CN1371292A - Radiopharmaceutical products and their preparation procedure - Google Patents
Radiopharmaceutical products and their preparation procedure Download PDFInfo
- Publication number
- CN1371292A CN1371292A CN00812300A CN00812300A CN1371292A CN 1371292 A CN1371292 A CN 1371292A CN 00812300 A CN00812300 A CN 00812300A CN 00812300 A CN00812300 A CN 00812300A CN 1371292 A CN1371292 A CN 1371292A
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- polysaccharide
- group
- chelate
- radiation medicine
- alkyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 17
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- 230000002799 radiopharmaceutical effect Effects 0.000 title abstract description 7
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 229910052751 metal Inorganic materials 0.000 claims abstract description 13
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052713 technetium Inorganic materials 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
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Classifications
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- 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
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
-
- 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
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
- A61K51/065—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules conjugates with carriers being macromolecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
The present invention relates to radiopharmaceutical products and their preparation procedure. These products can be used for pulmonary scintigraphy or for therapy. They comprise a polysaccharide and sequestering groups of formulae R-NH-, R-N=, and formula (I) in which R is a hydrocarbonic or aromatic group comprising at least one atom of sulphur, and R' is an atom of hydrogen or an alkyl grouping such as methyl, said sequestering groups forming a chelate type complex with a radioactive metal such as technetium.
Description
Technical field
Radiation medicine that the present invention relates to be used to diagnose or treat and preparation method thereof.Form in particular to particle suspension liquid, specifically be used for the lung scintigraphy, with the radiation medicine of when suspecting pulmonary infarction, diagnosing by labelled with radioisotope.
In this application, use the product of particle form, it is preferably spherical and magnitude range is 10-100 μ m.In fact, because the diameter of pulmonary capillary is about 7 μ m, this granule keeps being blocked in the capillary tube after intravenous injection, thereby makes it can manifest the unusual of lung hemoperfusion.
Obviously these products must satisfy some pharmacy restrictive conditions.Particularly, they must have suitable vivo degradation speed, this degradation rate should be enough slowly to carry out imaging, as passing through the gamma-rays camera imaging, minimum is about 1 hour, but will enough cause that to be unlikely permanent pulmonary capillary blocks rapidly simultaneously, and this obstruction can cause a small amount of thrombosis.In addition, these products must be nontoxic to organ, and they must be by the sterilization of autoclaving or irradiation, they must be easily by radioactive metal labelling and can be with the packaged of the test kit of stable labelling.
Prior art
For example, specially permit application FR A-2 273 516 by all France of the PHARMACIA AKTIEBOLAG company of inhabitation Sweden in 1975 and described employing nettedization of chloropropylene oxide and employing
99mThe amyl group pectin microsphere of the simple mixtures labelling of TC is used for the purposes of lung perfusion scintigraphy.There is inconvenience in these granules.In fact, only have used amyl group pectin hydroxyl can allow this mixture labelling, and unfortunately they only can not make labelling stable with the faint key that technetium forms.In addition, described preparation method is used a large amount of solvent and emulsifying agents of removing from made granule of being difficult to.And, on this grain type, be difficult to accurately measure and control definite net and form speed.
In addition, the document does not have to describe the test kit compatible with conventional nuclear medicine application.In fact, for the human injection, need carry out many processing as stannum is added in the aseptic bottle, centrifugal, store suspension etc., they may with aseptic require incompatible.
At last, the solution instability of gained, and recognize that to be used for chloropropylene oxide that net forms be very deleterious and mutagenicity.
The present inventor has proved other shortcoming of these microparticles in following comparative example 1 and 2.
Specially permit application FR-A-2 285 857 by all France of the PHARMAGIA FINE CHEMICALS AB company of inhabitation Sweden in 1975 and described the purposes that is bonded on the different chelating agen and is aided with the polyoses grain of labelled with radioisotope.These granules comprise the chelate group by covalent bonds, form binding radioactivity with chelate type coordination compound on this chelate group is examined, it mainly comprises at least 4, preferred 5-8 at least nucleolus and two metal-complexing atoms around metal with 5-6 group.For example this polysaccharide is for adopting the polysaccharide of nettedization of chloropropylene oxide or epibromohydrin chemistry.Except labelling, these granules exist with in the past in the identical problem of granule described in the FR-A-2 273 516.And the document is not enumerated any example with mtc labeled.And this labeling method is included in radioelement and is heated to 100 ℃ under existing, washing behind labelling and drying, and it may be incompatible with the restrictive condition of the thought of above-mentioned labelling kit and aseptic use.
Though described labeling method allows at metastable mode marking particle, it can not prepare (particularly because it contains chloropropylene oxide) pharmaceutically accepted and the labelling kit that easily is used for the nuclear medicine service.
Therefore can not adapt to the pharmacy restrictive condition and can not be developed at the microsphere described in the above special permission application.And they never are used for the lung scintigraphy.From then on such product goes out of use.
Product and the derivant thereof based on albumin-serum paid close attention in many researchs that are used to improve new radiation medicine of having been carried out since 1975.In fact these blood products meet the pharmacy restrictive condition and can specifically be used for the lung scintigraphy.They are present products used in nuclear medicine.For example 1975, M.A.Davis described the radioactive grain that is used for pulmonary perfusion study at document " radiopharmaceuticals (Radiopharmaceuticals) N.Y. " 1975, the 267-281 pages or leaves.The granule described in the document for the radiation iodinating serum albumin (
131I-MAA) big aggregation or with technetium (
99mTC-HAM) human serum albumin's of the degeneration of labelling microsphere.Preferably
99mThe TC-HAM microsphere, because its even particle size, scope is between 40 and 50 μ m.And the document has been described the required general features of this radiopharmaceuticals granule.
The document of R.Guiraud " big aggregation and radioactivity microsphere I ", Radiopharmaceuticals (nuclear pharmacy), 1997,519 have described big aggregation of albumin (MAA) and HAM body.It has been described by the stannous chloride solution method, with this little aggregation of Tc 99m 99Tc labelling and microgranule.It points out that also the best size of microgranule is 15 ± 5 μ m.It mentions organic spherex body.
At present, these usefulness
99mBig aggregation of the human serum albumin of Tc labelling and microsphere are used for nuclear medicine most.But there is inconvenience in they.For example, diversity of each batch of human albumin and quality make the preparation difficulty of diagnostic reagent sometimes, contain the granule of size and number change.But one of main inconvenience is Qi Renyuan, and it has the problem of the serious type of infected by HIV mortally, hepatitis or Creutz Fil spy-Jacob (Creutzfeld-Jacob) disease.
Therefore, can have the non-people's of deriving from
99mThe microsphere of Tc labelling is for guaranteeing that intact safety is favourable.
Consider this, nearest document: A.C.Perkins, Nuclear MedicineCommunications, 1999,1-3 has described the method that replaces obtaining the radiation medicine from blood.It mentions the purposes of recombined material, synthetic polymer and polypeptide especially.But the document is not mentioned polysaccharide.
Invention is described
Clear and definite purpose of the present invention is can easily be labeled by providing, as using
99mThe radiation medicine of Tc labelling and overcome the inconvenience of above-mentioned prior art products, show very good lung and hold back, this medicine is proved nontoxic, easily biological-degradable, easily sterilization and can being packaged into to being easy to labelling, stable and satisfy the packing of the pharmacy restrictive condition of this series products by the present inventor on rat.These advantages and other advantage will obtain proof from following description.
Radiation medicine of the present invention is characterised in that it comprises polysaccharide, and its condition is a chelate group by being covalently bound on the polysaccharide, and chelate group be selected from following formula radicals R-NH-, R-N=and
Wherein, R is alkyl or the aryl that comprises at least one sulphur atom, and R ' is hydrogen atom or alkyl such as methyl, and described chelate group and the radioactive metal that is selected from technetium, rhenium, copper, yttrium, erbium, gallium and samarium form the coordination compound of chelate type jointly.
The available alkyl of R ' can be a straight or branched, and preferably has 1-5 carbon atom.
According to the present invention, the form of the soluble or microgranule of polysaccharide.According to the present invention, polysaccharide can be selected from native starch, cellulose or netted amyl group pectin.
For example, native starch can be a corn starch.
Polysaccharide can be the form of microgranule, for example the form of microsphere.
The present inventor has proved that also modified cellulose of the present invention provides good lung to hold back and than adopting the slower elimination speed of starch.Therefore modified cellulose of the present invention can also be used for radiotherapy, for example uses one of rhenium, copper or above-mentioned metal labelling, because its required radiotherapy of microgranule have more corresponding to use the long half-lift.
According to the present invention, chelate group can be selected from the group of following formula:
R wherein
1, R
2, R
3, R
4And R
5Be hydrogen atom, saturated or unsaturated alkyl, carboxyl or aryl independently,
For example, they can be selected from the following formula group:
According to the present invention, be used for the microgranule of lung scintigraphy method diagnosis such as the size of microsphere shape and can be 0.01-100 μ m, preferred 10-50 μ m, and be used for the treatment of be 0.1-5 μ m.
According to the present invention, to compare with the sugar of polysaccharide type, the level of chelate group can be 0.1-50%, is preferably 2-15%.
According to the present invention, in the radiation medicine, when particularly it was used to diagnose, radioactive metal can be
99mTc or gallium-67.
For example, can be the situation of radiation medicine when being used for the lung scintigraphy.
According to the present invention, in the radiation medicine, when particularly it was used for the treatment of, radioactive metal can be rhenium-186 or 188, copper-64 or 67,90Y, erbium-169 or samarium-153.
According to the present invention, this radiation medicine can be the form of the microsphere suspension in the acceptable liquid on the physiology or freeze in form.
The present invention also provides the preparation method of radiation medicine of the present invention, and this preparation method may further comprise the steps:
(a) adopt periodate to control the oxidation of polysaccharide, these polysaccharide such as above-mentioned polysaccharide,
(b) polysaccharide that makes oxidation with contain formula R-NH
2Or
Primary amine functional group or hydrazine reaction,
(c) wherein, R is alkyl or the aryl that comprises at least one sulphur atom, so that with the metal-chelating base of covalent manner convolution R-NH-, R-N=or R-NH-N=on polysaccharide, and R ' is hydrogen atom or alkyl, as methyl,
(d) make polysaccharide that comprises chelate group and the radioactive metal reactant salt that is selected from technetium, rhenium, copper, yttrium, erbium and samarium.
The oxidation of periodate control can be to be suitable for starch, glucosan or cellulose oxidation and at C.L.Mehltretter, " Methods in Carbohydrate Chemistry ", IV volume, 1964 described oxidations.It is used for following embodiment.
According to the present invention, the chemical compound that contains primary amine functional group can be corresponding to formula NH
2-(CH
2)
n-SH, wherein n is the integer between 1 and 5, and can comprise in step (b) with (c) with borohydride sodium and reduce the replenish step of this chemical compound.
According to the present invention, be attached to chemical compound on the polysaccharide corresponding to the chemical compound of following formula:
According to the present invention, regulate the level that is fixed on the chelate group on the polysaccharide by the oxidation level of the polysaccharide in the control above-mentioned steps (a).For example, the oxidation level of polysaccharide can be 10-50%, and the level of chelate group can 2-15%.
For example in order to use
99mTc labelling polysaccharide of the present invention, the present inventor adopts two step method for transformation.
This method is described as in the first step, finishes the oxidation of polysaccharide with periodate control.Like this, the independent unit of oxidizing glucose produces two aldehyde radicals on the ortho position after following chemical reaction figure:
The oxidation level of polysaccharide is that can change and easy the adjusting.In fact, the productive rate of this kinds of oxidation reaction also can calculate oxidation level by the periodate quantity that adds near 100%.Generally speaking, adopt and to be lower than 50% oxidation level only to modify macromolecular structure slightly.Can by the colour measurement method easily measurement range be the actual oxidation level of 1-100%.
In second step, making the polysaccharide of oxidation is RNH with containing general formula
2Or RNHNH
2Amine or the molecular reaction of diazanyl form can the chelating technetium chelate group.Obtain the part or the thiosemicarbazones of Schiff's base type like this.
Second step can be summarized as follows:
Wherein:
1. R=NR
1(C=S) SR
2(Schiff's base that discharges from two sulfur carbazates)
2. R=NR
1(C=S) NR
2R
3(thiosemicarbazones)
3. R=aryl (aromatic schiff base)
4. R=alkyl (alkyl Schiff's base); Schiff's base in this case is unsettled, and can finish second reduction step of C=N key and borohydrides so that it is stable, obtains amine C-NHR key then.
According to the present invention, step (c) can be for comprising the polysaccharide microsphere body and the pertechnetate of chelate group in the presence of Reducing agent such as stannous chloride
99mThe contact of Tc solution.
According to the present invention, oxidation microgranule like this, microsphere for example as corn starch or have the starch of netted amyl group pectic matrix, is attached to it the molecule such as dithio carbazic acid (dithiocarbazate) the S-methyl ester that contain amine or hydrazine functional group then.The granule that this mode is modified can be by labelling easily, as using
99mThe Tc labelling.
Therefore, the present invention specifically provides the microgranule for preparing from starch granules substrate, and there is not above-mentioned albuminous inconvenience in this microgranule.In addition, starch is described as a kind of excipient in pharmacopeia, so it is obtain easily low with cost.
Microgranule of the present invention can be sterilized as irradiation sterilization in addition easily and is processed into the advantage of the test kit of easy labelling.
And the used particulate oxide level present inventor has also proved according to the present invention according to the present invention in can be improved the lung clearance rate, and this is impossible for adopting the human albumin microsphere.
Another advantage of the present invention is that this method is simple to operate: reaction condition as mild as a dove: under the room temperature reaction, in water-bearing media, the sxemiquantitative productive rate.In addition, with the chelatropic reaction of technetium be quantitative, they at room temperature take place and without final purification, thereby make it can adapt to the aseptic and simple requirement of preparation of using the technetium test kit required in hospital environment.
The present invention also provides the diagnostic kit that can be used for the lung scintigraphy.This test kit comprises:
Contain first bottle of polysaccharide of the present invention, that is to say that its condition is a chelate group by being covalently bound on this polysaccharide, and chelate group be selected from following formula radicals R-NH-, R-N=and
Wherein, R is alkyl or the aryl that comprises at least one sulphur atom, and R ' wherein is hydrogen atom or alkyl such as methyl.
According to the present invention, polysaccharide can be the form of microgranule, as is the microsphere shape, and this microgranule can be freeze dried form or be in suspension in the pharmaceutically acceptable liquid.
Reagent of the present invention may further include second bottle that contains stannous chloride, and this stannous chloride is preferably lyophilized form, and perhaps the polysaccharide in first bottle is freeze dried form, and during as particulate form, first bottle can contain the lyophilizing stannous chloride in addition.。
The embodiment of the following stated proved test kit of the present invention stable at least 12 months.
Therefore, radiation medicine of the present invention shows as radiopharmaceuticals and uses, as is used for lung perfusion or the required character of radiocurable lung scintigraphy.
Also find out other advantage about embodiments of the invention below reading.
Embodiment
Embodiment 1
After screening between the 10-40 μ m, the corn starch suspension in the preparation 10g pharmacopeia, this suspension contains 10% water of having an appointment, and promptly contains 0.055 mole glucose in 100ml water.Add 0.0168 mole of sodium metaperiodate (0.3 the equivalent) (NaIO that is dissolved in the 100ml water
4), i.e. 3.6g.Stirred suspension 18 hours under the room temperature then.Filtering solution also uses 20ml water to clean Oxytarch 5 times, cleans 2 times with 50ml acetone then.Vacuum drying starch obtains 10g 30% Oxytarch (productive rate=100%).
In the 60ml volume ratio is preparation 10g 30% Oxytarch suspension in water/alcohol mixture of 2/1.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), i.e. 0.011 mole dithio carbazic acid S-methyl ester (NH
2NH (C=S) SCH
3), M=122, i.e. 1.34g.Stirred suspension is 18 hours under the room temperature.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain the modified starch of about 10g.It is 5.4%g that the elementary analysis of powder draws sulfur content, dithio carbazic acid S-methyl ester (DTCZ) corresponding to 7% in conjunction with level (100 theoretic aldehyde functional groups 7 unitary dithio carbazates, promptly 100 glucose units are in conjunction with 14 dithio carbazic acid ester units).Therefore combination rate is 70%.So obtain 10g 30% oxidation and 7% starch that is attached on the DTCZ.
With
99mThe Tc labeling reaction
The starch of the modification like this of 10mg is added in the bottle of penicillin type.Add the 4ml physiological serum then, add 10 μ g SnCl subsequently
2, 2H
2O (20 μ l concentration in 0.1N Hcl are 0.5mg/ml solution).Add 1ml then
99mTcO
4 -Solution (5mc).Agitating solution 15 clocks also filter 1ml solution to carry out radiochemical purity control (RCP) on the microfilter of 0.22 μ m, then with 2ml physiological serum wash filtrate.The labelling microsphere is retained on the filter, and on the contrary, radioimpurity radioactive impurity is not attached on the microsphere and finds in filtrate.Radiochemical purity corresponding to:
RCP=(activity/gross activity on the filter) * 100
It is 98.9%.
Embodiment 2
Starch conversion
Handle as embodiment 1, but during oxidation reaction, adopt 0.2 equivalent periodate.Obtain 20% Oxytarch.
Carry out association reaction in the mode identical, obtain 20% oxidation and 7% starch that is attached on the DTCZ with embodiment 1.
With
99mThe Tc labeling reaction
Handle as embodiment 1.Radiochemical purity (RCP) is 99%.
Embodiment 3
Starch conversion
Handle as embodiment 1, but during oxidation reaction, adopt 0.1 equivalent periodate.Obtain 10% Oxytarch.
Carry out association reaction in the mode identical, obtain 10% oxidation and 7% starch that is attached on the DTCZ with embodiment 1.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 98.8%.
Embodiment 4
1 processing obtains 10g 30% Oxytarch as embodiment.The suspension of preparation 10g 30% Oxytarch in 60ml water/ethanol (2/1 volume) mixture.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), i.e. 0.011 mole N-methyl-dithio carbazic acid S-methyl ester (NH
2N (CH
3) (C=S) SCH
3), M=136, i.e. 1.50g.Stirred suspension is 18 hours under the room temperature.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain about 10g modified starch.It is 5% that the elementary analysis of powder draws sulfur content, dithio carbazic acid S-methyl ester corresponding to 6.5% is in conjunction with level (100 theoretic aldehyde functional groups 6.5 unitary dithio carbazates, promptly 100 glucose units are in conjunction with 13 dithio carbazic acid ester units).Therefore combination rate is 65%.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 95%.
Embodiment 5
Starch conversion
1 processing obtains 10g 30% Oxytarch as embodiment.The suspension of preparation 10g 30% Oxytarch in 60ml water/ethanol (2/1 volume) mixture.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), i.e. 0.011 mole 4-phenyl 3-thiosemicarbazide (NH
2NH) (C=S) NH (C
6H
5), M=167, i.e. 1.83g.Stirred suspension is 18 hours under the room temperature.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain about 10g modified starch.It is 3.16% that the elementary analysis of powder draws sulfur content, and corresponding 8% 4-phenyl 3-thiosemicarbazide is in conjunction with level (thiosemicarbazide of 100 theoretic aldehyde functional groups unit 8s, promptly 100 glucose units are in conjunction with 16 thiosemicarbazide unit).Therefore combination rate is 80%.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 98%.
Embodiment 6
Starch conversion
1 processing obtains 10g 30% Oxytarch as embodiment.The suspension of preparation 10g 30% Oxytarch in 60ml water/ethanol (2/1 volume) mixture.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), i.e. 0.011 mole 4-methyl 3-thiosemicarbazide (NH
2NH) (C=S) NH (CH
3), M=105, i.e. 1.15g.Stirred suspension is 18 hours under the room temperature.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain about 10g modified starch.It is 2.9% that the elementary analysis of powder draws sulfur content, 4-methyl 3-sulfo-half carbazone corresponding to 7.3% is in conjunction with level (100 theoretic aldehyde functional groups 7.3 unitary thiosemicarbazides, promptly 100 glucose units are in conjunction with 14.6 sulfo-s, half carbazone unit).Therefore combination rate is 73%.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 97%.
Embodiment 7
Starch conversion
1 processing obtains 10g 30% Oxytarch as embodiment.The suspension of preparation 10g 30% Oxytarch in 60ml water/ethanol (2/1 volume) mixture.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), promptly 0.011 mole 4,4-dimethyl 3-thiosemicarbazide (NH
2NH) (C=S) N (CH
3)
2, M=119, i.e. 1.30g.Stirred suspension is 18 hours under the room temperature.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain about 10g modified starch.It is 3% that the elementary analysis of powder draws sulfur content, corresponding to 7.5% 4,4-dimethyl 3-sulfo-half carbazone (3-thiosemicarbazone) is in conjunction with level (100 theoretic aldehyde functional groups 7.5 unitary thiosemicarbazides, promptly 100 glucose units are in conjunction with 15 sulfo-s, half carbazone unit).Therefore combination rate is 75%.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 96%.
Embodiment 8
Starch conversion
1 processing obtains 10g 30% Oxytarch as embodiment.The suspension of preparation 10g 30% Oxytarch in 60ml water/ethanol (2/1 volume) mixture.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), i.e. 0.011 mole 4-pi-allyl 3-thiosemicarbazide (NH
2NH) (C=S) NH (CH
2CH=CH
2), M=131, i.e. 1.44g.Stirred suspension is 18 hours under the room temperature.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain about 10g modified starch.It is 3% that the elementary analysis of powder draws sulfur content, 4-pi-allyl 3-thiosemicarbazide corresponding to 7.5% is in conjunction with level (100 theoretic aldehyde functional groups 7.5 unitary thiosemicarbazides, promptly 100 glucose units are in conjunction with 15 sulfo-s, half carbazone unit).Therefore combination rate is 75%.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 98%.
Embodiment 9
Starch conversion
1 processing obtains 10g 30% Oxytarch as embodiment.The suspension of preparation 10g 30% Oxytarch in 60ml water/ethanol (2/1 volume) mixture.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), i.e. 0.011 mole 3-thiosemicarbazide (NH
2NH) (C=S) NH
2, M=91, i.e. 1g.Stirred suspension is 18 hours under the room temperature.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain about 10g modified starch.It is 2.9% that the elementary analysis of powder draws sulfur content, 3-thiosemicarbazide corresponding to 7.3% is in conjunction with level (100 theoretic aldehyde functional groups 7.3 unitary thiosemicarbazides, promptly 100 glucose units are in conjunction with 14.6 sulfo-s, half carbazone unit).Therefore combination rate is 73%.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 95%.
Embodiment 10
Starch conversion
1 processing obtains 10g 30% Oxytarch as embodiment.The suspension of preparation 10g 30% Oxytarch in 60ml water/ethanol (2/1 volume) mixture.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), i.e. 0.011 mole 2-aminothiophenol (C
6H
4) (NH
2) (SH), M=125, i.e. 1.37g.Stirred suspension is 18 hours under the room temperature.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain about 10g modified starch.It is 3% that the elementary analysis of powder draws sulfur content, and the 2-aminothiophenol corresponding to 7.5% is in conjunction with level (100 theoretic aldehyde functional groups 7.5 unitary aminothiophenols, promptly 100 glucose units are in conjunction with 15 aminothiophenol unit).Therefore combination rate is 75%.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 94%.
Embodiment 11
Starch conversion
1 processing obtains 10g 30% Oxytarch as embodiment.The suspension of preparation 10g 30% Oxytarch in 60ml water/ethanol (2/1 volume) mixture.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), i.e. 0.011 mole 2-mercaptoethylmaine (or 2-aminoothyl mercaptan) (NH
2CH
2CH
2SH), M=91, i.e. 1g.Stirred suspension is 18 hours under the room temperature.Add 0.015 mole of borohydride sodium (NaBH then
4) be used for stable Schiff's base (non-aromatic schiff base instability) and make its reaction 1 hour with what reduction formed.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain about 10g modified starch.It is 3.4% that the elementary analysis of powder draws sulfur content, and the 2-mercaptoethylmaine corresponding to 8.5% is in conjunction with level (100 theoretic aldehyde functional groups 8.5 unitary 2-mercaptoethylmaines, promptly 100 glucose units are in conjunction with 17 2-mercaptoethylmaine unit).Therefore combination rate is 85%.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 95%.
Embodiment 12
Starch conversion
1 processing obtains 10g 30% Oxytarch as embodiment.The suspension of preparation 10g 30% Oxytarch in 60ml water/ethanol (2/1 volume) mixture.Add then and be dissolved in alcoholic acid 0.1 equivalent of 10ml (0.1 * 0.055 * 2), i.e. 0.011 mole 2-amino-4-mercapto-triazole (C
4N
2H) (SH) (NH
2) M=116, i.e. 1.27g.Stirred suspension is 18 hours under the room temperature.Filtering solution is also used 20ml washing with alcohol modified starch 3 times, vacuum drying subsequently then.So obtain about 10g modified starch.It is 2.8% that the elementary analysis of powder draws sulfur content, and the amino 4-mercapto-triazole of the 2-corresponding to 7% is in conjunction with level (100 theoretic aldehyde functional groups 7 unitary mercapto-triazoles, promptly 100 glucose units are in conjunction with 14 mercapto-triazole unit).Therefore combination rate is 75%.
With
99mThe Tc labeling reaction
Carry out as embodiment 1.Radiochemical purity (RCP) is 85%.
The comparative example 1
Use the 10g screening without the pharmacopeia corn of chemical conversion and carry out the method identical to use with embodiment 1
99mTc carries out labelling.
RCP is 19%.
This embodiment has proved such fact well: the chemical modification of carrying out according to the present invention (chelate group is fixed) is for use
99mIt is necessary certainly that Tc carries out labelling.In addition, opposite with product of the present invention, if these microgranules without previous chemical conversion labelling, then can not obtain persistent lung and hold back.Therefore, these results and FR-A-2 273 516 described contradictions.
Embodiment 13
Cellulose modified
Handle as embodiment 1, but the cellulose between the 10 and 40 μ m of use screening.So obtain 30% oxidation and 7% starch that is attached on the DTCZ.
With
99mThe Tc labeling reaction
Handle as embodiment 1.RCP is 99.1%.
Embodiment 14
With the Sprague Dawley rat of the about 200g of penthiobarbital anesthesia body weight, and intravenous injection usefulness embodiment 1-9 and 13
99mThe different microsphere solution of Tc labelling.Each animal is accepted the solution of 0.2ml, i.e. every animal 0.2mc at penis blood vessel place.Then animal is placed under the gamma-rays camera and the continuous electrostatic image of taking in 3 hours.Realizing obtaining consecutive image after each image is taken for 15,000 times like this.Then, manually define with the zone to inject 15 minutes activity on the post-evaluation Different Organs.The following Table I of result provides.
Table I: result
| The activity of % intravenous injection after 15 minutes | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 |
| % lung activity | ???90％ | ???85％ | ???80％ | ???80％ | ???85％ |
| % liver activity | ??＜59％ | ???＜5％ | ???＜5％ | ???＜10％ | ???＜10％ |
| The lung half-life | 2 hours | 1 hour | 30 minutes | 2 hours | 2 hours |
| The activity of injection after 15 minutes in the quiet % arteries and veins | Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 | Embodiment 10 |
| % lung activity | ???85％ | ???85％ | ???85％ | ???85％ | ???90％ |
| % liver activity | ???＜5％ | ???＜5％ | ???＜5％ | ???＜5％ | ???＜5％ |
| The lung half-life | 2 hours | 2 hours | 2 hours | 2 hours | ＞4 hours |
Therefore the microsphere of noticing modification shows very good lung and holds back.In addition, can regulate the lung removing speed by changing the oxidation level shown in the embodiment 1,2 and 3 (oxidation level 30,20 and 10%).
Use cellulose can prolong removing speed (embodiment 10, half-life＞4 hour) considerablely.
The comparative example 2
In this embodiment, do not use native starch, and use netted amyl group pectin microsphere in the preparation of the employing chloropropylene oxide described in the patent FR-A-2 273 516.
Prepare netted spherex body
8g corn amyl group pectin is dissolved in the solution that 40ml contains 4g NaOH and 0.15g borohydride sodium.Allow amyl group pectolysis 24 hours.Stir the 60ml liquid paraffin with 800 rev/mins rotating speed then and be dissolved in 4ml hexane 1.6g soybean lecithin and prepare Emulsion.Add the water that contains that contains amyl group pectin then, then add the 3.2ml chloropropylene oxide.Emulsion is heated to 55 ℃, continues 4 hours, stir then and spend the night.With the washing with acetone of 250ml 3 times, the size of gained is about the microsphere of 50 μ m, drying, lyophilizing then.
With
99mThe Tc labelling
Handle as embodiment 1, but the SnCl of use 1mg
2, 2H
2O.RCP is 90%.
Starch conversion
Handle as embodiment 1, but use the 10g netted amyl group pectin microsphere of the employing chloropropylene oxide of preparation before.So obtain 10g 30% oxidation and the 7% amyl group pectin microsphere that is attached on the DTCZ.
With
99mThe Tc labeling reaction
Handle as embodiment 1.RCP is 99%.
Embodiment 15
Usefulness according to embodiment 14 identical operations mode test comparison embodiment 2
99mThe netted amyl group pectin microsphere of Tc labelling.The result is provided by following Table II.
Table II
| The activity of % intravenous injection after 15 minutes | The comparative example 2 | Embodiment 17 |
| % lung activity | ????＜10％ | ????85％ |
| % liver activity | ????70％ | ????＜5％ |
| The lung half-life | ??????- | 2 hours |
Notice that opposite with FRA-2 273 516 is to use
99mThe Tc labelling is not held back but show any lung without the netted amyl group pectin microsphere of chemical modification, this beyond doubt because
99mFaint combination the between Tc and the microsphere.On the other hand, the microsphere by chemical conversion of the present invention shows good lung and holds back.
Embodiment 16
The spherex body of preparation among the embodiment 1 (30% oxidation and 7% starch in conjunction with DTCZ) is used to produce aseptic labelling kit, and with standby
99mThe Tc labelling.
The microsphere sterilization
The 10g microsphere is added in the flask that curls, uses cobalt-60 light source irradiation then.
This microsphere was accepted the accumulated dose gamma-radiation of 25kGy in 20 hours.
The preparation test kit
With sterile manner the aseptic microsphere of 200mg is added in the reactor that contains 20ml NaCl 9/1000.Bubble the solution degassing by nitrogen, adding the concentration of 400 μ l in 0.1N HCl then is the SnCl of 0.5mg/ml
2, 2H
2O solution.Every bottle of 20 bottles separates 1ml solution, then lyophilizing and placing under the blanket of nitrogen.
Every bottle contains
10mg modification microsphere
10μg?SnCl
2，2H
2O
9mg?NaCl
With
99mThe Tc labelling
With 5ml TcO
4(Smc) solution is added in the bottle with lyophilized form and makes its reaction 15 minutes.
Handle as embodiment 1.RCP is 98.7%.
The Kit stability test
Under different temperatures, store the labelling kit of above-mentioned preparation, then test
99mThe Tc labeled reactant is to estimate its stability.The gained result is provided by following Table III:
Table III: RCP (%)
| Storage temperature | 6 months | 12 months |
| ????2-8℃ | ????98.5％ | ????98.4％ |
| ????25℃ | ????97％ | ????96％ |
| ????45℃ | ????94％ | ????90％ |
Notice that this test kit has very high stability under the temperature between 2 and 8 ℃.
Embodiment 17
With the Sprague Dawley rat of the about 200g of penthiobarbital anesthesia body weight, intravenous injection is with embodiment's 14 then
99mThe different microsphere solution of Tc labelling.Each animal is accepted the solution of 0.2ml, i.e. every animal 0.2mc at penis blood vessel place.Inject and put to death animal after 15 minutes.Check different organs then, calculate the radioactivity determination value in each organ, thereby determine the active percentage rate of each organ.The result is provided by following Table IV:
Table IV-result
The injected dose of % injection after 15 minutes
| Organ | Embodiment 1 | Embodiment 13 |
| Blood (1ml) | ????0.1％ | ????0.2％ |
| Liver | ????2.2％ | ????5.6％ |
| Kidney | ????0.4％ | ????0.4％ |
| Lung | ????91％ | ????82％ |
| Spleen | ????0.1％ | ????0.1％ |
| Intestinal | ????1.5％ | ????0.7％ |
| Bladder | ????0.1％ | ????1.3％ |
Therefore notice that native starch microsphere and netted starch matrix microsphere have very high lung and hold back, and a little less than in other organ, holding back.Therefore as if the sterile product of kit form is suitable for use as fully and replaces albumin and be used for radiocurable lung perfusion radiation medicine.
Embodiment 18
As at embodiment 13, use 30% oxidation and with 7% with the bonded cellulose of DTCZ.With the cellulose of rhenium 186 labellings modification like this to exemplify the purposes that carrier of the present invention is used for the treatment of.
With rhenium 186 labeling reactions
The 10mg modified cellulose is added in the penicillin type bottle.Add the 2ml physiological serum then, add the 20mg citric acid subsequently, add 1mg SnCl at last
2, 2H
2O (100 μ l concentration in 0.1N HCl are the solution of 10mg/ml).Then will be corresponding to the active 0.1mlReO of 2mc
4Solution is added in the flask contents.The heating flask is 30 minutes in 100 ℃ of water-baths.Measure radiochemical purity (RCP) by MF method as embodiment 1.
RCP＝92％
In order to prove the bonded stability between rhenium 186 and the cellulose microsphere body, carry out the vitro stability test.
37 ℃ of HSA (human serum albumin) incubation mixture of using 20mg/ml down.Obtain following result:
| Incubation | ????0 | 2 hours | 6 hours | 24 hours | 48 hours |
| ??RCP | ???92％ | ???92％ | ???91％ | ???89％ | ???90％ |
Therefore these results prove with the plain microsphere of rhenium 186 labeled fibers and have very high stability, and have proved the high stability of microsphere with respect to HSA itself.
The expert will easily understand the purposes that these results can be extrapolated to RE 188.
Embodiment 19
With the Sprague Dawley rat of the about 200g of penthiobarbital anesthesia body weight, inject the cellulose microsphere liquid solution among 0.2ml (0.1mc) embodiment 18 then with Re 186 labellings.
Subsequently animal is placed under the gamma-rays camera and recording picture in 48 hours.
Calculate the activity in useful zone as embodiment 14 then.
| The injection back time | 1 hour | 2 hours | 6 hours | 24 hours | 48 hours |
| % lung activity | ??80％ | ???85％ | ???85％ | ??85％ | ???90％ |
| % liver activity | ??＜5％ | ???＜5％ | ???＜5％ | ??＜5％ | ???＜5％ |
Therefore these results prove that the flat activity of edema caused by the lung disorder kept 48 hours at least, thereby this class microsphere can be used for the treatment of.
Most important clinical practice is to treat hepatocarcinoma after injection, and this injection is not an intravenous but direct injection enters Hepatic artery (metabolism radiotherapy).
Another possible application is that this class granule subcutaneous injection is advanced breast carcinoma.These granules that move by lymphsystem can be treated the signal node that is subjected to the cancerous cell infringement.
Claims (20)
1. radiation medicine that comprises polysaccharide, its condition are chelate groups by being covalently bound on the polysaccharide, and chelate group be selected from following formula radicals R-NH-, R-N=and
Wherein, R is alkyl or the aryl that comprises at least one sulphur atom, and R ' is hydrogen atom or alkyl or methyl, and described chelate group and the radioactive metal that is selected from technetium, rhenium, copper, yttrium, erbium, gallium and samarium form the coordination compound of chelate type jointly, and wherein this polysaccharide is the form of microgranule.
2. according to the radiation medicine of claim 1, wherein this chelate group is selected from the group of following formula:
Wherein, R
1, R
2, R
3, R
4And R
5Be hydrogen atom, saturated or unsaturated alkyl, carboxyl or aryl independently,
3. according to the radiation medicine of claim 2, wherein this chelate group is selected from the group of following formula:
4. according to arbitrary radiation medicine of claim 1-3, wherein this polysaccharide is selected from native starch, cellulose and netted amyl group pectin.
5. according to arbitrary radiation medicine of claim 1-5, wherein this particle size is between 0.01 and 100 μ m.
6. arbitrary radiation medicine of claim 1-5, wherein the level of chelate group is sugared with respect to glycan is 0.1-50%.
7. be used to prepare the purposes of diagnostic products according to arbitrary radiation medicine of claim 1-6, wherein this radioactive metal is
99mTc or
67Ga.
8. be used to prepare the purposes of medicine according to arbitrary radiation medicine of claim 1-6, wherein this radioactive metal is rhenium-186 or 188, copper-64 or 67, yttrium 90, erbium 169 or samarium 153.
9. the arbitrary radiation medicine according to claim 1-7 is used to prepare the purposes of lung scintigraphy with product, and wherein this radioactive metal is
99mTc.
10. according to arbitrary radiation medicine of claim 1-6, this radiation medicine is to be in form or the freeze dried form that the physiology goes up the microsphere suspension liquid in the acceptable liquid.
11. according to the preparation method of arbitrary radiation medicine of claim 1-6, this preparation method may further comprise the steps:
(a) adopt the periodate oxidation polysaccharide,
(b) make oxidation of polysaccharides and contain formula R-NH
2Or
Primary amine functional group or hydrazine reaction,
Wherein, R is alkyl or the aryl that comprises at least one sulphur atom, so that with the metal-chelating base of covalent manner convolution R-NH-, R-N=or R-NH-N=on polysaccharide, and R ' is hydrogen atom or alkyl or methyl,
(c) make polysaccharide that comprises chelate group and the radioactive metal reactant salt that is selected from technetium, rhenium, copper, yttrium, erbium and samarium.
12. according to the method for claim 11, the chemical compound that wherein contains primary amine functional group is corresponding to formula NH
2-(CH
2)
n-SH, wherein n is the integer of 1-5, and be included in step (b) and (c) between reduce the replenish step of this chemical compound by borohydride sodium.
13. according to the method for claim 11, the chemical compound that wherein is attached to oxidation of polysaccharides is corresponding to following formula:
14., wherein regulate the level that is fixed on the chelate group on the polysaccharide by the level of oxidation of polysaccharides in the controlled step (a) according to arbitrary method of claim 11-13.
15. according to the method for claim 14, wherein the oxidation level of polysaccharide is 10-50%.
16. according to the method for claim 14, wherein the level of chelate group is 2-15%.
17. according to arbitrary method of claim 10-16, wherein step (c) is in the presence of Reducing agent, makes the polysaccharide microsphere body and the pertechnetate that comprise chelate group
99mTcO
4 -The solution contact.
18. the diagnostic kit that can be used for the lung scintigraphy comprises:
Contain first bottle of polysaccharide, its condition is a chelate group by being covalently bound on this polysaccharide, and chelate group be selected from following formula radicals R-NH-, R-N=and
Wherein, R is alkyl or the aryl that comprises at least one sulphur atom, and R ' is hydrogen atom or alkyl or methyl, and wherein this polysaccharide is the form of freeze-drying particle or is in the suspension on the pharmaceutically acceptable liquid.
19., also comprise second bottle of the stannous chloride that contains lyophilized form according to the test kit of claim 18.
20. according to the test kit of claim 18, wherein the form of polysaccharide is the freeze-drying particle in first bottle, this first bottle also comprises freeze dried stannous chloride.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR99/10970 | 1999-09-01 | ||
| FR9910970A FR2797769B1 (en) | 1999-09-01 | 1999-09-01 | RADIOPHARMACEUTICAL PRODUCTS AND THEIR PREPARATION PROCESS |
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| Publication Number | Publication Date |
|---|---|
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Family
ID=9549465
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00812300A Pending CN1371292A (en) | 1999-09-01 | 2000-08-23 | Radiopharmaceutical products and their preparation procedure |
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|---|---|
| EP (1) | EP1210127A1 (en) |
| JP (1) | JP2003508455A (en) |
| KR (1) | KR20020040799A (en) |
| CN (1) | CN1371292A (en) |
| AU (1) | AU6463100A (en) |
| BG (1) | BG106438A (en) |
| BR (1) | BR0013729A (en) |
| CA (1) | CA2383517A1 (en) |
| CZ (1) | CZ2002782A3 (en) |
| EA (1) | EA200200307A1 (en) |
| EE (1) | EE200200105A (en) |
| FR (1) | FR2797769B1 (en) |
| HK (1) | HK1044893A1 (en) |
| HU (1) | HUP0202714A2 (en) |
| IL (1) | IL148076A0 (en) |
| MX (1) | MXPA02001923A (en) |
| NO (1) | NO20021001L (en) |
| NZ (1) | NZ517377A (en) |
| PL (1) | PL353803A1 (en) |
| SK (1) | SK2772002A3 (en) |
| WO (1) | WO2001015746A1 (en) |
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|---|---|---|---|---|
| CN101861171B (en) * | 2007-07-26 | 2013-07-17 | 希洛药物实验室 | Polysaccharides grafted by polyamine for preparing radioactive pharmaceutical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7462366B2 (en) | 2002-03-29 | 2008-12-09 | Boston Scientific Scimed, Inc. | Drug delivery particle |
| US7842377B2 (en) | 2003-08-08 | 2010-11-30 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
| US8012454B2 (en) | 2002-08-30 | 2011-09-06 | Boston Scientific Scimed, Inc. | Embolization |
| US7883490B2 (en) | 2002-10-23 | 2011-02-08 | Boston Scientific Scimed, Inc. | Mixing and delivery of therapeutic compositions |
| US7976823B2 (en) | 2003-08-29 | 2011-07-12 | Boston Scientific Scimed, Inc. | Ferromagnetic particles and methods |
| US7901770B2 (en) | 2003-11-04 | 2011-03-08 | Boston Scientific Scimed, Inc. | Embolic compositions |
| US7736671B2 (en) | 2004-03-02 | 2010-06-15 | Boston Scientific Scimed, Inc. | Embolization |
| US8173176B2 (en) | 2004-03-30 | 2012-05-08 | Boston Scientific Scimed, Inc. | Embolization |
| US7311861B2 (en) | 2004-06-01 | 2007-12-25 | Boston Scientific Scimed, Inc. | Embolization |
| US9000040B2 (en) | 2004-09-28 | 2015-04-07 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
| US7727555B2 (en) | 2005-03-02 | 2010-06-01 | Boston Scientific Scimed, Inc. | Particles |
| US7858183B2 (en) | 2005-03-02 | 2010-12-28 | Boston Scientific Scimed, Inc. | Particles |
| US7963287B2 (en) | 2005-04-28 | 2011-06-21 | Boston Scientific Scimed, Inc. | Tissue-treatment methods |
| US9463426B2 (en) | 2005-06-24 | 2016-10-11 | Boston Scientific Scimed, Inc. | Methods and systems for coating particles |
| US7947368B2 (en) | 2005-12-21 | 2011-05-24 | Boston Scientific Scimed, Inc. | Block copolymer particles |
| CN102977174B (en) * | 2012-12-19 | 2015-04-22 | 北京师范大学 | 99mTc(CO)3 nuclear-labeled macrocyclic polyamine triazole ring glucose-based complex as well as preparation and application of complex |
| PL240772B1 (en) | 2018-06-11 | 2022-06-06 | Nanothea Spolka Akcyjna | Method of producing polymer nanoparticles chelating radioactive isotopes for use in diagnostics and treatment |
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| SE7412164L (en) * | 1974-09-27 | 1976-03-29 | Pharmacia Ab | FUNDS FOR INTRAVASCULAR ADMINISTRATION |
| US5672334A (en) * | 1991-01-16 | 1997-09-30 | Access Pharmaceuticals, Inc. | Invivo agents comprising cationic metal chelators with acidic saccharides and glycosaminoglycans |
| WO1994005203A1 (en) * | 1992-09-04 | 1994-03-17 | The General Hospital Corporation | Biocompatible polymers containing diagnostic or therapeutic moieties |
| US5958372A (en) * | 1994-06-28 | 1999-09-28 | Nycomed Imaging As | Low viscosity chelating polymers for diagnostic imaging |
| FR2736834B1 (en) * | 1995-07-17 | 1997-08-29 | Cis Bio Int | RADIOPHARMACEUTICAL PRODUCTS WITH CARDIAC TROPISM COMPRISING A NITRURO COMPLEX OF A TRANSITIONAL METAL AND HAVING FAST MYOCARDIAL CLEARANCE |
-
1999
- 1999-09-01 FR FR9910970A patent/FR2797769B1/en not_active Expired - Fee Related
-
2000
- 2000-08-23 KR KR1020027002820A patent/KR20020040799A/en not_active Application Discontinuation
- 2000-08-23 CA CA002383517A patent/CA2383517A1/en not_active Abandoned
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- 2000-08-23 JP JP2001520157A patent/JP2003508455A/en active Pending
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- 2000-08-23 HU HU0202714A patent/HUP0202714A2/en unknown
- 2000-08-23 SK SK277-2002A patent/SK2772002A3/en unknown
- 2000-08-23 EP EP00951784A patent/EP1210127A1/en not_active Withdrawn
- 2000-08-23 MX MXPA02001923A patent/MXPA02001923A/en not_active Application Discontinuation
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- 2000-08-23 AU AU64631/00A patent/AU6463100A/en not_active Abandoned
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101861171B (en) * | 2007-07-26 | 2013-07-17 | 希洛药物实验室 | Polysaccharides grafted by polyamine for preparing radioactive pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| YU14202A (en) | 2004-09-03 |
| EE200200105A (en) | 2003-04-15 |
| BR0013729A (en) | 2002-05-07 |
| NO20021001L (en) | 2002-04-11 |
| JP2003508455A (en) | 2003-03-04 |
| HUP0202714A2 (en) | 2002-12-28 |
| FR2797769A1 (en) | 2001-03-02 |
| HK1044893A1 (en) | 2002-11-08 |
| NZ517377A (en) | 2003-08-29 |
| EA200200307A1 (en) | 2002-08-29 |
| AU6463100A (en) | 2001-03-26 |
| BG106438A (en) | 2002-09-30 |
| KR20020040799A (en) | 2002-05-30 |
| NO20021001D0 (en) | 2002-02-28 |
| SK2772002A3 (en) | 2002-09-10 |
| IL148076A0 (en) | 2002-09-12 |
| EP1210127A1 (en) | 2002-06-05 |
| FR2797769B1 (en) | 2003-07-25 |
| CZ2002782A3 (en) | 2002-08-14 |
| ZA200201057B (en) | 2003-07-30 |
| PL353803A1 (en) | 2003-12-01 |
| CA2383517A1 (en) | 2001-03-08 |
| WO2001015746A1 (en) | 2001-03-08 |
| MXPA02001923A (en) | 2003-07-21 |
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