WO1999026556A1 - Biodegradable intra vaginal devices - Google Patents
Biodegradable intra vaginal devices Download PDFInfo
- Publication number
- WO1999026556A1 WO1999026556A1 PCT/NZ1998/000169 NZ9800169W WO9926556A1 WO 1999026556 A1 WO1999026556 A1 WO 1999026556A1 NZ 9800169 W NZ9800169 W NZ 9800169W WO 9926556 A1 WO9926556 A1 WO 9926556A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- insert
- progesterone
- intra
- caprolactone
- days
- Prior art date
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
- A61D7/00—Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
- A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
- A61F6/14—Contraceptive devices; Pessaries; Applicators therefor for use by females intra-uterine type
- A61F6/142—Wirelike structures, e.g. loops, rings, spirals
- A61F6/144—Wirelike structures, e.g. loops, rings, spirals with T-configuration
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Definitions
- the present invention relates to improvements in and/or relating to intra vaginal devices or inserts.
- Our PCT/NZ97/00052 (published as WO 97/40776) discloses a variety of different forms of intra vaginal device of a variable geometry type for retention within the intra vaginal cavity of an animal.
- Such devices hitherto have primarily involved the use of a silicone rubber composition which as a matrix has been impregnated with the active pharmaceutical agent (eg; progesterone).
- variable geometry type devices typified by the CIDRTM devices of this company the impregnated matrix has primarily been supported on a spine of a resilient material such as nylon, the resilience of which is utilised for the variable geometry retention characteristics notwithstanding that such spine is usually fully overlaid with the impregnated matrix.
- polyesters possessing the ability to undergo biodegradation have been used to deliver pharmaceutical agents .
- a class of polymers possessing this characteristic and extensively utilized for the delivery of pharmaceutical agents are the polyesters.
- polymers examples include poly lactic acid, poly glycolic acid, poly ( ⁇ - caprolactone) and various co-polymers of lactide, glycolide and ⁇ -caprolactone.
- compositions utilizing these polymers are typically formulated as microspheres, microcapsules, films, rods or blocks. Retention within a body cavity has been achieved by a number of methods; the addition of dense fillers, injections or surgical implantation into muscle or subcutaneous area.
- the present invention relates to a device or insert designed to deliver progesterone over an extended period of time (2 to 20 days) upon insertion into the vagina of animals such as cattle, sheep, horses, pigs, goats, buffalo or deer.
- the device or insert is retained within the vagina by means of a flexible geometric arrangement (eg; of the arms and body).
- biodegradable polymers typified by poly( ⁇ -caprolactone) or a starch like saccharide
- an intra vaginally effective active agent such as progesterone (e.g. in concentration of from 5% to 70% w/w)] so as to provide appropriate in vivo release characteristics for the active agent over a period of intra vaginal retention required by the particular procedure whereupon, after extraction, the material is readily biodegradable following removal from the animal.
- a polymer such as a poly ( ⁇ -caprolactone) can be moulded notwithstanding its being impregnated with the active agent to provide not only the impregnated matrix but also to provide the variable geometry device without an obligatory presence of a spine or the like such as in the prior art devices.
- starch like saccharides have been found to be capable of being shaped to the same effect.
- the present invention consists in a device or insert for insertion into the vagina of a mammal, said device or insert consisting of a biodegradable polymer containing a pharmaceutical agent.
- the device or insert is vaginally retainable (preferably by variable geometry means at least partially dependent on the resilience of the biodegradable polymer) for at least 5 days in a target species.
- the agent is progesterone in the concentration of 5 to 70% w/w.
- the polymer is or includes poly ( ⁇ -caprolactone).
- the polymer is or includes a starch-like polysaccharide.
- the polymer may be a blend of the options and/or another polymer.
- biodegradable polymer includes therein both a cyclodextrin and an intra vaginally effective active ingredient.
- intra vaginally effective active agent means any compound or composition or complex that by means of delivery into the vaginal cavity of a mammal can be absorbed systemically by the mammal therefrom so as to achieve or suppress some physiological effect.
- examples include progesterone (eg: for oestrus synchronisation and other purposes) and oxytocin (eg: for milk let down).
- cyclodextrin includes any suitable cyclodextrin or mixtures thereof, eg: ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin and hydroxypropyl ⁇ -cyclodextrin.
- the cyclodextrin(s) comprise from 5 to 70% / w .
- the absorption enhancing agent is hydroxypropyl ⁇ -cyclodextrin in the concentration of 5 to 70% w / w .
- the device is of such geometry to facilitate retention in the vagina.
- the agent does not appear as a fine powder or crystals upon the surface of the device.
- the present invention is an intra vaginal device or insert for a target species mammal comprising or including an intra vaginally insertable, retainable and removable mass of at least primarily one or both of poly ( ⁇ -caprolactone) and a mouldable biodegradable starch-like polysaccharide, the mass by virtue of its resilience being of variable geometry which allows the intra vaginal insertion, retention and removal, wherein said mass includes therein sufficient progesterone therein such that for a target species a blood serum level of progesterone of greater than 2 ng / ml for a period of at least 5 days can follow intra vaginal insertion thereof and wherein after removal the mass is biodegradable after removal from the animal.
- target species is selected from cattle, sheep, horses, pigs, goats, buffalo and deer.
- said device or insert includes no supporting spine (eg; nylon or polyester).
- the progesterone inclusion is sufficient to deliver progesterone for a period from 2 to 20 days.
- said mass may include cyclodextrin.
- the present invention consists in the use or methods of use of such a device or any device of the present invention.
- the present invention also consists in a method of manufacture of an intra vaginal device which results in any device in accordance with the present invention.
- the invention consists in a method of manufacture of an intra vaginal device which comprises the step of including in a mouldable biodegradable polymer matrix both a cyclodextrin and an intra vaginally effective agent.
- the invention consists in the use inter alia for animal group oestrus synchrony purposes of devices or inserts of the present invention.
- said use is intra vaginal use for a period of from 2 to 20 days and said device has a capability in the target species mammal of providing for at least 5 days (if intra vaginally inserted for at least about 5 days) a blood serum level of progesterone of greater than 2 n 7 ml .
- all polymer(s) of the said mass if all, as is preferred, is to moulded
- the invention consists in a method of achieving with an animal (or group of animals) a blood serum level of progesterone of greater than 2 n ⁇ / ml for a period of at least 5 days, said method comprising inserting and retaining in the or each animal for at least the at least 5 day period a device or insert of the present invention.
- biodegradable polymers of choice are capable of being effectively impregnated with the pharmaceutical agent and optionally an absorption enhancement agent, being effectively moulded into the form of an intra vaginal device or insert of a kind reliant on variable geometry for retention, providing over the finite insertion period an appropriate tract to provide a desired pharmacological effect without detriment from any propensity of the polymer(s) to in vivo biodegrade, and, upon removal much lower in pharmaceutical agent content (see WO 97/40776), of providing no long term disposal problem owing to the propensity of the polymer(s) to biodegrade after removal from the animal.
- Figure 1 shows a device of variable geometry (the geometry being variable much in the way as discussed in WO 97/40776) but without a need for a spine of a dissimilar material (although if desired that can optionally be present),
- Figure 2 shows an in vitro cumulative progesterone release against the square- root-of-time (inserts manufactured from poly ( ⁇ -caprolactone) (thin line) or silicone
- Figure 3 shows an average plasma progesterone concentration against time following two rounds of vaginal treatment with a silicone insert of 134 cm 2 surface area ( D ) or a poly ( ⁇ -caprolactone) insert of 105 cm 2 surface area ( ⁇ ), both of which contain
- Figure 7 shows the percentage of initial mass lost for various poly ( ⁇ -caprolactone) formulations stored in compost over time
- Poly ( ⁇ -caprolactone) ( ⁇ ) poly ( ⁇ - caprolactone) with 10% w / w progesterone ( ⁇ )
- poly ( ⁇ -caprolactone) with 12.1% w / w lactose and 10.47% / w progesterone (*)
- poly ( ⁇ -caprolactone) with 43.8% w / w hydroxypropyl ⁇ -cyclodextrin and 10% w / w progesterone (*)
- poly ( ⁇ -caprolactone) with 39.9% w / w ⁇ -cyclodextrin and 9.7% w / w progesterone (•).
- Error bars are range
- Figure 8 shows plasma progesterone concentration against time following vaginal treatment for 7 days with a Mater-Bi insert of 58 cm 2 surface area with ( ⁇ ) or without
- a resilient mouldable or shapable "polymer" which is biodegradable is such that degradation of the impregnated matrix (but with a low residual active ingredient loading) will occur over time after removal from the animal after having served its purpose during an intra vaginal insertion of preferably from 2 to 20 days (eg; about 7 days). Minimal degradation (if any) occurs during the period of insertion.
- the device is wholly of the impregnated matrix which is poly ( ⁇ -caprolactone) impregnated with progesterone in the concentration of 5 to 70% w/w without any solid active pharmaceutical agent appearing as a fine powder or crystals on the surface of the device.
- the wings 1 are resilient with respect to the body 2 and in an intra vaginal injection mode can be reduced to a form or assume a position in an applicator in a known manner which facilitates insertion after which the resilience deploys the wings 1 to such condition as is required for retention.
- the resilience can be subsequently utilised to withdraw the device from within the vagina.
- a suitable source of poly ( ⁇ -caprolactone) is that product TONE 767TM from Union Carbide Specialty Polymers and Products, Danbury, Ct, USA.
- Starch-like polysaccharides that can likewise be impregnated and can be used for some or all of the device include MATER-BiTM available from Novamont, Italy.
- a preferred method of manufacturing of the device is as follows: Polymer poly ⁇ -caprolactone, starch-like polysaccharide or a blend of the two are mixed with active into a mixing vat using a suitable compound, eg; surfactant to adhere the active to the surface of the polymer granules or the use of compound extruded material..
- the polymer/active mixture is then loaded into the hopper of an injection moulding machine, and processed as a conventional thermoplastic, with machine set point parameters as per the technical recommendations of the polymer suppliers literature, and as per injection moulding standard practice.
- Key processing set points for poly ⁇ -caprolactone are: barrel temperatures ranging from 80 - 120°C with an injection pressure of 1600 bar. Total cycle time due to long cooling phase of approximately 55 seconds. Product is removed from the die and allowed to cool to equilibrium prior to packaging.
- the performance of the device while inserted and its effect upon withdrawal is substantially as discussed in WO 97/40776 but with the advantages of (i) biodegradability after removal from the animal and (ii) the preferred omission of a spine of resilient material .
- the preferred biodegradable polymers can be appropriately impregnated with an intra vaginally effective active agent such as progesterone (eg: in concentration of from 5% to 70% w/w) and an absorption enhancing agent such as hydroxypropyl ⁇ -cyclodextrin (eg: in concentrations of from 5% to 70% w/w) so as to provide appropriate release characteristics for the active agent over the period of intra vaginal retention.
- an intra vaginally effective active agent such as progesterone (eg: in concentration of from 5% to 70% w/w) and an absorption enhancing agent such as hydroxypropyl ⁇ -cyclodextrin (eg: in concentrations of from 5% to 70% w/w) so as to provide appropriate release characteristics for the active agent over the period of intra vaginal retention.
- the preferred device is wholly of the impregnated matrix which is poly ( ⁇ - caprolactone) impregnated with hydroxypropyl ⁇ -cyclodextrin in the concentration of 5 to 70% w/w.
- a suitable source of hydroxypropyl ⁇ -cyclodextrin is that product BETA W7 HP available from Wacker Chemicals Australia, Victoria, Australia.
- a preferred method of manufacture of the device is as follows: Polymer (poly ( ⁇ - caprolactone), starch-like polysaccharide or a blend of the two) are mixed with active and absorption agent into a mixing vat. The polymer/active/absorption agent mixture is then loaded into the hopper of an injection moulding machine; and processed as a conventional thermoplastic, with machine set point parameters as per technical recommendations of the polymers suppliers literature, and as per injection moulding standard practice. Key processing points are: barrel temperatures ranging from 60 - 250°C with an injection pressure of 1600 bar. Total cycle time due and allowed to cool to equilibrium prior to packaging.
- Figure 1 shows a device of variable geometry (the geometry being variable much in the way as discussed in WO 97/40776) but without a need for a spine of a dissimilar material (although if desired that can optionally be present),
- Figure 2 shows an in vitro cumulative progesterone release against the square- root-of-time. Inserts manufactured from poly ( ⁇ -caprolactone) (thin line) or silicone (thick line). When inserts of the type shown in Figure 1 manufactured from poly ( ⁇ - caprolactone) of surface area less than the silicone CIDR-BTM inserts are administered to cattle and plasma samples collected for plasma progesterone concentration analysis slightly lower levels are observed, Figure 3.
- Figure 3 shows an average plasma progesterone concentration against time following two rounds of vaginal treatment with a silicone insert of 134 cm 2 surface area (°) or a poly ( ⁇ -caprolactone) insert of 105 cm 2 surface area ( ⁇ ), both of which contain
- Figure 4 shows a percentage of initial mass lost for drug-loaded ( ⁇ ) and blank (°) poly ( ⁇ -caprolactone) inserts stored in compost overtime.
- Figure 5 shows a percentage of tensile performance lost for drug-loaded ( ⁇ ) and blank(°) poly ( ⁇ -caprolactone) inserts buried in compost over time.
- Figure 6 shows plasma progesterone concentration against time following vaginal treatment for 7 days with a silicone insert of 134 cm 2 surface area ( ⁇ ), poly ( ⁇ - caprolactone) insert of 115 cm 2 surface area ( ⁇ ) or poly ( ⁇ -caprolactone) with lactose insert of 115 cm 2 surface area (°).
- ⁇ 134 cm 2 surface area
- ⁇ poly ( ⁇ - caprolactone) insert
- ⁇ poly ( ⁇ -caprolactone) with lactose insert of 115 cm 2 surface area (°).
- Figure 7 shows the percentage of initial mass lost for various poly ( ⁇ -caprolactone) formulations stored in compost over time.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98961699A EP1039843A4 (en) | 1997-11-21 | 1998-11-23 | Biodegradable intra vaginal devices |
AU16962/99A AU758858B2 (en) | 1997-11-21 | 1998-11-23 | Biodegradable intra vaginal devices |
JP2000521763A JP2001523515A (en) | 1997-11-21 | 1998-11-23 | Mammalian vaginal insertion device and method of manufacture and use |
CA002311311A CA2311311C (en) | 1997-11-21 | 1998-11-23 | Biodegradable intra vaginal devices |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ329229 | 1997-11-21 | ||
NZ32922997A NZ329229A (en) | 1997-11-21 | 1997-11-21 | Biodegradable intravaginal devices |
NZ33059598 | 1998-06-05 | ||
NZ330596 | 1998-06-05 | ||
NZ330595 | 1998-06-05 | ||
NZ330596A NZ330596A (en) | 1998-06-05 | 1998-06-05 | Intravaginal devices allowing for increased uptake of active ingredients |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999026556A1 true WO1999026556A1 (en) | 1999-06-03 |
Family
ID=27353841
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NZ1998/000169 WO1999026556A1 (en) | 1997-11-21 | 1998-11-23 | Biodegradable intra vaginal devices |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1039843A4 (en) |
JP (1) | JP2001523515A (en) |
AU (1) | AU758858B2 (en) |
CA (1) | CA2311311C (en) |
WO (1) | WO1999026556A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001012101A1 (en) * | 1999-08-18 | 2001-02-22 | Interag | Multiple material dispensing |
WO2002045685A2 (en) * | 2000-12-08 | 2002-06-13 | Board Of Trustees Of University Of Illinois | Cristallizable/non crystallizable polymer composites |
WO2003024355A1 (en) * | 2001-09-20 | 2003-03-27 | Ashmont Holdings Limited | Intraruminal device |
WO2003065924A1 (en) * | 2002-02-08 | 2003-08-14 | Advanced Animal Technology Limited | Control of a biological function |
JP2004506482A (en) * | 2000-08-24 | 2004-03-04 | コーネル リサーチ ファンデーション インコーポレーテッド | Non-hormonal vaginal contraceptive device |
US6758840B2 (en) | 2000-04-20 | 2004-07-06 | Metris Therapeutics Limited | Drug delivery device |
US6776164B2 (en) | 1998-06-05 | 2004-08-17 | Interag | Enhanced intravaginal devices |
WO2004091570A1 (en) * | 2003-04-17 | 2004-10-28 | Interag | Method of treatment |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4732763A (en) * | 1978-10-17 | 1988-03-22 | Stolle Research And Development Corporation | Active/passive immunization of the internal female reproductive organs |
EP0388234A1 (en) * | 1989-03-17 | 1990-09-19 | Carter Holt Harvey Plastic Products Group Limited | A drug administering device for insertion in a body cavity of an animal |
US5116619A (en) * | 1988-08-30 | 1992-05-26 | Lee Roy Morgan | Vaginal progesterone tablet |
WO1993024154A1 (en) * | 1992-06-03 | 1993-12-09 | Fuisz Technologies, Ltd. | Biodegradable controlled release melt-spun delivery system |
WO1997034932A2 (en) * | 1996-03-20 | 1997-09-25 | British Technology Group Limited | Compositions containing starch excipients |
WO1997040776A1 (en) | 1996-05-01 | 1997-11-06 | Dec International Nz Limited | Synchronising of animal oestrus and intra vaginal devices useful therein |
US5739176A (en) * | 1988-10-03 | 1998-04-14 | Atrix Laboratories, Inc. | Biodegradable in-situ forming implants and methods of producing the same |
WO1998053758A1 (en) * | 1997-05-28 | 1998-12-03 | Dec International Nz Limited | Intra-vaginal device for pigs |
-
1998
- 1998-11-23 JP JP2000521763A patent/JP2001523515A/en active Pending
- 1998-11-23 EP EP98961699A patent/EP1039843A4/en not_active Withdrawn
- 1998-11-23 AU AU16962/99A patent/AU758858B2/en not_active Ceased
- 1998-11-23 WO PCT/NZ1998/000169 patent/WO1999026556A1/en active IP Right Grant
- 1998-11-23 CA CA002311311A patent/CA2311311C/en not_active Expired - Fee Related
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4732763A (en) * | 1978-10-17 | 1988-03-22 | Stolle Research And Development Corporation | Active/passive immunization of the internal female reproductive organs |
US5116619A (en) * | 1988-08-30 | 1992-05-26 | Lee Roy Morgan | Vaginal progesterone tablet |
US5739176A (en) * | 1988-10-03 | 1998-04-14 | Atrix Laboratories, Inc. | Biodegradable in-situ forming implants and methods of producing the same |
EP0388234A1 (en) * | 1989-03-17 | 1990-09-19 | Carter Holt Harvey Plastic Products Group Limited | A drug administering device for insertion in a body cavity of an animal |
WO1993024154A1 (en) * | 1992-06-03 | 1993-12-09 | Fuisz Technologies, Ltd. | Biodegradable controlled release melt-spun delivery system |
WO1997034932A2 (en) * | 1996-03-20 | 1997-09-25 | British Technology Group Limited | Compositions containing starch excipients |
WO1997040776A1 (en) | 1996-05-01 | 1997-11-06 | Dec International Nz Limited | Synchronising of animal oestrus and intra vaginal devices useful therein |
WO1998053758A1 (en) * | 1997-05-28 | 1998-12-03 | Dec International Nz Limited | Intra-vaginal device for pigs |
Non-Patent Citations (1)
Title |
---|
See also references of EP1039843A4 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6776164B2 (en) | 1998-06-05 | 2004-08-17 | Interag | Enhanced intravaginal devices |
WO2001012101A1 (en) * | 1999-08-18 | 2001-02-22 | Interag | Multiple material dispensing |
US7083590B1 (en) | 1999-08-18 | 2006-08-01 | Interag | Multiple material dispensing |
US6758840B2 (en) | 2000-04-20 | 2004-07-06 | Metris Therapeutics Limited | Drug delivery device |
JP2004506482A (en) * | 2000-08-24 | 2004-03-04 | コーネル リサーチ ファンデーション インコーポレーテッド | Non-hormonal vaginal contraceptive device |
WO2002045685A2 (en) * | 2000-12-08 | 2002-06-13 | Board Of Trustees Of University Of Illinois | Cristallizable/non crystallizable polymer composites |
WO2002045685A3 (en) * | 2000-12-08 | 2003-05-22 | Univ Illinois | Cristallizable/non crystallizable polymer composites |
WO2003024355A1 (en) * | 2001-09-20 | 2003-03-27 | Ashmont Holdings Limited | Intraruminal device |
WO2003065924A1 (en) * | 2002-02-08 | 2003-08-14 | Advanced Animal Technology Limited | Control of a biological function |
WO2004091570A1 (en) * | 2003-04-17 | 2004-10-28 | Interag | Method of treatment |
Also Published As
Publication number | Publication date |
---|---|
CA2311311C (en) | 2008-05-06 |
AU758858B2 (en) | 2003-04-03 |
EP1039843A1 (en) | 2000-10-04 |
AU1696299A (en) | 1999-06-15 |
JP2001523515A (en) | 2001-11-27 |
EP1039843A4 (en) | 2007-12-26 |
CA2311311A1 (en) | 1999-06-03 |
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