EP1583519A1 - Hochdruck-tablettierung für arzneimittelformulierungen - Google Patents
Hochdruck-tablettierung für arzneimittelformulierungenInfo
- Publication number
- EP1583519A1 EP1583519A1 EP03800248A EP03800248A EP1583519A1 EP 1583519 A1 EP1583519 A1 EP 1583519A1 EP 03800248 A EP03800248 A EP 03800248A EP 03800248 A EP03800248 A EP 03800248A EP 1583519 A1 EP1583519 A1 EP 1583519A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pressure
- gpa
- fused
- particles
- active pharmaceutical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
Definitions
- the invention relates to the field of pharmacology and, in particular, to sustained-release formulations for active pharmaceutical ingredients.
- the invention also relates to methods for preparing such formulations by high pressure compaction of an active pharmaceutical ingredient.
- sustained-release systems in the prior art have employed a finely milled or micronized preparation of the active pharmaceutical ingredient as a starting point in the formulations.
- the release of the active pharmaceutical ingredient into the body is then controlled using matrices, membranes or other inactive ingredients or devices.
- examples of methods and devices known in the art for sustained release formulations include liposomes, bioerodible matrices (e.g., PLA/PGLA matrices), drug-permeable implants (e.g., U.S. Pat. No. 3,993,073 to Zaffaroni), implants with drug-permeable and drug-impermeable membranes (e.g., U.S. Pat. No. 5,378,475 to Smith et al.), and osmotic drug delivery systems (e.g., U.S. Pat. No.4,439,196 to Higuchi).
- Prior art sustained-release delivery systems with large particles of an active pharmaceutical ingredient such as insulin, corticosteroids, or penicillins, employ techniques as solvation crystallization, thermal crystallization, or seeding crystallization to produce the larger particles.
- the pressure is maintained for a period of between 30 sec. and 10 min. In other embodiments, the pressure is maintained for a period of between 60 sec. and 5 min. In yet other embodiments, the pressure is maintained for a period of between 90 sec. and 3 min.
- the sample prior to compaction includes micronized particles including the active pharmaceutical ingredient.
- the invention provides pharmaceutical preparations of pressure-fused particles comprising an active pharmaceutical ingredient in which the pressure-fused particles include an active pharmaceutical ingredient subjected to high pressure compaction at a pressure of between 0.1 GPa and 10 GPa. In some embodiments, the pressure is between 0.5 GPa and 7.5 GPa. In other embodiments, the pressure is between 1 GPa and 5 GPa.
- the pressure-fused particles have a maximum dimension between 20 ⁇ m and 800 ⁇ m. In other embodiments, the pressure-fused particles have a maximum dimension between 40 ⁇ m and 400 ⁇ m. In yet other embodiments, the pressure-fused particles have a maximum dimension between 100 ⁇ m and 250 ⁇ m.
- Figure 2 presents data regarding the in vivo release of the active pharmaceutical nifedipine from a compacted sample including pressure-fused microparticles of the invention over a sustained-release period.
- the particles of the invention are substantially spherical in some embodiments, the particles can be any solid geometric shape which is not inconsistent with the principles of the invention, including, without limitation, ellipsoids, cylinders, polyhedrons, disks and irregular shapes.
- Disk means any solid body which is significantly smaller in a first dimension relative to the two perpendicular dimensions. Such bodies may be variously described as disks, wafers, or planar bodies, including, without limitation, bodies which are circular, elliptical or polygonal in the plane perpendicular to the first dimension.
- Semi-Permeable As used herein, the term “semi-permeable” means permeable to some molecules but not to others. As used herein, semi-permeable polymeric coatings are permeable to at least water and the active pharmaceutical ingredient within the particles of the invention.
- Biocompatible means characterized by not causing a toxic, injurious or immunological response when brought into contact with living tissue, particularly human or other mammalian tissue.
- Biodegradable means capable of partially or completely dissolving or decomposing in living tissue, particularly human or other mammalian tissue. Biodegradable compounds can be degraded by any mechanism, including, without limitation, hydrolysis, catalysis and enzymatic action.
- Pseudo-Zero-Order Kinetics As used herein, the term "pseudo-zero-order kinetics" means sustained-release of the active pharmaceutical ingredient which exhibits kinetics which is zero-order (i.e., independent of concentration) or between zero-order and first order (i.e., proportional to concentration) kinetics over the sustained-release period, where the concentration is based on the total amount of the active pharmaceutical ingredient contained within the particles. In some embodiments, the release exhibits kinetics which are less than proportional to the square root of the concentration of the active pharmaceutical ingredient over the sustained-release period.
- a variable which is described as having values between 0 and 2 can take the values 0, 1 or 2 if the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values > 0 and ⁇ 2 if the variable is inherently continuous.
- the present invention depends, in part, upon the discovery that the application of high pressure compaction to powdered or micronized pharmaceutical preparations can cause physical but non-chemical transformations to an alternative state with substantially slower rates of dissolution and, consequently, increased utility in the preparation of sustained-release formulations.
- pharmaceutical preparations subjected to high pressure compaction exhibit dissolution kinetics which are superior to conventional crystalline or amorphous packed powder preparations for sustained-release administration of active pharmaceutical ingredients.
- high pressure compaction causes a physical but non-chemical transformation of state to form pressure-fused particles which, in some embodiments, exhibit hyaline or glassy characteristics but, in other embodiments, retain crystalline or amorphous characteristics.
- the resultant pressure-fused particles have different dissolution characteristics and, in particular, slower rates of dissolution.
- the amount of pressure is sufficient to produce a compacted sample having a density of between 1 g/cm 3 and 40 g/cm 3 , between 2 g/cm 3 and 20 g/cm 3 , and between 4 g/cm 3 and 10 g/cm 3 . In some embodiments, the amount of pressure is sufficient to produce pressure-fused microparticles having a density of between 1 g/cm 3 and 40 g/cm 3 , between 2 g/cm 3 and 20 g/cm 3 , and between 4 g/cm 3 and 10 g/cm 3 .
- the invention also depends, in part, upon the recognition that, if a larger particle of a pharmaceutical preparation is introduced, there will be a sustained-release effect due to the decreased surface area-to-volume ratio of the larger particles.
- the particle if the particle is formulated to be substantially flat or planar, then the kinetics of drug release will more nearly approximate constant or zero-order kinetics.
- the particles of the invention can be used for parenteral administration.
- the administration will be by injection (e.g., subcutaneous, intravenous, intramuscular, intraocular), or by introduction to a wound site or during surgery (e.g., lavage or irrigation of a wound or surgical site).
- the particles can be sufficiently small to form a suspension and, in certain embodiments, the particles can be sufficiently small for injection through a hypodermic needle.
- the particles have a maximum dimension of between 20 ⁇ m and 800 ⁇ m, between 40 ⁇ m and 400 ⁇ m, or between 100 ⁇ m and 250 ⁇ m.
- the resulting compacted sample can be subjected to sieving to obtain particles of a desired size.
- the compacted sample can be pressed through a sieve with an exclusion limit of between 20 ⁇ m and 800 ⁇ m, between 40 ⁇ m and 400 ⁇ m, or between 100 ⁇ m and 250 ⁇ m.
- the compacted samples or sieved particles can be subjected to milling to produce fused particles of smaller size or with different geometries. For example, in some embodiments, pressure-fused particles are milled to produce spheres whereas in other embodiments the pressure-fused particles are milled to produce disks.
- biocompatible and biodegradable polymers examples include poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly( ⁇ -caprolactone) (PCL), poly(valerolactone) (PVL), poly( ⁇ -decalactone) (PDL), poly(l,4-dioxane-2,3-dione), poly(l,3-dioxane-2-one), poly(para-dioxanone) (PDS), poly(hydroxybutyric acid) (PHB), poly(hydroxyvaleric acid) (PHV), and poly( ⁇ -malic acid) (PMLA).
- PLA poly(lactic acid)
- PGA poly(glycolic acid)
- PLA poly(lactic-co-glycolic acid)
- PCL poly( ⁇ -caprolactone)
- PVL poly(valerolactone)
- PVL poly( ⁇ -decalactone)
- PDS poly(
- Non-limiting examples of anti-psychotics include benzodiazepines such as olanzapine (ZyprexaTM), clozapine, loxapine, and quetiapine; benzisoxazole derivatives such as risperidone (RisperdalTM) and molindone, and pimozide.
- benzodiazepines such as olanzapine (ZyprexaTM), clozapine, loxapine, and quetiapine
- benzisoxazole derivatives such as risperidone (RisperdalTM) and molindone, and pimozide.
- Non-limiting examples of anti-epileptics include hydantoins such as dilantin; barbiturates such as phenobarbital; deoxybarbiturates such as primidone; iminostilbenes such as cabamazepine; succinimides such as ethosuximide; benzodiazepines such as clonazepam; as well as valproic acid, gabapentin, levetiracetam, tiagabine, topiramate and zonisamide.
- hydantoins such as dilantin
- barbiturates such as phenobarbital
- deoxybarbiturates such as primidone
- iminostilbenes such as cabamazepine
- succinimides such as ethosuximide
- benzodiazepines such as clonazepam
- valproic acid gabapentin, levetiracetam, tiagabine, topiramate and zonisamide.
- Non-limiting examples of anti-Parkinson agents include levodopa preparations such as levodopa benserazide and levodopa/carbidopa; ergot dopamine agonists such as bromocriptine, cabergoline, and pergolide; non-ergot dopamine agonists such pramipexole, ropinerole, and spomorphine; catechol-O-methyltransferase inhibitors such as entacapone and tolcapone; monoamine oxidase B inhibitors such as selegiline;
- HIV protease inhibitors include ritonavir, indinavir, nelfinavir, saquinavir, amprenavir and lopinavir.
- nucleoside reverse transcriptase inhibitors include the nucleoside-based reverse transcriptase inhibitors zidovudine, didanosine, stavudine, zalcitabine, lamuvidine, and abacavir, and the non-nucleoside-based reverse transcriptase inhibitors include delavirdine, efavirenez and nevirapine.
- Non-limiting examples of taxanes include paclitaxel and docetaxel.
- Non-limiting examples of alkylating agents include the nitrogen mustards, alkyl sulfonate, nitrosurea, ethylenimine and methylmelamine, triazene classes, cyclophosphamide, ifosamide, thiotepa, melphalan, busulfan, carmustine, clorambucil, hexamethylmelamine and streptozocin.
- Non-limiting examples of immunosuppressive agents that suppress the immune system includes the corticosteroids, the purine antagonists such as azathioprine, cyclosporine, tacrolimun, sirolimus and mycophenolate mofetil.
- Non-limiting examples of other active pharmaceutical ingredients potentially useful in the invention include vinca alkaloids such as vincristine and vinblastine; platinum coordination complexes such as cisplatin and carboplatin; isoflavones such as genistein, formomonetin, daidzein and equol; epidophylotoxins such as etoposide and teniposide; camptothecins such as topotecan,and crizecan; folic acid analogues such as methotrexate; pyrimidine analogues such as 5-fluorouracil, floxuridine, and cytosine arabinoside; and purine analogues such as 6-mercaptopurine, 6-thioguanine, and 2-deoxycoformycin; as well as the anti-alcoholism medication disulfiram
- the density of the compacted sample was approximately 4 g/cm 3 .
- the high pressure compaction produced a "fused" or “glassy” wafer of olanzapine that was removed from the press.
- the compacted sample was then forced through a 60 mesh sieve grating with apertures of approximately 250 ⁇ m to produce roughly cuboidal particles.
- Poly vinyl alcohol (PVA) was obtained with a mol. wt. range of 124,000- 186,000. Excess PVA was heated in water at 65 °C. After cooling, the PVA solution was decanted and mixed with core particles prepared as described above. The core particles were swirled in a beaker of the PVA solution for several seconds, and vacuum-filtered onto #42 filter paper (Whatman, Inc., Clifton, NJ) in a 9 cm diameter Buchner funnel. The filter paper with retained coated core particles was transferred to a watch glass and dried at 155°C or 165°C for 10 minutes. This process was repeated 4-5 times.
- micronized olanzapine (90% of particles ⁇ 5 ⁇ m in diameter) from a commercial supplier (Dr. Reddy Labs, Upper Saddle River, NJ) was compared with the dissolution of coated microparticles of olanzapine prepared as described above. Powder dissolution testing was carried out in distilled water at 25°C. A 2-3 mg sample of the powder in 25 ml of water was 50% dissolved at approximately 1 minute, and was completely dissolved in 2.5 minutes.
- Coated microparticle dissolution testing was also carried out in distilled water at 25°C. A 2-3 mg sample was placed in 25 ml of water. The microparticles were completely covered by the solution. Every 24 h for 5 days, 5 ml of the supernatant solution was carefully removed and replaced with fresh media, avoiding mixing of the buffer, to simulate physiological "sink” conditions.
- Figure 1 represents the data regarding the release of the active pharmaceutical ingredient from the coated microparticles over time. As shown in the figure, the rate of release was substantially constant or pseudo-zero-order over several days. The release rate from the PVA- coated microparticles dried at the lower temperature was greater, indicating that drying temperature can be used to vary permeability and release rate.
- HPLC high performance liquid chromatography
- 3-5 male Sprague-Dawley rats were cannulated through the jugular vein to allow venous access.
- ketamine 60 mg/kg
- medetomidine 0.3 mg/kg
- the backs of the rats were shaved and an incision approximately 6 mm in length was made in the skin.
- the subcutaneous tissues were spread using blunt scissors and 6 mg/kg of the compacted sample was placed into the subcutaneous tissues approximately 5 mm from the incision site. The incision was closed with staples and topical antibiotic applied.
- Venous samples were taken through the cannula periodically for approximately two weeks to determine plasma levels of the active pharmaceutical ingredients.
- the assays had sensitivities of approximately 1 ng/ml. Histological examination of the implantation sites was carried out in all animals. Animals appeared to remain healthy and to gain weight normally. By postmortem histological examination of the implantation sites, there was no evidence of local toxicity, tissue reaction or infection.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (71)
Application Number | Priority Date | Filing Date | Title |
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US43550602P | 2002-12-20 | 2002-12-20 | |
US43549702P | 2002-12-20 | 2002-12-20 | |
US43544502P | 2002-12-20 | 2002-12-20 | |
US43516302P | 2002-12-20 | 2002-12-20 | |
US43516202P | 2002-12-20 | 2002-12-20 | |
US43503802P | 2002-12-20 | 2002-12-20 | |
US43548802P | 2002-12-20 | 2002-12-20 | |
US43503702P | 2002-12-20 | 2002-12-20 | |
US43533802P | 2002-12-20 | 2002-12-20 | |
US43550702P | 2002-12-20 | 2002-12-20 | |
US43550802P | 2002-12-20 | 2002-12-20 | |
US43541502P | 2002-12-20 | 2002-12-20 | |
US43563002P | 2002-12-20 | 2002-12-20 | |
US43555702P | 2002-12-20 | 2002-12-20 | |
US43533602P | 2002-12-20 | 2002-12-20 | |
US43550102P | 2002-12-20 | 2002-12-20 | |
US43544702P | 2002-12-20 | 2002-12-20 | |
US43550502P | 2002-12-20 | 2002-12-20 | |
US43556502P | 2002-12-20 | 2002-12-20 | |
US43549402P | 2002-12-20 | 2002-12-20 | |
US43550902P | 2002-12-20 | 2002-12-20 | |
US43563202P | 2002-12-20 | 2002-12-20 | |
US43555802P | 2002-12-20 | 2002-12-20 | |
US43510602P | 2002-12-20 | 2002-12-20 | |
US43549602P | 2002-12-20 | 2002-12-20 | |
US43541602P | 2002-12-20 | 2002-12-20 | |
US43542302P | 2002-12-20 | 2002-12-20 | |
US43544902P | 2002-12-20 | 2002-12-20 | |
US43538802P | 2002-12-20 | 2002-12-20 | |
US43513202P | 2002-12-20 | 2002-12-20 | |
US43537202P | 2002-12-20 | 2002-12-20 | |
US43549502P | 2002-12-20 | 2002-12-20 | |
US43507502P | 2002-12-20 | 2002-12-20 | |
US435506P | 2002-12-20 | ||
US435415P | 2002-12-20 | ||
US435075P | 2002-12-20 | ||
US435557P | 2002-12-20 | ||
US435565P | 2002-12-20 | ||
US435416P | 2002-12-20 | ||
US435501P | 2002-12-20 | ||
US435445P | 2002-12-20 | ||
US435038P | 2002-12-20 | ||
US435495P | 2002-12-20 | ||
US435449P | 2002-12-20 | ||
US435497P | 2002-12-20 | ||
US435338P | 2002-12-20 | ||
US435372P | 2002-12-20 | ||
US435496P | 2002-12-20 | ||
US435630P | 2002-12-20 | ||
US435488P | 2002-12-20 | ||
US435494P | 2002-12-20 | ||
US435388P | 2002-12-20 | ||
US435162P | 2002-12-20 | ||
US435132P | 2002-12-20 | ||
US435447P | 2002-12-20 | ||
US435163P | 2002-12-20 | ||
US435509P | 2002-12-20 | ||
US435336P | 2002-12-20 | ||
US435037P | 2002-12-20 | ||
US435106P | 2002-12-20 | ||
US435505P | 2002-12-20 | ||
US435632P | 2002-12-20 | ||
US435558P | 2002-12-20 | ||
US435507P | 2002-12-20 | ||
US435423P | 2002-12-20 | ||
US435508P | 2002-12-20 | ||
US45072203P | 2003-02-28 | 2003-02-28 | |
US450722P | 2003-02-28 | ||
US45499703P | 2003-03-14 | 2003-03-14 | |
US454997P | 2003-03-14 | ||
PCT/US2003/041392 WO2004058222A1 (en) | 2002-12-20 | 2003-12-22 | High pressure compaction for pharmaceutical formulations |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1583519A1 true EP1583519A1 (de) | 2005-10-12 |
Family
ID=32686487
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03800248A Pending EP1583519A1 (de) | 2002-12-20 | 2003-12-22 | Hochdruck-tablettierung für arzneimittelformulierungen |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1583519A1 (de) |
AU (3) | AU2003299983A1 (de) |
WO (2) | WO2004058223A1 (de) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007049304A2 (en) * | 2005-10-27 | 2007-05-03 | Jubilant Organosys Limited | Stable coated pharmaceutical formulation of olanzapine and process for preparing the same |
GB0522474D0 (en) * | 2005-11-03 | 2005-12-14 | Actavis Group | A pharmaceutical formulation |
ES2279715B1 (es) | 2005-12-26 | 2008-06-01 | Laboratorios Lesvi, S.L. | Formulacion oral de olanzapina. |
EP2819741B1 (de) | 2012-02-27 | 2018-03-28 | O-Ray Pharma, Inc. | Feststoffarzneimittelimplantate zur intracochlearen freisetzung von therapeutika zur behandlung von ohrerkrankungen |
US8652527B1 (en) | 2013-03-13 | 2014-02-18 | Upsher-Smith Laboratories, Inc | Extended-release topiramate capsules |
US9101545B2 (en) | 2013-03-15 | 2015-08-11 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
MX2015013457A (es) | 2013-03-21 | 2016-05-16 | Eupraxia Pharmaceuticals USA LLC | Composicion inyectable de liberación sostenida y metodo para su uso con el fin de tratar la inflamación en las articulaciones y el dolor asociado con ella. |
US11351124B2 (en) * | 2015-10-27 | 2022-06-07 | Eupraxia Pharmaceuticals Inc. | Sustained release of formulations of local anesthetics |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2515898A (en) | 1947-09-15 | 1950-07-18 | Lilly Co Eli | Procaine penicillin and therapeutic compositions |
US2627491A (en) | 1950-07-15 | 1953-02-03 | Wyeth Corp | Penicillin salts of substituted alkylene diamines |
US3867519A (en) * | 1972-04-27 | 1975-02-18 | Alza Corp | Bioerodible drug delivery device |
US4623588A (en) | 1984-02-06 | 1986-11-18 | Biotek, Inc. | Controlled release composite core coated microparticles |
US5271946A (en) | 1988-04-20 | 1993-12-21 | Asta Pharma Aktiengesellschaft | Controlled release azelastine-containing pharmaceutical compositions |
JPH08337498A (ja) * | 1995-04-13 | 1996-12-24 | Sumitomo Electric Ind Ltd | ダイヤモンド粒子、ダイヤモンド合成用粒子及び圧密体並びにそれらの製造方法 |
US6398991B1 (en) * | 1998-06-25 | 2002-06-04 | Coorstek, Inc. | Processes for making a silicon carbide composition |
-
2003
- 2003-12-22 EP EP03800248A patent/EP1583519A1/de active Pending
- 2003-12-22 AU AU2003299983A patent/AU2003299983A1/en not_active Abandoned
- 2003-12-22 WO PCT/US2003/041391 patent/WO2004058223A1/en active Application Filing
- 2003-12-22 WO PCT/US2003/041392 patent/WO2004058222A1/en active Application Filing
- 2003-12-22 AU AU2003299982A patent/AU2003299982B2/en not_active Expired
-
2010
- 2010-03-23 AU AU2010201138A patent/AU2010201138A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO2004058222A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU2003299982A1 (en) | 2004-07-22 |
AU2003299983A1 (en) | 2004-07-22 |
WO2004058222A1 (en) | 2004-07-15 |
AU2003299982B2 (en) | 2010-04-29 |
WO2004058223A1 (en) | 2004-07-15 |
AU2010201138A1 (en) | 2010-04-15 |
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Legal Events
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