WO2005002541A2 - Process for preparing formulations of lipid-regulating drugs - Google Patents

Process for preparing formulations of lipid-regulating drugs Download PDF

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Publication number
WO2005002541A2
WO2005002541A2 PCT/US2004/021361 US2004021361W WO2005002541A2 WO 2005002541 A2 WO2005002541 A2 WO 2005002541A2 US 2004021361 W US2004021361 W US 2004021361W WO 2005002541 A2 WO2005002541 A2 WO 2005002541A2
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WO
WIPO (PCT)
Prior art keywords
admixture
granulated
drag
drug
lipid
Prior art date
Application number
PCT/US2004/021361
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French (fr)
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WO2005002541A3 (en
Inventor
Yihing Qiu
Jacqueline Wardrop
Original Assignee
Abbott Laboratories
Priority date (The priority date 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 date listed.)
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Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to CA2531097A priority Critical patent/CA2531097C/en
Priority to MXPA06000111A priority patent/MXPA06000111A/en
Priority to EP04777483A priority patent/EP1643975A2/en
Priority to JP2006518798A priority patent/JP5134818B2/en
Publication of WO2005002541A2 publication Critical patent/WO2005002541A2/en
Publication of WO2005002541A3 publication Critical patent/WO2005002541A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to a new process for preparing solid formulations of lipid- regulating drugs.
  • U.S. Patent No. 4,961,890 discloses a process for preparing a controlled release formulation containing fenofibrate in an intermediate layer in the form of crystalline microparticles included within pores of an inert matrix.
  • the formulation is prepared by a process involving the sequential steps of dampening said inert core with a solution based on said binder, then projecting said fenofibrate microparticles in a single layer onto said dampened core, and thereafter drying, before said solution based on said binder dissolves said fenofibrate microparticles, and repeating said three steps in sequence until said intermediate layer is formed.
  • EP0793958A2 discloses a process for producing a fenofibrate solid dosage form utilizing fenofibrate, a surface active drug and polyvinyl pyrrolidone in which the fenofibrate particles are mixed with a polyvinyl pyrrolidone solution. The thus obtained mixture is granulated with an aqueous solution of one or more surface active drugs, and the granules thus produced are dried.
  • PCT Publication No. WO 82/01649 discloses a fenofibrate formulation having granules that are comprised of a neutral core that is a mixture of saccharose and starch.
  • the neutral core is covered with a first layer of fenofibrate, admixed with an excipient and with a second micropor- ous outer layer of an edible polymer.
  • U.S. Patent No. 5,645,856 discloses the use of a carrier for hydrophobic drugs, including fenofibrate, and pharmaceutical compositions based thereon.
  • the carrier comprises a digestible oil and a pharmaceutically-acceptable surfactant component for dispersing the oil in vivo upon administration of the carrier, which comprises a hydrophilic surfactant, said surfactant component being such as not to substantially inhibit the in vivo lipolysis of the digestible oil.
  • 6,383,517 discloses a process for preparing a solid formulation of fenofibrate comprising dissolving the fenofibrate in a surfactant solution, premixing an excipient, wet granulating the mixture, drying the mixture and forming a finished dosage form.
  • the prior art processes obtain small particles of fenofibrate by the use of co- micronization steps and/or require the presence of surfactants. These processes result in formulations that may not have maximized dissolution characteristics, and may cause gastro intestinal irritation.
  • the present invention is directed to a process for preparing a solid formulation of a lipid- regulating drug.
  • the process comprises dissolving the lipid-regulating drug in a solvent free of surfactants, premixing one or more excipients to generate an admixture, wet granulating the lipid- regulating drug solution and the premix to form a granulated drug admixture and drying the mixture.
  • the dried granulated admixture may then be sized and formed into a final dosage form.
  • the mixture may be granulated by techniques well-known in the art, preferably by a fluidized bed or by means of a low shear or high shear mixer.
  • the final oral dosage form may be prepared by techniques well-known to those skilled in the art by sizing the mixture and dry blending the resultant particles with excipients into the final oral dosage form, preferably as a tablet or capsule.
  • the formulation thus produced may be administered directly as a granulated product, diluted into an appropriate vehicle for administration, encapsulated into hard gelatin shells or capsules for administration, or administered by other means obvious to those skilled in the art.
  • the lipid regulating drug may be any suitable pharmaceutically active compound, preferably a fibrate and more preferably fenofibrate.
  • the bulk lipid-regulating drug can be prepared by any available method, as for example the compound fenofibrate may be prepared by the procedure disclosed in U.S. Patent No.
  • lipid-regulating drug is then dissolved in a solution with a suitable solvent such as, for example, acetone, methylene chloride, ethanol or chloroform in amounts ranging from 0.5 to
  • a premix of excipients is prepared by conventional techniques. Suitable excipients include, for example, binders, fillers and disintegrants such as lactose, starch, polyvinyl pyrrolidone, sodium starch glycolate and microcrystalline cellulose.
  • the lipid-regulating drug solution and excipient premix are then mixed together.
  • the resulting mixture is then granulated, for example, in a fluidized bed or a low or high shear mixer and dried by well-known solvent evaporation techniques, as for example, spray drying, fluid bed, tray drying, rotary atomizing, spinning disk drying, or evaporation under atmospheric or reduced pressure.
  • the resultant material may then be sized, if necessary and formulated into a finished dosage form, for example, a tablet or capsule by conventional techniques such as direct compression or other means.
  • a finished dosage form for example, a tablet or capsule by conventional techniques such as direct compression or other means.
  • the elimination of the surfactant results in a process having reduced raw material and capital costs, ease of manufacture, potential reduction of gastrointestinal side effects and the ability to prepare tablets and capsules more readily.
  • Example 2 Fenofibrate (25g) was dissolved in 10 mL acetone. Lactose anhydrous (57g), Aircel pH 101 (lOg), Povidone K30 (4g) and sodium starch glycolate (4g) were premixed. The premix was mixed with above solution. The wet mass was tray dried in an oven at 40-55 C. The dried solid was milled, sieved through a screen and the 30-120 mesh portion collected. The collected particles were filled into a hard gelatin capsule.
  • Example 3 In vitro dissolution rates of the capsules produced in Examples 1 and 2 were compared with that of the reference, Lipanthyl, the marketed capsule product, which contains the same amount of the active. USP apparatus II was used for testing.
  • in vitro dissolution profiles of the reference capsules and capsules of the present invention are shown in Figure 1. The data indicate that the dissolution rate of representative capsules of the present invention are comparable to the reference capsules. Based on U.S. Patent No. 4,895,726, in vitro dissolution results can be correlated to in vivo absorption in humans. Thus, equivalent or increased dissolution in vitro can result in bioavailability equivalent to the reference in humans.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

A process for preparing a formulation of a lipid-regulating drug comprising dissolving said lipid-regulating drug in a solvent free of surfactant, premixing an excipient, wet granulating the drug solution/excipient mixture, drying the mixture and forming a final dosage form.

Description

PROCESS FOR PREPARING FORMULATIONS OF LIPID-REGULATING DRUGS
Field of the Invention The present invention relates to a new process for preparing solid formulations of lipid- regulating drugs.
Background of the Invention 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethylester, also known as fenofibrate, is representative of a broad class of compounds having pharmaceutical utility as lipid-regulating drags. More specifically, this compound is part of a lipid-regulating drug class of compounds commonly known as fibrates, and is disclosed in U.S. Patent No. 4,058,552. Fenofibrate has been prepared in several different formulations, c.f., U.S. Patent No. 4,800,079 and U.S. Patent No. 4,895,726. U.S. Patent No. 4,895,726 discloses a co-micronized formulation of fenofibrate and a solid surfactant. U.S. Patent No. 4,961,890 discloses a process for preparing a controlled release formulation containing fenofibrate in an intermediate layer in the form of crystalline microparticles included within pores of an inert matrix. The formulation is prepared by a process involving the sequential steps of dampening said inert core with a solution based on said binder, then projecting said fenofibrate microparticles in a single layer onto said dampened core, and thereafter drying, before said solution based on said binder dissolves said fenofibrate microparticles, and repeating said three steps in sequence until said intermediate layer is formed. European Patent Application No. EP0793958A2 discloses a process for producing a fenofibrate solid dosage form utilizing fenofibrate, a surface active drug and polyvinyl pyrrolidone in which the fenofibrate particles are mixed with a polyvinyl pyrrolidone solution. The thus obtained mixture is granulated with an aqueous solution of one or more surface active drugs, and the granules thus produced are dried. PCT Publication No. WO 82/01649 discloses a fenofibrate formulation having granules that are comprised of a neutral core that is a mixture of saccharose and starch. The neutral core is covered with a first layer of fenofibrate, admixed with an excipient and with a second micropor- ous outer layer of an edible polymer. U.S. Patent No. 5,645,856 discloses the use of a carrier for hydrophobic drugs, including fenofibrate, and pharmaceutical compositions based thereon. The carrier comprises a digestible oil and a pharmaceutically-acceptable surfactant component for dispersing the oil in vivo upon administration of the carrier, which comprises a hydrophilic surfactant, said surfactant component being such as not to substantially inhibit the in vivo lipolysis of the digestible oil. U.S. Patent No. 6,383,517 discloses a process for preparing a solid formulation of fenofibrate comprising dissolving the fenofibrate in a surfactant solution, premixing an excipient, wet granulating the mixture, drying the mixture and forming a finished dosage form. The prior art processes obtain small particles of fenofibrate by the use of co- micronization steps and/or require the presence of surfactants. These processes result in formulations that may not have maximized dissolution characteristics, and may cause gastro intestinal irritation. It is an object of the present invention to provide small particles of lipid- regulating drugs, more preferably fenofibrate, having comparable dissolution and absorption characteristics to those particles of such drugs prepared by the prior art techniques without the need of micronizing the lipid-regulating drug or utilizing surfactants.
Summary of the Invention The present invention is directed to a process for preparing a solid formulation of a lipid- regulating drug. The process comprises dissolving the lipid-regulating drug in a solvent free of surfactants, premixing one or more excipients to generate an admixture, wet granulating the lipid- regulating drug solution and the premix to form a granulated drug admixture and drying the mixture. The dried granulated admixture may then be sized and formed into a final dosage form. The mixture may be granulated by techniques well-known in the art, preferably by a fluidized bed or by means of a low shear or high shear mixer. The final oral dosage form may be prepared by techniques well-known to those skilled in the art by sizing the mixture and dry blending the resultant particles with excipients into the final oral dosage form, preferably as a tablet or capsule. The formulation thus produced may be administered directly as a granulated product, diluted into an appropriate vehicle for administration, encapsulated into hard gelatin shells or capsules for administration, or administered by other means obvious to those skilled in the art.
Brief Description of the Drawing Figure 1 is a graph showing the dissolution characteristics of representative compositions prepared by the process of the present invention and a prior art composition.
Detailed Description of the Invention The lipid regulating drug may be any suitable pharmaceutically active compound, preferably a fibrate and more preferably fenofibrate. The bulk lipid-regulating drug can be prepared by any available method, as for example the compound fenofibrate may be prepared by the procedure disclosed in U.S. Patent No.
4,658,552, or the procedure disclosed in U.S. Patent No. 4,739,101, both herein incorporated by reference. The lipid-regulating drug is then dissolved in a solution with a suitable solvent such as, for example, acetone, methylene chloride, ethanol or chloroform in amounts ranging from 0.5 to
8.0, preferably 1.0 to 5.0 parts by weight lipid lowering drug. A premix of excipients is prepared by conventional techniques. Suitable excipients include, for example, binders, fillers and disintegrants such as lactose, starch, polyvinyl pyrrolidone, sodium starch glycolate and microcrystalline cellulose. The lipid-regulating drug solution and excipient premix are then mixed together. The resulting mixture is then granulated, for example, in a fluidized bed or a low or high shear mixer and dried by well-known solvent evaporation techniques, as for example, spray drying, fluid bed, tray drying, rotary atomizing, spinning disk drying, or evaporation under atmospheric or reduced pressure. The resultant material may then be sized, if necessary and formulated into a finished dosage form, for example, a tablet or capsule by conventional techniques such as direct compression or other means. The elimination of the surfactant results in a process having reduced raw material and capital costs, ease of manufacture, potential reduction of gastrointestinal side effects and the ability to prepare tablets and capsules more readily. The invention will be understood more clearly from the following non-limiting representative examples:
Example 1 Fenofibrate (25 g) was dissolved in 10 mL acetone. Lactose anhydrous (67g), Povidone K30 (4g) and sodium starch glycolate (4g) were premixed. The premix was granulated with the above solution. The wet granules were tray dried overnight in an oven at approximately 40- 55*0. The dried granules were sieved through a screen, the 30-120 mesh portion was collected and filled into a hard gelatin capsule. In vitro dissolution rate of the capsules were compared with that of the reference, Lipanthyl, the marketed capsule product, which contains the same amount of the active. USP apparatus II was used for testing. The test conditions were: paddle speed = 50 rpm; dissolution medium = 50 mM SDS solution; temperature = 37 >C. Dissolution samples were removed at predetermined time points and analyzed by UV spectrophotometry at 286 nm.
Example 2 Fenofibrate (25g) was dissolved in 10 mL acetone. Lactose anhydrous (57g), Aircel pH 101 (lOg), Povidone K30 (4g) and sodium starch glycolate (4g) were premixed. The premix was mixed with above solution. The wet mass was tray dried in an oven at 40-55 C. The dried solid was milled, sieved through a screen and the 30-120 mesh portion collected. The collected particles were filled into a hard gelatin capsule. Example 3 In vitro dissolution rates of the capsules produced in Examples 1 and 2 were compared with that of the reference, Lipanthyl, the marketed capsule product, which contains the same amount of the active. USP apparatus II was used for testing. The test conditions were: paddle speed = 50 rpm; dissolution medium = 50 mM SDS solution; temperature 37 "C. 5mL dissolu- tion samples were removed at pre-determined time points and assayed by UV spectrophotometry at 286 nm. In vitro dissolution profiles of the reference capsules and capsules of the present invention are shown in Figure 1. The data indicate that the dissolution rate of representative capsules of the present invention are comparable to the reference capsules. Based on U.S. Patent No. 4,895,726, in vitro dissolution results can be correlated to in vivo absorption in humans. Thus, equivalent or increased dissolution in vitro can result in bioavailability equivalent to the reference in humans.

Claims

1. A process for preparing a drag formulation comprising the steps of: dissolving a lipid-regulating drag in a solvent free of surfactant to form a drag solution; premixing an excipient to generate an admixture; wet granulating the admixture and the drag solution to form a granulated drug admixture; and drying the granulated admixture.
2. The process of claim 1 wherein the lipid-regulating drag is a fibrate.
3. The process of claim 2 wherein the fibrate is fenofibrate.
4. The process of claim 1 wherein the drying step includes evaporating the solvent.
5. The process of claim 4 wherein the evaporating is performed under vacuum.
6. The process of claim 1 wherein the drying step is accomplished using a fluid bed, tray dryer or rotary atomizer.
7. The process of claim 1 comprising the additional step of adding other excipients.
8. The process of claim 1 comprising the additional step of forming a final dosage form.
9. A process for preparing a drag formulation comprising the steps of: dissolving a lipid-regulating drag in a solvent free of surfactant to form a drag solution; premixing an excipient to generate an admixture; wet granulating the admixture and the drag solution to form a granulated drug admixture; drying the granulated admixture; and tableting the dried granulated admixture.
10. A process for preparing a drug formulation comprising the steps of: dissolving a lipid-regulating drug in a solvent free of surfactant to form a drug solution; premixing an excipient to generate an admixture; wet granulating the admixture and the drug solution to form a granulated drug admixture; drying the granulated admixture; and filling capsules with the dried granulated admixture.
11. The process of claim 1 wherein the excipient is one or more members selected from the group consisting of lactose, starch, polyvinyl pyrrolidone, magnesium stearate, and other pharmaceutically-acceptable excipients .
12. The process of claim 1 wherein the admixture is granulated in a fluidized bed.
13. The process of claim 1 wherein the admixture is granulated in a low shear or high shear mixer.
14. A composition prepared by the process of claim 1.
15. A composition prepared by the process of claim 3.
16. A method for treating of hyperlipidemia comprising the step of administering the final drug formulation prepared by the process of claim 9.
17. A method for treating of hyperlipidemia comprising the step of administering the final drag formulation prepared by the process of claim 10.
18. A method for treating of hyperlipidemia comprising the administration of the formulation prepared by the process of claim 3.
PCT/US2004/021361 2003-07-02 2004-07-02 Process for preparing formulations of lipid-regulating drugs WO2005002541A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA2531097A CA2531097C (en) 2003-07-02 2004-07-02 Process for preparing formulations of lipid-regulating drugs
MXPA06000111A MXPA06000111A (en) 2003-07-02 2004-07-02 Process for preparing formulations of lipid-regulating drugs.
EP04777483A EP1643975A2 (en) 2003-07-02 2004-07-02 Process for preparing formulations of lipid-regulating drugs
JP2006518798A JP5134818B2 (en) 2003-07-02 2004-07-02 Method for the manufacture of lipid controlled drug formulations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US61362203A 2003-07-02 2003-07-02
US10/613,622 2003-07-02

Publications (2)

Publication Number Publication Date
WO2005002541A2 true WO2005002541A2 (en) 2005-01-13
WO2005002541A3 WO2005002541A3 (en) 2005-09-15

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EP (1) EP1643975A2 (en)
JP (2) JP5134818B2 (en)
CA (1) CA2531097C (en)
MX (1) MXPA06000111A (en)
WO (1) WO2005002541A2 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982001649A1 (en) * 1980-11-19 1982-05-27 Laruelle Claude New galenic preparation of phenofibrate,method for the obtention thereof,its application as a medicine
EP0625351A1 (en) * 1993-05-19 1994-11-23 MERZ + CO. GmbH & Co. Use of Etofibrate and pharmaceutical compositions containing etofibrate in the treatment of diabetic angio- and retinopathy
US6383517B1 (en) * 1999-01-29 2002-05-07 Abbott Laboratories Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04103525A (en) * 1990-08-22 1992-04-06 Sanwa Kagaku Kenkyusho Co Ltd Production of sustainable pharmaceutical preparation for poorly water-soluble medicine
GB9806312D0 (en) * 1998-03-24 1998-05-20 Smithkline Beecham Plc Novel formulations
FR2795961B1 (en) * 1999-07-09 2004-05-28 Ethypharm Lab Prod Ethiques PHARMACEUTICAL COMPOSITION CONTAINING MICRONIZED FENOFIBRATE, A SURFACTANT AND A BINDING CELLULOSIC DERIVATIVE AND PREPARATION METHOD

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982001649A1 (en) * 1980-11-19 1982-05-27 Laruelle Claude New galenic preparation of phenofibrate,method for the obtention thereof,its application as a medicine
EP0625351A1 (en) * 1993-05-19 1994-11-23 MERZ + CO. GmbH & Co. Use of Etofibrate and pharmaceutical compositions containing etofibrate in the treatment of diabetic angio- and retinopathy
US6383517B1 (en) * 1999-01-29 2002-05-07 Abbott Laboratories Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption

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Publication number Publication date
CA2531097A1 (en) 2005-01-13
JP5134818B2 (en) 2013-01-30
CA2531097C (en) 2012-10-09
EP1643975A2 (en) 2006-04-12
JP2007530415A (en) 2007-11-01
JP2012149078A (en) 2012-08-09
MXPA06000111A (en) 2006-04-27
WO2005002541A3 (en) 2005-09-15

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