US20050207996A1 - Use of osteopontin in dental formulations - Google Patents

Use of osteopontin in dental formulations Download PDF

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Publication number
US20050207996A1
US20050207996A1 US11/000,028 US2804A US2005207996A1 US 20050207996 A1 US20050207996 A1 US 20050207996A1 US 2804 A US2804 A US 2804A US 2005207996 A1 US2005207996 A1 US 2005207996A1
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Prior art keywords
osteopontin
dental
opn
preventing
formulation
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Abandoned
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US11/000,028
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English (en)
Inventor
Hans Burling
Esben Sorensen
Hans Bertelsen
Anders Jorgensen
Gitte Graverholt
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Arla Foods AMBA
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Arla Foods AMBA
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Priority to US11/000,028 priority Critical patent/US20050207996A1/en
Assigned to ARLA FOODS AMBA reassignment ARLA FOODS AMBA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JORGENSEN, ANDERS STEEN, GRAVERHOLT, GITTE, BURLING, HANS, BERTELSEN, HANS, SORENSEN, ESBEN SKIPPER
Publication of US20050207996A1 publication Critical patent/US20050207996A1/en
Priority to US12/363,661 priority patent/US7763236B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention concerns dental formulations.
  • the invention concerns the use of osteopontin (OPN) for significantly reducing plaque bacterial growth on tooth enamel.
  • OPN osteopontin
  • Dental plaque is a complex biofilm that accumulates on the hard tissues (teeth) in the oral cavity. Although over 500 bacterial species comprise plaque, colonization follows a regimented pattern with adhesion of initial colonizers to the enamel salivary pellicle followed by secondary colonization through bacterial adhesion. It is well known that a range of streptococci species belong to the early colonizers. It is therefore important to control the adhesion of these bacteria. A variety of adhesins and molecular interactions underlie the adhesive interactions and contribute to plaque development and ultimately to diseases such as caries and periodontal disease.
  • the enamel of teeth is comprised of hydroxyapatite.
  • hydroxyapatite In the mouth a natural equilibrium exists between, on the one hand, hydroxyapatite being dissolved from the enamel of the teeth and, on the other, hydroxyapatite being formed on or in the teeth from substances occurring naturally in the saliva.
  • demineralization a cariogenic condition arises which is referred to as demineralization.
  • fluoride is often incorporated in toothpaste.
  • fluoride can give rise to fluorose, especially if the patient is swallowing the toothpaste or another dentrifrice or oral hygiene product, which is often the case, for example for small children. It can also be a problem in areas with rather high amounts of fluoride in the drinking water.
  • the purpose of this patent application is to propose the use of an indigenous milk protein, osteopontin, added to a dental formulation to control or inhibit the growth of bacteria on the tooth surface and thereby prevent or reduce plaque formation and caries.
  • WO 03/059304 proposes an oral care composition containing a fluoride ion source and CPP fraction. This formulation stabilizes the calcium phosphate added to the oral formulation in an amorphous form and at the same time stabilizes the fluoride level in the formulation.
  • WO 00/07454 describes GMP which, added to a special food formulation based on milk, has an anticariogenic effect on rats.
  • OPN In contrast to CPP and GMP peptides, OPN introduces a new dimension in the oral cavity, through its potential to bioactively influence the attachment of oral organisms to the enamel and thus affect the development of caries. Like CPP and GMP, OPN also has an effect on the levels of amorphous calcium phosphate in the saliva available for tooth repair.
  • OPN thus has several functions in the dental care context.
  • OPN in e.g. toothpaste and mouthwash is that it is a natural protein component in bovine milk and thus there is a limited need for clinical testing.
  • osteopontin used in oral formulations reduce bacterial adherence and growth on enamel surfaces.
  • the invention is about oral compositions, containing osteopontin including toothpaste, mouthwash and chewing gum as well as related compositions.
  • the invention relates to the use of osteopontin for reducing plaque bacterial growth on tooth enamel and dental formulations containing osteopontin.
  • osteopontin or “OPN” means osteopontin obtained from milk, including naturally occurring fragments or peptides derived from OPN by proteolytic cleavage in the milk, or genesplice-, phosphorylation-, or glycosylation variants as obtainable from the method proposed in WO 01/49741.
  • the milk can be milk from any milk producing animals, such as cows, camels, goats, sheep, dromedaries and llamas.
  • OPN from bovine milk is preferred due to the availability. All amounts are based on native bovine milk OPN, but can easy be corrected to the corresponding amounts of an active fraction thereof or OPN from another source. OPN or derivates thereof can also be genetically prepared.
  • the dental formulations can be any dentifrice or related product of relevance in oral hygiene, such as for example toothpowder, tooth gel, dental mouthwash, mouth spray or chewing gum.
  • Osteopontin (OPN) is an acidic, highly phosphorylated, sialic acid rich, calcium binding protein. OPN binds 28 moles of phosphate and about 50 moles of Ca per mole. The isoelectric point is about 3.0.
  • the protein exists in many tissues in the body and plays a role as a signalling and regulating protein. It is an active protein in biomineralization processes. OPN is expressed by a number of cell types including bone cells, smooth muscle cells and epithelial cells.
  • OPN is present in bovine milk.
  • a typical concentration is 20 mg per l.
  • OPN can relatively simply be isolated by anion chromatography from e.g. acid whey at pH 4.5 as described by patent WO 01/497741 A2 or WO 02/28413. Purity of up to 90-95% can easily be obtained.
  • the amount of osteopontin is normally between about 50 mg OPN and about 1500 mg osteopontin per kg dental formulation. However, smaller amount will also have an effect. Higher amounts can be used, but the effect will not be essentially increased.
  • a useful amount is 100-1000 mg OPN per kg, preferably 200-500 mg, and most preferred about 350 mg. Larger amounts will presumably not give better results and is therefore not recommended, because OPN is a rather expensive ingredient.
  • compositions of the subject invention are as already mentioned in the form of as tooth-pastes, tooth-gels and tooth powders.
  • Components of such toothpaste and tooth-gels include one or more of the following: a dental abrasive (from about 10% to about 50%), a surfactant (from about 0.5% to about 10%), a thickening agent (from about 0.04% to about 0.5%), a humectant (from about 0.1% to about 3%), a flavouring agent (from about 0.04% to about 2%), a sweetening agent (from 0.1% to about 3%), a colouring (from about 0.01% to about 0.5%) and water (from 2% to 45%).
  • Anticaries agents contain from 0.001% to about 1% OPN.
  • Anti-calculus agents contain from about 0.1% to about 13% OPN.
  • Tooth powders are substantially free from all liquid components.
  • compositions of the subject invention are dental mouth washes, including mouth sprays.
  • Components of such mouth washes and mouth sprays typically include one or more of the following: water (from about 45% to about 95%), ethanol (from about 0% to about 25%), a humectant (from about 0% to about 50%), a surfactant (from about 0.01% to about 7%), a flavouring agent (from about 0.04% to about 2%), a sweetening agent from (from about 0.1% to about 3%). and a colouring agent (from about 0.001% to about 0.5% anti-caries agent including OPN, from about 0.001% to 1% and an anti-calculus agent (from about 0.1% to about 13%).
  • a third area of application is in chewing gum formulations of various compositions in general terms.
  • OPN binds to hydroxyapatite surfaces in a stable way.
  • the film cannot be removed by rinsing with water or buffer.
  • OPN influences the adherence of bacteria on the tooth analogue surface.
  • HA hydroxyapatite
  • non-coated and BSA (bovine serum albumin) treated HA discs were used as a reference for OPN coated HA surfaces.
  • Osteopontin was prepared by Arla Foods amba with a chromatographic purity of about 95%.
  • Bovine serum albumin (BSA) was purchased from Sigma-Aldrich.
  • SDS Sodium dodecylsulphate
  • All other chemicals were of analytical grade and the water used was of Milli-Q quality.
  • Pre-treatments of substrates and adsorption experiments were performed in phosphate buffer containing 0.01 M phosphate and 0.05 M sodium chloride at pH 7. All glassware and pipette tips, etc as well as buffers were sterilised by autoclavation. Protein solutions used in experiments were sterilised by filtration (cut-off 0.22 ⁇ m).
  • Stimulated saliva for the experiments was collected after chewing a piece of paraffin. A summary of the donors of stimulated salivary samples is shown in Appendix 1.
  • HA Hydroxyapatite
  • substrates were treated in mild detergent solution and thoroughly rinsed in water. Finally, they were rinsed in ethanol and water. Substrates were stored in 70% ethanol until use when they were rinsed with water and dried in a flow of nitrogen. After drying, substrates used in ellipsometry measurements were plasma cleaned in low pressure residual air (10-30 Pa) using a radio frequency glow discharge unit (Harrick PDC 3XG, Harrick Scientific Corp., Ossining, N.Y.).
  • Substrate surfaces were pre-incubated for 1 h in protein solution at 37° C. Substrates were then rinsed with buffer and incubated at 37° C. for 40 h. Stirring was applied during pre-treatment and incubation in the experiments. After incubation the HA discs were rinsed with buffer.
  • OPN OPN with salivary proteins on HA substrates
  • ellipsometry is an optical method to measure the changes in polarization of light upon reflection at a surface (3).
  • the instrument used was a Rudolph thin film ellipsometer, type 436 (Rudolph Research, Fairfield, N.J.), equipped with a xenon lamp filtered to 4015 ⁇ , and operated in a set-up as described by Landgren and Jönsson (1993).
  • ⁇ and ⁇ for the bare substrate the position of the intensity minimum was established. From the changes in ⁇ and ⁇ upon adsorption the thickness and the refractive index for the adsorbed protein film were calculated according to McCrackin et al.
  • the basic agar media employed for the isolation of micro organisms were blood agar (8), Mitis Salivarius agar (MSA, Difco Lab.), Mitis Salivarius-bacitracin (MSB) agar (9), Candida Selective agar according to Nickerson (Merck), Mac Conkey agar (Difco Lab) and Staphylococcus medium 110 (Difco Lab).
  • Saliva samples were transported in conventional VMG II (viability preserving) medium, vortex-mixed within 24 h of collection, diluted and inoculated onto blood, MSA and MSB agars.
  • Blood agar was incubated in an anaerobic chamber (10% hydrogen, 10% carbon dioxide in nitrogen) for 4 days and, MSA agar in an atmosphere of 5% carbon dioxide for 2 days.
  • the total number of colony-forming units (CFU) on the agar plates was counted with the aid of a stereomicroscope.
  • micro organisms attached to the discs were removed by sonication in a Sonics Vibracell with a microtip using 10 pulses of 1 second. Removal of cells by sonication was confirmed to be efficient by the lack of observed microbial growth.
  • the desorbate samples were vortex-mixed, diluted and inoculated into the following media: blood agar, MSA, Candida Selective agar, Mac Conkey agar and Staphylococcus medium 110.
  • Blood agar was incubated in an anaerobic chamber (10% Hydrogen, 10% Carbon Dioxide in Nitrogen) for 5 days, the MSA in an atmosphere of 5% Carbon Dioxide for 2 days and, Candida Selective agar, Mac Conkey agar and Staphylococcus medium 110 aerobically for 2 days.
  • the total number of CFU on the agars was counted with the aid of a stereomicroscope.
  • the CFU on MSA was analysed paying special attention to morphology, size and number of different colony types.
  • Gram-positive, catalase negative cocci in chains were considered to be streptococci and these isolates will be identified to species and subspecies levels based on characteristics described previously (10).
  • FIG. 1 the effect of adsorption temperature is shown. From this figure it can be seen that the adsorption of OPN on the HA surfaces happens almost instantaneously. A larger amount of OPN was absorbed at higher temperature (37° C.), although, rinsing resulted in some desorption at 37° C. to a stable surface load of 1 mg per m 2 . To simulate the chemical effect of tooth brushing SDS was added to the cuvette for five minutes, followed by rinsing with buffer. After this cleaning step there was no significant difference in adsorbed amount at the two temperatures.
  • OPN gives a surface coverage of the HA discs that is stable although a reduction in film thickness is obtained after water rinse and SDS treatment.
  • the counts of bacteria shown in table 1 and 2 desorbed by mild sonification show for HA discs treated with OPN solutions with concentration 0.1 mg/ml and 1 mg/ml respectively a significant effect on adherence of bacteria both in total counts on blood agar and MSA agar plates for all salivary donors.
  • HA discs treated with BSA or saliva exhibited more bacteria on the surfaces.
  • the total counts of micro organisms were 10- to 1000-fold lower on OPN-coated discs than on the control discs (saliva or BSA-coated).
  • the stimulated saliva samples exhibited a highly diverse microbial composition which is considered to be a common characteristic of the salivary microflora. Of interest was the finding that significantly fewer streptococci colonized the OPN-coated than the control discs.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oral & Maxillofacial Surgery (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Cosmetics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US11/000,028 2003-12-01 2004-12-01 Use of osteopontin in dental formulations Abandoned US20050207996A1 (en)

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US11/000,028 US20050207996A1 (en) 2003-12-01 2004-12-01 Use of osteopontin in dental formulations
US12/363,661 US7763236B2 (en) 2003-12-01 2009-01-30 Use of osteopontin in dental formulations

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US52582803P 2003-12-01 2003-12-01
DKPA200301777 2003-12-01
DKPA200301777 2003-12-01
US11/000,028 US20050207996A1 (en) 2003-12-01 2004-12-01 Use of osteopontin in dental formulations

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US (2) US20050207996A1 (de)
EP (1) EP1689350B1 (de)
JP (2) JP5160091B2 (de)
KR (1) KR101287347B1 (de)
CN (1) CN1889922B (de)
AT (1) ATE385190T1 (de)
AU (1) AU2004294673B2 (de)
BR (1) BRPI0417098B1 (de)
CA (1) CA2547654C (de)
DE (1) DE602004011629T2 (de)
DK (1) DK1689350T3 (de)
ES (1) ES2298843T3 (de)
NZ (1) NZ547431A (de)
PT (1) PT1689350E (de)
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WO (1) WO2005053628A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190083363A1 (en) * 2016-03-17 2019-03-21 The Regents Of The University Of California Compositions for the remineralization of dentin

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2014011594A (es) * 2012-03-28 2015-07-06 Arla Foods Amba Aglomerados de nanoparticulas que contienen osteopontina y particulas que contienen calcio y/o estroncio.
WO2015106049A1 (en) * 2014-01-10 2015-07-16 Wm. Wrigley Jr. Company Methods of detecting and quantifiying bacteria contained on or within chewing gum

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US3895922A (en) * 1972-08-02 1975-07-22 Mc Donnell Douglas Corp Ring pad stress coined structure
US3943748A (en) * 1973-01-17 1976-03-16 King John O Jun Coldwork system with delay split sleeve
US3951561A (en) * 1972-01-28 1976-04-20 Mcdonnell Douglas Corporation Stress coining tool fastened joint
US4164807A (en) * 1974-03-19 1979-08-21 King John O Jun Method of forming a coldworked joint
US4423619A (en) * 1981-06-15 1984-01-03 Fatigue Technology, Inc. Apparatus and method for prestressing a countersunk fastener hole
US4433567A (en) * 1981-11-12 1984-02-28 Grumman Aerospace Corporation Method for working holes
US4665732A (en) * 1983-09-30 1987-05-19 West Coast Industries, Inc. Method and apparatus for hole coldworking
US4670252A (en) * 1985-05-24 1987-06-02 The Procter & Gamble Company Treatment of oral diseases
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US6266991B1 (en) * 2000-04-03 2001-07-31 Albert S. Kuo Coldwork holes with reusable seamless SMA sleeve
US20020058013A1 (en) * 2000-10-20 2002-05-16 Yuusuke Nonomura Oral treatment/care agent
US20020197267A1 (en) * 2000-08-16 2002-12-26 Yoshinari Kumagai Integrin binding motif containing peptides and methods of treating skeletal diseases
US6551990B2 (en) * 1998-12-07 2003-04-22 University Of Washington Methods of inhibiting ectopic calcification
US20030105015A1 (en) * 1999-05-03 2003-06-05 Zymogenetics, Inc. Methods for promoting growth of bone, ligament, and cartilage using zvegf4
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JP2002060342A (ja) * 2000-08-17 2002-02-26 Gc Corp グラスアイオノマー系フッ素塗布材
NZ507335A (en) * 2000-10-05 2004-10-29 New Zealand Dairy Board Bone health compositions derived from milk comprising an acidic protein fraction but that does not contain CGMP
JP2002097124A (ja) * 2001-08-22 2002-04-02 Sangi Co Ltd 歯磨組成物
JP2003310170A (ja) * 2002-04-26 2003-11-05 Meiji Seika Kaisha Ltd チューインガム組成物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3566662A (en) * 1969-04-28 1971-03-02 Boeing Co Coldworking method and apparatus
US3951561A (en) * 1972-01-28 1976-04-20 Mcdonnell Douglas Corporation Stress coining tool fastened joint
US3895922A (en) * 1972-08-02 1975-07-22 Mc Donnell Douglas Corp Ring pad stress coined structure
US3943748A (en) * 1973-01-17 1976-03-16 King John O Jun Coldwork system with delay split sleeve
US4164807A (en) * 1974-03-19 1979-08-21 King John O Jun Method of forming a coldworked joint
US4423619A (en) * 1981-06-15 1984-01-03 Fatigue Technology, Inc. Apparatus and method for prestressing a countersunk fastener hole
US4433567A (en) * 1981-11-12 1984-02-28 Grumman Aerospace Corporation Method for working holes
US4665732A (en) * 1983-09-30 1987-05-19 West Coast Industries, Inc. Method and apparatus for hole coldworking
US4670252A (en) * 1985-05-24 1987-06-02 The Procter & Gamble Company Treatment of oral diseases
US4956991A (en) * 1989-12-01 1990-09-18 Grumman Aerospace Corporation Variable depth cold working tool
US5127254A (en) * 1991-07-10 1992-07-07 Fatigue Technology, Inc. Method and apparatus for split sleeve cold expansion of openings in structural members
US5943898A (en) * 1998-02-17 1999-08-31 Kuo; Albert S. Method and apparatus to coldwork holes
US6230537B1 (en) * 1998-03-17 2001-05-15 Stresswave, Inc. Method and apparatus for producing beneficial stresses around apertures by use of focused stress waves, and improved fatigue life products made by the method
US6551990B2 (en) * 1998-12-07 2003-04-22 University Of Washington Methods of inhibiting ectopic calcification
US20030105015A1 (en) * 1999-05-03 2003-06-05 Zymogenetics, Inc. Methods for promoting growth of bone, ligament, and cartilage using zvegf4
US6266991B1 (en) * 2000-04-03 2001-07-31 Albert S. Kuo Coldwork holes with reusable seamless SMA sleeve
US20020197267A1 (en) * 2000-08-16 2002-12-26 Yoshinari Kumagai Integrin binding motif containing peptides and methods of treating skeletal diseases
US20020058013A1 (en) * 2000-10-20 2002-05-16 Yuusuke Nonomura Oral treatment/care agent
US6875422B2 (en) * 2000-10-20 2005-04-05 Yuusuke Nonomura Oral treatment/care agent
US6860932B2 (en) * 2002-09-12 2005-03-01 Yoshiki Oshida Dental and medical cement

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190083363A1 (en) * 2016-03-17 2019-03-21 The Regents Of The University Of California Compositions for the remineralization of dentin

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WO2005053628A1 (en) 2005-06-16
EP1689350B1 (de) 2008-01-30
US7763236B2 (en) 2010-07-27
AU2004294673A1 (en) 2005-06-16
ES2298843T3 (es) 2008-05-16
JP2007512379A (ja) 2007-05-17
DE602004011629T2 (de) 2009-01-29
RU2006122208A (ru) 2008-01-10
BRPI0417098B1 (pt) 2015-07-07
PT1689350E (pt) 2008-03-20
DK1689350T3 (da) 2008-06-02
EP1689350A1 (de) 2006-08-16
KR101287347B1 (ko) 2013-07-23
US20090202449A1 (en) 2009-08-13
DE602004011629D1 (de) 2008-03-20
CN1889922B (zh) 2010-11-24
CA2547654C (en) 2012-09-25
NZ547431A (en) 2010-03-26
RU2385162C2 (ru) 2010-03-27
JP5160091B2 (ja) 2013-03-13
KR20060123235A (ko) 2006-12-01
CN1889922A (zh) 2007-01-03
CA2547654A1 (en) 2005-06-16
AU2004294673B2 (en) 2010-05-20
JP2012211195A (ja) 2012-11-01
ATE385190T1 (de) 2008-02-15
BRPI0417098A (pt) 2007-03-13

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