WO2003026702A1 - Particulate imaging contrast agents - Google Patents

Particulate imaging contrast agents Download PDF

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Publication number
WO2003026702A1
WO2003026702A1 PCT/GB2002/004322 GB0204322W WO03026702A1 WO 2003026702 A1 WO2003026702 A1 WO 2003026702A1 GB 0204322 W GB0204322 W GB 0204322W WO 03026702 A1 WO03026702 A1 WO 03026702A1
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Prior art keywords
formulation
contrast agent
imaging contrast
inhaler
particles
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PCT/GB2002/004322
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French (fr)
Inventor
Richard Alan Johnson
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Upperton Limited
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Publication of WO2003026702A1 publication Critical patent/WO2003026702A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0476—Particles, beads, capsules, spheres
    • A61K49/048—Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer

Definitions

  • This invention relates to the formulation and administration of imaging contrast agents to the lungs, especially contrast agents for magnetic resonance imaging (MRI) or X-ray imaging.
  • imaging contrast agents especially contrast agents for magnetic resonance imaging (MRI) or X-ray imaging.
  • contrast agents are typically highly radio-opaque materials, while for MRI imaging they are typically paramagnetic species that affect the relaxation times of the medium into which they are introduced.
  • an imaging contrast agent formulation for administration to the lung comprising solid particles of an imaging contrast agent.
  • Suitable particles For administration to the lung such particles are preferably fine enough to penetrate deep into the lung. Suitable particles will generally have a mass median diameter of less than 10 ⁇ m, more preferably less than 5 ⁇ m.
  • an inhaler charged with one or more doses of an imaging contrast agent in the form of solid particles.
  • the inhaler may be a pressurized metered dose inhaler (MDI), in which case the solid particles will be suspended in a propellant medium such as a hydrofluorocarbon propellant.
  • a propellant medium such as a hydrofluorocarbon propellant.
  • propellants are those known as 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • MDI formulations may also comprise other constituents conventional in such formulations such as surfactants or suspending aids etc.
  • the inhaler may be a dry powder inhaler (DPI) device, in which case the contrast agent is entrained in an airflow through the device, most commonly caused by inhalation by the patient.
  • DPI formulations may comprise the particles of contrast agent in admixture with larger particles of other carrier materials (eg lactose) in order to facilitate filling of the formulation into the device and dispensing of the formulation from the device.
  • carrier particles preferably have a mass median diameter greater than 50 ⁇ m and less than 200 ⁇ m.
  • a method of enhancing the contrast of images of a patient's lungs comprises administering an imaging contrast agent in the form of solid particles by inhalation to the lungs prior to generation of the image.
  • the solid particles of contrast agent are preferably formed by a spray drying technique.
  • a spray drying technique provides a simple one-step process by which commercially available liquid X-ray and MRI contrast agents can be converted into dry powder formulations, for delivery via the pulmonary route.
  • mixed particles comprising not only the contrast agent, but also other materials, eg a medicament.
  • Such particles may be used, for instance, as a means of monitoring the deposition of the other materials (eg medicament) in the lung.
  • the formulation according to the invention may also be advantageous in that it may permit a high degree of control over the deposition of the contrast agent in the lung.
  • the particle size distribution of the formulation may be chosen in such a way as to control the depth to which the particles can penetrate into the lungs.
  • the formulation may also offer advantages in comparison to solution or gas phase formulations in terms of stability and shelf life.
  • X-ray imaging contrast agents that may be used in the invention include a variety of iodine-containing compounds that have suitable properties for such use. Such compounds are generally soluble and may be ionic or non-ionic.
  • iopamidol One particular example of such an X-ray contrast agent is that known as iopamidol.
  • MRI contrast agents that may be used include a variety of compounds comprising paramagnetic metal ions. Suitable such ions include iron, manganese and, particularly, gadolinium. Suitable compounds are commonly used in the form of chelates, and a particular example of a suitable MRI contrast agent is gadolinium chelate.
  • Figure 1 shows size distributions of two batches of X-ray contrast agent prepared in Example a1)
  • Figure 2 is an electron micrograph of X-ray contrast agent prepared in Example a1);
  • Figure 3 shows CT images of rat lungs (a) before and (b) after administration of X- ray contrast agent prepared by the method of Example a1);
  • Figure 4 shows the size distribution of MRI contrast agent prepared by the method of Example b1)
  • Figure 5 is an electron micrograph of MRI contrast agent particles prepared by the method of Example b1).
  • Figure 6 shows magnetic resonance images of excised rat lungs (a) before and (b) after administration of MRI contrast agent prepared by the method of Example b1).
  • Spray drying parameters were optimised and those which gave the optimal particle size were determined.
  • Niopam 300 Lot No. 0572, 61.2%), corresponding to 32.68ml of Niopam
  • the solution was spray dried using a Buchi Mini Spray Dryer model B-191 , fitted with a Schlick 2-fluid atomisation nozzle (model 970/0) using the following parameters:
  • the particles were recovered from the cyclone collection jar.
  • the particles produced at higher pressure (3.0barg) were very cohesive and relatively more difficult to handle.
  • the particles produced at lower pressure (O. ⁇ barg) were easier to handle, with less cohesion and better flow properties. This is consistent with the size data.
  • the deposition of the X-ray contrast microparticles was also assessed using an in vitro lung model, in the form of a Multi Stage Liquid Impactor (MSLI).
  • MSLI Multi Stage Liquid Impactor
  • the capsule was fired into the MSLI under a flow rate of 60L/min (Copley pump, Nottingham UK), with 3 actuations (10 seconds each) being used per capsule. A minimum of 3 seconds was left between each actuation.
  • the MSLI, inhaler and capsule were subsequently washed with water.
  • Each of the recovered washings were diluted 1/40, and read on a spectrophotometer (Shimadzu UV-160), set at 242nm. A calibration curve was used to calculate the concentration of iopamidol present in each washing.
  • Stages 3 and 4 are generally accepted to represent deposition in the deep lung of humans.
  • the lungs of 3 adult male Sheffield strain Wistar rats were removed surgically.
  • the lungs were inflated at 1 ⁇ cm H 2 0 with air through the cannulated trachea, and ⁇ maintained by a continuous stream of air (from a cylinder) over a column of water.
  • the lungs were administered with 3 doses of the X-ray contrast particles (see Table 2) by suspending them in chloroform and spraying into the lung using a MicrosprayerTM (Series IA-1 B Intratracheal Aerosoliser, Penn-Century Inc., 0 Pennsylvania USA).
  • CT images of the rat lungs were obtained BEFORE and AFTER contrast agent 5 was administered.
  • the CT imaging was performed with a General Electric (GE Medical Systems) HiSpeed CT/I, operating with a volume acquisition of 1 mm, a pitch of 1.0, and reconstructions of 0.8 mm slices.
  • GE Medical Systems General Electric (GE Medical Systems) HiSpeed CT/I
  • the ex vivo lungs were kept inflated throughout, and kept damp whilst positioned ⁇ on the tray.
  • An initial scout view was performed to localise the lungs, followed by pre-contrast (control) CT scans.
  • Gadolinium chelate was a commercially available MR contrast imaging agent
  • the prepared solution was noted to be clear and colourless.
  • the particles were recovered from the cyclone collection jar.
  • a Malvern Aerosizer was used to produce size data on the batch of particles. The results confirmed that the particles produced were of the desired size distribution (see Figure 4).
  • the imaging properties of the MRI particles were assessed in an ex-vivo rat lung.
  • the lungs of 2 adult male Sheffield strain Wistar rats were removed surgically.
  • the lungs were inflated at 1 ⁇ cm H 2 0 with air through the cannulated trachea, and maintained by a continuous stream of air (from a cylinder) over a column of water.
  • the lungs were administered with 2 doses of the MRI contrast particles (see Table 3) by suspending them in chloroform and spraying into the lung using a MicrosprayerTM (Series IA-1 B Intratracheal Aerosoliser, Penn-Century Inc., Pennsylvania USA).
  • Figure 6 shows MR scans of the rat lungs pre- and post-administration of 5.0mg of gadolinium chelate.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nanotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

An imaging contrast agent formulation comprises solid particles of an imaging contrast agent. The formulation may be administered to the lungs by inhalation, eg using an inhaler charged with one or more doses of the formulation. The solid particles of the imaging contrast agent are preferably formed by spray drying.

Description

PARTICULATE IMAGING CONTRAST AGENTS
This invention relates to the formulation and administration of imaging contrast agents to the lungs, especially contrast agents for magnetic resonance imaging (MRI) or X-ray imaging.
It is known to enhance the contrast of images obtained by techniques such as MRI or X-ray imaging, by the prior administration of suitable contrast agents. In the case of X-ray imaging such agents are typically highly radio-opaque materials, while for MRI imaging they are typically paramagnetic species that affect the relaxation times of the medium into which they are introduced.
It is also known to administer contrast agents to a patient's lungs by inhalation. Such administration has conventionally been carried out by means of a nebulised solution or gas phase administration.
There have now been devised improvements to contrast agents for administration by inhalation.
According to a first aspect of the invention, there is provided an imaging contrast agent formulation for administration to the lung, the formulation comprising solid particles of an imaging contrast agent.
For administration to the lung such particles are preferably fine enough to penetrate deep into the lung. Suitable particles will generally have a mass median diameter of less than 10μm, more preferably less than 5μm.
As the formulation according to the first aspect of the invention is intended for administration by inhalation, it will normally be dispensed from an inhaler device. Thus, according to another aspect of the invention there is provided an inhaler charged with one or more doses of an imaging contrast agent in the form of solid particles.
The inhaler may be a pressurized metered dose inhaler (MDI), in which case the solid particles will be suspended in a propellant medium such as a hydrofluorocarbon propellant. Examples of such propellants are those known as 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. MDI formulations may also comprise other constituents conventional in such formulations such as surfactants or suspending aids etc.
Alternatively, the inhaler may be a dry powder inhaler (DPI) device, in which case the contrast agent is entrained in an airflow through the device, most commonly caused by inhalation by the patient. DPI formulations may comprise the particles of contrast agent in admixture with larger particles of other carrier materials (eg lactose) in order to facilitate filling of the formulation into the device and dispensing of the formulation from the device. The carrier particles preferably have a mass median diameter greater than 50μm and less than 200μm.
According to a third aspect of the invention, there is provided a method of enhancing the contrast of images of a patient's lungs, which method comprises administering an imaging contrast agent in the form of solid particles by inhalation to the lungs prior to generation of the image.
The solid particles of contrast agent are preferably formed by a spray drying technique. Such a method provides a simple one-step process by which commercially available liquid X-ray and MRI contrast agents can be converted into dry powder formulations, for delivery via the pulmonary route.
It may also be possible to form mixed particles comprising not only the contrast agent, but also other materials, eg a medicament. Such particles may be used, for instance, as a means of monitoring the deposition of the other materials (eg medicament) in the lung.
The formulation according to the invention may also be advantageous in that it may permit a high degree of control over the deposition of the contrast agent in the lung. For example, the particle size distribution of the formulation may be chosen in such a way as to control the depth to which the particles can penetrate into the lungs. The formulation may also offer advantages in comparison to solution or gas phase formulations in terms of stability and shelf life.
X-ray imaging contrast agents that may be used in the invention include a variety of iodine-containing compounds that have suitable properties for such use. Such compounds are generally soluble and may be ionic or non-ionic. One particular example of such an X-ray contrast agent is that known as iopamidol.
MRI contrast agents that may be used include a variety of compounds comprising paramagnetic metal ions. Suitable such ions include iron, manganese and, particularly, gadolinium. Suitable compounds are commonly used in the form of chelates, and a particular example of a suitable MRI contrast agent is gadolinium chelate.
The invention will now be described in greater detail, by way of illustration only, with reference to the following Examples and accompanying Figures, in which
Figure 1 shows size distributions of two batches of X-ray contrast agent prepared in Example a1);
Figure 2 is an electron micrograph of X-ray contrast agent prepared in Example a1); Figure 3 shows CT images of rat lungs (a) before and (b) after administration of X- ray contrast agent prepared by the method of Example a1);
Figure 4 shows the size distribution of MRI contrast agent prepared by the method of Example b1);
Figure 5 is an electron micrograph of MRI contrast agent particles prepared by the method of Example b1); and
Figure 6 shows magnetic resonance images of excised rat lungs (a) before and (b) after administration of MRI contrast agent prepared by the method of Example b1).
A) X-rav contrast agents
a1) Making solid particles : X-ray contrast agents
Spray drying parameters were optimised and those which gave the optimal particle size were determined.
Two batches of particles were produced for further characterisation. The following conditions were used to produce the particles. The only variable that was changed was the atomisation pressure
Working at room temperature (24°C), the following solution was prepared:
• 20g iopamidol (Niopam 300, Lot No. 0572, 61.2%), corresponding to 32.68ml of Niopam
• 100ml absolute ethanol
• 267.32ml pyrogen free purified water (PFPW) The prepared solution was noted to be clear and colourless, and corresponded to 5% iopamidol in 25% ethanol.
The solution was spray dried using a Buchi Mini Spray Dryer model B-191 , fitted with a Schlick 2-fluid atomisation nozzle (model 970/0) using the following parameters:
Inlet temperature 125°C
Starting outlet temperature 80 - 88°C Liquid feed rate 3ml/min
Atomisation pressure 3.0barg (batch 1) or
O.δbarg (batch 2) Drying air setting 100%
The particles were recovered from the cyclone collection jar.
a2) Characterising the solid particles : X-ray contrast agent
Size Analysis
A Malvern Aerosizer was used to produce size data on the 2 batches of particles. The results confirmed that the particles produced at the higher pressure (3.0barg) were smaller and had a narrower size distribution than particles produced at lower pressure (O.δbarg). The size distributions of the two batches are shown in Figure 1.
Physical Properties
The particles produced at higher pressure (3.0barg) were very cohesive and relatively more difficult to handle. The particles produced at lower pressure (O.δbarg) were easier to handle, with less cohesion and better flow properties. This is consistent with the size data.
Aerodynamic Properties
The deposition of the X-ray contrast microparticles was also assessed using an in vitro lung model, in the form of a Multi Stage Liquid Impactor (MSLI). For each run of the MSLI, 1 gelatin capsule (Capsugel Coni-Snap #3, Belgium) was filled with 50mg of formulation, and placed in a dry powder inhaler.
The capsule was fired into the MSLI under a flow rate of 60L/min (Copley pump, Nottingham UK), with 3 actuations (10 seconds each) being used per capsule. A minimum of 3 seconds was left between each actuation. The MSLI, inhaler and capsule were subsequently washed with water.
Each of the recovered washings were diluted 1/40, and read on a spectrophotometer (Shimadzu UV-160), set at 242nm. A calibration curve was used to calculate the concentration of iopamidol present in each washing.
The results generated confirmed that the "larger" particles tended to deposit more in the upper stages (equivalent to the upper airways) whilst the "smaller" particles tended to deposit in the lower stages (equivalent to deep lung).
The results for the "small" microparticles are shown below in Table 1. Stages 3 and 4 are generally accepted to represent deposition in the deep lung of humans.
Table 1
Deposition of "small" microparticles (Batch 1) in MLSI. Data calculated ex-device
Figure imgf000008_0001
Figure imgf000009_0001
Electron Microscopy
Images generated confirmed the microparticles were generally spherical and had δ smooth surfaces. The sizes appeared consistent with the size data generated by the Aerosizer (see Figure 2).
Imaging with Ex-vivo Rat Lung
0 The imaging properties of the smaller particles were assessed in an ex-vivo rat lung.
The lungs of 3 adult male Sheffield strain Wistar rats were removed surgically. The lungs were inflated at 1δcm H20 with air through the cannulated trachea, and δ maintained by a continuous stream of air (from a cylinder) over a column of water.
The lungs were administered with 3 doses of the X-ray contrast particles (see Table 2) by suspending them in chloroform and spraying into the lung using a Microsprayer™ (Series IA-1 B Intratracheal Aerosoliser, Penn-Century Inc., 0 Pennsylvania USA).
Table 2
Figure imgf000009_0002
CT images of the rat lungs were obtained BEFORE and AFTER contrast agent 5 was administered. The CT imaging was performed with a General Electric (GE Medical Systems) HiSpeed CT/I, operating with a volume acquisition of 1 mm, a pitch of 1.0, and reconstructions of 0.8 mm slices.
The ex vivo lungs were kept inflated throughout, and kept damp whilst positioned δ on the tray. An initial scout view was performed to localise the lungs, followed by pre-contrast (control) CT scans.
The lungs were subsequently instilled with formulation, and a new scout view performed for localisation, followed by post-contrast CT scans. 0
Results confirmed that all doses showed contrast enhancement in all of the regions through the lungs. The images of the rat lungs after administration of the lowest dose are shown in Figure 3.
δ B) MRI contrast agents
b1) Making the particles : MRI contrast agent
Working at room temperature (24°C), the following solution was prepared: 0
• Gadolinium chelate* 8ml
• absolute ethanol 25ml
• pyrogen free purified water 67ml
5 * Gadolinium chelate was a commercially available MR contrast imaging agent
The prepared solution was noted to be clear and colourless.
The solution was spray dried using a Buchi Mini Spray Dryer model B-191 , fitted 0 with a Schlick 2-fluid atomisation nozzle (model 970/0) using the following parameters: Inlet temperature 60°C
Starting outlet temperature 40°C
Liquid feed rate 1ml/min Atomisation pressure 2.0barg
Drying air setting 100%
The particles were recovered from the cyclone collection jar.
b2) Characterising the particles : MRI contrast agent
Size Analysis
A Malvern Aerosizer was used to produce size data on the batch of particles. The results confirmed that the particles produced were of the desired size distribution (see Figure 4).
Electron Microscopy
Images generated confirmed the microparticles were generally spherical and had smooth surfaces. The sizes appeared consistent with the size data generated by the Aerosizer (See Figure 5).
Imaging with Ex-vivo Rat lung
The imaging properties of the MRI particles were assessed in an ex-vivo rat lung.
The lungs of 2 adult male Sheffield strain Wistar rats were removed surgically. The lungs were inflated at 1δcm H20 with air through the cannulated trachea, and maintained by a continuous stream of air (from a cylinder) over a column of water. The lungs were administered with 2 doses of the MRI contrast particles (see Table 3) by suspending them in chloroform and spraying into the lung using a Microsprayer™ (Series IA-1 B Intratracheal Aerosoliser, Penn-Century Inc., Pennsylvania USA).
Table 3
Figure imgf000012_0001
Contrast enhancement was observed with both doses. Figure 6 shows MR scans of the rat lungs pre- and post-administration of 5.0mg of gadolinium chelate.

Claims

Claims
1. An imaging contrast agent formulation for administration to the lung, the formulation comprising solid particles of an imaging contrast agent. δ
2. A formulation as claimed in Claim 1 , wherein the particles have a mass median diameter of less than 10μm.
3. A formulation as claimed in Claim 2, wherein the particles have a mass 0 median diameter of less than δμm.
4. A formulation as claimed in any preceding claim, wherein the solid particles are suspended in a propellant medium.
δ δ. A formulation as claimed in Claim 4, wherein the propellant medium comprises one or more hydrofluorocarbon propellants.
6. A formulation as claimed in Claim δ, wherein the one or more hydrofluorocarbon propellants are selected from the group consisting of 1 ,1 ,1 ,2- 0 tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
7. A formulation as claimed in any one of Claims 1 to 3, in which the solid particles are admixed with larger particles of a carrier material.
δ 8. A formulation as claimed in Claim 7, wherein the carrier material is lactose.
9. A formulation as claimed in Claim 7 or Claim 8, wherein the carrier material has a mass median diameter of greater than δOμm and less than 200μm.
0 10. A formulation as claimed in any preceding Claims, which further comprises a medicament.
11. A formulation as claimed in any preceding claim, wherein the imaging contrast agent is an X-ray imaging contrast agent.
δ 12. A formulation as claimed in Claim 11 , wherein the X-ray imaging contrast agent is an iodine-containing compound.
13. A formulation as claimed in Claim 12, wherein the X-ray imaging contrast agent is iopamidol. 0
14. A formulation as claimed in any one of Claims 1 to 10, wherein the imaging contrast agent is a magnetic resonance imaging (MRI) contrast agent.
1δ. A formulation as claimed in Claim 14, wherein the MRI contrast agent is a δ compound comprising ferromagnetic metal ions.
16. A formulation as claimed in Claim 1δ, wherein the metal ions are selected from the group consisting of gadolinium, manganese and iron.
0 17. A formulation as claimed in Claim 16, wherein the MRI contrast agent is gadolinium chelate.
18. An inhaler charged with one or more doses of an imaging contrast agent in the form of solid particles. δ
19. An inhaler as claimed in Claim 18, wherein the inhaler is a pressurized dose inhaler.
20. An inhaler as claimed in Claim 19, which contains an imaging contrast 0 agent formulation as claimed in any one of Claims 4 to 6.
21. An inhaler as claimed in Claim 18, wherein the inhaler is a dry powder inhaler.
22. An inhaler as claimed in Claim 21 , which contains an imaging contrast δ agent formulation as claimed in any one of Claims 7 to 9.
23. A method of enhancing the contrast of images of a patient's lungs, which method comprises administering an imaging contrast agent in the form of solid particles by inhalation to the lungs prior to generation of the image. 0
24. A method as claimed in Claim 23, wherein the imaging contrast agent is administered using an inhaler as claimed in any one of Claims 18 to 22.
2δ. A method of preparing an imaging contrast agent formulation for δ administration to the lung, which method comprises a) forming a solution of the imaging contrast agent in a solvent; and b) spray-drying said solution.
26. A method as claimed in Claim 26, wherein the solvent comprises ethanol 0 and/or water.
PCT/GB2002/004322 2001-09-25 2002-09-24 Particulate imaging contrast agents WO2003026702A1 (en)

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WO2011061341A1 (en) * 2009-11-23 2011-05-26 Bracco Imaging Spa Process for the preparation of gadobenate dimeglumine complex in a solid form
CN111772659A (en) * 2020-08-18 2020-10-16 广州医科大学附属第一医院（广州呼吸中心） Method for rat respiratory tract inhalation VSP lung imaging

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WO1998052617A2 (en) * 1997-05-22 1998-11-26 Nycomed Imaging As Contrast media for imaging of lung draining lymph nodes, administered through the lungs
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FR2352556A1 (en) * 1976-05-26 1977-12-23 Pasteur Institut Nasal and oral powder inhaler for medicines etc. - uses cyclone chamber to entrain powder into air stream
US5372800A (en) * 1993-03-31 1994-12-13 Sterling Winthrop Inc. Compositions of iodophenyl esters and iodophenyl sulfonates in film-forming materials for visualization of the gastrointestinal tract
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EP0677332A2 (en) * 1994-04-08 1995-10-18 Sievers, Robert, E. Methods and apparatus for fine particle formation
WO1998052617A2 (en) * 1997-05-22 1998-11-26 Nycomed Imaging As Contrast media for imaging of lung draining lymph nodes, administered through the lungs
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011061341A1 (en) * 2009-11-23 2011-05-26 Bracco Imaging Spa Process for the preparation of gadobenate dimeglumine complex in a solid form
EP2327395A1 (en) * 2009-11-23 2011-06-01 Bracco Imaging S.p.A Process for the preparation of gadobenate dimeglumine complex in a solid form
CN102724964A (en) * 2009-11-23 2012-10-10 伯拉考成像股份公司 Process for the preparation of gadobenate dimeglumine complex in a solid form
JP2013511497A (en) * 2009-11-23 2013-04-04 ブラッコ・イメージング・ソシエタ・ペル・アチオニ Method for producing solid gadobenate dimeglumine complex
KR101624504B1 (en) * 2009-11-23 2016-05-26 브라코 이미징 에스.피.에이. Process for the preparation of gadobenate dimeglumine complex in a solid form
CN106986784A (en) * 2009-11-23 2017-07-28 伯拉考成像股份公司 For the method for the Gadobenate Dimeglumine complex compound for preparing solid form
US9795695B2 (en) 2009-11-23 2017-10-24 Bracco Imaging S.P.A. Process for the preparation of gadobenate dimeglumine complex in a solid form
CN113105346A (en) * 2009-11-23 2021-07-13 伯拉考成像股份公司 Process for the preparation of gadobenate dimeglumine complexes in solid form
CN111772659A (en) * 2020-08-18 2020-10-16 广州医科大学附属第一医院（广州呼吸中心） Method for rat respiratory tract inhalation VSP lung imaging

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