, and ibuprofen.
  • the biologically active compound is capable of withstanding temperatures that are typical in uncooled dry milling, which may exceed 80° C. Therefore, compounds with a melting point about 80° C. or greater are suitable.
  • the media mill may be cooled, thereby allowing compounds with significantly lower melting temperatures to be processed according to the method of the invention.
  • a simple water-cooled mill will keep temperatures below 50° C., or chilled water could be used to further lower the milling temperature.
  • a reaction mill could be designed to run at any temperature between say ⁇ 190 to 500° C.
  • the biologically active compound substrate is obtained in a conventional form commercially and/or prepared by techniques known in the art.
  • the particle size of the biologically active compound substrate be less than about 100 ⁇ m, as determined by sieve analysis. If the coarse particle size of the biologically active compound substrate is greater than about 100 ⁇ m, then it is preferred that the particles of the biologically active compound substrate be reduced in size to less than 100 ⁇ m using a conventional milling method such as airjet or fragmentation milling.
  • the biologically active compound in nanoparticulate form comprises nanoparticles of biologically active compound of an average particle size diameter less than 1000 nm, preferably less than 500 nm, preferably less than 350 nm, preferably less than 200 nm, preferably less than 100 nm, preferably less than 75 nm, more preferably less than 50 nm, and in some cases less than 30 nm.
  • the biologically active compound in nanoparticulate form comprises nanoparticles of biologically active compound of between about 1 nm to about 200 nm, or more preferably between about 5 nm to about 100 nm, more preferably between about 5 and 50 nm, more preferably still between about 10 nm to about 40 nm.
  • the nanoparticles of biologically active compound are between about 20 nm and 30 nm in size. These sizes refer to nanoparticles either fully dispersed or partially agglomerated. For example, where two 20 nm particles agglomerate, the resulting entity is a nanoparticle about 40 nm in size and thus would still be considered a nanoparticle within the meaning of the invention.
  • the nanoparticles of biologically active compound will preferably have an average size less than 200 nm, more preferably less than 100 nm, more preferably less than 75 nm, more preferably less than 50 nm, and more preferably less than 40 nm, where the average size refers to nanoparticles either fully dispersed or partially agglomerated as described above.
  • the nanoparticles of the biologically active compound in nanoparticulate form are distributed in size so that at least 50% of the nanoparticles have a size within the average range, more preferably at least 60%, more preferably at least 70%, and still more preferably at least 75% of the nanoparticles have a size within the average range.
  • Agglomerates comprising particles of biologically active compound in nanoparticulate form, said particles having a mean particle size within the ranges specified above, should be understood to fall within the scope of the present invention, regardless of whether the agglomerates exceed 1000 nm in size.
  • the biologically active compound substrate and the grinding compound are dry milled for the shortest time necessary to form the solid dispersion or solution of the biologically active compound in nanoparticulate form in the grinding compound to minimise any possible contamination from the media mill and/or the plurality of milling bodies.
  • This time varies greatly, depending on the biologically active compound and the grinding compound, and may range from as short as 5 minutes to several hours. Dry milling times in excess of 2 hours may lead to degradation of the biologically active compound in nanoparticulate form and an increased level of undesirable contaminants.
  • Suitable rates of agitation and total milling times are adjusted for the type and size of milling apparatus as well as the milling media, the weight ratio of the substrate biologically active compound and grinding compound mixture to the plurality of milling bodies, the chemical and physical properties of the substrate biologically active compound and grinding compound, and other parameters that may be optimized empirically.
  • the time may range from between 5 minutes and 2 hours, 5 minutes and 1 hour, 5 minutes and 45 minutes, 5 minutes and 30 minutes, and 10 minutes and 20 minutes.
  • the method further comprises the step of;
  • Any portion of the grinding compound may be removed, including but not limited to 10%, 25%, 50%, 75%, or substantially all of the grinding compound.
  • a significant portion of the milled grinding compound may comprise particles of a size similar to and/or smaller than the particles comprising the biologically active compound in nanoparticulate form.
  • portion of the milled grinding compound to be separated from the particles comprising the biologically active compound in nanoparticulate form comprises particles of a size similar to and/or smaller than the particles comprising the biologically active compound in nanoparticulate form, separation techniques based on size distribution are inapplicable.
  • the method of the present invention may involve separation of at least a portion of the milled grinding compound from the biologically active compound in nanoparticulate form by techniques including but not limited to electrostatic separation, magnetic separation, centrifugation (density separation), hydrodynamic separation, froth flotation.
  • the step of removing at least a portion of the milled grinding compound from the biologically active compound in nanoparticulate form may be performed through means such as selective dissolution, washing, or sublimation.
  • the grinding compound possesses solubility properties in a solvent different from the biologically active compound in nanoparticulate form and the step of removing at least a portion of the grinding compound from the biologically active compound in nanoparticulate form is performed by washing the solid dispersion or solution of the biologically active compound in nanoparticulate form in the grinding compound with the solvent.
  • Appropriate solvents may be acid, alkaline or neutral aqueous solutions, or an organic solvent. This may be any solvent in which the drug is insoluble but the matrix is soluble or alternatively in which the biologically active compound in nanoparticulate form and grinding compound may be separated by differential centrifugation.
  • appropriate grinding compound include a number of highly water soluble inorganic salts.
  • a particularly appropriate grinding compound is thus a water soluble salt as this facilitates facile separation of the grinding compound from the biologically active compound in nanoparticulate form by contacting the solid solution or dispersion of the biologically active compound in nanoparticulate form in the grinding compound with water.
  • water soluble inorganic salts include: sodium sulphate, sodium chloride, sodium metabisulphite, sodium thiosulphate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulphate, magnesium sulphate, potash alum, potassium chloride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate.
  • Preferred water soluble inorganic salts include sodium chloride, ammonium chloride, potash alum, potassium chloride, potassium bromide and sodium sulphate, especially anhydrous sodium sulphate.
  • the grinding compound is sodium chloride.
  • the sodium chloride may be provided in dendritic, granular or ordinary cubic form.
  • the biologically active compound in nanoparticulate form resulting from at least partial removal of the grinding compound may require stabilization with a surface stabilizer.
  • surface stabilizers include CTAB, cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, stearic acid esters and salts, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methyl
  • Facilitating agents may also include at least one cationic surface stabilizer selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, and a phospholipid.
  • Facilitating agents may also include at least one surface stabilizer selected from the group consisting of cationic lipids, benzalkonium chloride, sulfonium compounds, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C 12-15 dimethyl hydroxyethyl ammonium chloride, C 12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromid
  • the preferred stabilizer is CTAB.
  • Those of skill in the art will appreciate that a wide variety of other surface stabilizers are suitable for such stabilization.
  • the present invention includes biologically active compounds in nanoparticulate form at least partially separated from the grinding compound by the methods described above, the use of such in the preparation of a medicament, and the treatment of an animal, including man, by the administration of a therapeutically effective amount of the biologically active compounds in nanoparticulate form by way of the medicament.
  • a highly advantageous aspect of the present invention is that certain grinding compounds appropriate for use in the method of the invention (in that they physically degrade to the desired extent under dry milling conditions) are also pharmaceutically acceptable and thus appropriate for use in a medicament.
  • the method of the present invention does not involve complete separation of the grinding compound from the biologically active compound in nanoparticulate form
  • 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 milled 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.
  • the medicament may include only the biologically active compound in nanoparticulate form and the grinding compound or, more preferably, the biologically active compounds in nanoparticulate form and 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.
  • a highly advantageous aspect of the present invention is that certain grinding compounds appropriate for use in the method of the invention (in that they physically degrade to a desirable extent under dry milling conditions) are also appropriate for use in an agricultural chemical composition.
  • the method of the present invention does not involve complete separation of the grinding compound from the biologically active compound in nanoparticulate form
  • the present invention encompasses methods for the production of a agricultural chemical composition incorporating both the biologically active compound in nanoparticulate form and at least a portion of the milled grinding compound, agricultural chemical composition so produced and methods of use of such compositions.
  • the agricultural chemical composition may include only the biologically active compound in nanoparticulate form and the grinding compound or, more preferably, the biologically active compounds in nanoparticulate form and grinding compound may be combined with one or more acceptable carriers, as well as any desired excipients or other like agents commonly used in the preparation of agricultural chemical compositions.
  • 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.
  • the present invention encompasses a method for the manufacture of a medicament comprising a therapeutically active compound in nanoparticulate form, the method comprising the steps of:
  • the solid dispersion or solution may then be separated from the milling bodies and removed from the mill.
  • the grinding compound is separated from the dispersion or solution. 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 milling of the grinding compound, is sufficient to inhibit reagglomeration of the biologically active compound in nanoparticulate form.
  • the grinding compound is not chemically nor mechanically reactive with the pharmaceutical compound under the dry milling conditions of the method of the invention.
  • the medicament is a solid dosage form, however, other dosage forms may be prepared by those of ordinary skill in the art.
  • the method may comprise the step of:
  • 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 present invention includes medicaments manufactured by said methods, and methods for the treatment of an animal, including man, by the administration of a therapeutically effective amount of the biologically active compounds in nanoparticulate form by way of said medicaments.
  • a facilitating agent is also comprised in the mixture to be milled.
  • facilitating agents appropriate for use in the invention include diluents, surface stabilizers, binding agents, filling agents, lubricating agents, sweeteners, flavouring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents and agents that may form part of a medicament, including a solid dosage form, or other material required for other specific drug delivery, such as the agents and media listed below under the heading Medicinal and Pharmaceutical Compositions, or any combination thereof.
  • the present invention encompasses pharmaceutically acceptable compounds in nanoparticulate form produced according to the methods of the present invention, compositions including such compounds, including compositions comprising such compounds together with at least a portion of the grinding compound.
  • agglomeration of the particles may sometimes occur forming larger particles. Due to the unique nature of the process described, these new agglomerated particles may have unique physical properties, through, for instance, having new polymorphic structures or nano-structured morphologies. Unique polymorphic structures and or the presence of nano structures morphologies may result in therapeutically beneficial properties including improved bioavailability.
  • a composition of the invention comprises substantially pure pharmaceutically acceptable compounds in nanoparticulate form.
  • the preferred composition retains at least a portion of the grinding compound.
  • the pharmaceutically acceptable compounds in nanoparticulate form within the compositions of the invention are present at a concentration of between about 0.1% and about 99.0% by weight.
  • concentration of pharmaceutically acceptable compounds in nanoparticulate form within the compositions will be about 5% to about 80% by weight, while concentrations of 10% to about 50% by weight are highly preferred.
  • concentration will be in the range of about 10 to 15% by weight, 15 to 20% by weight, 20 to 25% by weight, 25 to 30% by weight, 30 to 35% by weight, 35 to 40% by weight, 40 to 45% by weight or 45 to 50% by weight for the composition prior to any later removal (if desired) of any portion of the grinding compound.
  • the relative concentration of pharmaceutically acceptable compounds in nanoparticulate form in the composition may be considerably higher depending on the amount of the grinding compound that is removed. For example, if all of the grinding compound is removed the concentration of nanoparticles in the preparation may be approach 100% by weight (subject to the presence of facilitating agents).
  • the dispersion of pharmaceutically acceptable compounds in nanoparticulate form in the grinding compound will be dependent on the weight percentage concentration of pharmaceutically acceptable compounds in nanoparticulate form Depending on that weight percentage concentration, nanoparticles of the pharmaceutically acceptable compounds in nanoparticulate form will be “dispersed” in the grinding compound if at least 0.1% of the nanoparticles are separated by the grinding compound. Preferably, greater than 10% of the nanoparticles will be spatially separated from each other by the grinding compound. More preferably at least 15, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 92, 95, 98 or 99% of the nanoparticles will be spatially separated from each other by the grinding compound.
  • compositions produced according to the present invention are not limited to the inclusion of a single species of pharmaceutically acceptable compounds in nanoparticulate form. More than one species of pharmaceutically acceptable compounds in nanoparticulate form may therefore be present in the composition. Where more than one species of pharmaceutically acceptable compounds in nanoparticulate form is present, the composition so formed may either be prepared in a dry milling step, or the pharmaceutically acceptable compounds in nanoparticulate form may be prepared separately and then combined to form a single composition.
  • the medicaments of the present invention may include the pharmaceutically acceptable compound in nanoparticulate form, optionally together with at least a portion of the grinding compound, combined with one or more pharmaceutically acceptable carriers, as well as other agents commonly used in the preparation of pharmaceutically acceptable compositions.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for parenteral administration, intravenous, intraperitoneal, intramuscular, sublingual, transdermal or oral administration.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for the manufacture of medicaments is well known in the art. Except insofar as any conventional media or agent is incompatible with the pharmaceutically acceptable compound in nanoparticulate form, use thereof in the manufacture of a pharmaceutical composition according to the invention is contemplated.
  • compositions may include one or more of the following examples:
  • Medicaments of the invention suitable for use in animals and in particular in man typically must be sterile and stable under the conditions of manufacture and storage.
  • the medicaments of the invention comprising the biologically active compound in nanoparticulate form can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • Actual dosage levels of the biologically active compound in the medicament of the invention may be varied in accordance with the nature of the biologically active compound, as well as the potential increased efficacy due to the advantages of providing and administering the biologically active compound in nanoparticulate form (e.g., increased solubility, more rapid dissolution, increased surface area of the biologically active compound in nanoparticulate form, etc.).
  • therapeutically effective amount will refer to an amount of biologically active compound in nanoparticulate form required to effect a therapeutic response in an animal. Amounts effective for such a use will depend on: the desired therapeutic effect; the route of administration; the potency of the biologically active compound; the desired duration of treatment; the stage and severity of the disease being treated; the weight and general state of health of the patient; and the judgment of the prescribing physician.
  • the biologically active compound in nanoparticulate form, optionally together with at least a portion of the grinding compound, of the invention may be combined into a medicament with another biologically active compound, or even the same biologically active compound.
  • a medicament may be achieved which provides for different release characteristics—early release from the biologically active compound in nanoparticulate form, and later release from a larger average size biologically active compound in nanoparticulate form or a non-nanoparticulate biologically active compound.
  • Medicaments of the invention can be administered to animals, including man, in any pharmaceutically acceptable manner, such as orally, rectally, pulmonary, intravaginally, locally (powders, ointments or drops), transdermal, or as a buccal or nasal spray.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, pellets, and granules.
  • the dosage forms may also comprise buffering agents.
  • incorporating any of the normally employed excipients, such as those previously listed, and generally 10-95% of the biologically active agent in nanoparticulate form, and more preferably at a concentration of 25%-75% will form a pharmaceutically acceptable non-toxic oral composition.
  • Medicaments of the invention may be parenterally administered as a solution of the biologically active agent in nanoparticulate form suspended in an acceptable carrier, preferably an aqueous carrier.
  • an acceptable carrier preferably an aqueous carrier.
  • aqueous carriers e.g. water, buffered water, 0.4% saline, 0.3% glycine, hyaluronic acid and the like. These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration.
  • medicaments of the invention are preferably supplied along with a surface stabilizer and propellant.
  • the surface stabilizer must, of course, be non-toxic, and preferably soluble in the propellant.
  • Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters, such as mixed or natural glycerides may be employed.
  • the surface stabilizer may constitute 0.1%-20% by weight of the composition, preferably 0.25-5%. The balance of the composition is ordinarily propellant.
  • a carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery.
  • Medicaments of the invention may also be administered via liposomes, which serve to target the active agent to a particular tissue, such as lymphoid tissue, or targeted selectively to cells.
  • Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.
  • the nanocomposite microstructure composition is incorporated as part of a liposome, alone or in conjunction with a molecule that binds to or with other therapeutic or immunogenic compositions.
  • the biologically active compound in nanoparticulate form can be formulated into a solid dosage form (e.g., for oral or suppository administration), together with at least a portion of the grinding compound then there may be little or no need for further stabilizing the dispersion since the grinding compound may effectively act as a solid-state stabilizer.
  • the nanoparticles comprising the biologically active compound in nanoparticulate form may require further stabilization once the solid carrier has been substantially removed to ensure the elimination, or at least minimisation of particle agglomeration.
  • Therapeutic uses of the medicaments of the invention include pain relief, anti-inflammatory, migraine, asthma, and other disorders that require the active agent to be administered with a high bioavailability.
  • the minor analgesics such as cyclooxygenase inhibitors (aspirin related drugs) may be prepared as medicaments according to the present invention.
  • Medicaments of the invention may also be used for treatment of eye disorders. That is, the biologically active compound in nanoparticulate form may be formulated for administration on the eye as an aqueous suspension in physiological saline, or a gel. In addition, the biologically active compound in nanoparticulate form may be prepared in a powder form for administration via the nose for rapid central nervous system penetration.
  • Treatment of cardiovascular disease may also benefit from biologically active compounds in nanoparticulate form according to the invention, such as treatment of angina pectoris and, in particular, molsidomine may benefit from better bioavailability.
  • medicaments of the present invention include treatment of hair loss, sexual dysfunction, or dermal treatment of psoriasis.
  • the present invention encompasses particulate amorphous raloxifene, pharmaceutically acceptable raloxifene salts and solvates. Methods for the preparation of such amorphous compounds are described in U.S. Pat. No. 6,713,494 (Eli Lilly and Company).
  • raloxifene or the pharmaceutically acceptable salt or solvate of the present invention is crystalline, the present invention should not be understood to be limited to any particular polymorph thereof.
  • Pharmaceutically acceptable salts of the present invention may be formed from a range of organic or inorganic acids.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like.
  • Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caproate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphat
  • a preferred salt is the hydrochloride salt.
  • compositions may be prepared which exhibit improved in vitro dissolution profiles and in vivo bioavailability relative to some known raloxifene hydrochloride forms. Further, in some forms of the invention, these improvements may be achieved without importing characteristics that are disadvantageous from a manufacturing perspective.
  • the invention is characterised in that the particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof, in particulate form having a mean particle size of between about 10 nm and about 500 nm.
  • the mean particle size is between about 75 nm and about 500 nm. In one form of the invention, the mean particle size is between about 75 nm and about 400 nm. In one form of the invention, the mean particle size is between about 75 nm and about 300 nm. In one form of the invention, the mean particle size is between about 75 nm and about 200 nm. In one form of the invention, the mean particle size is between about 75 nm and about 100 nm.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a narrow particle size distribution.
  • about 90% of the particles have a particle size of less than about 500 nm.
  • the particles distribution can be measured with dynamic light scattering of a dispersion of the particles with the aid of sonication, and after centrifugation at 500 rcf for 30 seconds to remove larger agglomerates from the dispersion.
  • Other means to measure the particles size are for examples surface area measurements, and electron micrographs, which can be used to support the measured size distribution of the particles.
  • about 50% of the particles have a particle size of less than 500 nm. In another form of the invention, about 90% of the particles have a particle size of less than 500 nm. In one form of the invention, about 90% of the particles have a particle size of between about 100 and 500 nm. In one form of the invention, about 90% of the particles have a particle size of between about 75 nm and about 500 nm. In one form of the invention, about 90% of the particles have a particle size of between about 75 nm and about 400 nm. In one form of the invention, about 90% of the particles have a particle size of between about 75 nm and about 300 nm. In one form of the invention, about 90% of the particles have a particle size of between about 75 nm and about 200 nm. In one form of the invention, about 90% of the particles have a particle size of between about 75 nm and about 100 nm.
  • particle size In addition to the role of particle size in vitro dissolution and in vivo absorption, another important aspect is its role on the various operations of the drug product manufacturing process. While the particle size specification ensures consistent delivery of the drug molecule to the sites of absorption in the gastrointestinal tract, it also allows for better control during the wet granulation step of the tablet manufacturing process.
  • the granulation step is common to many tablet and capsule manufacturing operations and is typically driven by the addition of water to bring about the desired endpoint of the granulation.
  • a downstream unit operation dependent upon the granulation endpoint is the milling of the dried granulation and the resulting particle size distribution obtained on the granulation. It has been discovered that the incoming particle size of the active ingredient also effects the ultimate particle size distribution of the dry milled agglomerates formed during granulations.
  • Agglomerates comprising particles of raloxifene, a pharmaceutically acceptable salt or solvate thereof, said particles having a mean particle size of between about 10 nm and about 500 nm, should be understood to fall within the scope of the present invention, regardless of whether the agglomerates exceed 500 nm in size.
  • agglomerates of particles of raloxifene, or a pharmaceutically acceptable salt or solvate thereof, of the invention may afford the advantages of improved in vitro dissolution and in vivo bioavailability relative to some known raloxifene hydrochloride forms without attracting the processing disadvantages conventionally associated with decreased particle sizes.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area of in excess of 5 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 7 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 10 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 15 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 20 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 25 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 30 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 35 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 40 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 50 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area in excess of 55 m 2 /g.
  • the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof has a surface area of up to approximately 57 m 2 /g.
  • particulate crystalline raloxifene or a pharmaceutically acceptable salt or solvate thereof which, when administered orally to dogs, demonstrates a peak plasma concentration (C max ) of greater than 12 ng/mL.
  • particulate crystalline raloxifene or a pharmaceutically acceptable salt or solvate thereof which, when administered orally to dogs, demonstrates an area under the concentration versus time curve (AUC 0-t ) greater than 33 ng.h/mL.
  • particulate crystalline raloxifene or a pharmaceutically acceptable salt or solvate thereof which, when administered orally to dogs, demonstrates a median time to maximum plasma concentration (T max ) of within 1 hour.
  • the present invention further provides methods for producing said particulate raloxifene, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention comprises a method for producing a particulate raloxifene, or a pharmaceutically acceptable salt or solvate thereof, with a mean particle size of between about 10 nm and about 500 nm, the method comprising the step of:
  • the milling step is a dry milling step.
  • the mean particle size is between about 75 nm and about 500 nm. In one form of the invention, the mean particle size is between about 75 nm and about 400 nm. In one form of the invention, the mean particle size is between about 75 nm and about 300 nm. In one form of the invention, the mean particle size is between about 75 nm and about 200 nm. In one form of the invention, the mean particle size is between about 75 nm and about 100 nm.
  • about 50% of the particles have a particle size of less than about 500 nm.
  • about 90% of the particles have a particle size of between about 100 and 500 nm.
  • about 90% of the particles have a particle size of between about 75 nm and about 500 nm.
  • about 90% of the particles have a particle size of between about 75 nm and about 400 nm.
  • about 90% of the particles have a particle size of between about 75 nm and about 300 nm.
  • about 90% of the particles have a particle size of between about 75 nm and about 200 nm.
  • about 90% of the particles have a particle size of between about 75 nm and about 100 nm.
  • millable means that the grinding compound is capable of being physically degraded under the dry milling conditions of the method of the invention.
  • the milled grinding compound is of a comparable particle size to the nanoparticulate biologically active compound.
  • the grinding compound is harder than the solid raloxifene, pharmaceutically acceptable salt or solvate thereof, and is thus capable of physically degrading such under the dry milling conditions of the invention.
  • 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 raloxifene or the pharmaceutically acceptable salt or solvate thereof.
  • the solid dispersion or solution of raloxifene or the pharmaceutically acceptable salt or solvate thereof may then be separated from the milling bodies and removed from the mill.
  • the grinding compound is separated from the dispersion or solution. In a further aspect, at least a portion of the milled grinding compound is separated from the particulate raloxifene hydrochloride.
  • 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 particulate raloxifene, pharmaceutically acceptable salt or solvate thereof, and the extent of physical degradation of the grinding compound, is sufficient to inhibit reagglomeration of the raloxifene, pharmaceutically acceptable salt or solvate thereof.
  • the grinding compound is not chemically reactive with the pharmaceutical raloxifene, pharmaceutically acceptable salt or solvate thereof under the milling conditions of the invention.
  • the milled grinding compound is of a comparable particle size to the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof.
  • the physical properties of the grinding compound necessary to achieve the requisite degradation are dependant on the precise milling conditions. For example a harder grinding compound may degrade to a sufficient extent provided under more vigorous dry milling conditions.
  • Physical properties of the grinding compound relevant to the extent that the agent will degrade under dry milling conditions include hardness, friability, as measured by indicia such as fracture toughness and brittleness index.
  • the grinding compound is of low abrasivity.
  • Low abrasivity is desirable to minimise contamination of the dispersion or solution of the particulate raloxifene hydrochloride in the grinding compound by the milling bodies and/or the milling chamber of the media mill.
  • An indirect indication of the abrasivity can be obtained by measuring the level of milling-based contaminants.
  • the grinding compound has a low tendency to agglomerate during dry milling. While it is difficult to objectively quantify the tendency to agglomerate during milling, it is possible to obtain a subjective measure by observing the level of “caking” of the grinding compound on the milling bodies and the milling chamber of the media mill as dry milling progresses.
  • the grinding compound may be an inorganic or organic compound.
  • the grinding compound is selected from the following: sodium hydrogen sulfate, sodium hydrogen carbonate, sodium hydroxide, or succinic acid; crystalline organic acids, for example (but not limited to) fumaric acid, maleic acid, tartaric acid, citric acid); alternatively ammonium salts (or salts of volatile amines), for example (but not limited to) ammonium chloride, methylamine hydrochloride, ammonium bromide, crystalline hydroxides, hydrogen carbonates, hydrogen carbonates of pharmaceutical acceptable alkali metals, such as but not limited by, sodium, potassium, lithium, calcium, and barium, sodium sulphate, sodium chloride, sodium metabisulphite, sodium thiosulphate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulphate, magnesium sulphate, potash alum, potassium chloride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate.
  • 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 particulate raloxifene, pharmaceutically acceptable salt or solvate thereof by methods not dependent on particle size (such methods being inappropriate due to the degradation of the grinding compound).
  • selecting an appropriate grinding compound that also possesses solubility properties different from the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof allows separation of the two by relatively straightforward selective dissolution techniques. Examples of such grinding compounds are provided in the detailed description of the invention.
  • a particularly advantageous application of the method of the invention is the use of a water-soluble salt as a grinding compound.
  • 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 particulate raloxifene, pharmaceutically acceptable salt or solvate thereof 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.
  • the medicament may include only the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof together with the milled grinding compound or, more preferably, the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof 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.
  • the grinding compound is both appropriate for use in a medicament and readily separable from the particulate raloxifene, pharmaceutically acceptable salt or solvate thereof 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 particulate raloxifene, pharmaceutically acceptable salt or solvate thereof into a medicament.
  • the grinding compound is sodium chloride. In one form of the invention, the grinding compound is calcium carbonate.
  • the grinding compound is a compound that is considered GRAS (generally regarded as safe) by persons skilled in the pharmaceutical arts.
  • the step of substantially drying the solid raloxifene, pharmaceutically acceptable salt or solvate is performed by exposing the raloxifene hydrochloride to a drying agent under vacuum for a suitable period of time. Persons skilled in the art will be aware of a range of appropriate drying agents.
  • the drying agent is P 2 O 5 .
  • the number and size of milling bodies can be varied to alter the amount of energy applied during the milling. This results in variation of the size and characteristics of the resultant raloxifene.
  • the examples show certain combinations optimized for the current scale of manufacture, however those skilled in the art will appreciate that as the process is scaled, variations to milling media size, number and energy applied will be required to produce the same product.
  • the concentration of solid raloxifene, pharmaceutically acceptable salt or solvate, in the mixture of solid raloxifene solid raloxifene, pharmaceutically acceptable salt or solvate, and the millable grinding compound is between about 5% and about 25% v/v.
  • the concentration is between about 5% and about 20% v/v.
  • the concentration is between about 10% and about 15% v/v. In one form of the invention, the concentration is about 15% v/v.
  • the milling bodies are preferably chemically inert and rigid.
  • chemically-inert means that the milling bodies do not react chemically with the rolixifene hydrochloride or the grinding compound.
  • the milling bodies are essentially resistant to fracture and erosion in the milling process.
  • the milling bodies are desirably provided in the form of bodies which may have any of a variety of smooth, regular shapes, flat or curved surfaces, and lacking sharp or raised edges.
  • suitable milling bodies can be in the form of bodies having ellipsoidal, ovoid, spherical or right cylindrical shapes.
  • the milling bodies are provided in the form of one or more of beads, balls, spheres, rods, right cylinders, drums or radius-end right cylinders (i.e., right cylinders having hemispherical bases with the same radius as the cylinder).
  • the milling media bodies desirably have an effective mean particle diameter (i.e. “particle size”) between about 0.1 and 30 mm, more preferably between about 1 and about 15 mm, still more preferably between about 3 and 10 mm.
  • particle size an effective mean particle diameter
  • the milling bodies may comprise various materials such as ceramic, glass, metal or polymeric compositions, in a particulate form.
  • Suitable metal milling bodies are typically spherical and generally have good hardness (i.e. RHC 60-70), roundness, high wear resistance, and narrow size distribution and can include, for example, balls fabricated from type 52100 chrome steel, type 316 or 440C stainless steel or type 1065 high carbon steel.
  • Preferred ceramic materials may be selected from a wide array of ceramics desirably having sufficient hardness and resistance to fracture to enable them to avoid being chipped or crushed during milling and also having sufficiently high density. Suitable densities for milling media can range from about 1 to 15 g/cm 3 . Preferred ceramic materials can be selected from steatite, aluminum oxide, zirconium oxide, zirconia-silica, yttria-stabilized zirconium oxide, magnesia-stabilized zirconium oxide, silicon nitride, silicon carbide, cobalt-stabilized tungsten carbide, and the like, as well as mixtures thereof.
  • Preferred glass milling media are spherical (e.g. beads), have a narrow size distribution, are durable, and include, for example, lead-free soda lime glass and borosilicate glass.
  • Polymeric milling media are preferably substantially spherical and can be selected from a wide array of polymeric resins having sufficient hardness and friability to enable them to avoid being chipped or crushed during milling, abrasion-resistance to minimize attrition resulting in contamination of the product, and freedom from impurities such as metals, solvents, and residual monomers.
  • Preferred polymeric resins can be selected from crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethylmethacrylate, polycarbonates, polyacetals, vinyl chloride polymers and copolymers, polyurethanes, polyamides, high density polyethylenes, polypropylenes, and the like.
  • crosslinked polystyrenes such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethylmethacrylate, polycarbonates, polyacetals, vinyl chloride polymers and copolymers, polyurethanes, polyamides, high density polyethylenes, polypropylenes, and the like.
  • Polymeric resins typically can have densities ranging from about 0.8 to 3.0 g/cm 3 . Higher density polymeric resins are preferred.
  • the milling media can be composite particles comprising dense core particles having a polymeric resin adhered thereon. Core particles can be selected from materials known to be useful as milling media, for example, glass, alumina, zirconia silica, zirconium oxide, stainless steel, and the like. Preferred core materials have densities greater than about 2.5 g/cm 3 .
  • the milling media are formed from a ferromagnetic material, thereby facilitating removal of contaminants arising from wear of the milling media by the use of magnetic separation techniques.
  • metals have the highest specific gravities, which increase grinding efficiency due to increased impact energy.
  • Metal costs range from low to high, but metal contamination of final product can be an issue.
  • Glasses are advantageous from the standpoint of low cost and the availability of small bead sizes as low as 0.004 mm.
  • specific gravity of glasses is lower than other media and significantly more milling time is required.
  • ceramics are advantageous from the standpoint of low wear and contamination, ease of cleaning, and high hardness.
  • the milling bodies comprise a plurality of steel balls of approximately 3 cm 3 volume and 40 g mass.
  • the solid raloxifene, or pharmaceutically acceptable salt or solvate thereof, and grinding compound, in the form of crystals, powders, or the like, are combined in suitable proportions with the plurality of milling bodies in a milling chamber that is mechanically agitated (i.e., with or without stirring) for a predetermined period of time at a predetermined intensity of agitation.
  • a milling apparatus is used to impart motion to the milling bodies by the external application of agitation, whereby various translational, rotational or inversion motions or combinations thereof are applied to the milling chamber and its contents, or by the internal application of agitation through a rotating shaft terminating in a blade, propeller, impeller or paddle or by a combination of both actions.
  • the solid raloxifene hydrochloride and the grinding compound is influenced by a wide variety of processing parameters including: the type of milling apparatus; the intensity of the forces generated, the kinematic aspects of the process; the size, density, shape, and composition of the milling bodies; the weight ratio of the raloxifene hydrochloride and grinding compound mixture to the milling bodies; the duration of milling; the physical properties the grinding compound; the atmosphere present during activation; and others.
  • the media mill is capable of repeatedly or continuously applying mechanical compressive forces and shear stress to the biologically active compound substrate and the grinding compound.
  • Suitable media mills include but are not limited to the following: high-energy ball, sand, bead or pearl mills, basket mill, planetary mill, vibratory action ball mill, multi-axial shaker/mixer, stirred ball mill, horizontal small media mill, multi-ring pulverizing mill, and the like, including small milling media.
  • the milling apparatus also can contain one or more rotating shafts.
  • the dry milling is effected in a ball mill.
  • dry milling being carried out by way of a ball mill.
  • examples of this type of mill are attritor mills, nutating mills, tower mills, planetary mills, vibratory mills and gravity-dependent-type ball mills.
  • dry milling in accordance with the method of the invention may also be achieved by any suitable means other than ball milling.
  • dry milling may also be achieved using jet mills, rod mills, roller mills or crusher mills.
  • the particle size of the solid raloxifene, or pharmaceutically acceptable salt or solvate thereof be less than about 100 ⁇ m, as may be determined by sieve analysis. If the coarse particle size of the solid raloxifene or pharmaceutically acceptable salt or solvate thereof, is greater than about 100 ⁇ m, then it is preferred that the particles of the solid raloxifene, or pharmaceutically acceptable salt or solvate thereof, be first reduced in size to less than 100 ⁇ m using a conventional milling method such as airjet or fragmentation milling.
  • compositions comprising, or Formulated Using, Particulate Raloxifene, or Pharmaceutically Acceptable Salt or Solvate Thereof, According to the Invention
  • the present invention also provides pharmaceutical compositions comprising or formulated using the said particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof.
  • compositions of the invention may include a pharmaceutically acceptable carrier, wherein “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the pharmaceutically acceptable carrier is suitable for parenteral, intravenous, intraperitoneal, intramuscular, sublingual, transdermal or oral administration.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for the manufacture of pharmaceutical compositions is well known in the art. Except insofar as any conventional media or agent is incompatible with the particulate raloxifene hydrochloride of the invention, use thereof in the manufacture of a pharmaceutical composition according to the invention is contemplated.
  • compositions according to the invention may include one or more of the following additives:
  • compositions suitable for use in animals and in particular in man typically must be sterile and stable under the conditions of manufacture and storage.
  • the pharmaceutical composition comprising nanoparticles can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • compositions of the invention can be administered to humans and animals in any pharmaceutically acceptable manner, such as orally, rectally, pulmonary, intravaginally, locally (powders, ointments or drops), transdermal, or as a buccal or nasal spray.
  • Raloxifene is subject to significant first-pass metabolism, which impacts on bioavailability.
  • Conventionally formulated raloxifene is generally considered not to be amenable to transdermal delivery.
  • the particulate raloxifene, or pharmaceutically acceptable salt or solvate of the present invention is more amenable to such delivery.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, pellets, granules, and the like. Such dosage forms may also comprise buffering agents.
  • compositions of the invention may be parenterally administered as a solution of the particulate raloxifene hydrochloride suspended in an acceptable carrier, preferably an aqueous carrier.
  • an acceptable carrier preferably an aqueous carrier.
  • aqueous carriers e.g., water, buffered water, 0.4% saline, 0.3% glycine, hyaluronic acid and the like.
  • These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered.
  • the resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration.
  • compositions of the invention are preferably supplied along with a surface stabilizer and propellant.
  • the surface stabilizer must be non-toxic, and preferably soluble in the propellant.
  • Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters, such as mixed or natural glycerides may be employed.
  • the surface stabilizer may constitute 0.1%-20% by weight of the composition, preferably 0.25-5%. The balance of the composition is ordinarily propellant.
  • a carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery.
  • compositions of the invention may also be administered via liposomes, which serve to target the active agent to a particular tissue, such as lymphoid tissue, or targeted selectively to cells.
  • liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.
  • the nanocomposite microstructure composition is incorporated as part of a liposome, alone or in conjunction with a molecule that binds to or with other therapeutic or immunogenic compositions.
  • the compounds of this invention are well suited to formulation as sustained release dosage forms.
  • the formulations can also be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, and/or over a period of time.
  • Such formulations may include coatings, envelopes, or protective matrices which may be made from polymeric substances or waxes.
  • Suitable surface stabilisers may include CTAB, cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, stearic acid esters and salts, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline
  • Suitable surface stabilisers may also include a cationic surface stabilizer selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, and a phospholipid.
  • a cationic surface stabilizer selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, and a phospholipid.
  • Suitable surface stabilisers may also include a surface stabilizer selected from the group consisting of cationic lipids, benzalkonium chloride, sulfonium compounds, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C 12-15 dimethyl hydroxyethyl ammonium chloride, C 12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium
  • the preferred surface stabilizer is CTAB.
  • the surface stabilizer of the pharmaceutical composition is the same surface stabilizer as that used in the method. As would be understood by person skilled in the art, it may be desirable to add further quantities of the surface stabilizer to the particulate raloxifene hydrochloride for the purposes of preparing a pharmaceutical composition.
  • the water-soluble diluent of the pharmaceutical composition is the same as the grinding compound used in the method.
  • the pharmaceutical composition of the invention is an oral dosage form comprising particulate raloxifene according to the invention, or pharmaceutically acceptable salt or solvate thereof, according to the invention, a surfactant in the form of CTAB, and a water-soluble diluent in the form of sodium chloride.
  • the particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof may be administered along with an effective amount of an additional therapeutic agent, including but not limited to estrogen, progestin, benzothiophene compounds including raloxifene, naphthyl compounds having antiestrogen activity, bisphosphonate compounds such as alendronate and tiludronate, parathyroid hormone (PTH), including truncated and/or recombinant forms of PTH such as, for example, PTH (1-34), calcitonin, bone morphogenic proteins (BMPs), or combinations thereof.
  • PTH parathyroid hormone
  • BMPs bone morphogenic proteins
  • estradien includes compounds having estrogen activity and estrogen-based agents.
  • Estrogen compounds useful in the practice of the present invention include, for example, estradiol estrone, estriol, equilin, equilenin, estradiol cypionate, estradiol valerate, ethynyl estradiol, polyestradiol phosphate, estropipate, diethylstibestrol, dienestrol, chlorotrianisene, and mixtures thereof.
  • Estrogen-based agents include, for example, 17-.alpha.-ethynyl estradiol (0.01-0.03 mg/day), mestranol (05-0.15 mg/day), and conjugated estrogenic hormones such as PremarinTM (Wyeth-Ayerst; 0.2-2.5 mg/day).
  • progestin includes compounds having progestational activity such as, for example, progesterone, norethynodrel, norgestrel, megestrol acetate, norethindrone, progestin-based agents, and the like.
  • Progestin-based agents include, for example, medroxyprogesterone such as ProveraTM (Upjohn; 2.5-10 mg/day), norethylnodrel (1.0-10.0 mg/day), and norethindrone (0.5-2.0 mg/day).
  • a preferred estrogen-based compound is PremarinTM, and norethylnodrel and norethindrone are preferred progestin-based agents.
  • the method of administration of each estrogen- and progestin-based agent is consistent with that known in the art.
  • a mixture consisting of a biologically active compound in the form of 0.439 g of diclofenac acid (DCA)
  • Ultra-fine particles of diclofenac acid in nanoparticulate form were recovered by removing the grinding compound through washing with dilute hydrochloric acid. The washed powder was subsequently dried at room temperature for several hours in air.
  • the dispersion was washed as follows. To obtain 0.25 g of diclofenac particles varying amounts of dispersion were used, depending on the volume percentage. For a 15 vol % DCA dispersion, 2.339 g was slowly added to 40 mL of a vigorously stirred solution of 0.01 M HCl and 1 mM CTAB (cetyl trimethyl ammonium bromide) in a conical flask. The sample was stirred for 30 minutes and filled into 15 mL plastic tubes for centrifugation (falcon tubes).
  • CTAB cetyl trimethyl ammonium bromide
  • the sample was then subjected to 3 repeats of: centrifugation (whereas the centrifugation speed was increased for each washing step from 5,000 g to 8,000 g and finally to 12,000 g for a period of 3 minutes), removal of supernatant, addition of 0.01 M HCl and 1 mM CTAB, and redispersion by vortex and ultrasound sonication (5-10 seconds each).
  • the SEM and TEM images demonstrate that nanoparticles of a diameter in the order of 100-200 nm size range after washing.
  • BET results illustrated in FIG. 1 show the highest surface area (11.755 ⁇ 0.1035 m 2 /g) obtained was for the 5 vol % DCA.
  • Dynamic light scatter (DLS) analysis showed particle sizes of 160 ⁇ 30 nm.
  • the resulting dispersion for the 15 vol % sample, stabilized with the surface stabilizer CTAB was found to comprise the diclofenac acid form of the drug (by XRD, FTIR and DSC), with nanoparticles less than 200 nm and the majority on the order of 30-50 nm.
  • TEM of the DCA in nanoparticulate form (after washing the dispersion and stabilized with the surface stabilizer CTAB) also showed both spherical and nonspherical nanoparticles, the nonspherical particles appearing to be rod-shaped, having a minor-axis dimension of about 30 nm and a major-axis dimension of about 150 nm.
  • DSC analysis of the melting point of the DCA in nanoparticulate form confirmed its identity as diclofenac acid, with a melting point in the range of 175-185° C.
  • FIG. 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.
  • a biologically active compound in the form of 0.39 g of conventional olanzapine powder A biologically active compound in the form of 0.39 g of conventional olanzapine powder,
  • a milling apparatus (a 70 cm 3 stainless steel ball mill container) with grinding compound in the form of 3.68 g of NaCl, thereby providing the mixture at 9.6 and 90.4 weight % respectively, corresponding to 15 and 85 volume %, with a total volume of 2 cm 3 .
  • Milling media comprising 40 g of 10 mm steel balls (10 pieces) were employed in the container.
  • the milling apparatus was closed under house vacuum prior to milling. Cooling was achieved with compressed air flow (100 kcpa).
  • the mixture was dry milled for 15 minutes and 180 minutes, the composition resulting after milling for both times comprised olanzapine in nanoparticulate form dispersed in the grinding medium NaCl.
  • SEM scanning electron microscopy
  • Milling media comprising 40 g of 10 mm steel balls (10 pieces) were employed in the mill. Cooling was achieved with compressed air flow (100 kcpa). Milling time was 15 minutes and the composition resulting after milling comprised DCA in nanoparticulate form dispersed in NH 4 Cl grinding compound.
  • the nanoparticle size can be seen from a representative TEM after washing ( FIG. 5 ) and is about 200 nm in diameter (washing with 0.01 M HCl and 1 mM CTAB was performed as described for DCA NaCl milling).
  • the melting point of DSC shows that the nanoparticles are obtained as the diclofenac acid ( FIG. 6 ).
  • the melting point of diclofenac acid is after literature at 182° C., one can see a melting point at 177° C., the shift is probably due to the small particles size.
  • the large peak at 194° C. is due to NH 4 Cl.
  • the water-soluble diluent of the pharmaceutical composition is the same as the grinding compound used in the method.
  • the pharmaceutical composition of the invention is an oral dosage form comprising particulate raloxifene according to the invention, or pharmaceutically acceptable salt or solvate thereof, according to the invention, a surfactant in the form of CTAB, and a water-soluble diluent in the form of sodium chloride.
  • the particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof may be administered along with an effective amount of an additional therapeutic agent, including but not limited to estrogen, progestin, benzothiophene compounds including raloxifene, naphthyl compounds having antiestrogen activity, bisphosphonate compounds such as alendronate and tiludronate, parathyroid hormone (PTH), including truncated and/or recombinant forms of PTH such as, for example, PTH (1-34), calcitonin, bone morphogenic proteins (BMPs), or combinations thereof.
  • PTH parathyroid hormone
  • BMPs bone morphogenic proteins
  • estradien includes compounds having estrogen activity and estrogen-based agents.
  • Estrogen compounds useful in the practice of the present invention include, for example, estradiol estrone, estriol, equilin, equilenin, estradiol cypionate, estradiol valerate, ethynyl estradiol, polyestradiol phosphate, estropipate, diethylstibestrol, dienestrol, chlorotrianisene, and mixtures thereof.
  • Estrogen-based agents include, for example, 17-.alpha.-ethynyl estradiol (0.01-0.03 mg/day), mestranol (05-0.15 mg/day), and conjugated estrogenic hormones such as PremarinTM (Wyeth-Ayerst; 0.2-2.5 mg/day).
  • progestin includes compounds having progestational activity such as, for example, progesterone, norethynodrel, norgestrel, megestrol acetate, norethindrone, progestin-based agents, and the like.
  • Progestin-based agents include, for example, medroxyprogesterone such as ProveraTM (Upjohn; 2.5-10 mg/day), norethylnodrel (1.0-10.0 mg/day), and norethindrone (0.5-2.0 mg/day).
  • a preferred estrogen-based compound is PremarinTM, and norethylnodrel and norethindrone are preferred progestin-based agents.
  • the method of administration of each estrogen- and progestin-based agent is consistent with that known in the art.
  • the present invention further provides the use of the said particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for alleviating pathologies, including osteoporosis, serum lipid lowering, and inhibiting endometriosis, uterine fibrosis, and breast cancer, and the use of compositions comprising or formulated using the said particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof, for alleviating pathologies, including osteoporosis, serum lipid lowering, and inhibiting endometriosis, uterine fibrosis, and breast cancer.
  • the present invention provides a method for the treatment of a pathology, such as osteoporosis, serum lipid lowering, and inhibiting endometriosis, uterine fibrosis, and breast cancer by administration of a therapeutically effective amount of particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof, according to the invention.
  • a pathology such as osteoporosis, serum lipid lowering, and inhibiting endometriosis, uterine fibrosis, and breast cancer by administration of a therapeutically effective amount of particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof, according to the invention.
  • the particular dosage of particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof, required to treat, inhibit, or prevent the symptoms and/or disease of a mammal, including humans, suffering from the above maladies according to this invention will depend upon the particular disease, symptoms, and severity, as well as the potential increased efficacy due to particulate form of the raloxifene, or pharmaceutically acceptable salt or solvate thereof, (e.g., increased solubility, more rapid dissolution, increased surface area).
  • Amounts effective for such a use will depend on: the desired therapeutic effect; the route of administration; the potency of the therapeutically active agent; the desired duration of treatment; the stage and severity of the disease being treated; the weight and general state of health of the patient; and the judgment of the prescribing physician.
  • accepted and effective doses will be from 15 mg to 1000 mg, and more typically from 15 mg to 80 mg.
  • Such dosages will be administered to a patient in need of treatment from one to three times each day or as often as needed for efficacy, generally for periods of at least two months, more typically for at least six months, or chronically.
  • the particulate raloxifene, or pharmaceutically acceptable salt or solvate thereof, of this invention can be administered by a variety of routes, the selection of which will be decided by the attending physician.
  • raloxifene compounds of the current invention may be made according to established procedures, such as those detailed in U.S. Pat. Nos. 4,133,814, 4,418,068, and 4,380,635, and European Patent Application 95306050.6, Publication No. 0699672, Kjell, et al., filed Aug. 30, 1995, published Mar. 6, 1996, all of which are herein incorporated by reference.
  • European Patent Application number 0670162 A1 published on Sep. 6, 1995, is herein incorporated by reference.
  • raloxifene hydrochloride (0.5805 g) was introduced with NaCl (5.5208 g) into a steel vessel (75 cm 3 ) with milling bodies comprising 10 ⁇ 10 mm steel balls.
  • the total volume of the raloxifene hydrochloride/salt mixture was 3 cm 3 with 15 vol % of drug.
  • Both the raloxifene hydrochloride and the sodium chloride grinding compound were kept dry prior to milling by storage under vacuum and over P 2 O 5 .
  • the steel milling chamber was closed under vacuum to remove moisture and air, to reduce degradation/oxidization.
  • the milling chamber was mounted on a Spex ball mill and was shaken for 15 min and cooled by a stream of compressed air. This resulted in the formation of a solid-dispersion consisting of raloxifene hydrochloride dispersed within a matrix of fine NaCl.
  • the milling chamber was then carefully opened to release the vacuum, and closed to allow any airborne particles to settle.
  • the milling chamber was then opened in a fume hood to prevent inhalation of the fine particles, and the contents transferred through a 2 mm sieve (to remove the milling bodies) into 8 mL glass vials and stored in a vacuum desiccator over P 2 O 5 .
  • the solid-dispersion was washed as follows.
  • the solid dispersion was mixed with 0.1 g of the surfactant CTAB, and placed in a 25 mL Schott bottle. 20 mL of ice cooled solution of 0.1 M HCl and 1 mM cetyl trimethyl ammonium bromide (CTAB) were added.
  • CTAB cetyl trimethyl ammonium bromide
  • the sample was then subjected to the following (3 ⁇ ): centrifugation (the centrifugation speed was increased for each washing step from 6000 g to 8000 g and finally to 12000 g for a period of 3 minutes each), removal of supernatant, addition of 0.01 M HCl and 1 mM CTAB, and redispersion by vortex mixing.
  • the dispersion was then transferred onto a watch glass and dried over a stream of air. After drying for about 3 hours the suspension dried down to form a dry layer on the glass surface, this was stored over night in a vacuum desiccator over P 2 O 5 . This yielded 0.48 g of dried powder which was stored in a glass vial in a vacuum desiccator.
  • the dissolution properties of the particulate raloxifene hydrochloride were tested with a USP apparatus in simulated gastric conditions, and compared with commercial raloxifene hydrochloride. About 60 mg of particulate raloxifene hydrochloride and commercial raloxifene hydrochloride, respectively, were introduced into gelatin capsules. The dissolution properties were followed as a function of solution concentration versus time.
  • the dissolution conditions were as follows: 1 L of 0.1 M HCl containing 2 g of NaCl were degassed and brought to 37° C. in a USP conform dissolution vessel to paddle and stirred at about 80 rpm.
  • the raloxifene hydrochloride was either tested as powder or in gelatin capsule with a metal sinker. For each time point, 2 mL of sample were removed from the solution, to remove larger aggregates it was centrifuged for 1 min at 10000 g and 1.5 ml was taken from the top of the solution and the concentration was measured using a Waters HPLC running a method validated with respect to specificity, linearity, precision and repeatability.
  • the dissolution profile in FIG. 8 shows significantly enhanced solubility properties of the particulate raloxifene hydrochloride as opposed to the commercial raloxifene hydrochloride, this can be seen for example in a nearly five fold increase in solution concentration after 50 minutes in simulated intestinal fluid. To understand these data it needs to be emphasized that the conditions were kept close to the marketed dosage of raloxifene and the concentration of 60 mg of drug per liter are well above the solubility.
  • the commercial raloxifene HCl particles seem to have a broad size distribution with glassy particles of up to several micrometers.
  • small structures in the size of about 100-200 nm are a predominant feature ( FIG. 9 b ).
  • the particle-like structures show a size of about 100-200 nm ( FIGS. 9 c and d ).
  • the size determined by SEM is in good agreement with the size distribution of the dispersion before drying by dynamic light scatter (DLS) ( FIG. 10 ).
  • the particles size was determined with a Malvern HPPS dynamic light scattering apparatus with a size distribution after number of 128 ⁇ 53 nm (number weighted) in intensity a second peak of 300 nm was detected. Prior to the measurement any larger aggregates or agglomerates were removed by 1 min centrifugation at 6000 g, and only the supernatant was analyzed. This indicates that the particles obtained in the milling process did not significantly grow during the washing procedure.
  • the melting point shows a ten degree Celsius reduced onset for nanoparticulate raloxifene HCl, as compared to the commercial product, being further evidence for a reduced particle size ( FIG. 11 ).
  • the XRD-spectra ( FIG. 12 ) shows that the nanoparticulate raloxifene HCl appears to be in the same crystalline phase as the commercial raloxifene HCl, and suggest that the particles remain crystalline.
  • the relative broadening of the peaks of the nanoparticles raloxifene as compared to the commercial raloxifene is a further indicator of the reduced particles size.
  • the solution 1 H-NMR-spectra shown in FIG. 13 , confirms that the compound is identical to the commercial raloxifene HCl, it was also determined that about 2 w % of the surfactant CTAB are present after washing and drying.
  • the solution 1 H NMR spectra were measured of about 10 mg of particulate raloxifene HCl and commercial raloxifene HCl (data not shown) dissolved in d6-DMSO.
  • the FT-IR-spectra shows further the chemical identity of raloxifene HCl and the nanoparticulate raloxifene HCl.
  • raloxifene hydrochloride (0.3867 g) was introduced with NaCl (3.672 g) into a steel vessel (75 cm 3 ) with milling bodies comprising 10 ⁇ 10 mm steel balls.
  • the total volume of the raloxifene hydrochloride/salt mixture was 2 cm 3 with 15 vol % of drug.
  • Both the raloxifene hydrochloride and the sodium chloride grinding compound were used without any additional drying step prior to the milling.
  • the steel milling chamber was closed under vacuum to remove moisture from the air, and to reduce degradation/oxidization.
  • the milling chamber was mounted on a Spex ball mill and was shaken for 15 min and cooled by a stream of compressed air. This resulted in the formation of a solid-dispersion consisting of raloxifene hydrochloride dispersed within a matrix of fine NaCl.
  • the milling chamber was then carefully opened to release the vacuum, and closed to allow any airborne particles to settle.
  • the milling chamber was then opened in a fume hood to prevent inhalation of the fine particles, and the contents transferred through a 2 mm sieve (to remove the milling bodies) into 8 mL glass vials and stored in a vacuum desiccator over P2O5.
  • the solid-dispersion was washed as follows. About 4.1 g of the solid dispersion was placed in a 25 mL Schott bottle, and added 20 mL of ice cooled solution of 0.1 M HCl and 1 mM sodium dodecyl sulfate (SDS) was added. The bottle was closed and immediately mounted in the Spex ball mill and shaken for 1 min. After the shaking procedure a pale yellow dispersion was formed, and stored in an ice bath prior to centrifugation. The sample was then subjected to a centrifugation step at 6000 g for a period of 3 minutes, and the supernatant was removed. The sample was dispersed with 4 mL of 0.1 M HCl and 1 mM SDS solution.
  • SDS sodium dodecyl sulfate
  • the dispersion was then transferred onto a watch glass and dried over a stream of air. After drying for about 3 hours the suspension dried down to form a dry layer on the glass surface, this was stored over night in a vacuum desiccator over P 2 O 5 .
  • the XRD shows that after milling and washing the crystal structure of raloxifene HCl is lost, and the broad increase in intensity from 10 to 35 (2 Theta) is indicative for an amorphous phase ( FIG. 15 ).
  • the XRD spectrum shows the different processing stage, before milling, after milling, and after washing.
  • the commercial Raloxifene HCl shows distinct peaks that are due to its crystalline state. Prevalent peaks after salt milling are mostly due to sodium chloride and the usage of an aluminium sample holder, the peaks of raloxifene HCl can not be identified, as they are too dilute in the matrix. After the one washing step some peaks of the sodium chloride remain, but only a broad band of raloxifene HCl can be seen, which can be attributed to amorphous phase.
  • the SEM shows that some small particles were formed with a size of about 100-200 nm. Some of the particles seem to be slightly elongated ( FIG. 16 ).
  • the BET surface area was measured to be 10.6 m 2 /g, which confirms that a material with high surface was formed and supports results from the SEM image.
  • the IR-spectra in particular the peak at 2960 cm ⁇ 1 , indicates that raloxifene HCl salt is present in the in both the milled and milled and washed samples ( FIG. 17 ). Some peaks are less pronounced then in the pure raloxifene HCl spectra, but this might be due to the remaining salt.
  • the SEM of the starting shows large pieces of glassy looking raloxifene base, and has no fine structure, but is very smooth ( FIG. 18 a and b).
  • the SEM after salt milling shows in contrast a fine structure with small particles of about 100 nm in diameter that form larger agglomerates ( FIG. 18 c and d ). The particles are looking uniform in shape and no difference between salt or drug can be observed.
  • the dispersion was then washed by centrifugation using 15 mL Falcon tubes and a centrifugation speed of 5,000 g. The supernatant was discarded and the sediment was dispersed with 30 mL of 0.01 M Tris-buffer (pH 9) and 1 mM SDS by shaking. A further centrifugation at 5,000 g followed and the pellet was dispersed with 3 mL of 0.01 M Tris (pH 9) and 1 mM SDS.
  • the dispersion was dried over a nitrogen stream and the vacuum dried.
  • the SEM image in FIG. 20 reveals a fine structure on the nanoscale, which shows structures of under 100 nm. The particles seem to have dried in a network like structure, probably bridged by the polymeric surfactant Plasdone.
  • the BET surface area indicated a very large surface area of 57.7178 ⁇ 0.4095 m 2 /g. Calculating with a density of 1.3 g/cm 3 , and assuming monodispersed nanoparticles, the particles diameter with such a surface area would be about 80 nm. (For a density of 1.2 g/cm 3 : 85 nm and for 1.4 g/cm 3 , 70 nm).
  • the XRD shows that the raloxifene base is amorphous and the resulting product after washing is likewise amorphous, it also shows the distinctly different peaks to the raloxifene HCl salt ( FIG. 21 ).
  • the powder XRD shows that raloxifene (ralox) free base is retained after milling and washing.
  • the spectra of the salt milling sample is dominated by the strong peak of NaCl; after washing the lower intensity of the NaCl peaks shows that the amount of NaCl is greatly reduced and reveals the amorphous phase of raloxifene free base.
  • the raloxifene free base seems to contain still a small amount of NaCl, as compared to the sample directly after salt milling before the salt matrix was removed.
  • the particulate raloxifene hydrochloride had the following properties: >75% of the particles were in the range of 220-350 nm in size, with >90% in the range of 160-342 nm.
  • Differential scanning calorimetry, or DSC showed an approximate 10° C. reduction in the onset of melting as compared to the comparison API.
  • Dissolution of the particulate raloxifene under standard conditions in simulated gastric fluid and simulated intestinal fluid (60 mg in 1 L fluid) showed a significant increase in dissolution as compared to the comparison API.
  • approximately 15 mg/L of particulate raloxifene was detected versus 8 mg/L of comparison API for SGF; and 4.5 mg/L versus 0.75 mg/L for SIF.
  • Raloxifene was administered as an oral dose with three male plus three female dogs each receiving one of the two preparations on each of two dosing occasions. Eleven plasma samples were collected from each animal in the 24 hour period following each dose and these were all available for determination of raloxifene concentration.
  • Plasma samples were transported to the TetraQ-ADME laboratories on dry ice and all were in an intact (frozen) condition upon arrival.
  • the concentration of raloxifene in the plasma samples was determined by an LC-MS/MS assay developed and validated by TetraQ-ADME.
  • Pharmacokinetic analysis was performed using purpose-written macros for Excel Software. Standard model-independent pharmacokinetic methods were used. Nominal sampling times were used in the calculations. The plasma raloxifene concentrations were used to determine the following parameters:
  • C max Maximum plasma concentration read directly from the raw data.
  • T max Time at which C max was achieved also read directly from the raw data.
  • k e Terminal elimination rate constant which was determined as the slope of the regression line of best fit to the approximately log-linear terminal elimination phase (using the least squares linear regression function in the Excel 2003 software). The data from the final three or four measurable concentrations were used in the regression analysis for all data sets.
  • t1 ⁇ 2 Terminal elimination half-life In 2/k e
  • Concentration values less than the lower limit of quantification (LLOQ) which occurred prior to the first measurable concentration were set to zero.
  • AUC t- ⁇ Area under the plasma-concentration-time curve from the time of the last measured plasma concentration to infinity, as determined by the formula C t /k e , where C t is the concentration value calculated on the line of best fit at the time when the last measured plasma concentration occurred, and k e is the terminal elimination rate constant as defined above.
  • the individual subject data have been plotted using linear concentration scales and are presented in FIG. 23 .
  • the iCeutica raloxifene HCl nanoparticles are generally labelled as Test Substance 1 and the commercial available raloxifene HCl is labelled as Test Substance 2.
  • Test Substance 1 The iCeutica raloxifene HCl nanoparticles are generally labelled as Test Substance 1 and the commercial available raloxifene HCl is labelled as Test Substance 2.
  • the mean ⁇ SD values at each nominal sampling time for each dosing group are shown in tabular and graphical form in FIG. 24 .
  • Mean ⁇ SD data for each dosing group are displayed in FIG. 25 .
  • An additional comparison is made for C max and AUC 0-t results for the two dosing groups in FIG. 26 .
  • FIG. 27 shows SEM pictures illustrating resultant particles of approximately 700 nm, 500 nm and less than 50 nm.
  • raloxifene hydrochloride (0.5805 g) was introduced with lactose (4.284 g) into a steel vessel (75 cm 3 ) with milling bodies comprising 10 ⁇ 10 mm steel balls.
  • the total volume of the raloxifene hydrochloride/lactose mixture was 3 cm 3 with 15 vol % of drug.
  • Both the raloxifene hydrochloride and the lactose grinding compound were kept dry prior to milling by storage under vacuum and over P 2 O 5 .
  • the steel milling chamber was closed under vacuum to remove moisture and air, to reduce degradation/oxidization.
  • the milling chamber was mounted on a Spex ball mill and was shaken for 15 min and cooled by a stream of compressed air. This resulted in the formation of a solid-dispersion consisting of raloxifene hydrochloride dispersed within a matrix of lactose.
  • the milling chamber was then carefully opened to release the vacuum, and any airborne particles allowed to settle.
  • the milling chamber was opened in a fume hood to prevent inhalation of the fine particles, and the contents transferred through a 2 mm sieve (to remove the milling bodies) into 8 mL glass vials and stored in a vacuum desiccator over P 2 O 5 .
  • the mixture of drug and lactose grinding compound contain particles below 100 nm which are believed to represent the raloxifene drug.
  • FIG. 28 a shows that some small particles well below 5 micron meters are formed after milling. At higher magnification a substructure, that shows particles with nano particle elements of about 100 nm can be seen
  • the milling chamber was mounted on a Spex ball mill and was shaken for 15 min and cooled by a stream of compressed air. This resulted in the formation of a solid-dispersion consisting of olanzapine free base dispersed within the lactose grinding compound.
  • the milling chamber was then carefully opened to release the vacuum, and closed to allow any airborne particles to settle.
  • the milling chamber was then opened in a fume hood to prevent inhalation of the fine particles, and the contents transferred through a 2 mm sieve (to remove the milling bodies) into 8 mL glass vials and stored in a vacuum desiccator over P 2 O 5 .
  • fine particles can be obtained after milling in a lactose grinding compound.
  • GRAS compounds can be used as a grinding compound for the purposes of the present invention.
  • some grinding compounds may offer specific advantages.
  • olanzapine-lactose grinding compound mixtures produced under similar conditions to olanzapine-sodium chloride grinding compound mixtures appear to exhibit superior flowability, which is advantageous in automated formulation systems.

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