NZ710839B2 - Method and reagent for preparing a diagnostic composition - Google Patents
Method and reagent for preparing a diagnostic composition Download PDFInfo
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- NZ710839B2 NZ710839B2 NZ710839A NZ71083914A NZ710839B2 NZ 710839 B2 NZ710839 B2 NZ 710839B2 NZ 710839 A NZ710839 A NZ 710839A NZ 71083914 A NZ71083914 A NZ 71083914A NZ 710839 B2 NZ710839 B2 NZ 710839B2
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- Prior art keywords
- excipient solution
- solution according
- concentration
- contrast agent
- excipient
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 58
- 239000003153 chemical reaction reagent Substances 0.000 title description 2
- 239000002872 contrast media Substances 0.000 claims abstract description 78
- FKNQFGJONOIPTF-UHFFFAOYSA-N sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229910001415 sodium ion Inorganic materials 0.000 claims abstract description 31
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229910001424 calcium ion Inorganic materials 0.000 claims abstract description 29
- 238000007865 diluting Methods 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 105
- BFVVDRUCXCIALU-UHFFFAOYSA-N 5-[[3-[3,5-bis(2,3-dihydroxypropylcarbamoyl)-N-formyl-2,4,6-triiodoanilino]-2-hydroxypropyl]-formylamino]-1-N,3-N-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide Chemical group OCC(O)CNC(=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(N(CC(O)CN(C=O)C=2C(=C(C(=O)NCC(O)CO)C(I)=C(C(=O)NCC(O)CO)C=2I)I)C=O)=C1I BFVVDRUCXCIALU-UHFFFAOYSA-N 0.000 claims description 39
- 229950004332 Ioforminol Drugs 0.000 claims description 39
- 238000002156 mixing Methods 0.000 claims description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 238000010790 dilution Methods 0.000 claims description 15
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 229960004359 iodixanol Drugs 0.000 claims description 13
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 8
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical group [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000007983 Tris buffer Substances 0.000 claims description 6
- 230000001276 controlling effect Effects 0.000 claims description 6
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 5
- 239000002738 chelating agent Substances 0.000 claims description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 5
- 159000000007 calcium salts Chemical class 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 230000036541 health Effects 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 229960000281 trometamol Drugs 0.000 claims description 2
- 150000003385 sodium Chemical group 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 229940039231 CONTRAST MEDIA Drugs 0.000 description 20
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000003384 imaging method Methods 0.000 description 7
- 238000011065 in-situ storage Methods 0.000 description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 210000004351 Coronary Vessels Anatomy 0.000 description 4
- 238000002583 angiography Methods 0.000 description 4
- 238000002059 diagnostic imaging Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000004369 Blood Anatomy 0.000 description 3
- -1 NaCl Chemical class 0.000 description 3
- 210000002381 Plasma Anatomy 0.000 description 3
- 208000003663 Ventricular Fibrillation Diseases 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- NTHXOOBQLCIOLC-UHFFFAOYSA-N Iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 2
- 231100000494 adverse effect Toxicity 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000002708 enhancing Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 210000000601 Blood Cells Anatomy 0.000 description 1
- YVPYQUNUQOZFHG-UHFFFAOYSA-N Diatrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 description 1
- 229940116559 IODINATED X-RAY CONTRAST MEDIA Drugs 0.000 description 1
- NJKDOADNQSYQEV-UHFFFAOYSA-N Iomeprol Chemical compound OCC(=O)N(C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NJKDOADNQSYQEV-UHFFFAOYSA-N 0.000 description 1
- 229960004647 Iopamidol Drugs 0.000 description 1
- 229940029407 Ioxaglate Drugs 0.000 description 1
- TYYBFXNZMFNZJT-UHFFFAOYSA-N Ioxaglic acid Chemical compound CNC(=O)C1=C(I)C(N(C)C(C)=O)=C(I)C(C(=O)NCC(=O)NC=2C(=C(C(=O)NCCO)C(I)=C(C(O)=O)C=2I)I)=C1I TYYBFXNZMFNZJT-UHFFFAOYSA-N 0.000 description 1
- 208000001083 Kidney Disease Diseases 0.000 description 1
- GGGDNPWHMNJRFN-UHFFFAOYSA-N Metrizoic acid Chemical compound CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I GGGDNPWHMNJRFN-UHFFFAOYSA-N 0.000 description 1
- 206010029149 Nephropathy Diseases 0.000 description 1
- 206010029151 Nephropathy Diseases 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 210000000746 body regions Anatomy 0.000 description 1
- 230000036459 cardiodepression Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000002604 chemotoxic Effects 0.000 description 1
- 230000000295 complement Effects 0.000 description 1
- 230000004059 degradation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 229960005423 diatrizoate Drugs 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 230000000004 hemodynamic Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960001025 iohexol Drugs 0.000 description 1
- 229960000780 iomeprol Drugs 0.000 description 1
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 231100000803 sterility Toxicity 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- 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
-
- 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
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
-
- 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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
The present invention provides an aqueous, excipient solution suitable for diluting a diagnostic composition comprising a contrast agent. The excipient solution comprises a sodium ion concentration of about 100 -140 mM and a calcium ion concentration of about 0.8 - 1.2 mM. Alternatively, the molar ratio between sodium ion concentration and calcium ion concentration is between about 80 and 175. Also provided are methods of making and using the excipient solution, as well as a kit comprising the excipient solution. atio between sodium ion concentration and calcium ion concentration is between about 80 and 175. Also provided are methods of making and using the excipient solution, as well as a kit comprising the excipient solution.
Description
Method and Reagent for Preparing a Diagnostic Composition
FIELD OF THE INVENTION
The present invention is directed to ease individual dosing of X-ray contrast media. More
specifically, the present invention is directed to a novel dilution media and a method of using
the media for the mixing of concentrated X-ray contrast medium which will result in an
isotonic injection. Also provided is a kit for performing the novel method. Also disclosed
herein is a system for performing the novel method.
Background of the invention:
All diagnostic imaging is based on the achievement of different signal levels from different
structures within the body so that these structures can be seen. Thus in X-ray imaging for
example, for a given body structure to be visible in the image, the X-ray attenuation by that
structure must differ from that of the surrounding tissues. The difference in signal between
the body structure and its surroundings is frequently termed contrast and much effort has been
devoted to means of enhancing contrast in diagnostic imaging since the greater the contrast or
definition between a body structure or region of interest and its surroundings the higher the
conspicuity or quality of the images and the greater their value to the physician performing
the diagnosis. Moreover, the greater the contrast the smaller the body structures that may be
visualized in the imaging procedures, i.e. increased contrast can lead to increased discernible
spatial resolution and conspicuity.
In techniques such as X-ray, one approach for improving the diagnostic quality factor has
been to introduce contrast enhancing materials formulated as contrast media into the body
region being imaged. Thus for X-ray, early examples of contrast agents were insoluble
inorganic barium salts which enhanced X-ray attenuation in the body zones into which they
distributed. For the last 50 years the field of X-ray contrast agents has been dominated by
soluble iodine containing compounds. Commercial available contrast media (CM) containing
iodinated contrast agents are usually classified as ionic monomers such as diatrizoate
(Gastrografen™), ionic dimers such as ioxaglate (Hexabrix™), nonionic monomers such as
iohexol (Omnipaque™), iopamidol (Isovue™), iomeprol (Iomeron™) and the non-ionic
dimer iodixanol (Visipaque™). The clinical safety of iodinated X-ray contrast media has
continuously been improved over the recent decades through development of new agents;
TM TM
from ionic monomers (Isopaque ) to non-ionic monomers (e.g. Omnipaque ) and non-
ionic dimers (e.g. Visipaque ). However, even the highly refined X-ray contrast media
currently on the market exhibit a low degree of undesirable clinical side effects, such as
Contrast Induced Nephropathy (CIN), adverse cardiac events, and delayed adverse reactions
(DARs). Consequently, there is a clinical need for a new and safer X-ray contrast medium,
especially with regards to diagnostic investigations involving patients where there is a high
risk of these side effects. Typically one desirable characteristic of X-ray contrast media has
been high iodine content, frequently measured in milligrams iodine per milliliter, such as 270-
400 mg I/ml. However, to reduce the risk of adverse events, especially in susceptible subjects,
to improve patient safety and to reduce costs, there is now a desire to reduce the amount of X-
ray contrast media administered to patients undergoing X-ray examinations. At the same time,
there is a need for providing contrast media of higher iodine concentrations when needed.
Accordingly, there is need for provision of patient friendly X-ray contrast media at various
concentrations.
The number of coronary arteriography procedures continues to increase consistent with the
expanding capabilities of coronary interventions. In coronary arteriography the blood in the
coronary arteries should ideally be completely replaced by a bolus of iodinated radiographic
contrast media to maximize the attenuation of radiographs and thereby optimize diagnostic
imaging. When contrast media replaces blood, the contrast media molecules cause
chemotoxic and osmotic effects in the coronary vessels and also alterations in electrolyte
concentrations, viscosity, and oxygen tension. These alterations may influence contractile
force and cardiac rhythm and cause ventricular fibrillation (VF). Selective injection of
contrast media into the coronary arteries induces regional electrophysiologic and
hemodynamic effects. Serious ventricular arrhythmias, as well as cardiodepression, are
known complications of coronary arteriography that may be related to the contrast media.
WO91/13636 and WO90/11094, both of Nycomed AS (now GE Healthcare AS), are directed
to X-ray contrast media and to their formulations including different salts. There are also
numerous studies on the advantages of formulations of X-ray contrast agents with the
inclusion of salts, mainly NaCl, in the literature. Of particular relevance is the study by Chai
et al. (Acta. Radiol. 2004, 11, 583-593) where it is shown that a formulation of iodixanol
containing 19 mM NaCl and 0.3 mM CaCl exhibits a lower frequency of ventricular
fibrillation than iodixanol alone.
of GE Healthcare AS discloses a new class of compounds and their use as
X-ray contrast agents. The compounds are dimers containing two linked iodinated phenyl
groups. The bridge linking the two iodinated phenyl groups is a straight C to C alkylene
chain optionally substituted by one to six –OH or OCH groups. A range of compounds are
covered by the general formula (I) of the application and many specific compounds are
suggested. Compound I, which is one specific dimeric X-ray contrast agent named Ioforminol,
falling within the formula I, has been found by the applicant to have favourable properties:
O H H O
O I OH I O
HO N N OH
OH OH
I I I I
HO N O O N OH
OH OH
Compound I: 5-[formyl-[3-[formyl-[3,5-bis(2,3-dihydroxypropylcarbamoyl)-2,4,6-
triiodophenyl]amino]hydroxypropyl]amino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-
triiodobenzene-1,3-dicarboxamide.
There is a need for providing patient friendly X-ray contrast media at various concentrations
in situ.
Brief summary of the invention:
Disclosed herein are novel procedures, systems and excipient solutions for in situ provision of
a contrast media at a user defined concentrations. An automated procedure according to
embodiments of the current disclosure describes increased user safety, flexibility and user
friendliness.
In one aspect, the present invention provides an aqueous, excipient solution comprising a
sodium ion and a calcium ion wherein the molar ratio between sodium ion concentration and
calcium ion concentration is between 80 and 175, and wherein said excipient solution is
suitable for diluting a diagnostic composition comprising a contrast agent, and wherein the
contrast agent is ioforminol or iodixanol.
In another aspect, the present invention provides a kit, comprising an aqueous, excipient
solution according to an aspect of the invention in a first container; a diagnostic composition
comprising a concentrated contrast agent solution in a second container, wherein the contrast
agent is ioforminol or iodixanol; and a user instruction manual.
In a third aspect, the present invention provides a method for dilution of a diagnostic
composition comprising a contrast agent, which method comprises
i) determining a desired dosage amount and dosage concentration for a patient;
ii) calculating a required amount of the diagnostic composition and a required
amount of the aqueous, excipient solution according to an aspect of the
invention, based on the desired dosage amount and dosage concentration;
iii) delivering the required amount of the diagnostic composition to a mixing
chamber; and
iv) delivering the required amount of the excipient solution to the mixing chamber,
wherein the contrast agent is ioforminol or iodixanol.
In a fourth aspect, the present invention provides a method for producing an aqueous,
excipient solution according to an aspect of the invention, comprising
i) predicting the molar amount of sodium ion and calcium ion suitable for the excipient
using a chemiometrical model, based on the salt composition of the diagnostic
formulation;
ii) making the aqueous, excipient solution according to the predicted molar amount of
sodium ion and calcium ion.
In one embodiment, disclosed herein is an aqueous, excipient solution, which solution
comprises a sodium ion and a calcium ion, wherein said excipient solution is suitable for
diluting a diagnostic composition comprising a contrast agent.
In another embodiment, disclosed herein is a kit, comprising an aqueous, excipient solution
according to an aspect of the invention in a first container; a diagnostic composition
comprising a contrast agent in a second container; and a user instruction manual.
In another embodiment, disclosed herein is a method for dilution of a diagnostic composition
comprising a contrast agent, which method comprises
i) determining a desired dosage amount and dosage concentration for a patient;
ii) calculating a required amount of the diagnostic composition and a required amount of
the aqueous, excipient solution according to an aspect of the invention, based on
the desired dosage amount and dosage concentration;
iii) delivering the required amount of the diagnostic composition to a mixing chamber;
iv) delivering the required amount of the excipient solution to the mixing chamber.
In other embodiments, disclosed herein are a method for producing an aqueous, excipient
solution according to an aspect of the invention; a method of diagnosis, as well as a method of
in vivo imaging detection.
Detailed description of the invention:
In diagnostic imaging procedures where contrast agents are administered to a patient, it is
desirable that the amount of contrast agent used may be adjusted based on the individual
patient. Thus, the contrast agent concentration and injection volume best suited for the
individual can be achieved. Factors that affect the right concentration and injection volume
for any patient may depend on, for example, the type of examination, age, weight or physical
health of the patient.
Disclosed herein are novel procedures, systems and excipient solutions for in situ generation
of a contrast media at a user defined concentrations. Thus, a contrast agent may be
manufactured at one higher concentration, and the user (hospital/doctor) may dilute to a
desired concentration just prior to use. However, the isotonicity of the solution is maintained
throughout the concentration range.
Isotonicity – A solution is isotonic with human blood plasma if no net water migration takes
place over the blood cell membranes after mixing the solution with human blood. This means
that the measured osmolality of the solution is equal to that of human blood plasma (approx.
290 mOsmol/kg water). This is the goal for any parenteral drug formulation, being more
important if injection volumes are relatively large (typically > 10 ml) and if injection rate is
fast.
Thus, in one embodiment, disclosed herein is an aqueous, excipient solution, which solution
comprises a sodium ion and a calcium ion, wherein said excipient solution is suitable for
diluting a diagnostic composition comprising a contrast agent. In certain embodiments, the
aqueous, excipient solution includes a pharmaceutically acceptable carrier, preferably pure
water.
In certain embodiments, the aqueous, excipient solution comprises a sodium ion concentration
of about 100 -140 mM and a calcium ion concentration of about 0.8 – 1.2 mM.
In a preferred embodiment, the excipient solution comprises a sodium ion concentration of
between about 110 - 130 mM. In a more preferred embodiment, the excipient solution
comprises a sodium ion concentration of between about 115-125 mM. In a most preferred
embodiment, the excipient solution comprises a sodium ion concentration of about 119 mM.
In a preferred embodiment, the excipient solution comprises a calcium ion concentration of
between about 0.9-1.1 mM. In a more preferred embodiment, the excipient solution comprises
a calcium ion concentration of between about 1.00-1.05 mM. In a most preferred embodiment,
the excipient solution comprises a calcium concentration of about 1.03 mM.
In one embodiment, disclosed herein is an aqueous, excipient solution, which solution
comprises a sodium ion and a calcium ion, wherein the molar ratio between sodium ion
concentration and calcium ion concentration is between about 80 and 175.
In a preferred embodiment, the molar ratio between sodium ion concentration and calcium ion
concentration is between about 90 and 130. In a more preferred embodiment, the molar ratio
between sodium ion concentration and calcium ion concentration is between about 115-120.
In one embodiment, the sodium ion and calcium ion are from sodium salt and calcium salt
comprising a counter ion such as chloride. The selection of a counter ion in the aqueous,
excipient solution preferably follows the counter ion used in the X-ray contrast media. In a
preferred embodiment, the sodium salt is sodium chloride and the calcium salt is calcium
chloride.
In certain embodiments, the excipient solution further comprises an ingredient that protects
the contrast agent from degradation. In a preferred embodiment, the ingredient is a pH
controlling agent. The pH controlling agent may be a pH buffer. An exemplary pH controlling
agent is Tris (tromethamol, THAM). In another preferred embodiment, the ingredient is a
chelating agent. An exemplary chelating agent is EDTA (Calcium sodium edetate). In more
preferred embodiments, the excipient solution comprises both a pH controlling agent and a
chelating agent is EDTA.
An unexpected discovery was made during research in contrast agent formulation that certain
contrast agent may be diluted using an aqueous, excipient solution, over a large iodine
concentration, while maintaining isotonicity. Thus, with an aqueous, excipient solution of a
proper salt combination, a concentrated contrast agent solution may be diluted to any desired
iodine concentration for patient administration.
An example of a contrast agent that may suitably be diluted is ioforminol, having the formula:
O H H O
O I OH I O
HO N N OH
OH OH
I I I I
HO N O O N OH
OH OH
Ioforminol may be prepared as outlined in . A general procedure is outlined
on pages 16-20, and a specific method for preparation is provided in Example 1 of WO
2009/008734. The application, with its description of a process for
preparation is hereby incorporated by reference.
Compared to theoretical value where one molecule acts as one hydrated particle in aqueous
solution, the compound ioforminol has a lower osmolality. This means that more than one
molecule of ioforminol acts as one hydrated particle, indicating a loose form of clustering
between single molecules of the compound. Further, there apparently is no dilution effect.
Thus, in certain embodiments, the contrast agent diluted by the aqueous, excipient solution is
ioforminol. Ioforminol solution of 270 mg I/ml, 320 mg I/ml, or even 350 mg I/ml, may be
used as the concentrated contrast agent for dilution, using the aqueous, excipient solution
provided according to embodiments of the invention. The excipient solution enables
formulation of any concentration of ioforminol between about 70 and 320 mg I/ml by means
of in situ dilution from a high concentration ioforminol injection solution available, as long as
the high concentration, isotonic ioforminol injection solution has an identical Na/Ca molar
ratio.
Similar effect, albeit to a lesser extent, is observed for Iodixanol (Visipaque). Thus, a similar
aqueous, excipient solution can be developed for Iodixanol, or any contrast agent that displays
a similar effect.
In certain embodiments, the excipient solution contains the same components as a
concentrated contrast agent solution, except the contrast agent.
In a particular embodiment, the invention provides an aqueous, excipient solution consisting
of Tris (Trometamol) at 10 mM, NaCa-EDTA at 0.27 mM, NaCl at 119 mM and CaCl at
1.03 mM, for diluting a diagnostic composition comprising an ioforminol contrast agent. The
excipient solution (i.e., dilution medium) acts as a complement for the ioforminol solution’s
composition to ensure isotonicity after dilution. Thus, the concentrated ioforminol solution
would have the same concentration of Tris and EDTA, but a far lower concentration of NaCl
and CaCl in order to be isotonic. The mixing of the concentrated ioforminol solution with the
excipient solution in any ratio that generates an ioforminol concentration of 70-320 mg I/ml
will yield an isotonic solution as well.
In a fourth aspect, the invention provides a method for producing an aqueous, excipient
solution according to the first aspect of the invention. The method comprises first predicting
the molar amount of sodium ion and calcium ion suitable for the excipient using a
chemometrical model which describes the linear correlation between contrast agent
concentration, salt concentration and osmolality (Y):
Y (osmolality, mOsmol/kg) = 0.675 x Ioforminol concentration (mg I/ml) + 2.78 x Na
concentration (mM) – 47.6;
then making the aqueous, excipient solution according to the predicted molar amount of
sodium ion and calcium ion.
In one embodiment, disclosed herein is a system for the in situ dilution of a contrast agent
prior to use. It is described software, equipment and an aqueous, excipient solution for
diluting a concentrated contrast agent solution to any concentration and volume required by
any procedure and patient.
Equipment for homogeneous blending of two liquids is well known in the market. For the
purpose of preparing a contrast agent solution, it is important that the blending process is
performed under sterile condition and the solutions are made of pharmaceutical grade
components.
The system for the in situ dilution of a contrast agent also requires a software and algorithm to
steer the mixing of the excipient solution and the concentrated contrast agent solution. The
software also ensures mixing homogeneity and sterility. Software and algorithms suitable for
these applications are well-known.
In one embodiment, disclosed herein is a kit, comprising an aqueous, excipient solution
according to certain embodiments of the invention in a first container; a diagnostic
composition comprising a concentrated contrast agent solution in a second container; and a
user instruction manual.
In certain embodiments, the contrast agent is ioforminol. In a preferred embodiment, the
contrast agent has a concentration of between about 70-320 mg l/ml.
In certain embodiments, the aqueous, excipient solution contains the same components as the
diagnostic composition, except the contrast agent.
In certain embodiments, the kit further comprises an instrument for homogeneous blending of
the aqueous, excipient solution and the diagnostic composition under sterile conditions.
In certain embodiments, the kit further comprises a software that controls the mixing regime
resulting in any desired combination of contrast agent concentration and volume.
In one embodiment, disclosed herein is a method for dilution of a diagnostic composition
comprising a contrast agent, which method comprises
i) determining a desired dosage amount and dosage concentration for a patient;
ii) calculating a required amount of the diagnostic composition and a required amount of
the aqueous, excipient solution, based on the desired dosage amount and dosage
concentration;
iii) delivering the required amount of the diagnostic composition to a mixing chamber;
iv) delivering the required amount of the excipient solution to the mixing chamber.
In certain embodiments, the method for dilution of a diagnostic composition further
comprises mixing the diagnostic composition and the excipient solution in the mixing
chamber.
In certain embodiments, the desired dosage amount and dosage concentration are determined
based in part on the age, weight and physical health of the patient.
The diagnostic composition disclosed herein is preferably for use as an X-ray contrast media
in X-ray diagnoses or X-ray imaging. The composition may be administered as a bolus
injection or by infusion. Further, the composition may be administered by intravascular,
intravenous or intra-arterial administration. Alternatively, the composition may also be
administered orally.
In one embodiment, disclosed herein is a method of diagnosis comprising administering a
diagnostic composition prepared according to an aspect of the invention to a human or animal
body, examining the body with a diagnostic device and compiling data from the examination.
In one embodiment, disclosed herein is a method of in vivo imaging detection comprising the
following steps;
i) administering a detectable quantity of the diagnostic composition prepared
according to an aspect of the invention;
ii) allowing the administered composition to distribute;
iii) detecting signals emitted by the contract agent of the distributed composition,
iv) generating an image representative of the location and/or amount of said signal.
The method of imaging is a method of X-ray imaging and in a preferred embodiment, the
method of detection is a method of coronary arteriography, and more preferably the
diagnostic composition is administered as a bolus injection to the coronary arteries.
Examples:
The following examples are intended only to illustrate methods and embodiments in
accordance with the invention, and as such should not be construed as imposing limitations
upon the claims.
Example 1.
Ioforminol 320 mg I/ml injection contains 640 mg ioforminol/litre. With a molar weight of
1522,13 Dalton, this would be 420.3 mM. This concentrated solution contains 699 g water per
litre. Density is 1.357 kg/litre, thus the weight of one litre Ioforminol 320 mg I/ml injection is
1.357 kg. Water is therefore only about half of the weight. Theoretical estimation of
osmolality would be 601.5 mOsmol/kg water given 420.3 mM ioforminol, no dissociation
under dissolution and 699 g water as solvent.
Knowing that blood plasma osmolality is approx. 290 mOsmol/kg water, such a solution
would be hypertonic by a factor 2 even without other components/solutes. Yet measured
osmolality of the complete formulation of ioforminol 320 mg I/ml was around 290
mOsmol/kg water. When one subtracts the contribution to osmolality of the other components
in the formulation (Tris, EDTA, NaCl and CaCl ), the net contribution of ioforminol was
around 129 mOsmol/kg, not around 600 mOsmol/kg. This is approximately 22% of the
expected theoretical osmolality if every ioforminol molecule would act as one hydrated
particle.
This can be attributed to the very high concentration of ioforminol in the 320 mg I/ml solution.
Hence one would expect the percentage contribution to osmolality from ioforminol to
increase rapidly upon dilution of such a solution from 320 to 70 mg I/ml. However, the
percentage only increases to approximately 36% when the concentrated ioforminol
composition was diluted more than fourfold. The result of this phenomenon is the linear
correlation between ioforminol concentration, salt concentration and osmolality in the interval
70 – 330 mg I/ml Ioforminol.
Even after autoclaving, a sterilising procedure where aqueous solutions are subjected to
121°C for approximately15 minutes, this percentage contribution does not change.
Equilibration at high temperatures therewith indicates that the measured osmolality is real and
no slow equilibrium causes the unexpected low contribution of ioforminol on osmolality upon
dilution.
The effect of this is a linear correlation between ioforminol concentration and NaCl
concentration to obtain isotonicity in the range 70-330 mgI/ml.
While the particular embodiment of the present invention has been shown and described, it
will be obvious to those skilled in the art that changes and modifications may be made
without departing from the teachings of the invention. The matter set forth in the foregoing
description and accompanying drawings is offered by way of illustration only and not as a
limitation. The actual scope of the invention is intended to be defined in the following claims
when viewed in their proper perspective based on the prior art.
Claims (31)
- Claim 1: An aqueous, excipient solution comprising a sodium ion and a calcium ion wherein the molar ratio between sodium ion concentration and calcium ion concentration is between 80 and 175, and wherein said excipient solution is suitable for diluting a diagnostic 5 composition comprising a contrast agent, and wherein the contrast agent is ioforminol or iodixanol.
- Claim 2: The excipient solution according to claim 1, wherein the molar ratio between sodium ion concentration and calcium ion concentration is between 90-130.
- Claim 3: The excipient solution according to claim 1, wherein the molar ratio between sodium ion concentration and calcium ion concentration is between 115-120.
- Claim 4: The excipient solution according to claim 1, wherein the sodium ion concentration is 15 100 -140 mM and the calcium ion concentration is 0.8 – 1.2 mM.
- Claim 5: The excipient solution according to claim 4, wherein the sodium ion concentration is between 110 - 130 mM. 20
- Claim 6: The excipient solution according to claim 4, wherein the sodium ion concentration is between 115-125 mM.
- Claim 7: The excipient solution according to claim 4, wherein the sodium ion concentration is 119 mM.
- Claim 8: The excipient solution according to claim 4, wherein the calcium ion concentration is between 0.9-1.1 mM.
- Claim 9: The excipient solution according to claim 4, wherein the calcium ion concentration 30 is between 1.00-1.05 mM.
- Claim 10: The excipient solution according to claim 4, wherein the calcium concentration is 1.03 mM.
- Claim 11: The excipient solution according to claim 1 or claim 4, wherein the sodium ion and calcium ion are from sodium salt and calcium salt comprising counter ions is chloride.
- Claim 12: The excipient solution according to claim 11, wherein the sodium salt is sodium 5 chloride and the calcium salt is calcium chloride.
- Claim 13: The excipient solution according to claim 1 or claim 4, further comprising a pH controlling agent. 10
- Claim 14: The excipient solution according to claim 13, further comprising a chelating agent.
- Claim 15: The excipient solution according to claim 14, wherein the pH controlling agent is TRIS and the chelating agent is EDTA. 15
- Claim 16: The excipient solution according to claim 1 or claim 4, wherein the solution contains the same components as the diagnostic composition, except the contrast agent.
- Claim 17: The excipient solution according to claim 1, wherein the excipient solution consists of Tris (Trometamol) at 10 mM, NaCa-EDTA at 0.27 mM, NaCl at 119 mM and CaCl at 20 1.03 mM.
- Claim 18: The excipient solution according to any one of the above claims, wherein the contrast agent is ioforminol. 25
- Claim 19: A kit, comprising an aqueous, excipient solution according to any one of claims 1-18 in a first container; a diagnostic composition comprising a concentrated contrast agent solution in a second container, wherein the contrast agent is ioforminol or iodixanol; and a user instruction manual.
- Claim 20: The kit according to claim 19, wherein the contrast agent is ioforminol.
- Claim 21: The kit according to claim 19, wherein the contrast agent has a concentration of between 70-320 mg l/ml.
- Claim 22: The kit according to claim 19, wherein the aqueous, excipient solution contains the same components as the diagnostic composition, except the contrast agent. 5
- Claim 23: The kit according to claim 19, further comprising an instrument for homogeneous blending of the aqueous, excipient solution and the diagnostic composition under sterile conditions.
- Claim 24: The kit according to claim 19, further comprising a software that controls the 10 mixing regime resulting in any desired combination of contrast agent concentration and volume.
- Claim 25: A method for dilution of a diagnostic composition comprising a contrast agent, which method comprises 15 v) determining a desired dosage amount and dosage concentration for a patient; vi) calculating a required amount of the diagnostic composition and a required amount of the aqueous, excipient solution of claim 1 or claim 4, based on the desired dosage amount and dosage concentration; vii) delivering the required amount of the diagnostic composition to a mixing chamber; 20 and viii) delivering the required amount of the excipient solution to the mixing chamber, wherein the contrast agent is ioforminol or iodixanol.
- Claim 26: The method of claim 25, further comprising mixing the diagnostic composition and 25 the excipient solution in the mixing chamber
- Claim 27: The method of claim 25, wherein the desired dosage amount and dosage concentration are determined based in part on the age, weight and health of the patient. 30
- Claim 28: A method for producing an aqueous, excipient solution of claim 4, comprising i) predicting the molar amount of sodium ion and calcium ion suitable for the excipient using a chemiometrical model, based on the salt composition of the diagnostic formulation; ii) making the aqueous, excipient solution according to the predicted molar amount of sodium ion and calcium ion.
- Claim 29: The excipient solution according to any one of claims 1 to 18, substantially as 5 herein described with reference to any example thereof.
- Claim 30: The kit according to any one of claims 19 to 24, substantially as herein described with reference to any example thereof. 10
- Claim 31: The method according to any one of claims 25 to 28, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361805556P | 2013-03-27 | 2013-03-27 | |
US61/805,556 | 2013-03-27 | ||
US201361839019P | 2013-06-25 | 2013-06-25 | |
US61/839,019 | 2013-06-25 | ||
PCT/US2014/021138 WO2014158965A1 (en) | 2013-03-27 | 2014-03-06 | Method and reagent for preparing a diagnostic composition |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ710839A NZ710839A (en) | 2020-10-30 |
NZ710839B2 true NZ710839B2 (en) | 2021-02-02 |
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