JPH10158197A - Lymphatic imaging contrasting medium - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition for lymphatic imaging use, applicable by an indirect but parenteral means and having increased contrast by using a specific water-soluble polymer as a component. SOLUTION: This imaging medium contains (A) a physiologically permissible water-soluble polymer having a molecular weight of >=1 kD and effective for diagnostic use in combination with (B) at least one pharmaceutically permissible carrier or vehicle. The component A is preferably an iodinated polymer, especially a polyiodinated polymer agent composed of a recurring unit of the formula ((a) and (b) are each 1-4; (c) is O or 1-4; X is a 1st linking group giving 0, 1, 2, 3 or 4 atomic chains between iodophenyl groups; L is a 2nd hydrophi1lc linking group giving a chain having a molecular weight of <=5,000 between iodophenyl groups).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a method for contrast-enhanced imaging, particularly for MR and X-ray imaging of the lymphatic system, and to a contrast agent composition useful therefor.

[0002] The condition of the lymphatic system of the human body is often critical to the treatment of treatment in cancer patients. It is therefore highly desirable to be able to perform diagnostic imaging of the lymphatic system in order to detect the presence or expression of an abnormality therein.

Water-soluble contrast agents of the type commonly used in diagnostic imaging modalities, such as iohexol and GdDTPA-BMA, do not accumulate enough in the lymphatic system to obtain their contrast enhancement.

[0004] Therefore, currently available diagnostic imaging techniques are practically limited in their effectiveness for lymphoid imaging. Ethiodol, an oily ethyl ester of iodinated fatty acids present in poppy seed oil
(Ethiodol) is currently used for x-ray lymphography (ie, lymphangiography). However, this agent affects healthy tissues and requires painful procedures, cannulation and direct injection into lymphatic vessels, and requires a very long time to be cleared from the lymphatic system. It has significant disadvantages. More recently, it has been discovered that subcutaneously administered microcrystalline suspensions of substantially insoluble radiopaque materials can be used to provide contrast in x-ray imaging of the lymphatic system. However, such microcrystalline materials also have potential disadvantages. For example, microparticulates are only slowly removed from the imaging site, are difficult to produce with a uniform particle size, and must be formulated with a surfactant to stabilize the suspension. The inclusion of additional materials in the contrast medium, such as surfactants, creates risks from toxicity issues and ensures that further obstacles must be overcome before formal product approval can be obtained. Of course, it is.

[0005] Surprisingly, however, it has been found that subcutaneously administered water-soluble polymeric contrast agents are effective in obtaining lymphoid image contrast.

Accordingly, in one aspect, the present invention relates to administering a diagnostically effective contrast agent to the human or animal (preferably mammalian) body and to at least a portion of the body's lymphatic system. Producing a contrast-enhanced image, wherein the agent is at least 1 kD (preferably at least 1 kD).
10 kD, particularly preferably at least 20 kD, e.g. 2 mD
Human or animal (preferably mammal), characterized in that it is a water-soluble polymeric material having a molecular weight of less than or equal to 100 kD, and is indirectly administered parenterally, preferably in the form of a solution. An imaging method wherein at least a portion of the lymphatic system in the body of the subject is contrast enhanced.

[0007] In a further aspect, the present invention relates to an indirect method for use in a diagnostic method comprising indirectly parenterally administering said contrast medium and then producing a contrast enhanced image of at least a portion of the lymphatic system. But at least 1 kD physiologically acceptable to produce a diagnostic imaging contrast medium that can be administered parenterally
It provides the use of a diagnostically effective contrast agent which is a water-soluble polymer having a molecular weight of preferably (at least 10 kD, particularly preferably at least 20 kD, for example up to 2 mD, preferably up to 100 kD).

Also, from a further perspective, the present invention is preferably an aqueous solution, which is physiologically acceptable,
At least 1 kD (preferably at least 10 kD, particularly preferably at least 20 kD, e.g.
Indirect but non-invasive use for lymphography containing a water-soluble polymer having a molecular weight of less than 2 mD, preferably less than 100 kD) with at least one pharmaceutically acceptable carrier or excipient. Provided is a diagnostic contrast agent composition capable of oral administration.

Indirect parenteral administration according to the present invention includes administration to tissues or mucous membranes below the skin or mucous membranes, such as injection, infusion or placement of a depot. Thus, administration may be subcutaneous, intramuscular, peritumoral, intraperitoneal, and submucosal (ie, intratracheally, intracervical, etc.), or by pulmonary deposition. Subcutaneous administration is preferred. Thus, administration according to the present invention differs from direct lymphography, which involves administering contrast media directly to lymphatic vessels or nodes, and also involves locating major vessels and administering contrast media there. Also different from intravenous or intraarterial administration. However, when the water-soluble contrast agent of the present invention is used, direct injection into the lymphatic system is also effective.

[0010] Diagnostically effective means that the polymeric contrast agent has at least one component (labeling substance) that is effective in producing contrast in the chosen imaging modality. Preferred imaging modalities include X-ray (eg, CT), MRI, ray imaging, scintigraphy, magnetic tomography, SPECT
, PET, electrical impedance tomography, etc., preferably X-ray, MRI or scintigraphy.

For MRI, suitable labeling substances include non-hydrogen atoms having a non-zero nuclear spin, or more preferably paramagnetic, such as transition metals, such as Mn,
Metal ions or metal cluster ions of Fe or Cr, or lanthanoids such as Gd and Dy. Other suitable paramagnetic metal ions are known from the patent literature for MR contrast media, including the patent publications cited herein. MR imaging is preferably T ₁ -weighted imaging, but in the case of T ₂ and T ₂ ^* agents (eg, dysprosium-labeled materials), T ₂ -weighted imaging is also useful.

For X-rays, the labeling substance is conveniently a heavy atom (for example, one having an atomic number of 37 or more) and contains iodine or a metal of Group 5 or higher, such as Bi, Pb, Ba or
Conveniently W. Here, suitable heavy atoms are known from the patent literature, including the publications relating to heavy metal cluster ions. Metals useful as MR imaging agents, although less effective than the heavy metals described above, are also useful for X-rays.

[0013] For light imaging, the labeling substance is a chromophore or fluorophore, such as triphenylmethane or cyanine, or a fluorescent metal ion (eg, europium).

Regarding scintigraphy, PET and SPECT
In some cases, the labeling substance is a radioactive labeling substance,
Metal radionuclides such as Sc, Fe, Pb, Ga, Y, Bi, Mn,
Cu, Cr, Zn, Ge, Mo, Tc, Ru, In, Sm, Sn, Sb, W, R
e, Po, Ta or Tl radionuclides, eg⁴⁴Sc,⁶⁴C
u,⁶⁷Cu,¹¹¹In,²¹²Pb,⁶⁸Ga,⁹⁰Y,²¹²Bi,⁵²F
e, ⁴³Sc or⁵⁵Co.

When the labeling substance is a metal, the labeling substance may be a metal chelating group (for example, EDTA,
It is convenient to incorporate DTPA, DOTA, DO3A, TMT, etc.) and metallize this chelating agent with metal ions to incorporate it into the polymeric agent. These chelating agents may form part of the polymer backbone, or may be present additionally or alternatively on pendant side chains.

When the labeling substance is a non-metallic, such as iodine or an organic chromophore, it may be included in a repeating unit of the backbone polymer (eg, an iodinated phenyl chain component), or Optionally, it may be present on the pendant side chain.

To ensure water solubility, the polymeric agents of the present invention may incorporate hydrophilic groups (eg, polyhydroxyalkyl or polyalkyleneoxy groups) into the polymer backbone, or alternatively or optionally. Preferably, it is incorporated into a pendant side chain.

The polymeric structure of the agents according to the invention can be linear, branched or highly branched (eg dendritic).
c)). However, linear and dendrimeric polymers are preferred.

Thus, by way of example, the polymeric agent has the formula

[0020]

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(Wherein the polymer backbone repeating unit, PB, incorporates a labeling substance (eg, an iodine atom or metallated chelating group) and / or a hydrophilic backbone segment (eg, a polyalkyleneoxy linking group). , N is zero or a positive integer and SC
The (side chain) may incorporate a labeling substance (eg, an iodine atom or metallated chelating group) and / or a repeating unit of a hydrophilic segment (eg, a hydroxypoly (alkyleneoxy) group).

The polyiodinated polymeric agent used in accordance with the present invention may, for example, be of the formula

[0023]

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Wherein a and b are integers having a value of 1-4; c is zero or an integer having a value of 1-4; X is zero between the iodinated phenyl groups; 1, 2
L is a first linking group that provides a chain of 1, 3 or 4 atoms; and L provides a chain of molecular weight of 5000 or less between the iodinated phenyl groups, preferably has a pendant hydroxy group, and (A second hydrophilic linking group in which ether oxygen is incorporated in the polyalkyleneoxy residue). Phenyl: X or phenyl: L bond is a carbonyl group or an oxygen atom,
It is particularly advantageous for example to be amide or ether functional.

Thus, by way of example, such a compound has the formula

[0026]

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Wherein a is 1, 2, 3, or 4, preferably 2 or 3; b is 1, 2, 3, or 4,
C is 0, 1, 2, 3 or 4, preferably 0 or 1; R is H, or an alkyl, aryl, acyl, Aroyl or aralkyl (for example, 20
Or less, preferably containing 6 or less carbon atoms)
R 'is an alkylene, optionally substituted (e.g., by hydroxy or hydroxyalkyl), optionally interrupted by one or more oxygen or sulfur atoms;
Be _2-20 alkylene; X is 0, 1, 2 or 3 of the linking group providing an atom, for example a bond, an oxygen atom, a _{carbonyl, SO, SO 2, CH 2} , C (CH 3) 2 or, And R "is a hydroxy, H2, NHAc, or other hydrophilic group).

Such compounds include mono- or oligophenyl alcohols (eg, bisphenol-A,

[0029]

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Epoxide-introducing agent following iodination of (1,3,5-trihydroxybenzene)

[0031]

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Treatment with a diamine (eg, H ₂
N (CH ₂ ) ₂ O (CH ₂ ) ₂ NH ₂ ). Treatment of this polymer with acetic anhydride converts any amine hydrogens to CH ₃ CO 2, and base treatment hydrolyzes the unwanted esters formed.

Alternatively, starting from an iodinated mono- or oligophenyldicarboxylic acid,
(E.g., using SOCl ₂₎ to activate the diamine (e.g., above-described ones or alkylenediamine, for example _{NH 2 (CH 2) 2 NH} 2) were allowed to react with, alpha, omega chlorocarbonyl polyalkylene oxide Or α, ω bisepoxy compound

[0034]

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Polymerization may be carried out using Examples of other suitable polymer structures and chelating groups are described in WO94 / 08624, WO94 / 0
8629, WO95 / 26754, WO92 / 08494, EP-A-288256, WO93 / 2
1957, WO90 / 12050, WO91 / 05762, WO93 / 06868, EP-A-430
863 and the references cited therein.

The polymer agent used according to the present invention comprises 1
It is preferred to have a molecular weight in the range of 20002000 kD, for example 3-70 kD, especially 10-50 kD. In the method according to the invention, the contrast agent is preferably of particular interest, preferably in an aqueous solution or less preferably as an aqueous suspension, for example in the hand, arm, foot, leg, crotch, chest or neck. Conveniently, the injection or infusion is at one or more injection sites relatively close to or upstream of the lymph nodes or lymph vessels. The dosage is preferably relatively low in volume, for example 0.05-50 for humans.
ml, preferably 2.0-10 ml, the larger volume is
As a series of smaller injections, for example, 5 × 2 ml or 10 × 1 ml is administered. Imaging is performed immediately or after a delay of minutes to days. However, it is preferred that the imaging be performed 30 minutes to 2 days after injection, especially 1 hour to 18 hours.

Generally, doses of 0.0001 to 5.0 mmol of chelated diagnostically effective metal are effective to achieve adequate contrast enhancement. Most MRI
For applications, the preferred dosage of imaging metal is 0.02-1.2 mmol / kg body weight (e.g., 5-200 m
(For example, 20-100 mM), while for X-ray applications it is generally 0.5-2.0 mmol / kg.
Is effective to achieve x-ray attenuation. The preferred dosage for most X-ray applications is the
0.8-1.5 mmol / kg body weight. If the agent is iodinated, a dose of 10-400 mgI / kg will generally be used. For scintigraphic applications, doses of 0.0001-4 mmol of radionuclide / kg body weight are commonly used.

The polymer contrast agent of the present invention can be prepared by using conventional pharmaceutical or veterinary auxiliaries such as emulsifiers, fatty acid esters, gelling agents, stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents and the like. And may be in a form suitable for subcutaneous administration or pre-use formulation for injection or infusion. Thus, the polymeric compound may be in conventional pharmaceutical dosage forms, such as powders, solutions, suspensions, dispersants, and the like; however, in physiologically acceptable carrier media such as distilled water for injection. Solutions are generally preferred.

The polymeric compounds may be formulated for administration using physiologically acceptable carriers or excipients in a manner entirely within the skill of the art. For example, the compound may be suspended or dissolved in an aqueous medium, optionally with a pharmaceutically acceptable excipient, and the resulting solution or suspension is sterilized. Suitable additives include, for example, physiologically biocompatible buffers (eg, tromethamine hydrochloride), chelating agents (eg, DTPA, DTPA-
Bisamides or uncomplexed polychelators) or calcium chelate complexes (e.g., calcium DTPA, CaNa
DTPA-bisamide, a calcium polychelator or CaNa salt of a polychelator (e.g., 0.01 to 10 mole percent based on the chelated diagnostically effective metal), or a calcium or sodium salt (e.g., , Calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate) (e.g., 1 to 50 mole percent).

Parenterally administrable forms, such as suspensions and solutions, should be sterile and free of physiologically unacceptable agents to minimize any irritation or other adverse effects upon administration. Osmolality equal or almost equal to plasma, e.g. 100-400 mOsm / kg
And therefore the contrast medium is
It is preferably isotonic or slightly hypertonic. In extreme cases, hypotonic solutions can be used to advantage with small injection volumes. Suitable vehicles include:
Parenteral solutions such as saline injection, Ringer's injection, dextrose injection, dextrose and saline injection, lactated Ringer's injection, and other solutions such as R
emington's Pharmaceutical Sciences, 15th ed., East
on: Mack Publishing Co., pp. 1405-1412 and 1461
-1487 (1975), and The National Formulary XIV,
14th ed.Washington: American Pharmaceutical Assoc
aqueous vehicles that are conventionally used to administer those described in Iiation (1975). The solution is compatible with preservatives, antibacterial agents, buffers and antioxidants, and excipients and chelating agents conventionally used for parenteral solutions, and can be used in the manufacture, storage, and manufacture of products. Or it may contain other additives that do not interfere with use.

The various references mentioned herein are hereby incorporated by reference.

[0042]

The invention will now be further described by way of the following non-limiting examples.

[0043]

Example 1 Synthesis of NC 66368 A synthesis scheme is shown below.

[0044]

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Polyoxyethylene bis (chloride) (2 ) A solution of polyethylene glycol [(1), average molecular weight 1.45K] (1000 g, 0.69 mol) in 1.5 L of toluene (60-80 ° C.) was charged with SOCl _2. (200 ml, 2.76 mol) and DMF (10 ml)
Added dropwise over minutes. The reaction mixture was heated in a steam bath for 1 hour. According to TLC analysis (CH ₂ Cl ₂ : MeOH; 6: 1)
It was found that a very small amount of starting material still remained.
Another 20 ml of SOCl ₂ was added to the reaction, which was heated on a steam bath for another 20 minutes to complete the reaction. Cool the reaction to 0 ° C. using an ice bath, then add 1N NaOH
(2.5 L) was carefully poured to neutralize the solution and the layers were separated. The aqueous layer was washed with _{CH 2 Cl 2 (3 × 1} L), CH ₂ Cl ₂ layer was collected, washed with water (2 × 1 L), dried over MgSO _4. It was filtered and concentrated under reduced pressure to give a pale yellow oil. To the residue, TBME (2 L) was added with cooling and stirring to precipitate the product. The filtered product was dried in an oven under vacuum overnight and 941 g (94
%) To give the title compound as a white solid.

Calculated value for C ₆₄ H ₁₂₈ O ₃₁ Cl ₂ : C, 52.49;
H, 8.81; Cl, 4.84. Found: C, 51.94; H, 8.43; Cl, 5.00. Polyoxyethylene bis (azide) (3) Polyoxyethylene bis (chloride) in 1500ml DMF
To a suspension of ((2), 500 g, 0.336 mol) and KI (139 g, 0.841 mol) was added NaN ₃ (109 g, 1.68 mol). The suspension was heated in a steam bath at 70 ° C. for 12 hours to give a yellowish solution. After cooling the reaction to room temperature, 2.5 L of water was added and the solution was extracted with CH ₂ Cl ₂ (3 × 1 L). The collected CH ₂ Cl ₂ layers were washed with water (3 × 1 L), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a pale yellow oil.
The product was precipitated by adding TBME (1 L) to the residue with cooling and stirring. The filtered product was dried in an oven at room temperature under vacuum overnight and 452 g (90
%) Of PEG diazide as a white solid.

Calculated value for C ₆₄ H ₁₂₈ O ₃₁ N ₆ : C, 52.09;
H, 8.73; N, 5.69. Found: C, 52.50; H, 8.58; Cl, 5.11. Polyoxyethylene bis (amine) (4) Polyoxyethylene bis (azide) in 1 L of 1N HCl
To a solution of ((3), 176 g, 0.117 mol) was added Pd / C (17.6 g). This suspension was hydrogenated at 45 PSI for 15 hours. An aliquot removed from this reaction was TLC (CH ₂ Cl ₂ : MeO
H; 4: 1) indicated that it was no longer the starting material and the catalyst was removed by careful filtration using a short plug of Celite. The filtrate was neutralized with 10% NaOH to pH = 5-6 and extracted with CH ₂ Cl ₂ (3 × 600 ml) to remove impurities. The aqueous solution is neutralized with 35% NaOH and pH> 10
And extracted with CH ₂ Cl ₂ (2 × 500 ml). CH ₂ Cl ₂ layer,
After washing with water (500 ml) and saturated saline (500 ml), MgSO ₄
And dried. The filtrate was concentrated under reduced pressure to give a pale yellow oil. The product was precipitated by adding TBME (1 L) to the residue with cooling and stirring. The filtered product is dried in an oven at room temperature under vacuum overnight,
138 g (81% yield) of the title compound were obtained as a white solid.

Calculated value for C ₆₄ H ₁₃₂ O ₃₁ N ₂ : C, 53.92;
H, 9.33; N, 1.96. Found: C, 53.24; H, 9.35; Cl, 1.66. NC 66368 5500 ml of polyoxyethylene bis (amine) in water
((4), 550g, 0.380 mol) solution with triethylamine (15
9 ml, 1.14 mol) and DTPA-dianhydride (DTPA-d
ianhydride) ((5), 149 g, 0.418 mol) was added. The suspension was stirred at room temperature to give a clear solution after 10 minutes.
The reaction was stirred for another 50 minutes and GdCl _{3 in} 2000 ml of water
_{· 6H 2 O (156g, 0.418} mol) was added. The reaction mixture was checked with PAR reagent and only slight excess
GdCl ₃ · 6H ₂ O was confirmed to have been added. The complex solution (pH = 2) is neutralized with 10% NaOH to about pH 5, then
Diafiltration was performed 10 times using a Pellicon diafiltration apparatus equipped with a 10K cutoff filter. A 10% NaCl (USP grade) solution (filtered using a 0.22 micron filter) was used for the first four times and water for the remaining six times. At the end of the diafiltration, the solution is concentrated to half its original volume (pH = 7), filtered using a 0.22 micron filter and then
Lyophilized for many days and found Mw = 20,200 (by SEC-HPLC analysis using polyethylene glycol Mw standard) and ICP analysis left a sponge-like product containing 7.09% w / w Gd. (532 g, 80%).
[C ₈₀ H ₁₅₂ GdN ₅ O ₄₀ ] _x : Analytical calculation: C, 48.50; H, 7.73;
N, 3.53. (H ₂ corrected for O) Found: C, 48.14;
H, 7.91; Cl, 3.29.

[0049]

Example 2 Synthesis of NC 22181 The synthesis scheme is shown below.

[0050]

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NC 22181 Hexamethylenediamine ((7), 200 g, 1.72 in 4 L of DMSO)
mol) solution, triethylamine (810 ml, 5.52 mol)
And DTPA-dianhydride ((5), 664 g, 1.84 mol) were added. The suspension was stirred at room temperature for 45 hours to give a pale yellow solution. 4 L of EtOAc was added to this solution and the product precipitated as an oil. The solvent was decanted and the oily product was further washed with EtOAc (2 × 2 L).
After drying the oily product under vacuum for 1 hour,
Was dissolved in water and added _{GdCl 3 · 6H 2 O (312g} ). The solution was neutralized to about pH 5 with NaOH and filtered using a 0.45 micron filter. The filtered solution was diafiltered 10 times using a Pellicon diafiltration device with a 10K cutoff filter.
A 10% NaCl (USP grade) solution (filtered using a 0.22 micron filter) was used for the first five times and water for the remaining five times.

At the end of the diafiltration, the solution was concentrated to half its original volume (pH = 7), filtered using a 0.22 micron filter and then lyophilized for 3 days to give Mw = 18,900 (polyethylene glycol (By SEC-HPLC analysis employing Mw standard) and ICP analysis left a sponge-like product containing 22.00% w / w Gd (203 g). Elemental analysis: [C ₂₀ H ₃₂ GdN ₅ O ₈ ] _x : Analytical calculation (corrected for H ₂ O and NaCl): C, 33.54; H,
5.70; N, 9.78. Found: C, 33.44; H, 5.77; N, 9.6
3; Na, 0.69; Cl, 0.98.

[0053]

Example 3 The composition NC 66368 (Example 1) is aseptically dissolved in physiological saline supplemented with sufficient TRIS buffer and the solution in buffer is added.
mM was made. The resulting solution was passed through a sterile 0.2 μm filter and placed in a glass vial with a Teflon finished stopper and a conventional metal crimp stopper. The vial was sealed and heat sterilized at 121 ° C. for 15 minutes. The final composition of this solution was: NC 66368 80 mM Gd NaCl 0.4 wt% TRIS (pH 8.0) 20 mM.

[0054]

Example 4 600 mg of composition NC 22181 (Example 2) was aseptically dissolved in saline (10 ml) supplemented with sufficient TRIS buffer to make a 10 mM solution in buffer. . The resulting solution is sterilized 0.
Passed through a 2 μm filter and placed in a glass vial with a Teflon finished stopper and a conventional metal crimp stopper. The vial was sealed and heat sterilized at 121 ° C. for 15 minutes. The final composition of this solution was: [Gd] 80 mM NaCl 0.9% TRIS (pH 8.0) 10 mM.

[0055]

Example 5 Rabbit Imaging Rabbits were injected subcutaneously with 2 × 0.25 ml of the composition of Example 3 in the right forelimb, and 24 hours after the injection, an image was taken at 1.5 T using MRI. FIG. 1 attached is a generated MR image, which shows a right axillary node (enlarged box) compared to a left axillary node (indicated by an arrow) as a control. ) Indicates that there was substantial contrast enhancement.

[0056]

Example 6 Rabbit Imaging NC 66368 was transferred to a New Zealand white rabbit (New Zealand).
0.064 and 0.128 mmol on the forefoot of the white rabbit)
A dose of Gd / kg body weight (1 and 2 ml injection respectively) was administered subcutaneously. T _1- MR imaging of weights after injection
Performed at 0, 0.16, 0.33, 0.5, 2 and 24 hours, the detected popliteal contrast enhancement is shown in Table 1 below:

[0057]

[Table 1]

[0058]

Example 7 Imaging of NC 22181 in Rabbits A solution of NC 22181 (Example 4) in saline was applied to the front paws of New Zealand white rabbits at 0.1 ml and 2.0 ml doses (approximately 0.006, 0.015, 0.064 and 0.128 mM). Gd / kg
(Body weight). T _1- MR imaging of the load was performed 24 hours after the injection, and as a result, the following degree of enhancement (%)
was gotten.

[0059]

[Table 2]

It is clear that this solution, even at very low doses, is effective in enhancing lymph nodes after subcutaneous injection.

[Brief description of the drawings]

FIG. 1 shows the results obtained by administering a composition of the present invention to a rabbit and performing MR imaging.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor, Bacon, Edward Earl. (72) Inventor Toner, John El. 19087-8630, Pennsylvania, USA Wayne, Devon Park Drive 466 Nicomd I.N. (72) Inventor Na, George Sea. [Reasons] In this patent application, in the column of "address or whereabouts" of the inventor, "Individual Park Drive, 466 Nicomed, I.N., 19087-8630, Pennsylvania, U.S.A." We have filed an application for “Park Drive 466, Wayne, Pennsylvania 19087-8630”. This is due to a mistake, so we will correct the inventor's “address or whereabouts” column. United States Pennsylvania 19087-8630, Wayne, Devon Park Drive 466 Nicomd I.N. Inside

Claims (7)

[Claims] 1. An indirect, but indirect but containing, physiologically acceptable and diagnostically effective water-soluble polymer having a molecular weight of at least 1 kD together with at least one pharmaceutically acceptable carrier or excipient. A parenterally administrable contrast composition for lymphography. 2. The composition according to claim 1, wherein said polymer material is an iodinated polymer. 3. The formula: Wherein a and b are integers having a value of 1-4; c is zero or an integer having a value of 1-4;
X is zero, 1, 2, 3, or 4 between iodophenyl groups
L is a second hydrophilic linking group that provides a chain of molecular weight of 5,000 or less between the iodophenyl groups). Item 10. The composition according to Item 1. 4. The composition according to claim 3, wherein X is a repeating unit of amide or ether functionality. 5. The method according to claim 1, wherein the repeating unit is of the formula: Wherein a is 1, 2, 3, or 4; b is 1,
2, 3 or 4; c is 0, 1, 2, 3 or 4
R comprises H or 20 or fewer carbon atoms;
R ′ is alkyl, aryl, acyl, aroyl or aralkyl, optionally substituted with a hydroxy group;
X is 0, 1; C _2-20 alkylene, optionally substituted and optionally interrupted by one or more oxygen or sulfur atoms;
A linking group giving a chain of 1, 2 or 3 atoms; and R "
Is a hydroxy, H 2, NHAc, or other hydrophilic group). 6. A subcutaneously administrable diagnostic imaging contrast medium for use in a diagnostic method comprising indirectly but parenterally administering the contrast medium and then producing a contrast enhanced image of at least a portion of the lymphatic system. Use of a diagnostically effective contrast medium which is a physiologically acceptable, water-soluble polymer having a molecular weight of at least 1 kD for the manufacture. 7. Administering a diagnostically effective contrast agent to the human or animal body and producing a contrast enhanced image of at least a portion of the body's lymphatic system, wherein the agent comprises at least 1k
A method of contrast-enhanced imaging of at least a portion of the lymphatic system of a human or animal body, wherein the method is a water-soluble polymeric material having a molecular weight of D and is administered indirectly but parenterally.