LUPIN EX. 1001
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
`Page 1
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`

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`Page 2
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`US 8,999,387 B2
`Page 2
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`OTHER PUBLICATIONS
`
`Office Action in corresponding Colombia Patent Application No.
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`
`* cited by examiner
`
`(51)
`
`Int. Cl.
`A6111 9/48
`A6111 9/51
`A6111 9/00
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl.
`CPC .......... .. A6111 9/5115 (2013 01); A6111 9/5123
`(2013.01); A61119/513 (2013.01); A6111
`9/0087 (2013.01); A6111 9/14 (2013.01); A6111
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`
`(56)
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`Page 2
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`U.S. Patent
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`Apr. 7, 2015
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`Apr. 7, 2015
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`Sheet 13 of 20
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`U.S. Patent
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`Apr. 7, 2015
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`Sheet 14 of 20
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`US 8,999,387 B2
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`Page 16
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`

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`U.S. Patent
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`Apr. 7, 2015
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`Sheet 15 of 20
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`US 8,999,387 B2
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`U.S. Patent
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`Apr. 7, 2015
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`Sheet 16 of 20
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`US 8,999,387 B2
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`Apr. 7, 2015
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`U.S. Patent
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`Apr. 7, 2015
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`Sheet 18 of 20
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`US 8,999,387 B2
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`U.S. Patent
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`Apr. 7, 2015
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`Sheet 19 of 20
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`US 8,999,387 B2
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`U.S. Patent
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`Apr. 7, 2015
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`Sheet 20 of 20
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`US 8,999,387 B2
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`

`
`1
`FORMULATION OF DICLOFENAC
`
`RELATED APPLICATIONS
`
`US 8,999,387 B2
`
`2
`
`This application is a continuation and claims priority to
`U.S. application Ser. No. 13/266,122, filed Feb. 16, 2012,
`which is a U.S. national stage under 35 USC §371 of Inter-
`national Application Number PCT/AU2010/000471, filed on
`23 Apr. 2010, which claims priority to AU Application No.
`2009901748, filed on 24 Apr. 2009 and U.S. Application No.
`61/172,291, filed on 24 Apr. 2009, the entire contents of
`which applications is hereby incorporated by reference.
`
`FIELD OF THE INVENTION
`
`The present invention relates to methods for producing
`particles of diclofenac using dry milling processes as well as
`compositions comprising diclofenac, medicaments produced
`using diclofenac in particulate form and/or compositions, and
`to methods of treatment of an animal, including man, using a
`therapeutically effective amount of diclofenac administered
`by way of said medicaments.
`
`BACKGROUND
`
`Poorbioavailability is a significant problem encountered in
`the development of compositions in the therapeutic, cos-
`metic, agricultural and food industries, particularly those
`materials containing a biologically active material that is
`poorly soluble in water at physiological pH. An active mate-
`rial’s bioavailability is the degree to which the active material
`becomes available to the target tissue in the body or other
`medium after systemic administration through, for example,
`oral or intravenous means. Many factors affect bioavailabil-
`ity, including the form of dosage and the solubility and dis-
`solution rate of the active material.
`
`In therapeutic applications, poorly and slowly water-
`soluble materials tend to be eliminated from the gastrointes-
`tinal tract before being absorbed into the circulation. In addi-
`tion, poorly soluble active agents tend to be disfavored or even
`unsafe for intravenous administration due to the risk of par-
`ticles of agent blocking blood flow through capillaries.
`It is known that the rate of dissolution of a particulate drug
`will
`increase with increasing surface area. One way of
`increasing surface area is decreasing particle size. Conse-
`quently, methods ofmaking finely divided or sized drugs have
`been studied with a view to controlling the size and size range
`of drug particles for pharmaceutical compositions.
`For example, dry milling techniques have been used to
`reduce particle size and hence influence drug absorption.
`However, in conventional dry milling the limit of fineness is
`reached generally in the region of about 100 microns (100,
`000 nm), at which point material cakes on the milling cham-
`ber and prevents any further diminution ofparticle size. Alter-
`natively, 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 pro-
`cess, however, is prone to contamination, thereby leading to a
`bias in the pharmaceutical art against wet milling. Another
`alternative milling technique, commercial airj et milling, has
`provided particles ranging in average size from as low as
`about 1 to about 50 microns (1,000-50,000 nm).
`There are several approaches currently used to formulate
`poorly soluble active agents. One approach is to prepare the
`active agent as a soluble salt. Where this approach cannot be
`employed, alternate (usually physical) approaches are
`employed to improve the solubility of the active agent. Alter-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
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`
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`
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`
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`
`nate approaches generally subject the active agent to physical
`conditions that change the agent’s physical and or chemical
`properties to improve its solubility. These include process
`technologies such as micronization, modification ofcrystal or
`polymorphic structure, development of oil based solutions,
`use of co-solvents, surface stabilizers or complexing agents,
`micro-emulsions, supercritical fluid and production of solid
`dispersions or solutions. More than one of these processes
`may be used in combination to improve formulation of a
`particular therapeutic material. Many of these approaches
`commonly convert a drug into an amorphous state, which
`generally leads to a higher dissolution rate. However, formu-
`lation approaches that result in the production of amorphous
`material are not common in commercial formulations due to
`
`concerns relating to stability and the potential for material to
`re-crystallize.
`These techniques for preparing such pharmaceutical com-
`positions tend to be complex. By way of example, a principal
`technical difliculty encountered with emulsion polymeriza-
`tion is the removal of contaminants, such as unreacted mono-
`mers or initiators (which may have undesirable levels of
`toxicity), at the end of the manufacturing process.
`Another method of providing reduced particle size is the
`formation of pharmaceutical drug microcapsules, which
`techniques include micronizing, polymerisation and co-dis-
`persion. However, these techniques suffer from a number of
`disadvantages including at least the inability to produce suf-
`ficiently small particles such as those obtained by milling, and
`the presence of co-solvents and/or contaminants such as toxic
`monomers which are diflicult to remove, leading to expensive
`manufacturing processes.
`Over the last decade, intense scientific investigation has
`been carried out to improve the solubility of active agents by
`converting the agents to ultra fine powders by methods such
`as milling and grinding. These techniques may be used to
`increase the dissolution rate of a particulate solid by increas-
`ing the overall surface area and decreasing the mean particle
`size.
`
`U.S. Pat. No. 6,634,576 discloses examples ofwet-milling
`a solid substrate, such as a pharrnaceutically active com-
`pound, to produce a “synergetic co-mixture”.
`International Patent Application PCT/AU2005/001977
`(Nanoparticle Composition(s) and Method for Synthesis
`Thereof) describes, inter alia, a method comprising the step of
`contacting a precursor compound with a co-reactant under
`mechanochemical synthesis conditions wherein a solid-state
`chemical reaction between the precursor compound and the
`co-reactant produces therapeutically active nanoparticles dis-
`persed in a carrier matrix. Mechanochemical synthesis, as
`discussed in International Patent Application PCT/AU2005/
`001977, refers to the use of mechanical energy to activate,
`initiate or promote a chemical reaction, a crystal structure
`transformation or a phase change in a material or a mixture of
`materials, for example by agitating a reaction mixture in the
`presence of a milling media to transfer mechanical energy to
`the reaction mixture, and includes without limitation “mecha-
`nochemical activation”, “mechanochemical processing”,
`“reactive milling”, and related processes.
`International Patent Application PCT/AU2007/000910
`(Methods for the preparation of biologically active com-
`pounds in nanoparticulate form) describes,
`inter alia, a
`method for dry milling raloxifene with lactose and NaCl
`which produced nanoparticulate raloxifene without signifi-
`cant aggregation problems.
`One limitation ofmany ofthe prior art processes is that they
`are not suitable for commercial scale milling. The present
`invention provides methods for overcoming the problems
`
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`US 8,999,387 B2
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`3
`identified by the prior art by providing a milling process
`which provides particles with increased surface area, yet can
`also be scaled up to a commercial scale.
`One example of a therapeutic area where this technology
`could be applied in is the area of acute pain management.
`Many pain medications such as diclofenac are commonly
`prescribed as pain relief for chronic pain. As a result they are
`commonly taken on a daily basis to maintain an effective
`therapeutic level. Diclofenac is a poorly water soluble drug so
`dissolution and absorbtion to the body is slow. So a method
`such as the present invention which provides for improved
`dissolution, will likely provide much faster absorption result-
`ing in a more rapid onset of the therapeutic effect. By using a
`method such as the present invention, which provides faster
`absorption, a drug such as diclofenac, could be used more
`readily to treat acute pain as well as chronic pain.
`Although the background to the present invention is dis-
`cussed in the context ofimproving the bioavailability ofmate-
`rials that are poorly or slowly water soluble, the applications
`ofthe methods ofthe present invention are not limited to such,
`as is evident from the following description of the invention.
`Further, although the background to the present invention
`is largely discussed in the context of improving the bioavail-
`ability of therapeutic or pharmaceutical compounds,
`the
`applications of the methods of the present invention are
`clearly not limited to such. For example, as is evident from the
`following description, applications of the methods of the
`present invention include but are not limited to: nutraceutical
`and nutritional compounds, complementary medicinal com-
`pounds, veterinary therapeutic applications and agricultural
`chemical applications, such as pesticide, fungicide or herbi-
`cide.
`
`Furthermore an application of the current invention would
`be to materials which contain a biologically active compound
`such as, but not limited to a therapeutic or pharmaceutical
`compound, a nutraceutical or nutrient, a complementary
`medicinal product such as active components in plant or other
`naturally occurring material, a veterinary therapeutic com-
`pound or an agricultural compound such as a pesticide, fun-
`gicide or herbicide. Specific examples would be the spice
`turmeric that contains the active compound curcumin, or flax
`seed that contains the nutrient ALA an omega 3 fatty acid. As
`these specific examples indicate this invention could be
`applied to, but not limited to, a range of natural products such
`as seeds, cocoa and cocoa solids, coffee, herbs, spices, other
`plant materials or food materials that contain a biologically
`active compound. The application of this invention to these
`types of materials would enable greater availability of the
`active compound in the materials when used in the relevant
`application. For example where material subject to this inven-
`tion is orally ingested the active would be more bioavailable.
`
`SUMMARY OF THE INVENTION
`
`In one aspect the present invention is directed to the unex-
`pected finding that particles of a biologically active material
`can be produced by dry milling processes at commercial
`scale. In one surprising aspect the particle size produced by
`the process is equal to or less than 2000 nm. In another
`surprising aspect the particle size produced by the process is
`equal to or less than 1000 nm. In another surprising aspect the
`crystallinity of the active material is unchanged or not sub-
`stantially changed. In a preferred embodiment the present
`invention is directed to the unexpected finding that particles
`of diclofenac can be produced by dry milling processes at
`commercial scale.
`
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`Thus in a first aspect the invention comprises a method
`producing a composition, comprising the steps of dry milling
`a solid biologically active material and a millable grinding
`matrix in a mill comprising a plurality of milling bodies, for
`a time period sufficient to produce particles of the biologi-
`cally active material dispersed in an at least partially milled
`grinding material.
`In one preferred embodiment, the average particle size,
`determined on a particle number basis, is equal to or less than
`a size selected from the group 2000 nm, 1900 nm, 1800 nm,
`1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm,
`1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500
`nm, 400 nm, 300 nm, 200 nm and 100 nm. Preferably, the
`average particle size is equal to or greater than 25 nm.
`In another preferred embodiment, the particles have a
`median particle size, determined on a particle volume basis,
`equal or less than a size selected from the group 2000 nm,
`1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm,
`1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700
`nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm.
`Preferably, the median particle size is equal to or greater than
`25 nm. Preferably, the percentage of particles, on a particle
`volume basis, is selected from the group consisting of: 50%,
`60%, 70%, 80%, 90%, 95% and 100% less than 2000 nm (%
`<2000 nm). Preferably, the percentage of particles, on a par-
`ticle volume basis, is selected from the group consisting of:
`50%, 60%, 70%, 80%, 90%, 95% and 100% less than 1000
`nm (% <1000 nm). Preferably, the percentage of particles, on
`a particle volume basis, is selected from the group consisting
`of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,
`95% and 100% less than 500 nm (% <500 nm). Preferably, the
`percentage ofparticles, on a particle volume basis, is selected
`from the group consisting of: 0%, 10%, 20%, 30%, 40%,
`50%, 60%, 70%, 80%, 90%, 95% and 100% less than 300
`nm (% <300 nm). Preferably, the percentage ofparticles, on a
`particle volume basis, is selected from the group consisting
`of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,
`95% and 100% less than 200 nm (% <200 nm). Preferably, the
`Dx of the particle size distribution, as measured on a particle
`volume basis, is selected from the group consisting of less
`than or equal to 10,000 nm, 5000 nm, 3000 nm, 2000 nm,
`1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm,
`1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700
`nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, and 100 nm;
`wherein x is greater than or equal to 90.
`In another preferred embodiment, the crystallinity profile
`of the biologically active material is selected from the group
`consisting of: at least 50% of the biologically active material
`is crystalline, at least 60% of the biologically active material
`is crystalline, at least 70% of the biologically active material
`is crystalline, at least 75% of the biologically active material
`is crystalline, at least 85% of the biologically active material
`is crystalline, at least 90% of the biologically active material
`is crystalline, at least 95% of the biologically active material
`is crystalline and at least 98% of the biologically active mate-
`rial is crystalline. More preferably, the crystallinity profile of
`the biologically active material is substantially equal to the
`crystallinity profile of the biologically active material before
`the material was subjected to the method as described herein.
`In another preferred embodiment, the amorphous content
`of the biologically active material is selected from the group
`consisting of: less than 50% of the biologically active mate-
`rial is amorphous, less than 40% of the biologically active
`material is amorphous, less than 30% of the biologically
`active material is amorphous, less than 25% of the biologi-
`cally active material is amorphous, less than 15% of the
`biologically active material is amorphous, less than 10% of
`
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`US 8,999,387 B2
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`5
`the biologically active material is amorphous, less than 5% of
`the biologically active material is amorphous and less than
`2% of the biologically active material is amorphous. Prefer-
`ably,
`the biologically active material has no significant
`increase in amorphous content after subjecting the material to
`the method as described herein.
`
`In another preferred embodiment, the milling time period
`is a range selected from the group consisting of: betwe