US20070039618A1 - Delivery system - Google Patents

Delivery system Download PDF

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Publication number
US20070039618A1
US20070039618A1 US11/586,983 US58698306A US2007039618A1 US 20070039618 A1 US20070039618 A1 US 20070039618A1 US 58698306 A US58698306 A US 58698306A US 2007039618 A1 US2007039618 A1 US 2007039618A1
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United States
Prior art keywords
medicament
member
characterised
delivery device
inhaler
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Abandoned
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US11/586,983
Inventor
Philip Braithwaite
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Innovata Biomed Ltd
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Innovata Biomed Ltd
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Family has litigation
Priority to GBGB9913047.8A priority Critical patent/GB9913047D0/en
Priority to GB9913047.8 priority
Priority to GBGB9916283.6A priority patent/GB9916283D0/en
Priority to GB9916283.6 priority
Priority to PCT/GB2000/002017 priority patent/WO2000074754A2/en
Priority to US98099902A priority
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26315636&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20070039618(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Innovata Biomed Ltd filed Critical Innovata Biomed Ltd
Priority to US11/586,983 priority patent/US20070039618A1/en
Publication of US20070039618A1 publication Critical patent/US20070039618A1/en
Assigned to INNOVATA BIOMED LIMITED reassignment INNOVATA BIOMED LIMITED CHANGE OF ADDRESS Assignors: INNOVATA BIOMED LIMITED
Assigned to INNOVATA BIOMED LIMITED reassignment INNOVATA BIOMED LIMITED CORRECTIVE ASSIGNMENT TO CORRECT THE REMOVE SERIAL NO. 11326231 PREVIOUSLY RECORDED AT REEL: 032947 FRAME: 0636. ASSIGNOR(S) HEREBY CONFIRMS THE CHANGE OF ADDRESS. Assignors: INNOVATA BIOMED LIMITED
Application status is Abandoned legal-status Critical

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0065Inhalators with dosage or measuring devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00Special media to be introduced, removed or treated
    • A61M2202/06Solids
    • A61M2202/064Powder

Abstract

There is described a medicament delivery device which comprises a medicament reservoir, a medicament delivery passage and a metering member adapted to transfer a measured dose of medicament from the medicament reservoir to the delivery passage characterized in that the device is provided with a moisture proof barrier. The medicament delivery device is especially suited for use as an inhaler. There is therefore also described an inhaler which provides improved airflow for the dispersion of medicament, and a method of treating patients suffering from a respiratory disorder.

Description

  • This application is a continuation of U.S. patent application Ser. No. 09/980,999, filed under 35 U.S.C. 371, based on PCT International Application No. PCT/GB00/02017, filed Jun. 5, 2000, which claims priority to Great Britain Patent Application Nos. 9913047.8 and 9916283.6, filed Jun. 5, 1999 and Jul. 13, 1999, respectively, both of which are hereby incorporated by reference in their entirety.
  • FIELD OF THE INVENTION
  • This invention relates to a novel form of medicament delivery system and to novel methods of treatment.
  • In particular the invention provides a medicament delivery device, such as an inhaler, which is adapted to be moisture resistant and/or provides improved air flow through the device.
  • BACKGROUND OF THE INVENTION
  • It is well established that delivery devices adapted for the delivery of dry powder medicaments suffer from the problem of contact with moisture. Such problems are present particularly when hygroscopic medicaments are used or when climatic conditions give rise to high humidity. Medicament inhalers are known to suffer from such and moisture contamination of dry powder inhalers has long been held to be undesirable since the dry powder medicament may become clogged, creating problems in delivering correct dosages of medicament. Furthermore, some inhaled medicaments are themselves inherently moisture sensitive. Therefore, there has long been a desire to provide a dry powder inhaler that is resistant to moisture, that is, one that protects a medicament reservoir from moisture contamination either from the environment or from exhalation by a patient using the device and various attempts have been made to mitigate the problem.
  • Most attempts which have been made aim to reduce the moisture which comes into contact with a medicament, such attempts generally comprise the use of an additional chamber containing a desiccant.
  • International Patent Application No WO 98/41261 describes an inhalation device which includes a chamber for containing a desiccant, e.g. silica gel. Whilst the use of a desiccant gel does remove some moisture, the system is disadvantageous in that, inter alia, the leak paths are too great for the available desiccant to cope with and therefore the desiccant is only effective for a few hours, whereas there is a need for moisture resistance if at least a few months.
  • Similarly, International Patent Application No WO 96/08284 describes an inhaler system provided with a reservoir wherein the closed end of the reservoir is also provided with a desiccant cartridge.
  • International Patent Application No WO 95/32752 also describes a medicament chamber included in an inhalation apparatus and provided with a container containing a desiccant.
  • We have now developed a medicament delivery device, e.g. a dry powder inhaler, which is able to provide a moisture proof barrier without the necessity of a desiccant.
  • SUMMARY OF THE INVENTION
  • Therefore, according to the invention we provide a medicament delivery device which comprises a medicament reservoir, a medicament delivery passage and a metering member adapted to transfer a measured dose of medicament from the medicament reservoir to the delivery passage characterised in that the device is provided with a moisture proof barrier.
  • The moisture proof barrier is preferentially a physical barrier as opposed to a chemical barrier, e.g. a desiccant, although it is within the scope of the present invention that a desiccant may be included in addition to the moisture proof barrier if desirable.
  • In a preferred embodiment the moisture proof barrier is positioned so as to prevent the ingress of moisture into the medicament reservoir, so that moisture is prevented from coming into contact with the medicament. In an especially preferred embodiment of the delivery device of the invention, the moisture proof barrier is a moisture proof sealing means.
  • In a preferred embodiment, the sealing means of the delivery device will operate by the delivery device being adapted to move from an inoperable position, in which the medicament reservoir is sealed, to an operative position, in which the seal is reversibly broken so that measurement and/or delivery of a dose of medicament may take place. The sealing means will generally comprise a resilient sealing member positioned at the end of the reservoir adjacent the metering member. Furthermore, the metering member is preferentially biased towards the resilient sealing member to improve the seal provided. Preferably the resilient sealing member is in a fixed position whilst the metering member moves from an inoperable to an operable position and thus from a sealing to a non-sealing position.
  • The resilient sealing member preferably comprises a cover adapted to fit the base of the medicament reservoir, the sealing member being provided with an aperture to permit transmission of the medicament. The resilient sealing member may comprise any conventionally known material, for example a natural or synthetic rubber, a silicon or a PTFE material, although other similar materials can be contemplated within the scope of this invention
  • The moisture proof barrier of the invention may be applied to any conventionally known medicament delivery system. However, in a preferred embodiment, the medicament delivery device is an inhaler. Whilst the moisture proof barrier may be applied to any conventionally known inhaler, it is an especially preferred aspect of the invention for the inhaler to be a dry powder inhaler (DPI). DPI's are known which operate with predetermined doses of medicament, for example, the medicament may be contained in a gelatin capsule which is ruptured to release the medicament. However, a preferred inhaler of the invention is a DPI which comprises a medicament reservoir and a metering member which is adapted to measure a selected amount of medicament for inhalation. Thus, in an especially preferred embodiment the metering member is rotatable from an operable to an inoperable position. The metering member may comprise a dispensing member and a moisture resistant member, e.g. a moisture resistant sleeve. In such an embodiment the moisture resistant member is provided with one or more measuring chambers adapted to measure a predetermined dosage of medicament. Thus, in the operable position, the position of measuring chamber of the metering member corresponds with the aperture in the resilient sealing member so that medicament enters the measuring chamber. The moisture resistant member may then be rotated so that the reservoir is sealed again by the wall of the moisture resistant member. At the same time the medicament is transferred from the measuring chamber of the moisture resistant sleeve to the dispensing chamber of the dispensing member
  • An example of a preferred DPI is CLICKHALER, produced by Innovata Biomed in the UK. Such a device is described in European Patent No 0 539 469. Thus, the metering member may be a frusto conical member such as described in European Patent No 0 539 469.
  • Therefore, the metering member may comprise a frusto conical dispensing member with a corresponding moisture resistant sleeve, such that the sleeve overlies the dispensing member. Thus, the measuring chamber may comprise outer side walls which are provided by an aperture in the wall of the moisture resistant sleeve and the base of the measuring chamber may be provided by the frusto conical wall of the dispensing member. Preferably the moisture resistant sleeve is provided with a plurality of apertures and thereby a plurality of measuring chambers.
  • The use of the frusto-conical shape in the wall of the metering member containing the measuring chambers allows a good seal to be obtained between the metering member and a seat against which the frusto-conical wall mates.
  • Therefore, the frusto conical metering member may itself comprise a combination of a frusto conical dispensing member and a frusto conical moisture resistant sleeve which forms a snug fit over the dispensing member. The moisture resistant sleeve may itself be moveable e.g. rotatable, from a sealing to a non-sealing position as herein before described and vice versa. Such a moisture resistant sleeve may comprise any conventionally known material but is preferentially a plastics material, e.g. the same material as the metering member.
  • The dispensing member and the moisture resistant sleeve can, preferentially, be adapted so as to act together as a medicament measuring/dispensing member. The preferred metering member comprises a dispensing member provided with one or more dispensing cups and a moisture resistant sleeve provided with one or more apertures. Preferably the dispensing member comprises a plurality of dispensing cups and the sleeve comprises a plurality of apertures. It is especially preferred that the dispensing member comprises an equivalent number of dispensing cups to apertures in the sleeve.
  • We have especially found that if the moisture resistant sleeve comprises a frusto hemispherical cone, then an improved seal is achieved between the medicament reservoir and the sleeve. When a frusto hemispherical cone sleeve is used, the arcuate base of the reservoir is able to make more uniform contact with the curved surface of the cone and therefore an improved seal is achieved. Thus, it is especially preferred that the outer walls of the cone are hemispherical. Furthermore, the inner walls of the cone are preferably contoured to form a good mate with the frusto conical dispensing member.
  • Thus, in operation, the metering member may be moved to a first position in which the medicament is transferred to a first measuring chamber in the moisture resistant sleeve, the device is then moved to a second position in which medicament is transferred from the measuring chamber to a dispensing cup in the dispensing member and then to a third position where medicament is delivered to the delivery passage.
  • The dispensing member may be a conventionally known member such as a frusto conical member described herein and in EP 0 539 469. However, we have also found the use of a moisture resistant sleeve permits a dispensing chamber to be provided with an air inlet, e.g. an air duct. Previously, the use of an air inlet was felt to be undesirable since it might effect the accuracy of the measurement of the medicament dose. However, by use of a system wherein the medicament is first transferred to a measuring chamber and then subsequently to a dispensing cup, the cup in the dispensing member may be provided with an air inlet without any loss in accuracy of the dosage delivered. Furthermore, improved air flow provides greater likelihood of complete emptying of the dispensing cup and thereby provides an inhaler with improved performance. Clearly, an inhaler with such improved performance is advantageous per se, regardless of whether such an inhaler is moisture resistant.
  • Thus according to an alternative feature of the invention we provide a dry powder inhaler which comprises a medicament reservoir, an inhalation passage for the delivery of the medicament and a metering member adapted to transfer a measured dose of medicament from the medicament reservoir to the inhalation passage characterised in that the metering member comprises a measuring member adapted to measure a pre-defined dosage of medicament and moveable from a measuring to a non-measuring position; and a dispensing member adapted to receive the measured dosage of medicament from the measuring member and to deliver the medicament to the inhalation passage, the dispensing member being moveable from a medicament receiving position to a medicament delivering position.
  • In the preferred embodiment the dispensing member is provided with one or more medicament dispensing cups, said cups being provided with a duct so as to provide a flow of air through the cup and into the inhalation passage upon operation of the device.
  • By the term dry powder we mean a medicament in finely divided form.
  • A variety of medicaments may be administered by using the inhaler of the invention, optionally with a conventionally known pharmaceutically acceptable adjuvant, diluent or carrier. Such medicaments are generally antibiotics, bronchodilators or other anti-asthma drugs. Such medicaments include, but are not limited to β2-agonists, e.g. fenoterol, formoterol, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol and terbutaline; non-selective beta-stimulants such as isoprenaline; xanthine bronchodilators, e.g. theophylline, aminophylline and choline theophyllinate; anticholinergics, e.g. ipratropium bromide; mast cell stabilisers, e.g. sodium cromoglycate and ketotifen; bronchial anti-inflammatory agents, e.g. nedocromil sodium; and steroids, e.g. beclomethasone dipropionate, fluticasone, budesonide and flunisolide; and combinations thereof.
  • Specific combinations of medicaments which may be mentioned include combinations of steroids, such as, beclomethasone dipropionate, fluticasone, budesonide and flunisolide; and combinations of to β2-agonists, such as, formoterol and salmeterol. It is also within the scope of this invention to include combinations of one or more of the aforementioned steroids with one or more of the aforementioned β2-agonists.
  • The inhaler of the invention is especially suitable for use in the treatment or alleviation of respiratory disorders. Thus according to the invention we also provide a method of administering a dry powder inhalation medicament using an inhaler as hereinbefore described.
  • We further provide a method of treatment of a patient with a respiratory disorder which comprises the administration of a combination of medicaments using an inhaler as hereinbefore described.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • The invention will now be described by way of example only and with reference to the accompanying drawings in which:
  • FIG. 1 is a perspective view of an inhalation device of the invention;
  • FIGS. 2 a-f are schematic representations of the sealing and measuring mechanism.
  • FIG. 3 is a perspective view of a moisture resistant sleeve comprising a frusto hemispherical cone, and
  • FIGS. 4 a-b are cross-sectional views of a moisture resistant sleeve comprising a frusto hemispherical cone.
  • DETAILED DESCRIPTION OF THE INVENTION
  • With reference to FIG. 1, a dry powder inhaler (1) comprises a medicament reservoir (2) comprising an essentially conical member; an inhalation passage (3) and a metering member (4). The inhalation passage (3) is connected to the medicament reservoir (2) by a reservoir support (5) and is itself connected to recess (6) which provides a seat for the metering member (4). The metering member (4) is rotatable about an axis (7) from a medicament receiving position, to a medicament delivery position and then to an emptying position to allowing any residual medicament to be emptied into a waste box (8).
  • The recess (6) is essentially frusto conical in shape to enable it to provide a seal for the metering member (4). The metering member (4) comprises a frusto conical moisture resistant sleeve (9) which forms a snug fit between recess (6) and a dispensing member (10). The dispensing member (10) is also provided with a back plate (11).
  • The moisture resistant sleeve (9) abuts against the resilient seal (9 a) to form a moisture resistant seal.
  • The moisture resistant sleeve (9) is also provided with a plurality of measuring chambers which comprise apertures (12) dimensioned to measure a predetermined amount of medicament and to fit over cups (13) in the dispensing member (10). In a preferred embodiment, each of the cups (13) are also provided with a duct (14). The medicament reservoir (2) is also provided with a moisture resistant, e.g. foil, cover (15) at its end (16) distal from the metering member (4).
  • With reference to FIG. 2, in which FIG. 2 a the metering device is in a closed position,
  • FIG. 2 b the metering device is in a measuring position,
  • FIG. 2 c the metering device is in a seal transitory position,
  • FIG. 2 d the metering device is in a medicament transfer position,
  • FIG. 2 e the metering device is in a medicament delivery position; and
  • FIG. 2 f the metering device is returned to the closed position.
  • In FIG. 2 a the metering device (4) is in the closed position and the medicament reservoir (2) is isolated and a seal formed between the sealing member (17) and the surface (18) of the moisture resistant sleeve (9). In FIG. 2 b, the moisture resistant sleeve (9) is rotated in an anti clockwise direction so that the aperture/measuring chamber (12) corresponds with the aperture in the sealing member (17). The aperture/measuring chamber (12) forms a cup with the surface of the dispensing member (10).
  • In FIG. 2 c the moisture resistant sleeve (9) is further rotated so that the aperture/measuring chamber (12) sits below the sealing member (17). The internal edge of the sealing member (17) scrapes any excess medicament from the aperture/measuring chamber (12) to leave a measured dose.
  • In FIG. 2 d the dispensing member (10) is rotated in an anticlockwise direction so that the dispensing cup (13) corresponds with the aperture/measuring chamber (12) allowing medicament to transfer from the aperture/measuring chamber (12) to the dispensing cup (13).
  • In FIG. 2 e both the dispensing member (10) and the moisture resistant sleeve (9) are rotated anticlockwise to expose them and the medicament to the inhalation passage (3). The patient can then inhale the medicament.
  • In FIG. 2 f the inhalation device remains in the closed position ready for use.
  • With reference to FIGS. 3 and 4, a moisture resistant sleeve (9) comprises a frusto hemispherical cone (22) wherein the outer surface (23) is arcuate. The inner surface (24) acts as a female member to form a snug fit with the frusto conical dispensing member (10). Downward pressure in the medicament reservoir (2) ensures a constant moisture tight seal between the sealing member (17) and the frusto hemispherical cone (22). Furthermore, referring to FIG. 4 c, the leading edge (25) of the sealing member (17) is capable of acting as a scraper or a cleaning edge, removing any excess medicament from the measuring chamber upon rotation of the metering member.
  • A variety of mechanisms may be used for the operation of the inhaler. One preferred mechanism is for movement from the closed to the measuring position to be achieved by removal of a mouth piece which is operably linked to the moisture resistor. Movement from the measuring position to the transitory position would use a mechanism similar to that described in EP 0 539 469, e.g. by depressing the button half way. Movement to the transfer position being achieved by further depressing the button, and then depression completely, moving the metering cone and the moisture resistor to the delivery position.

Claims (24)

1. A medicament delivery device which comprises a medicament reservoir, a medicament delivery passage and a metering member adapted to transfer a measured dose of medicament from the medicament reservoir to the delivery passage characterised in that the device is provided with a moisture proof barrier.
2. A medicament delivery device according to claim 1 characterised in that the moisture proof barrier is a moisture proof sealing means.
3. A medicament delivery device according to claim 1 characterised in that the moisture proof barrier is positioned to prevent ingress of moisture into the medicament reservoir.
4. A medicament delivery device according to claim 1 wherein the sealing means is adapted to move from an inoperable position in which the medicament reservoir is sealed, to an operable position in which the seal is broken so that measurement and/or delivery of a dose of medicament may take place.
5. A medicament delivery device according to claim 1 wherein the sealing means comprises a resilient sealing member positioned at the end of the medicament reservoir adjacent the metering member.
6. A medicament delivery device according to claim 5 wherein the metering member is biased towards the sealing member.
7. A medicament delivery device according to claim 1 characterised in that the delivery device is an inhaler.
8. A medicament delivery device according to claim 7 characterised in that the inhaler is a dry powder inhaler.
9. A medicament delivery device according to claim 4 characterised in that the metering member is rotatable from an operable to an inoperable position.
10. A medicament delivery device according to claim 1 characterised in that the metering member comprises a combination of a dispensing member and an outer sleeve.
11. A medicament delivery device according to claim 10 characterised in that the outer sleeve is a moisture resistant sleeve.
12. A medicament delivery device according to claim 10 characterised in that the outer sleeve is a moisture resistant sleeve that is adapted to act as a medicament measuring device.
13. A medicament delivery device according to claim 10 wherein the outer sleeve is a moisture resistant sleeve that is adapted to act as a medicament measuring device and has the form of a frusto hemispherical cone.
14. A medicament delivery device according to claim 1 characterised in that the device may be moved to a first position in which the medicament is transferred to a measuring chamber, the device is then moved to a second position in which medicament is transferred to a dispensing chamber and to a third position where medicament is delivered into the delivery passage.
15. A medicament delivery device which is an inhaler and comprises a medicament reservoir, an inhalation passage and a metering member provided with at least one dispensing cup and adapted to transfer a measured dose of medicament from the medicament reservoir to the inhalation passage characterised in that the dispensing cup is provided with an air duct.
16. An inhaler according to claim 15 characterised in that the device is provided with a moisture proof barrier.
17. An inhaler comprising a medicament reservoir, an inhalation passage for the delivery of the medicament and a metering member adapted to transfer a measured dose of medicament from the medicament reservoir to the inhalation passage characterised in that the metering member comprises a measuring member adapted to measure a pre-defined dosage of medicament and moveable from a measuring to a non-measuring position; and a dispensing member adapted to receive the measured dosage of medicament from the measuring member and to deliver the medicament to the inhalation passage, the dispensing member being moveable from a medicament receiving position to a medicament delivering position.
18. An inhaler according to claim 17 wherein the second member is provided with one or more medicament receiving cups, said cups being provided with an air duct so as to provide a flow of air through the passage and the cup into the inhalation passage upon operation of the device.
19. An inhaler comprising a medicament reservoir, an inhalation passage for the delivery of the medicament and a metering member adapted to transfer a measured dose of medicament from the medicament reservoir characterised in that the metering member is provided with a duct to allow air to be sucked through the metering member upon inhalation by a patient.
20. An inhaler according to claim 19 characterised in that the metering member comprises an outer sleeve and a dispensing member.
21. A medicament delivery device according to claim 20 characterised in that the duct is part of a measuring cup in the dispensing member.
22. A method of administering a medicament by inhalation which comprises the use by a patient of an inhaler according to claim 1.
23. A method of administering a dry powder inhalation medicament using an inhaler according to claim 7.
24. A method of treatment of a patient with a respiratory disorder which comprises the administration of a combination of medicaments using an inhaler according to claim 7.
US11/586,983 1999-06-05 2006-10-26 Delivery system Abandoned US20070039618A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
GBGB9913047.8A GB9913047D0 (en) 1999-06-05 1999-06-05 Inhaler
GB9913047.8 1999-06-05
GBGB9916283.6A GB9916283D0 (en) 1999-07-13 1999-07-13 Inhaler
GB9916283.6 1999-07-13
PCT/GB2000/002017 WO2000074754A2 (en) 1999-06-05 2000-06-05 Delivery system
US98099902A true 2002-05-20 2002-05-20
US11/586,983 US20070039618A1 (en) 1999-06-05 2006-10-26 Delivery system

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/586,983 US20070039618A1 (en) 1999-06-05 2006-10-26 Delivery system
US13/445,021 US20120199122A1 (en) 1999-06-05 2012-04-12 Delivery system

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/GB2000/002017 Continuation WO2000074754A2 (en) 1999-06-05 2000-06-05 Delivery system
US98099902A Continuation 2002-05-20 2002-05-20

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/445,021 Continuation US20120199122A1 (en) 1999-06-05 2012-04-12 Delivery system

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US20070039618A1 true US20070039618A1 (en) 2007-02-22

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US09/980,999 Expired - Fee Related US7207330B1 (en) 1999-06-05 2000-06-05 Delivery system
US11/586,983 Abandoned US20070039618A1 (en) 1999-06-05 2006-10-26 Delivery system
US13/445,021 Abandoned US20120199122A1 (en) 1999-06-05 2012-04-12 Delivery system

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Application Number Title Priority Date Filing Date
US09/980,999 Expired - Fee Related US7207330B1 (en) 1999-06-05 2000-06-05 Delivery system

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/445,021 Abandoned US20120199122A1 (en) 1999-06-05 2012-04-12 Delivery system

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US (3) US7207330B1 (en)
EP (1) EP1183061B2 (en)
JP (1) JP4540906B2 (en)
AT (1) AT294608T (en)
AU (1) AU777278B2 (en)
BR (1) BR0011343A (en)
CA (2) CA2725731A1 (en)
DE (1) DE60019920T2 (en)
ES (1) ES2241611T3 (en)
IL (1) IL146886D0 (en)
MX (1) MXPA01012533A (en)
NO (1) NO20015910L (en)
NZ (2) NZ515557A (en)
PL (1) PL352615A1 (en)
PT (1) PT1183061E (en)
WO (1) WO2000074754A2 (en)

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AU5088800A (en) 2000-12-28
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DE60019920D1 (en) 2005-06-09
US20120199122A1 (en) 2012-08-09
JP4540906B2 (en) 2010-09-08
JP2003501158A (en) 2003-01-14
US7207330B1 (en) 2007-04-24
EP1183061A2 (en) 2002-03-06
EP1183061B2 (en) 2012-10-17
PL352615A1 (en) 2003-08-25
DE60019920T2 (en) 2006-02-23
EP1183061B1 (en) 2005-05-04
NO20015910D0 (en) 2001-12-03
CA2373278A1 (en) 2000-12-14
IL146886D0 (en) 2002-08-14
AT294608T (en) 2005-05-15
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WO2000074754A3 (en) 2001-06-28
BR0011343A (en) 2002-03-12
CA2373278C (en) 2011-04-05
MXPA01012533A (en) 2003-10-14
PT1183061E (en) 2005-08-31
AU777278B2 (en) 2004-10-07
NZ524959A (en) 2004-12-24
WO2000074754A2 (en) 2000-12-14
NZ515557A (en) 2003-10-31

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