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: AU
`Number:
`2009901748
`Filing date:
`24 April 2009 (24.04.2009)
`
`Date of receipt at the International Bureau:
`
`26 May 2010 (26.05.2010)
`
`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
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`LUPIN EX. 1038
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
`

`
`PCT/AU2010/000471
`
`Australian Government
`
`Patent Office
`Canberra
`
`I, MICHAEL SHEEHAN, EXAMINATION SUPPORT AND SALES hereby
`certify that annexed is a true copy of the Provisional specification in connection
`with Application No. 2009901748 for a patent by ICEUTICA PTY LTD as filed
`on 24 April 2009.
`
`WITNESS my hand this
`Seventeenth day of May 2010
`
`~
`MICHAEL SHEEHAN
`EXAMINATION SUPPORT AND SALES
`
`Page 2
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`P/00/009 28/5/91
`Regulation 3.2
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`ORIGINAL
`
`AUSTRALIA
`
`Patents Act 1990
`
`PROVISIONAL SPECIFICATION
`
`Invention Title: A Novel Formulation of Diclofenac
`
`The invention is described in the followin~ statement:
`
`1 .
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`A Novel Formulation of Diclofenac
`
`Field of the Invention
`
`The present invention relates to methods for producing particles of diclofenac using dry
`milling processes ~s well as compositio.ns ·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.
`
`Backgr.ound
`
`Poor bioavail~bility is a significant problem encountered in the development of compositions
`in the therapeutic, cosmetic, agric_ultural and food industries, particularly those n:iaterials
`
`containing a biologically active material that is poorly solu~le 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 gast~ointestinal 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 dec'reasing · particle· size.
`
`Consequently, methods of making finely divided ~r 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 ha~e 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 gri~ding may ~e employed to reduce particle size, but flocculation restricts
`the lower particle size limit to approximately ·1Q microns (10.,000 nm). .The wet mil.ling
`process, however, is prone to contamination, thereby leading to a bias in the pharmayeutical
`art against wet milling. Another alternative milling technique,· commercial airjet milling, has
`
`provided particles ranging in average size from as l~w as about 1 to about ~O microns
`(1,000-50·,ooo nm).
`
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`Th~re are several approaches currently used to formulate poorly soluble active agents. One
`approach is to prepare the active agent a~ a sol~ble salt.. Where this approach cannot be
`. 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 .th.at change the agent's physical and or chemical prop~rties 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 c;>f solid
`
`dispersions or solutions. More than one of these proces~es 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 ryionomers 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 expen~ive _manufacturing processes.
`Over the last decade, iritt::nse scientific investigation has been· carried out to improve the
`
`solubility' of active agents by converting the agents to ultra fine powders by methods sych 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 usynergetic ~-mixture".
`.
`.
`.
`.
`International P~tent Application PCT/AU2005/001977 (Nanoparticle Composition(s) and
`Method for Synthesis Thereof) describes, inter alia, a method comprising the step of
`contacting a precursor compou.nd with a co-reactant under mechanochemical synthesis
`· conditions wherei~ a solid-state chemical reaction between the precursor compound and the
`co-reactant produces therapeutically active nanoparticles dispersed in a carrier matrix.
`in · International Patent Application
`Mechanochemical synthesis, as discussed
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`.
`
`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 ·
`
`"mechanochem.ical · activation", "mechanochemical processing", "reactive milling", . and
`
`related processes.
`
`International Patent Application PCT/AU2007/000910 (Methods for the preparation of
`biologically active compounds in nanoparticulate form) describes, inter a/ia, a method for dry
`milling raloxife~e ~ith lactose and NaCl which produce~ 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 protitems 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 a~ diclofenac are ·commonly
`
`prescribed as pain relief for chronic pain. As a result they are commonly taken on a da.ily
`.
`.
`.
`.
`basis to _maintai~ an effective therapeutic level. Diclofena·c is a poorly water so~uble drug so
`'dissolution and absorbtion to the b"ody is slow. So a method such as the present invention
`
`which provides for improved dissolution, wili likely provi~e much faster absorption resulti~g 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 diClofen~c. could be used more
`
`readily to treat acute pain as well as chronic pain.
`Although the background to the present invention is discussed in the context of improving
`. 'the bioavailability of materials that are poorly or slowly water solub!e, 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 th~ background to the present invention is large.ly discussed in the context
`of improving the bioavailability of therapeutic or pharmaceutical compounds, the appl!cations
`.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
`.ch~mic~I
`applicatlons, 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
`
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`components in plant or other natu~lly occurring material, a veterinary ther~peutic comp~und
`
`or an agricultural compound such as a pesticide, fungicide 9r herbicide. Specific examples
`wo.1,Jld be the spice turmeric that cont~ins .the active compound curcumin, or flax seed thaf
`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 in'-'.entlon 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 equal to or less than
`
`2000nm. In a.nother surprising aspect the particle size produced by the process is equal to or
`
`less than 1000nm. In another su.rprising 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 didofenac can be produced by dry milling
`processes at commercial scale.
`·
`
`Thus in a first aspect the invention comprises a method producing a composition, co~prising
`
`the steps of dry. milling a solid bi<;>logically active material and a millable grinding matrix in a
`mill comprising a plurality of milling bodies, (or 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, determ.ined 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
`parti~le 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, BOOnm, 700nm, 600nm, 500nm, 400 nm, 300nm, 200nm and 100 nm. Preferably,
`
`the median particle size is equal to or greater than 25nm. Prefera.bly, ·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 ~O %, 60%, 70%, 80%, 90%, 95% and
`100·%; less than 1000nm (% < 1000 nm} is selected from the group 50 %, 60%, 70%, 80%,
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`90%. 95% and 100 %; less than 500nm (% < 500 nm) is selected from the group 0%, 10%,
`
`20°k, 30%, 40%, 50 %, 60%, 70%, 80%, 90%, 95% and 100 %; less than 300nm (% < 300
`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, th~ 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. Mo~e pref~rably,
`
`the crystallinity profile of the biologically active material is S!Jbstantially 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, les5 than 5% of the biologically
`active material is amorphous and less than 2% of ~he 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 herei_n.
`
`In another preferred embodiment, ·the ~illing. 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
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`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:
`Preferably, ·tiie milling medium within th~ milljng apparatus Is mechanically agitated by 1, 2
`or 3 rotating shafts. Preferably, the meth9d is configured to produce th~ biologically active
`
`material in a continuous fashion. ·
`
`Preferably, the total combined amount of biologically active .material an.d grinding matrix in
`
`the mill at. any gi~en time Is equal to or greater than a mass selected from the group
`consisting of: 200 ~rams, 500 grams, 1 kg, 2kg, 5kg, 10kg, 20kg, 30k~. 50kg, 7~kg, 100kg, .
`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! lacti.tol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous
`
`lactose, lactose monohydrate, sucrose, maltose, trehalose, maltodextrins, dextrin, lnulin,
`
`dextrates, polydextrose, starch, wheat flour, com 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, potassfum 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, sodiu~
`
`thiosulfate, ammonium chloride, glauber~s . salt, ammonium
`metabisulphite. sodium
`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 ~ilica,
`
`alumina, titanium dioxide, talc, chalk, r:nica, 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 i:nonostearate . glycerol distearate .
`. glycery1 palmitostearate, glyceryl behenate, glyceryt caprylate, glyCE'.ryl oleate. benzalkonium
`chloride, CT AB,. CT AC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide,
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`benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, , poloxamer
`
`338, poloxamer 407 polyoxyl 2 stearyl ether, polyoxyl 100 stear:yl ether, polyoxyl 20 stearyl
`ether, polyoxyl 10 stearyl ether: polyoxyl 20 cetyl ether, polysorbate 29, polysorbate. 40,
`polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil,
`polyoxyl 40 castor oil, P<?lyoxyl 60 castor oil, polyoxyl 100 C?astor 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 a·lcohol, macrogel
`
`15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate,
`
`sucrose palmitate, sucrose stearate, sucrose distear.ate, sucrose laurate, glycocholic acid,
`
`sodium glycholate, cholic acid, soidum chelate, sodium deoxycholate, deoxycholic acid,
`sodium taurocholate, taurocholic acid, sodium· taurodeoxycholate, ta~rodeoxycholic acid, soy
`lecithin,
`phosphatidylcholine,
`.
`phosphatidylethanolamine,
`phosphatidylserine,
`
`phosphatidylinositol, PEG4000. PEG6000, PEG8000, PEG10000, PEG20000, . alkyl
`
`naphthalene sulfonate condensatE!/Lignosulfonate blend, calcium dodecylbenzene sulfonate,
`sodium. ~odecylbenzene sulfonate, diisopropyl naphthaenesulphonate, erythritol distearate,
`11aphthalen¢ sulfonate
`formaldehyde · condensate, nonylphenol · ethoxylate · (poe-30),
`tristyrylphenol ethoxyfate, polyoxyethyfene O 5) tallowalkylamines, sodium alkyl naphthalene
`sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium ~lkylbenzene sulfonate,
`
`sodium
`
`isopropyl naphthalene sulfonate, sodium methyl naphthalene
`
`formaldehyde
`
`sulfonate, sodium n-butyl naphthalerw sulfonate, tridecyl alcohol ethoxylate (poe-18),
`
`triethanolamine
`
`tristyrylphosphate ester,
`
`triethanolamine
`isodecanol phosph.ate ester,
`.
`.
`the
`tristyrylphenol ethoxylate · sulfate, bis(2-hydroxyethyl)tallowalkylamines. Preferably,
`concentration of the single (or first) material is selected from the group consisting of: 5 - 99
`% w/w, 10 - 95 % w/w, 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 t~e group consisting of: 5 - 50 % w/w, 5· - ·40 % w/w, 5 - 30 % wlw, of 5 - 20% w/w, 1 O -
`.
`.
`40 % w/w, 10 -30% wlw, 10 -20% w/w, 20 - 40% w/w, or 20 - 30% w/w or if the second or
`subsequent material is a surfactant or water soluble polymer the concer;itration is· selected
`from 0.1 -10 % w/w, 0.1 .;5, % w/w, 0.1 -2.5 % w/w, of 0.1 - 2% w/w, 0.1 -1 %, 0.5 -5% w/w,
`.
`.
`·0.5 -3% w/w, 0.5 -2% w/w, 0.5 - 1.5%, 0.5 -1 % w/w, of 0.75 - 1.25 % wlw, 0.75 -1% and
`1%w/w.
`
`Preferably, the grinding matrix is selected from the group co.nsisting of:
`
`(a) lactose monohydrate or lactose monohydrate combined with a material selected
`
`from the group consisting of: sodium pentane sulfate: sodium octadecyl sulfate;
`
`Brij700; Brij76; sodium · n-lauroyl sacrosine; l~cithin; docusate sodium; polyoxyl-
`
`40-stearate; Aerosil R972 fumed siliea; sodium lauryl sulfate or other alkyl sulfate
`
`surfactants with a chain length between C5 to C18; calcium carbonate; mali~
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`acid; tartaric acid; trisodium citrate dehydrate; 0,L-Malic acid; .Xylitol; Poloxamer
`407; Poloxamer 338; Poloxame~ 188; Polyvinyl pyrrolidone; lactose anhydrous;
`
`mannitol; microqf'Ystalline cellulo.se; sodium lauryl sulfate and polyethylene glycol
`
`40 stearate; sodiufT1 lai.Jryl sulfate anQ polyethylene glycol 100 stearate; sodium
`
`lauryl sulfate and PEG 3000; sodium lauryl sulphate and PEG 6000; sodium
`
`lauryl sulfate and Brij700; sodium lauryl sulfate and Poloxamer 407; sodium lauryl
`
`sulfate and Poloxamer 338 and sodium lauryl sulfate and Poloxamer 188.
`.
`.
`(b) lactose anhydrous or lactose anhydrous combined with a material selected from ·
`
`.
`
`the group consisting of: sodium pentane sulfate; sodium octadecyl sulfate;
`Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium: polyoxyl-
`40-stearate; Aerosil R972 fumed siliea; sodium lauryl sulfate or other alkyl sulfate
`surfactants with a chain length between C5 to C18; calcium carbonate; malic
`acid; tartaric acid; trisodium . citrate dehydrate; D,L-Malic acid; Xylitol; Polyvinyl
`
`pyrrolidone; lactose monohydrate; mannitol; microcrystalline cellulose; sodium
`
`lauryl sulfate and polyethylene glycol 40 stearate. sodium lauryl sulfate and
`polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium
`
`lauryl sulphate and PEG 6000, sodium lauryl sulfate and Brij700. sodium lauryl
`sulfate and Poloxamer 407, sodium laui'yl sulfate and Poloxamer 338. sodium
`
`lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338 and Poloxamer
`188.
`(c) mannitol or mannitol combined wit~ a material .selected from the group consisting
`
`of: sodium pentane sulfate; sodil!m octadecyl sulfate; B.rij700; Brij76; sodium n(cid:173)
`lauroyl sacrosine; lecithin; d~cusate sodium; polyoxyl-40-stearate; Aerosil R972
`
`fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain
`length between CS to C18; calcium carbonate; malic acid; t~rtaric acid; trisodium
`lactose
`citrate dehydrate; · D,L-M_alic acid; Xylitol; Polyvinyl pyrrolidone;
`monohydrate; microcrystalllne cellulose; lactose anhydrous;· sodium lauryl sulfate ·
`
`and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol
`
`100 stearate, sodium lauryl sulfate and PEG 3000, sodium la1,1ryl sulphate and
`.
`PEG 6000, sodium lauryl suifate and Brij700, sodium lauryl sulfate and
`.
`. Poloxainer 407, sodium lauryl sulfate and Poloxamer 338, _sodium lauryl sulfate
`and Poloxamer 188; Poloxamer 407, Poloxamer 338 and Poloxamer 188.
`(a) tartaric acid or tartaric acid combined with a material sele·cted from the group
`.
`.
`consisting of: sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76;
`sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate;
`.
`.
`.
`~erosil R972 t1.:1m.ed silica; sodium lauryt sulfate or other alkyl sulfate surfactants
`with a chain length between C5 to C18; calcium carbonate; malic acid; tri~odium
`
`~----------------·--· ···
`
`Page 11
`
`

`
`00
`
`""" c-
`
`.--(
`
`0
`0\
`0\
`0
`0
`N
`
`10 ·
`
`citrate dehydrate;
`
`D,L-M.alic acid; Xylitol; Polyvinyl pyrrolidone;_ la~tose
`monohydrate; microcrystalline cellulose; lactose anhydrous; mannitol; sodium
`
`lauryl sulfate and polyethylene glycol 40 · stearate. sodium . lauryl sulfate and
`
`polyethylene glycol 100 stearate, sodium_ lauryl i;ulfate and PEG 3000, sodium
`
`lauryl sulphate and PEG 6000, sodium lauryl sulfate .and Brij700, sodium lauryl
`
`sulfate and Poloxamer 407, ·sodium .lauryl sulfate and Poloxamer 338, sodium
`.
`.
`lauryl sulfate and Poloxamer 188; Poloxamer 407', Poloxamer 338 and Poloxamer
`188.
`
`(e) Xylitol or Xylitol combined with a material selected from the group consisting of:
`
`sodium pentane sulfate; sodium octadecyt sulfate; Brij700; Brij76; sodl_um n(cid:173)
`
`lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40_-stearate; Aero~il R972
`
`fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain
`
`length between C5 to C18; calcium carbonate; malic acid; tartaric acid; trisodium
`citrate dehydrate; D.L-Malic acid; Polyvinyl pyrrolidone; lactose monohydrate;
`
`microcrystalline cellulose; lactose anhydrous; mannitol; sodium lauryl sulfate and
`polyethylene glycol 40 stearate, sodium lauryl sulfate and poly~thylene glycol 100
`
`stearate, sodium l~uryl sulfate and PEG 3000. sodium lauryl sulphate and PEG
`6000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407,
`. sodium lauryl sulfate and Poloxa·mer 338, sodium lauryl sulfate and Poloxamer
`
`186; Poloxamer 407, Poloxamer 338 and Poloxamer 186.
`
`(f) microcrystalllne cellulose or microcrystalline cellulose combined with· a material
`selected from the group consisting of: sodium pentane sulfate; sodium octadecyl ·
`sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium;
`polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other ·
`.
`.
`.
`alkyl sulfate surfactants with a chain length between C5 to C18; calcium
`carbonate; malic aci~; tartaric acid; trisodium citrate . dehydrate; D,L-Malic acid;
`
`.·
`
`polyvinyl pyrrolidone; lactose monohydrate; xylitol; lactose anhydrous; mannitol ·
`sodium lauryl s1,.1lfate and polyethylene glycol 40 stearate, sodium lauryl. sulfate
`and polyethylene glycol 100 stearate, sodium lauryl sulfate. and PEG 3000,
`
`sodium lauryl sulphate.and PEG 6000, sodium lauryl sulfate and Brij700, sodium
`lauryl sulfate and Poloxamer 407, sodium _lauryl sulfate and Poloxamer 338,
`.sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338 and
`Poloxamer 188;
`
`(g) Kaolin combined with a material selected from the gro~p cor:isisting of: sodium
`pentane sulfate; sodium octadecyt ·sulfate; Brij700; Brlj76; sodium n-lauroyl
`.
`.
`.
`· sacrosine; lecithin; docusate sodium; pol,yoxyl-40-stearate; Aerosil R972 fumed
`.
`.
`silica; sodium lauryl ·Sulfate or other alkyl sulfate surfactants with -a· chain length
`
`Page 12
`
`

`
`11
`
`between CS to C18; calcium carbonate; malic acid; tartaric acid; trisodium citrate
`
`dehydrate; D,L-Malic acid; polyvinyl pyrrolidone; lactose monohydrate; xylitol;
`
`lactose· anhydrous; mannitol; microcrystalline cellulose; sodium lauryl sulfate and
`
`polyethylene glyc~l 4Q stearate, sodium lauryl sulfate and polyethylene glycol 100 •
`stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and .PEG
`
`6000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407,
`sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer
`
`188; . Poloxamer 407, Poloxam·er 338, Poloxamer 188, alkyl naphthalene
`·sulfonate c~ndensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate
`(Branched); Diisopropyl naphthaenesulphonate; erythritol distearate; linear and ·
`
`branched· dodecylbenze!'le sulfonic acids; Ne1phthalene Sulfonate Formaldehyde
`
`Condensate; nonylphenol ethoxylate; POE-30; Phosphate Esters, Tristyrylphenol
`
`Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl
`.
`.
`naphthalene sulfo~ate; sc:>dium alkyl naphthalene sulfonate condensate; sodium
`
`alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl
`Naphthalene; Formaldehyde Sulfonate; sodium salt· of n-butyl naphthalene
`
`sulfonate;
`tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol
`phosphate ester; Triethanolar.nine
`tristyrylphosphate ester; Tristyrylphenol
`
`Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.
`(h) Talc combined with a material selected from the group consisting of: sodium
`
`pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-iauroyl
`sacrosine; lecithin; docusate· sodium; polyoxyl-40-;;tearate; Aerosil R972 fumed
`.
`.
`silica; sodium ·1auryl sulfate or other alkyl sulfate surfactants with a chain length
`
`between CS to C18; calcium carbonate; malic acid; tartaric acid; trisodium citrate
`
`dehydrate; D,L-Malic acid; polyvinyl pyrrolidone; lactose monohydrate;· xylitol;
`
`lactose anhydrous; mannitol; microcrystaltine cellulose; sodium lauryl sulfate and
`pply~thylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100
`
`stearate, sodium lauryt sulfate and PEG 30QO, sodium lauryl sulphate and PEG
`6000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407,
`'
`sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer
`188; Poloxamer 407, Poloxamer 338, Poloxamer 1se. alkyl naphthalene
`sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate
`
`(Branched); Diisopropyl naphthaenesulphonate; erthritol distearate; linear and
`branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde
`Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol