Document made available under
`Patent Cooperation Treaty (PCT)
`
`the
`
`International application number: PCT/AU2010/000471
`
`International filing date:
`
`23 April 2010 (23 .04.2010)
`
`Document type:
`
`Certified copy of priority document
`
`Document details:
`
`Country/Office: US
`Number:
`611172,291
`Filing date:
`24 April 2009 (24.04.2009)
`
`Date of receipt at the International Bureau:
`
`18 October 2010 (18.10.2010)
`
`Remark:
`
`Priority document submitted or transmitted to the International Bureau in
`compliance with Rule 17. l(a),(b) or (b-bis)
`
`World Intellectual Property Organization (WIPO) - Geneva, Switzerland
`Organisation Mondiale de la Propriete Intellectuelle (OMPI) - Geneve, Suisse
`
`Page 1
`
`LUPIN EX. 1037
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
`

`
`~?~''''•W•'"'~-._..-.., .... _
`
`... , •• ,.,,, •• , ....... ,,,,,,.,.,.,, •• , •.•• 0000••••••00000000 .. oooooo"••n . .....-.-
`
`'\ ff
`
`-:~.'t(~)A~~~}·. 1.i{~f~*~]*~~1\~(~~~~1]}~·~::-:: ~Hi~~ ~:~:~~I{~\ ~~:~~~l~l~. ~·c(~i~~ll~l~;
`..................... ........ ................ • .................... ............................ ; ................... .
`_, ..... ~
`........................... " ..... ~ .........
`·" .( ........ ..... ., .........
`
`l.'nite<I Slnte1; Piltent nnd Trad l'rntffk O!Til~c
`
`September 15, 2010
`
`TIDS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`THE RECORDS OF THE UNITED STATES PA TENT AND TRADEMARK
`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
`APPLICATION THAT MET THE REQUffiEMENTS TO BE GRANTED A
`FILING DA TE UNDER 35 USC 111.
`
`APPLICATION NUMBER: 611172,291
`FILING DA TE: April 24, 2009
`
`THE COUNTRY CODE AND NUMBER OF YOUR PRIORITY
`APPLICATION, TO BE USED FOR FILING ABROAD UNDER THE PARIS
`CONVENTION, IS US61/172,291
`
`C<:rtil1cd by
`
`L!ndc.>r St-crctury of Conmwrl'c
`fm:· fotcllectunl Pr(lpcr1y
`:md Director of 1lw United Stat11s
`Putcnl mul Trndcm:irk Oflkl'
`
`Page 2
`
`

`
`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07 )
`Approved for use through 06/30/2010 OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Red uction Act of 1995, no persons are required lo respond to a collection or information unless it displays a valid OMS control number
`Provisional Application for Patent Cover Sheet
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c)
`
`lnventor(s)
`
`Inventor 1
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`I Remove I
`Country i
`
`Dodd
`
`Crawley
`
`AU
`
`Aaron
`
`Inventor 2
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`I Remove I
`Country i
`
`Meiser
`
`Mount Clarem<t'J·
`
`AU
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Norret
`
`Darlington
`
`AU
`
`Felix
`
`Inventor 3
`
`Marek
`
`Inventor 4
`
`I Remove I
`Country i
`
`I Remove I
`Country i
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`I Remove I
`Country
`
`i
`
`us
`
`I
`
`Add
`
`I
`
`Adrian
`
`Inventor 5
`
`Russell
`
`Rivervale
`
`AU
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`H
`
`William
`
`Bosch
`
`Bryn Mawr
`
`PA
`
`All Inventors Must Be Listed -Additional Inventor Information blocks may be
`generated within this form by selecting the Add button .
`
`Title of Invention
`
`A novel formulation of diclofenac
`
`Attorney Docket Number (if applicable)
`
`ICTC-153-USP
`
`Correspondence Address
`
`Direct all correspondence to (select one):
`
`(!) The address corresponding to Customer Number
`
`0 Firm or Individual Name
`
`Customer Number
`
`56935
`
`EFS - Web 1.0.1
`
`Page 3
`
`

`
`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07 )
`Approved for use through 06/30/2010 OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required lo respond to a collection or information unless it displays a valid OMS control number
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
`
`(!)No.
`0 Yes, the name of the U.S. Government agency and the Government contract number are:
`
`EFS - Web 1.0.1
`
`Page 4
`
`

`
`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (04-07 )
`Approved for use through 06/30/2010 OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required lo respond to a collection or information unless it displays a valid OMS control number
`
`Entity Status
`Applicant claims small entity status under 37 CFR 1 .27
`® Yes, applicant qualifies for small entity status under 37 CFR 1.27
`0 No
`Warning
`
`Petitioner/applicant is cautioned to avoid submitting personal information in documents filed in a patent application that may
`contribute to identity theft. Personal information such as social security numbers, bank account numbers, or credit card
`numbers (other than a check or credit card authorization form PT0-2038 submitted for payment purposes) is never required
`by the USPTO to support a petition or an application. If this type of personal information is included in documents submitted
`to the US PTO, petitioners/applicants should consider redacting such personal information from the documents before
`submitting them to USPTO. Petitioner/applicant is advised that the record of a patent application is available to the public
`after publication of the application (unless a non-publication request in compliance with 37 CFR 1.213(a) is made in the
`application) or issuance of a patent. Furthermore, the record from an abandoned application may also be available to the
`public if the application is referenced in a published application or an issued patent (see 37 CFR1 .14). Checks and credit
`card authorization forms PT0-2038 submitted for payment purposes are not retained in the application file and therefore are
`not publicly available.
`
`Signature
`
`Please see 37 CFR 1.4(d) for the form of the signature.
`
`Signature
`
`/markjrosen/
`
`Date (YYYY-MM-DD)
`
`2009-04-24
`
`First Name
`
`Mark
`
`Last Name
`
`Rosen
`
`Registration Number
`(If appropriate)
`
`39822
`
`This collection of information is required by 37 CFR 1.51. The information is required to obtain or retain a benefit by the public which is to
`file (and by the US PTO to process) an application. Confidentiality is governed by 35 U .S.C. 122 and 37 CFR 1.11 and 1.14. This collection
`is estimated to take 8 hours to complete, including gathering, preparing, and submitting the completed application form to the USPTO.
`Time will vary depending upon the individual case. Any comments on the amount of time you require to complete this form and/or
`suggestions for reducing this burden, should be sent to the Chief Information Officer. U.S. Patent and Trademark Office, U.S. Department
`of Commerce, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. This
`form can only be used when in conjunction with EFS-Web. If this form is mailed to the USPTO, it may cause delays in handling
`the provisional application.
`
`EFS - Web 1.0.1
`
`Page 5
`
`

`
`Privacy Act Statement
`
`The Privacy Act of 1974 (P. L. 93-579) requires that you be given certain information in connection with your submission of
`the attached form related to a patent application or paten . Accordingly, pursuant to the requirements of the Act, please be
`advised that: (1) the general authority for the collection of this information is 35 U.S.C. 2(b)(2); (2) furnishing of the
`information solicited is voluntary; and (3) the principal purpose for which the information is used by the U.S. Patent and
`Trademark Office is to process and/or examine your submission related to a patent application or patent. If you do not
`furnish the requested information, the U.S. Patent and Trademark Office may not be able to process and/or examine your
`submission, which may result in termination of proceedings or abandonment of the application or expiration of the patent.
`
`The information provided by you in this form will be subject to the following routine uses:
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`The information on this form will be treated confidentially to the extent allowed under the Freedom of Information
`Act (5 U.S.C. 552) and the Privacy Act (5 U.S.C 552a). Records from this system of records may be disclosed to the
`Department of Justice to determine whether disclosure of these records is required by the Freedom of Information
`Act.
`A record from this system of records may be disclosed, as a routine use, in the course of presenting evidence to
`a court, magistrate, or administrative tribunal, including disclosures to opposing counsel in the course of settlement
`negotiations.
`A record in this system of records may be disclosed, as a routine use, to a Member of Congress submitting a
`request involving an individual, to whom the record pertains, when the individual has requested assistance from the
`Member with respect to the subject matter of the record.
`A record in this system of records may be disclosed, as a routine use, to a contractor of the Agency having need
`for the information in order to perform a contract. Recipients of information shall be required to comply with the
`requirements of the Privacy Act of 1974 , as amended, pursuant to 5 U.S.C. 552a(m).
`A record related to an International Application filed under the Patent Cooperation Treaty in this system of
`records may be disclosed, as a routine use, to the International Bureau of the World Intellectual Property
`Organization , pursuant to the Patent Cooperation Treaty.
`A record in this system of records may be disclosed, as a routine use, to a n other federal agency for purposes
`of National Security review (35 U.S.C. 181) and for review pursuant to the Atomic Energy Act (42 U.S.C. 218(c)).
`A record from this system of records may be disclosed, as a routine use, to the Administrator, General Services,
`or his/her designee, during an inspection of records conducted by GSA as part of that agency's responsibility to
`recommend improvem ents in records management practices and programs, under authority of 44 U.S.C. 2904 and
`2906. Such disclosure shall be made in accordance with the GSA regulations governing inspection of records for this
`purpose, and any other relevant (i.e., GSA or Commerce) directive. Such disclosure shall not be used to make
`determinations about individuals.
`A record from this system of records may be disclosed, as a routine use, to the public after either publication of
`the application pursuant to 35 U.S.C. 122(b) or issuance of a patent pursuant to 35 U.S.C. 151 . Further, a record
`may be disclosed, subject to the limitations of 37 CFR 1.14, as a routine use, to the public if the record was filed in an
`application which became abandoned or in which the proceedings were terminated and which application is
`referenced by either a published application, an application open to public inspection or an
`issued patent.
`A record from this system of records may be disclosed, as a routine use, to a Federal, State. or local law
`enforcement agency, if the USPTO becomes aware of a violation or potential violation of law or regulation .
`
`Page 6
`
`

`
`1
`
`ORIGINAL
`
`UNITED STATES OF AMERICA
`
`PRIORITY DOCUMENT
`
`Invention Title:
`
`A n o vel formulation of dic lo fenac
`
`APPLICANT: iCEUTICA PTY LTD
`
`INVENTORS: Aaron Dodd, Felix Meiser, Marek Norret, Adrian Russell, H William Bosch
`
`The invention is described in the f ollowing statement :
`
`Page 7
`
`

`
`2
`
`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
`
`Poor bioavailability is a significant problem encountered in the development of compositions
`in the therapeutic, cosmetic, agricultural and food industries, particularly those materials
`
`containing a biologically active material that is poorly soluble in water at physiological pH.
`
`An active material'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 bioavailability,
`
`including the form of dosage and the solubility and dissolution rate of the active material.
`
`In therapeutic applications, poorly and slowly water-soluble materials tend to be eliminated
`
`from the gastrointestinal tract before being absorbed into the circulation. In addition, poorly
`
`soluble active agents tend to be disfavored or even unsafe for intravenous administration
`
`due to the risk of particles of agent blocking blood flow through capillaries.
`
`It is known that the rate of dissolution of a particulate drug will increase with increasing
`
`surface area. One way of increasing surface area
`
`is decreasing particle size.
`
`Consequently, methods of making finely divided or sized drugs have been studied with a
`
`view to controlling the size and size range of drug particles for pharmaceutica l 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 chamber and prevents any further diminution of particle size.
`
`Alternatively, wet grinding may be employed to reduce particle size, but flocculation restricts
`
`the lower particle size limit to approximately 10 microns (10,000 nm). The wet milling
`
`process, however, is prone to contamination, thereby leading to a bias in the pharmaceutical
`
`art against wet milling. Another alternative milling technique, commercial airjet milling, has
`
`provided particles ranging in average size from as low as about 1 to about 50 microns
`
`(1,000-50,000 nm).
`
`There are several approaches currently used to formulate poorly soluble active agents. One
`
`approach is to prepare the active agent as a soluble salt. Where this approach cannot be
`
`Page 8
`
`

`
`3
`
`employed, alternate (usually physical) approaches are employed to improve the solubility of
`
`the active agent. Alternate approaches generally subject the active agent to physical
`
`conditions that change the agent's physical and or chemica l properties to improve its
`
`solubility. These include process technologies such as micronization, modification of crystal
`
`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,
`
`formulation 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 compositions tend to be complex. By
`
`way of example, a principal technical difficulty encountered with emulsion polymerization is
`
`the removal of contaminants, such as unreacted monomers or initiators (which may have
`
`undesirable levels of toxicity), at the end of the manufacturing process.
`
`Another method of providing reduced particle size is the formation of pharmaceutical drug
`
`microcapsules, which techniques include micronizing, polymerisation and co-dispersion.
`
`However, these techniques suffer from a number of disadvantages including at least the
`
`inability to produce sufficiently small particles such as those obtained by milling, and the
`
`presence of co-solvents and/or contaminants such as toxic monomers which are difficult 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 increasing the overall surface area and decreasing the mean particle
`
`size.
`
`US Patent 6,634,576 discloses examples of wet-milling a solid substrate, such as a
`
`pharmaceutically active compound , to produce a "synergetic co-mixture".
`
`International Patent Application PCT/AU2005/001977 (Nanoparticle Composition(s) and
`
`Method for Synthesis Thereof) describes, inter a/ia, a method comprising the step of
`
`contacting a precursor compound with a co-reactant under mechanochemical synthesis
`
`conditions wherein a solid-state chemical reaction between the precursor compound and the
`
`co-reactant produces therapeutically active nanoparticles dispersed in a carrier matrix.
`
`Mechanochemical
`
`synthesis,
`
`as discussed
`
`in
`
`International Patent Application
`
`PCT/AU2005/001977, refers to the use of mechanical energy to activate, initiate or promote
`
`a chemical reaction, a crystal structure transformation or a phase change in a material or a
`
`Page 9
`
`

`
`4
`
`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.
`International Patent Application PCT/AU2007/00091 O (Methods for the preparation of
`biologically active compounds in nanoparticulate form) describes, inter alia, a method for dry
`
`milling raloxifene with lactose and NaCl which produced nanoparticulate raloxifene without
`
`significant aggregation problems.
`
`One limitation of many of the prior art processes is that they are not suitable for commercial
`
`scale milling. The present invention provides methods for overcoming the problems 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 resulting 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 inve ntion is discussed in the context of improving
`
`the bioavailability of materials that are poorly or slowly water soluble, the applications of the
`
`methods of the present invention are not limited to such, as is evident from the following
`
`description of the invention.
`
`Further, although the background to the present invention is largely discussed in the context
`
`of improving the bioavailability of therapeutic or pharmaceutical compounds, the applications
`
`of the methods of the present invention are clearly not limited to such. For example, as is
`
`evident from the following description, applications of the methods of the present invention
`
`include but are not limited to: nutraceutical and nutritional compounds, complementary
`
`medicinal compounds, veterinary
`
`therapeutic applications and agricultural chemical
`
`applications, such as pesticide, fungicide or herbicide.
`
`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 compound
`
`or an agricultural compound such as a pesticide, fungicide or herbicide. Specific examples
`
`Page 10
`
`

`
`5
`
`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 invention is
`
`orally ingested the active would be more bioavailable.
`
`Summary of the Invention
`
`In one aspect the present invention is directed to the unexpected 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 equa l to or less than
`
`2000nm. In another surprising aspect the particle size produced by the process is equal to or
`
`less than 1 OOOnm. In another surprising aspect the crystallinity of the active material is
`
`unchanged or not substantially 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.
`
`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 biologically 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, 1800nm,
`
`1700nm, 1600nm, 1500nm, 1400nm, 1300nm, 1200 nm, 1100nm, 1000nm, 900nm, 800nm,
`
`700nm, 600nm, 500nm, 400 nm, 300nm, 200nm and 100 nm. Preferably, the average
`
`particle size is equal to or greater than 25nm.
`
`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,
`
`1800nm, 1700nm, 1600nm, 1500nm, 1400nm, 1300nm, 1200 nm, 1100nm, 1000nm,
`
`900nm, 800nm, 700nm, 600nm, 500nm, 400 nm, 300nm, 200nm and 100 nm. Preferably,
`
`the median particle size is equal to or greater than 25nm. Preferably, the percentage of
`
`particles, on a particle volume basis, is selected from the group consisting of: less than
`
`2000nm (% < 2000 nm) is selected from the group 50 %, 60%, 70%, 80%, 90%, 95% and
`100 %; less than 1000nm (% < 1000 nm) is selected from the group 50 % , 60%, 70%, 80%,
`90%, 95% and 100 %; less than 500nm (% < 500 nm) is selected from the group 0%, 10%,
`
`20%, 30%, 40%, 50 %, 60%, 70%, 80%, 90%, 95% and 100 %; less than 300nm (% < 300
`
`Page 11
`
`

`
`6
`
`nm) is selected from the group 0%, 10%, 20%, 30%, 40%, 50 % , 60%, 70%, 80%, 90%,
`
`95% and 100 %; and less than 200nm (% < 200 nm) is selected from the group 0%, 10%,
`
`20%, 30%, 40%, 50 %, 60%, 70%, 80%, 90%, 95% and 100 %.
`
`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 material 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 material 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 biologically active
`
`material is amorphous, less than 15% of the biologically active material is amorphous, less
`
`than 10% of 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. Preferably, 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: between 10 minutes and 2 hours, between 10 minutes and 90 minutes,
`
`between 10 minutes and 1 hour, between 10 minutes and 45 minutes, between 10 minutes
`
`and 30 minutes, between 5 minutes and 30 minutes, between 5 minutes and 20 minutes,
`
`between 2 minutes and 10 minutes, between 2 minutes and 5 minutes, between 1 minutes
`
`and 20 minutes, between 1 minute and 10 minutes, and between 1 minute and 5 minutes.
`
`In another preferred embodiment, the milling medium is selected from the group consisting
`
`of: ceramics, glasses, polymers, ferromagnetics and metals. Preferably, the milling medium
`
`is steel balls having a diameter selected from the group consisting of: between 1 and 20 mm,
`
`between 2 and 15 mm and between 3 and 10 mm. In another preferred embodiment, the
`
`milling medium is zirconium oxide balls having a diameter selected from the group consisting
`
`of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm. Preferably, the
`
`dry milling apparatus is a mill selected from the group consisting of: attritor mills (horizontal
`
`or vertical), nutating mills, tower mills, pearl mills, planetary mills, vibratory mills, eccentric
`
`vibratory mills, gravity-dependent-type ball mills, rod mills, roller mills and crusher mills.
`
`Page 12
`
`

`
`7
`
`Preferably, the milling medium within the milling apparatus is mechanically agitated by 1, 2
`
`or 3 rotating shafts. Preferably, the method is configured to produce the biologically active
`
`material in a continuous fashion.
`
`Preferably, the total combined amount of biologically active material and grinding matrix in
`
`the mill at any given time is equal to or greater than a mass selected from the group
`
`consisting of: 200 grams, 500 grams, 1 kg , 2kg, 5kg, 1 Okg, 20kg, 30kg, 50kg, 75kg, 1 OOkg,
`
`150kg, 200kg. Preferably, the total combined amount of biologically active material and
`
`grinding matrix is less than 2000kg.
`
`Preferably,
`
`the biologically active material is selected from the group consisting of:
`
`diclofenac or a derivative or salt thereof.
`
`In another preferred embodiment, the grinding matrix is a single material or is a mixture of
`two or more materials in any proportion. Preferably, the single material or a mixture of two or
`
`more materials is selected from the group consisting of: mannitol, sorbitol, lsomalt, xylitol,
`
`maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous
`
`lactose, lactose monohydrate, sucrose, maltose, trehalose, maltodextrins, dextrin, lnulin,
`
`dextrates, polydextrose, starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour,
`
`tapioca starch, potato flour, potato starch, other flours and starches, milk powder, skim milk
`
`powders, other milk solids and dreviatives, soy flour, soy meal or other soy products,
`
`cellulose, microcystalline cellulose, microcystalline cellulose based co-blended materials,
`
`pregelatinized (or partially) starch, HPMC, CMC, HPC, citric acid, tartaric acid, malic acid,
`
`maleic acid fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate,
`
`sodium malate, sodium ascorbate, potassium citrate, potassium tartrate , potassium malate,
`
`sodium acetate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium
`
`carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, dibasic calcium
`
`phosphate,
`
`tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium
`
`metabisulphite, sodium
`
`thiosulfate, ammonium chloride, glauber's salt, ammonium
`
`carbonate, sodium bisulfate, magnesium sulfate, potash alum, potassium chloride, sodium
`
`hydrogen sulfate, sodium hydroxide, crystalline hydroxides, hydrogen carbonates,
`
`ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, thermal silica,
`
`alumina,
`
`titanium dioxide,
`
`talc, chalk, mica, kaolin, bentonite, hectorite, magnesium
`
`trisilicate, clay based materials or aluminium silicates, sodium lauryl sulfate, sodium stearyl
`
`sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium
`
`deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate , glycerol distearate
`
`glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium
`
`chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide,
`
`benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, , poloxamer
`
`338, poloxamer 407 polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl
`
`Page 13
`
`

`
`8
`
`ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40,
`
`polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil,
`
`polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil,
`
`polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100
`
`hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel
`
`15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbita n trioleate,
`
`sucrose palmitate, sucrose stearate, sucrose distearate, sucrose laurate, glycocholic acid,
`
`sodium glycholate, cholic acid, soidum cholate, sodium deoxycholate, deoxycholic acid,
`
`sodium taurocholate, taurocholic acid , sodium taurodeoxycholate, taurodeoxycholic acid, soy
`
`lecithin,
`
`phosphatidylcholine,
`
`phosphatidylethanolamine,
`
`phosphatidylserine,
`
`phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl
`naphthalene sulfonate condensate/Lignosulfonate blend, calcium dodecylbenzene sulfonate,
`
`sodium dodecylbenzene sulfonate, diisopropyl naphthaenesulphonate, erythritol distearate,
`
`naphthalene sulfonate
`
`formaldehyde condensate, nonylphenol ethoxylate
`
`(poe-30),
`
`tristyrylphenol ethoxylate, polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene
`
`sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate,
`
`sodium
`
`isopropyl naphthalene sulfonate, sodium methyl naphthalene
`
`formaldehyde
`
`sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18),
`
`triethanolamine
`
`isodecanol phosphate ester,
`
`triethanolamine
`
`tristyrylphosphate ester,
`
`tristyrylphenol ethoxylate sulfate, bis(2-hydroxyethyl)tallowalkylamines. Preferably,
`
`the
`
`concentration of the single (or first) material is selected from the group consisting of: 5 - 99
`% w/w, 10 - 95 % wlw, 15 - 85 % w/w, of 20 - 80% w/w, 25 - 75 % w/w, 30 - 60% w/w, 40 -
`50% w/w. Preferably, the concentration of the second or subsequent material is selected
`
`from the group consisting of: 5 - 50 % w/w, 5 - 40 % w/w, 5 - 30 % w/w, of 5 - 20% w/w, 10 -
`
`40 % w/w, 10 -30% w/w, 10 -20% w/w, 20 - 40% w/w