JPH07507800A - Transition and rare earth metal ions encapsulated in clay as contrast agents for the gastrointestinal tract - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] M Go Ai Tomo J Boi ≧ Worker P Pay n' J Power Prisoner Transferred it to Sheni-bi ♂ Roni” 2 U Ma is J Ha 1 Ni 11? Seven-two-two This is 1993 Part of No. 11 No. 081070.35P- for U.S. Patent filed May 27 [l There is a continuation application.

older brother Ωn member The present invention provides a contrast medium or It is related to imaging agents. The contrast agent or imaging agent is trivalent gadolinium It is a molecular sieve material that encapsulates two paramagnetic ions. molecules with inclusion substances The sieve is particularly suitable for transfusion and magnetic resonance imaging in the upper gastrointestinal tract. acts well as a contrast agent or image brightening agent.

Sophisticated methods such as MRI (Magnetic Resonance Imaging) and CT (Combined Tomography) The availability of methods has led to the increased use of contrast techniques in therapeutic and diagnostic testing. It's close to. Contrast imaging of the gastrointestinal tract is generally performed well with currently available contrast media. No images are available and only visualizing significant occlusive findings or anatomical abnormalities This is an area of particular interest because of the fact that

Barium sulfate and paramagnetic iron oxide are contrast agents traditionally used for examination of the gastrointestinal tract It is. The latter is generally known due to the paramagnetic properties of Fe2es, which makes it suitable for MHI testing. However, it has many disadvantages.These disadvantages include Blackening (bl, ack bowel), diarrheal side effects, and important analytical findings From the ground, there are effects caused by agglomeration. When paramagnetic iron aggregates, it becomes ferromagnetic. This can significantly change the contrast characteristics. Even if you get an image, the signal is black This makes it difficult to distinguish between non-contrast and contrast-enhanced areas.

The development of contrast agents, particularly for gastrointestinal examinations, has been slow. Historically, Superparamagnetic iron oxide for use in magnetic resonance imaging is the most Common. Some MR examinations of the small intestine have excellent contrast effects. Although achieved, blurred images and “metallic” artifacts in the distal portion of the intestine The incidence of these diseases has increased (Lonnemark et al., 1989).

Another test using superparamagnetic iron oxide tests the pancreatic head and tail of human patients. , the anterior border of the kidney, and near the aorta (near the aorta). However, in some patients In some cases, symptoms such as an attack of diarrhea (,.

No side effects have been observed (Hahn et al., 1990).

Magnetic resonance imaging is particularly useful for testing and diagnosis of tumors or inflammatory abdominal diseases. . 7 Paramagnetic species, typified by gadolinium, serve as contrast agents for these tests. However, the metal itself is toxic and cannot be used by humans.

However, trivalent gadolinium diethylenetriamine-pentaacetic acid (DTPA) The body is less toxic than the uncomplexed salt and has been tested in human patients. ing. Contrast imaging of the gastrointestinal tract has been reported, but a change was observed in contrast imaging of abdominal lesions. was more than 60% F of the magnetic resonance scan. Furthermore, almost 10% of patients Diarrhea and bloating were reported (Claussen et al., 1989).

A solid paramagnetic material in a sulfonated ion exchange resin for use in abdominal imaging. It has been proposed to encapsulate sex complexes. Encapsulation in such acid-stable substances This occurs in the stomach when a contrast agent is administered intravenously to image the gastrointestinal tract. It is estimated that significant metal elution is prevented (Braybrook and Ra11. 1989).

Coating superparamagnetic iron oxide onto a polymer carrier matrix as an oral contrast agent for MRI A full evaluation was conducted. Good images are generally obtained in the small intestine region, excluding the duodenum. However, at some concentrations, artifacts were observed in the stomach after administration of the contrast agent. The effective concentration range appeared to be very narrow due to the occurrence of t al, , 1989).

Contrast imaging that can be used for human contrast examinations, is effective after one administration, and is well tolerated. The need for a drug is clear. In particular, MHI contrast agents that can be applied to gastrointestinal examinations are visualization of anatomical findings, especially for distinguishing between normal and abnormal conditions such as tumors. It seems to be for iV. It is an effective and orally administered paramagnetic contrast agent that is currently in use. Paramagnetic contrast agents do not have the side effects commonly seen with gastrointestinal contrast agents that are currently in use. Iron and gadolinium complexes, which are currently available, will be significantly reduced in government. child These reported compounds have some drawbacks, such as toxicity and the inability to obtain good quality images. There's a problem. Although there are several reports on compositions such as carrier complexes and substrates, this Even with these compositions, parts of the small intestine cannot be sufficiently visualized, and side effects still exist. for example Although trivalent gadolinium is an excellent paramagnetic MRI contrast agent, it is toxic to humans. Its use is limited to the DTl'A complex, and the DTPA complex itself is Possibly toxic.

尤朋Ωcross string The present invention utilizes currently available selectable contrast imaging methods for imaging examinations, particularly for imaging of the gastrointestinal tract. One or more of the aforementioned issues or other issues related to the use of It is something. A non-toxic compound that preferentially binds paramagnetic metal ions within a lattice-like structure. 1., s-t'J-, light molecular sieves and light carriers have almost no toxicity, Excellent contrast properties have been revealed for Kozu-do. Fourth, metal imaging and diarrhea, etc. Superparamagnetism that causes side effects to patients 4!1. Many problems associated with the use of iron oxide is resolved.

In a part of the invention, paramagnetic metals, ions encapsulated in zeolites are t- is used as a contrast agent in humans. Paramagnetism and ions are It is preferentially bound to cations such as In order to maintain a well-maintained state, it is possible to obtain a clear contrast image with an effect of (f). .

Similarly, paramagnetic metal ions encapsulated in clay are useful as contrast agents. Especially suitable The common types of clay include smecta, i], and viscosity, examples of which include hectoclay. llectorite and montmorillonite (IIlontmOr There is clay (illonite). Smectite clay has two isomorphic substitutions. It has an octahedral or three octahedral layer structure, and it has a It is characterized by forming a layer of negative charge with a layer spacing of 10-15 angstroms. It is. Montmorillonite is a type of smectite and usually has a tetrahedral arrangement. Due to the exchange, they are mainly filled in an octahedral shape.

The presence of octahedral iron ions is common. Another smectite is heku It is similar to montmorillonite in that the charge layer is derived from octahedral substitution. It has the same three octahedral layer structure. Hectorite generally contains lithium and fluorine. (Wilson, 1987).

Made of paramagnetic metal ions encapsulated in zeolite molecular sieves or smectite clays The agent can be administered orally and there is little possibility of harmful metal ion leakage. It is not toxic. The preferred paramagnetic species are trivalent gadolinium and divalent manganese, which are or encapsulated in faujasite group zeolites such as NaX. Forms CaGdA or NaGdX, which is the most desirable form.

In general, the present invention relates to a paramagnetic material encapsulated in a zeolite or smectite clay. It is related to a contrast imaging method in which sexual ions are administered. The gravity method has never been used by humans. Most commonly used, but can also be used on animals by veterinarians, for example, to diagnose abnormalities of the gastrointestinal tract. It seems to be Noh. The amount of paramagnetic ions encapsulated within the zeolite or clay can be determined by The amount is sufficient to be effective as an agent or image brightening agent. Main departure A particularly useful feature of brightness is that the area contrasted by the encapsulated paramagnetic ions is bright. This is a good point. This is caused by superparamagnetic iron oxide that depicts black or black-gray areas. This is much more desirable than the resulting image. The brightly contrasted area is the drawing output dark contrast to visualize the anatomical findings in the area and identify the lesion. desirable for detecting

Paramagnetic ions encapsulated in zeolites and clays are particularly useful for contrast imaging in humans. It is for fJ'', and superparamagnetic 11. It has many advantages over iron oxide. superparamagnetic iron is , have a tendency to aggregate in the gastrointestinal tract, causing a transformation from paramagnetic to ferromagnetic properties. vinegar. Furthermore, when superparamagnetic iron oxide is administered in the amount required for 1 minute contrast imaging, it is It causes unpleasant side effects such as diarrhea and bloating. These side effects are caused by zeolite. No encapsulated divalent was observed when trinium was used. The present invention Some paramagnetic golds considered most useful for MRI examinations such as trivalent gadolinium It also solves the problems associated with the toxicity of the genus. The toxicity of trivalent gadolinium is Gadolinium is combined with dimethyltetraminopentaacetic acid (DTPA) to form gadolinium. It is reduced by forming complexes that are less toxic than salts. However, Gadri In some tests using Nium DTPA, side effects such as diarrhea and bloating can be detected. Similarly, problems similar to those when using superparamagnetic iron oxide are presented. Furthermore, the toxicity of the complex is not fully revealed. On the other hand, gadolinium encapsulated in zeolite Regarding this, no toxicity has been observed. This is a metal in the zeolite molecular sieve. This is probably because the ions are relatively tightly bound.

The present invention has been described using trivalent gadolinium and divalent manganese, but zeolite Other ionic species that can be ion-exchanged by the ion can also be used. For example, tetravalent banana Dium, trivalent vanadium, divalent copper, divalent nickel, trivalent chromium, divalent cobalt, There are divalent iron, trivalent iron, trivalent cobalt, etc. This contains chlorides, acetates, nitrates etc. Any of the numerous salts of these species can be used to exchange counterions present in the zeolite. Available for Examples of these include other ionic species capable of ion exchange, e.g. It is not intended to limit the inclusion of elements belonging to the lanthanide elements or rare earth elements. do not have.

There are many zeolites that can encapsulate paramagnetic ions and are therefore suitable for the practice of this invention. There are several. For example, synthetic zeolite type A, type X, type Y or type 5 zeolite are particularly useful (Breck, 1984; Rankel and Val Yocsik, 1983) o X-type and Y-type zeolites are A type zeolite is a lint type zeolite (LTA). ). Like mordenite class zeolites, chemical composition, cavity diameter or Many types of molecular sieves are available that differ in their natural incidence.

The shapes of these materials are composed of secondary building blocks that form the typical three-dimensional framework of molecules. It derives to some extent from the combination of positions. These shapes are based on ion exchange capacity, size Selectivity, which limits the passage of molecules, will have an effect on the absorption properties.

Many molecular sieves that are not considered zeolites also contain metal ions that are useful for imaging. Available for free. Zeolites are special molecules with an aluminosilicate framework structure. It's a child's sieve. The building blocks of zeolites are held together by a common oxygen atom. It is a tetrahedron of Si" and AI" that meet together, and extends as an infinite three-dimensional network. ing. When an isomorphic atom is substituted for aluminum or silicon (e.g. Galilee um, germanium or phosphorus), synthetic molecular sieves are made. Also atoms within the framework , Mn2" or Gd3". Especially ions Molecular sieves with exchange properties can be utilized similar to zeolites.

The ion exchange properties of zeolites allow them to absorb certain ions, especially a range of transition metal ions. This is particularly important in terms of preferential binding. actually encapsulated in zeolite The amount of metal ions used depends on the presence of other positively charged ions and the particular zeolite utilized. varies depending on the characteristics of the type. Therefore, for example, calcium zeolite type A is When mixed with dolinium salt and brought to equilibrium after a certain period of time, the final ion exchange The product contains both positively charged gadolinium ions and calcium ions. Become. However, if both transition metal ions and ions of Group 1 or 2 elements are present, These zeolites preferentially exchange ions with transition metal ions. However, the concentration of transition metal ions is higher than that of ions of elements belonging to Group I or Group 2. It becomes more expensive. In any proportion, there is no superiority with paramagnetic ions such as Gd'' or Mn''2. Preliminary binding is used when paramagnetic ions encapsulated in zeolite are used for contrast examinations. is sufficient to provide excellent MHI imaging properties.

In another embodiment of the invention, the complexed paramagnetic ions are zeolite or Enclosed in a clay matrix. 7. The intrazeolite or intraclay complex contains at least It can be prepared by two different methods. The two methods are (1) surrounding the complex; or (2) diffusing the ligand into the substrate and then synthesizing the substrate. This method forms a complex between a ligand and a metal ion within the molecule. Typical complex-forming substances includes 8-hydroxyquinoline, dipicolinic acid, phthalic acid, etc. Nanthroline, bipyridine, anthranilic acid, picolinic acid, salicylic acid, salicylic acid Ruamide, ethylenediaminediacetic acid or bis(salicylaldehyde)ethylene Many other ligands such as diamines are also available. These complex-forming substances This can vary depending on the particular paramagnetic ion chosen to form. Coordination One consideration in child selection is the number of occupied sites on the metal ion. General 4 to 6 bonds bind the metal ion more firmly. Take advantage of fewer joins In some cases, it may be desirable to use For example, in a bond between two metals, the surrounding metal Easy access to water. Image signal strength generally increases as surrounding water becomes more accessible. . This provides improved images even with small amounts of paramagnetic ions.

A second consideration in ligand selection is binding affinity. , like 4 to 6 pieces , the higher the number of ligands, the more likely it is to prevent the loss of potentially toxic free metal ions. This seems to be desirable because a stronger bonding force can be obtained. A polydentate ligand is generally forms more stable complexes and is desirable. Ligands do not need to have a charge , or may be charged if the complex is easily accessible to positive charges. Furthermore , the ligand may have paramagnetic functional groups such as nitrogen oxides. Combines with metal ions The additional ligand radicals would further enhance the contrast intensity.

Yet another embodiment of the invention provides ions as free metal ions in molecular sieves, for example. Paramagnetic metal ions exchanged and encapsulated and also encapsulated as metal complex ions It is a paramagnetic metal ion. Such a composition has a relatively large number of paramagnetic ions. The advantage of exchanged zeolites is that paramagnetic ions within the larger cavities of the zeolite It combines the advantages of retaining water, making it easier to access the surrounding water, It is also possible to strengthen the image strength. Complex formation, especially chelation, can lead to large The active species in the pores are localized and easily accessible to water, but the ions in the zeolite matrix are loss of energy is reduced. After being administered for diagnostic purposes, the zeolite is partially If it were to be resolved, the above would have to be considered.

Paramagnetic ions encapsulated in zeolites or clays are particularly useful in the pharmacology of these materials. A pharmaceutically acceptable formulation can be administered enterally, e.g. to animals or humans, using a nasogastric tube. This makes it particularly useful for MRI examinations of the gastrointestinal tract. Involved in testing or treatment of humans Oral administration is desirable for most applications.

To detect paramagnetic ions encapsulated in molecular sieves or clay after administration, magnetic Most preferably performed by resonance imaging, BaO and gastrogelaphy Conventional X-ray imaging and computed tomography CT can also be used. Z (atomic M) strong metals like gadolinium are also examples. It can be detected, for example, by monochromatic X-rays such as the Ni-Edge angiography. Furthermore, within the aforementioned matrix Some encapsulated metal complexes can be detected by fluorescence.

In the most preferred method of practicing the invention, the invention is utilized for imaging the gastrointestinal tract. Ru. Pharmaceutically acceptable formulations containing trivalent gadolinium encapsulated in a matrix are It is preferably orally administered to humans or animals, and detected by magnetic resonance imaging. trivalent moth Dolinium is calcium ^ type zeolite, sodium X type zeolite, hecto Seal in light or other suitable molecular sieves such as montmorillonite or clay. You can enter. In a preferred embodiment, encapsulated in zeolite or clay. The trivalent gadolinium is prepared in a carrier formulation prior to administration.

The metal ion complex encapsulated in the zeolite or clay of the present invention is pharmaceutically acceptable. Can be combined with possible prescription drugs, dispersants, and excipients. For oral preparations available as powders, granules, capsules, coated tablets, syrup formulations, and aqueous suspensions. can. Prescription drugs used can be solid or liquid and include calcium phosphate, carbonate, etc. Calcium, dextrose, sucrose, dextrin, sucrose ester, starch sorbitol, mannitol, crystalline cellulose, talc, kaolin, synthetic Aluminum Iate, Carboxymethylcellulose, Methylcellulose, Fucour Acid-resistant cellulose, alginate, polyvinylpyrrolidone, polyvinyl alcohol gum arabic, gum tragacanth, gelatin, bentonite, powdered agar, silane - Contains, but is not limited to, solids such as li, Tou-Een 80, carrageenan, and caramel. Not determined. Modified zeolite materials with residual charges or modifying groups are also available. This is thought to be adsorbed on various carrier substrates such as clay. be exposed.

Examples of suitable liquids for suspension include water, isotonic saline, diethanol, propylene chloride, Ren glycol, polyethytonone glycol, glycerol, Hartmann's solution, There are gel solutions, etc. The preferred liquid for suspension is EZpaque supernatant, which is Easily obtained from EZpaque after removal of Ba5O by heart separation or filtration. It will be done.

The most desirable delivery method is oral administration, as it is easier for patients to administer, but intravascular administration is , enterally, vaginally, and anally are also possible; It can also be introduced directly into the gastrointestinal tract from the desired site. Like sweeteners and citrus flavors Flavoring agents, including taste-masking substances, can also be added to oral preparations. coloring agents, preservatives, Other additives including excipients or antifoaming agents may also be included in the formulation. Parenteral benefits Examples of this include a retrograde internal examination and an examination to reveal vaginal secretions. blood vessels Internal administration is also expected to be effective. Particles such as colloidal iron oxide are associated with side effects. Stable molecular sieve particles are similarly problematic as carriers because they are injected into the bloodstream without It is suggested that it does not cause

The present invention can also be used in combination with body surface magnetic resonance imaging. for example , prosthetic limbs must be made specifically for lower leg, upper arm, hand or foot amputees. Must not be too expensive. With current methods, the photo only shows the skin surface, and the Etsukunu line is the bone It is time-consuming and difficult to display only high-density substances such as . magnetic resonance Imaging methods can display both bones and skin, so the remaining parts of the body This simplifies the design of prosthetics that must be made. Encapsulated in zeolite or clay Trivalent gadolinium appears to be ideal for this purpose. This material is desirable It is powdered enough to be easily applied to the skin surface, either as an aerosol or as an aerosol. aero Sols can be either dry powders or suspended in a suitable liquid such as water or alcohol! , hang A cloudy liquid may be used. The skin first contains benzointin, which helps the powder adhere to the surface. It is desirable to apply a chemical such as Ki. Another anticipated application is foot imaging. , useful in customizing foot orthoses for abnormal or damaged feet. Ru.

Imaging of surfaces as well as prosthetic surfaces such as metal surfaces can be obtained. In some cases, Especially when high resolution is required, surface irregularities can cause arcs due to uneven application. It is important that the coating be applied evenly so that it reflects the surface being inspected rather than artifacts. Sae and loyal.

Zeolites with appropriately sized crystals can be used as intravascularly administered magnetic resonance imaging contrast agents. It can also be used. Orally administered formulations may be preferred by patients; Advantages such as being able to visualize the velocity and contraction site can be obtained by entering the

The ionic species encapsulated in the zeolite or clay of the present invention is preferably EZ di supersant (available from E-ZM, or the trademark name of EZpaque) suspension in BaSO4 (used as supernatant of suspensions of BaSO4 sold in pharmacies) They are typically formulated as liquids or dispersions at low weight-to-volume ratios. Sutra For oral administration, the desired concentration of this formulation is about 1%. Higher concentration of zeolite Although it is possible to prepare a suspension of the above composition, if the purpose is 1aRI contrast When the weight ratio exceeds 1%, the contrast intensity decreases markedly. EZpaque supernatant A 1% suspension in seems to be indefinitely stable.

The distinct advantage of calcium gadolinium encapsulated in type A zeolite is that The concentration used for this is relatively low. For example, a 1% concentration of oral administration Cium gadolinium type A zeolite provides excellent images in 1llR test However, higher weight percent concentrations may be used depending on the formulation form. can. On the other hand, when barium sulfate is used in the same dispersion medium, 4 Concentrations of 0-50% by weight are required and precipitation is often a problem.

The most desirable paramagnetic ion for this type of gastrointestinal examination is trivalent gadolinium; Other metal ions listed in Table L can also be used. Bivalent manga encapsulated in zeolite Excellent results have also been obtained using the same method.

Gadolinium (I[+) encapsulated in clay is different from gadolinium encapsulated in zeolite. The advantage over the clay matrix is that the T1-weighted relaxation time (C-anced T+ relaxation time) is promoted. encapsulated paramagnetic Because of this effect on ions, a better MH can be obtained by utilizing less material. I images can be obtained. Thus, for example, hectorite and montmorillonite Soil provides an inexpensive substrate for paramagnetic ions and paramagnetic ion complexes, and also for metals and requires only small amounts of metal complexes, increasing efficiency and reducing costs. Can be done.

Those skilled in the art will appreciate that in zeolites or clays, complexes used for imaging Not only converted or free paramagnetic ions, but also exchanged with ′;:5 magnetic ions. You will understand that there is also a second ion. The second -r neon type is Depends on the clay or zeolite compound used to make it. For example, calciu Muzeolite, calcium type A zeolite, sodium zeolite or Group 1 zeolite and other salts formed from Group 2 elements. Alternatively, paramagnetic ions Before or after encapsulation, the parent zeolite is treated with cations, alkalis or alkalis. Can also be exchanged by potassium earth metal ions, transition or rare earth metal ions . Molecular sieves encapsulating paramagnetic ions can be used with hydroxyl ions, depending on the preparation method. It should be further understood that other ligands such as ions, chloride ions or water can also be included. It is.

All of these species can affect the properties of the encapsulated ions.

All or many of these may be related to the pharmacology of paramagnetic ions encapsulated in zeolites. may change or attenuate its effects.

Shamen Ω dish village view talk Figure 1 shows a 1% suspension of CaGdA 12 and 4 hours before MRI scanning. MHI scan of rabbit gastrointestinal tract obtained after two administrations of fluid via nasogastric tube It is.

Panel IA shows the effect of the presence of CaGdA in the stomach. panel Figure IB shows an image of the jejunal region of the small intestine with CaGdA present.

Figure 2 shows the results of a dog study obtained after administration of a 1% suspension of CaGdA via nasogastric tube. MRI scan of the gastrointestinal tract. Panels A and B show scans obtained 1 hour after administration. It's camp. Springs AC and D are scans obtained 3 hours after administration.

1's tlP The invention particularly relates to pharmaceutical compositions containing paramagnetic ions encapsulated in zeolites and Related to the use of pharmaceutical compositions as contrast agents or image brightening agents It is. Suitable paramagnetic ions are placed as “free” ions within the zeolite framework. A wide range of zeolites can be synthesized by It can be enclosed inside. Free ion refers to a charged species lacking a ligand. taste, but does not necessarily exclude interactions between charges with other species. this This type of interaction is due to the form of counterion interaction within the encapsulating zeolite framework. or as a compound forming the zeolite framework, e.g. aluminate It can occur as a substitution of the metal moiety of the salt.

Methods for preparing metal ions encapsulated in zeolites are known in the art and include: Generally based on the ion exchange properties of zeolites. Therefore, like gadolinium Paramagnetic ions are present in most zeolites belonging to the faujasite group, or in many types of zeolites, including molecular sieves with or ion exchange properties. It can be exchanged. Furthermore, aluminum silicate materials such as clay also contain paramagnetic ions. It is suitable for encapsulating liquid (typically water) nuclear spicules in contact with the clay. It has the further advantage of changing the relaxation properties of the ion. This kind of clay itself Although it has been shown to be useful as a contrast agent for magnetic resonance imaging, the images are not clear. It's rather dark (Bryant et al, 1990) In particular, the inventors found that when combined with paramagnetic complexes such as gadolinium ions, viscous It is found that the earth matrix enhances the image brightening properties of paramagnetic metals.

In addition to “free” metal ions encapsulated in zeolites, gold encapsulated in zeolites It has been discovered that useful contrast agents can be obtained from genus ion chelate complexes. Metal ions The chelate is formed in situ, i.e. after the ions have been encapsulated in the zeolite. or by synthesizing zeolite around the metal ion chelate. Examples are provided to demonstrate that metal ion complexes can be encapsulated using

Sodium type A and type and easily formed around gadolinium(III) complexes of phthalic acid. other Suitable ligands include salicylamide, salicylic acid, anthranilic acid, Lysine, tilpyridine, phenanthroline, ethylenediamine, bis(salicyl) aldehydes) ethylenediamine, ethylenediaminediacetic acid or equivalents.

As a general rule, chelated paramagnetic species are larger than free ions and therefore must be located in a larger space in the zeolite structure. As a result, paramagnetic Sexual ions have easier access to water than ions located in smaller spaces. paramagnetic a If the on content is similar, chelated ions in zeolite are more , the intensity is higher compared to the corresponding free ion.

Intensity measured using chelated paramagnetic ions encapsulated in zeolite Therefore, due to complex formation, the active metal within the large cavity becomes localized and becomes more accessible to water. It has been made clear that However, this chelated metal ion The use of both ions and ion-exchanged metal ions is not denied.

The number of paramagnetic complexes in zeolites is small (both two), as revealed here. It can be prepared by different methods. In other words, zeolite is synthesized around the complex. or by diffusing the ligand into the zeolite to form a complex. It can be prepared by In cases where the zeolite may be partially digested, It is also expected to act as a second line of defense against toxicity.

Although not all molecular sieves exhibit ion exchange properties, aluminum silicate Some species, such as silicoaluminum phosphate, metalloaluminum phosphate, etc., have this property. have. The complexed paramagnetic ions, as revealed here, , is expected to be useful for enveloping paramagnetic species. Therefore, most paramagnetic substances , or the range of zeolite-type compounds that can encapsulate metal ions without any loss. Expanded.

In certain applications, such as blood pool agents, In some cases, stability is not an important issue. In such cases, water coordination Chelates with a minimum number of ligands are desirable to maximize binding sites for Probably. In general, the more accessible the paramagnetic ions are to the surrounding water, the greater the measured signal strength. to ensure retention of toxic metal ions when stability is important. Multidentate ligands with multiple binding sites appear to be desirable.

The following specific examples illustrate preferred embodiments of the present invention. These specifics The examples are for the purpose of illustrating the invention and are not intended to limit it.

However Three gadolinium in zeolite=calcium zeolite (calcium ^ ) and 1 g of GdC and 202 g of 6B were mixed in about 100 ml of deionized water. , and stirred at 30°C for 18 hours. The obtained zeolite suspension was filtered with suction and diluted with nitric acid. It was thoroughly washed with deionized water until the silver test was negative for chloride ions. obtained CaGd8 was tested using a colorimetric indicator, xylenol orange. However, free Gd'' showed negative results.The zeolite was heated at 50°C in a vacuum oven. Dry overnight. The obtained sample contained 3.24% by weight of trivalent gadolinium. .

The weight of compositions obtained by similar methods using NaA, NaX, or NaY The quantitative composition is shown in Table 1. MnCLz used in place of GdC15 in NaX was exchanged to form MnNaX.

Table 1 The various zeolites shown in Table 1 are suspended in EZ dispersant. As shown in Table 2, the image intensity data It was recorded well.

Table 2 3B2.19], 2.42 0. :L259.49 8.45 0.01 228.97 B, 55 0.001 187.65 7.67 0.0001GmaX 454.08 19.91 112713.13’, 36.84 0.1349.54 13.93 0 ．． 01 219.17 10.84 0.00164.49 10.77 0.0001 GdNaA 365.06 12.51 11522.71 29.67 0. 1 391.05 8.90 0.01 237.03 9.37 0.001 193.79 B39 0.0001 GdCaA 40B, 25 47.061772.24 27.09 0. :L 2B0.11 10.38 0.01 230.0+1; 7.69 0.001200.32 8,56 0.000 1MnNaX 34.57 6.50 11312.4B 29.02 0.1 -453.10 16.17 0.01257.3+1; G, 90 0.00 1185.37 B, 66 0.00011 Average value All of the samples of this zeolite were mixed with EZpaque supernatant at the weight percentages indicated in the table. suspended in.

偲L Three gadolinium bis-8-hydroxyquine in zeolite Dolinium ■) 13.5g of aluminum isopropoxide and sodium hydroxide Mix 4.8g and heat at 90°C for 30 minutes, then add 18g of water with continued stirring. m1 was added. 6 g of silica, 4.8 g of sodium hydroxide in a Teflon beaker, A silicate solution was prepared by mixing 18 ml of water. After cooling the mixture to room temperature, The silicate solution and aluminum salt solution were mixed and 50 mL of water was added. Bis(8- Hydroxyquinoline) chlorogadolinium (nu) 0.18 g over 3 hours Stir it into the gel. The mixture is then poured into a sealed polypropylene bottle. Heated at 90°C for 16 hours. After cooling to room temperature, collect the crystals and wash with sufficient amount of water. did. Next, zeolite crystals were extracted with toluene for 24 hours in a Soxhlet extractor. Extracted and surface seeds removed. The crystals were filtered off with suction and dried at 100°C. sample contained 0.5-fold Fn96 gadolinium.

Table 3 shows various sets of chelated trivalent gadolinium encapsulated in zeolites. Weight percentage of metal ions in the composition, contrast intensity, weight percent of the solution used for measurement is shown. Values are water, air, dispersant, EZpaqu It is compared with e.

In love Zeolai hhJt entered Tasan Gadolinium Kosono J Rikigojo prayer X-jikubo Oji”” Lina SuI・Riu I, zeolite was ion-exchanged with GdCl3, and then thoroughly washed with water. , 3500C overnight and reacted with 8-hydroxyquinoline. In Gd"" 2.0 g of exchanged NaX was added to 1.8-hydroxyquinoline. including Og], 00m Slurry was carried out in ethanol for 24 hours. Filter the zeolite and ethanol and extracted with toluene to remove surface complexes. The sample weighs 2.77 It contained 96 Gd.

3 Gadolinium 4゛MF ■-Li-Sieve 5i (b 2g ((LO33 mol ) was prepared by dissolving it in 3.5 ml of 48% HF (0.1 mol). . An exothermic effect was observed. After cooling to room temperature, 0.4 g (IXIO-3 mol) of Gd Cl3.6*20 was added. The pH of the mixture was approximately 0. Next, 3ml of water Add 0.19 g (4°75 xio-'mol) of NaO + l dissolved in , caused an exothermic effect. After cooling to room temperature, 1.46 g (5,48 x 10-” mol) of TPABr was added dropwise followed by 14.3 ml of 29% NH40H ( 0.108 mol) was added. The pH of the mixture rose to 8''. Next, 25i1 Add water (1,55 mol), maintain p118-8.5 and incubate at room temperature for 2-4 hours. Ta. Autoclave (PARR) at 180°C for 24 hours to remove zeolite. Completed the synthesis of

Table 4 shows the gadolinium (I[I) exchanged zeolite with 8-hydroxyquino Various weight percentages of gadolinium in type X zeolite after treatment with phosphorus The strength against the elements is shown.

table[ l Average value 2 Each sample was suspended in EZpaque at the weight percent indicated in the table.

GdS+G encapsulated in type X zeolite treated with 38-hydroxyquinoline The content of d''+ is 3% by weight.

example[ I'm in love with a rabbit. EZpaque obtained by centrifuging CaGdA Ig with Ba5O The supernatant was suspended in 99 ml of a dispersion medium prepared. 12 hours and 4 hours of MRI Approximately 200 to 300 cc was injected into the rabbit using a pediatric nasogastric (NG) tube. was introduced into Gi's stomach. Perform regular MRI scans using a conventional T+ weighted sequence. It was. Figure 1 is an MRI scan 4 hours after the last dose. Brightness of the panel CaGdA was detected in the helmet, as indicated by the bright area. 12 after administration After some time, CaGdA outside the intestine passes through the small intestine, as shown in panel B1. It was concentrated in the 1-bidactyl membrane.

example Silicalite is produced by hydrothermal crystallization from a reaction mixture containing TPABr as template. A silicalite containing gadolinium and gadolinium was prepared. In this reaction, the crystal frame Part of the set is replaced by gadolinium τ, l−1 in the form of gadolinium . This metal is therefore an ion-exchanged cation encapsulated in a '1' sulfate. Not as a part of the basic structure, but as a part of the basic structure. j) The law has a modified framework such as zeolide, hectorite and montmori [Jsu It is expected that this method can be applied to the synthesis of viscosity-1 of (f).

-Unidol knee spring J2-2)Q The starting material v1 for the synthesis of contains 5102.48% l! F, Na01L NlI40 11, GdC! a　　61120, t, PaBr (rl-love day piluan monium bromide). The composition of the reaction mixture is i), J I-'' It was a bend.

5iOz: liF: NaOH: tPaBr: NILOH: l! 20]: 3: 0.14: 0.16 3.28: 47 Si/Gd molar ratio is +03 It was 15. The gel was prepared according to Example 4 and crystallized at 180'C for 24 hours. 9. Samples were characterized by FTIR, X-ray, and chemical analysis. . , +120 and benzene absorption were measured.

example[ The preparation method of paramagnetic ion or paramagnetic ion complex encapsulated in Viscous-L is as follows. The method is similar to the method for preparing zeolite complexes. Reacting the Na type of clay with the complex solution or by reacting the coordination P with clay exchanged with metal ions. Modification of secondary hectorite and montmorillonite clays with paramagnetic metal complexes did.

Encapsulated phenanthroline, bipyridine, 8-hydroxyquinoline, anthra Nilic acid, picric acid, salicylic acid, phthalic acid, salicylamide, ethylenedia Gd+3 complex of min-yu acetic acid, bis(salicylaldehyde)ethylenediamine Prepared. All compounds were characterized by XRD, IR1 UV if optical spectroscopy. The signs were revealed.

j Shimo Tomoe 3Ω voice 2 and 2 visible costumes ＼λhi no Ima Heta 1 - Light (1 gram) 1 Suspend in a liter of deionized water, stir for 24 hours, then gadolinium trichloride. (2 grams) was added and stirred for an additional 24 hours. Filter the clay 21 and centrifuge It was washed with water using a method and dried at 110°C. Grind clay into powder and heat at 400° The sample calcined for 3 hours at C.1 contained 563 gw Gd. This modified Relaxation of an aqueous suspension of clay in a field of 40M1lz vi-t, y) was determined to be 6.41 mt 'see'.

The first one - Puihi 1 year old 2 years old, 1 year old 1 year old, 1 year old, 1 year old, 1 month old, 2 years old, 4 years old, 2 years old, 4 years old Hectorite (1 gram), which had been exchanged by 7 l-:, -(1:I, v/v) and stirred for 7.4 hours. From C, 2,2゛- Bipyridine (0.5 grams) was dissolved in 20 mL of amethane, stirred for 12 hours, and then . The clay was filtered, washed with water and acetonin using the centrifugation method, and dried at 110°C. It was dry. This sample contained 0.703% by weight Gd. This modified viscous The relaxivity of the second aqueous suspension is in the 40 MHz field. Hectorite (10g Suspend 2 ml of rum) in deionized water, stir for 24 hours, and then add gadolinium. Lichloride (2 grams) was added and stirred for 24 hours. Filter and centrifuge the clay It was washed with water using a method and dried at 110'C. Grind the clay into powder Then, perform Soxhlet extraction with water for 4 hours. This sample weighs 2.62 Gd It contained. The relaxivity of the aqueous suspension of this modified clay is It was measured as 7.6mM for 1sec, -' at the cold temperature.

Pectolite (0,5 g) exchanged by gadolinium, 150 m Gd (phenanthroline), suspended in L of deionized water and stirred for 12 hours. s” (0.1 g) was added and stirred for another 24 hours. The clay was filtered and centrifuged. Using the separation method, it was washed with water and dried at 110''C. This M was 1.35 wt. The relaxivity of an aqueous suspension of this modified clay containing Gd of q6 is: It was measured to be 2.74 nM-'see-' in a 40 MHz field.

Suspend in hectolyton water exchanged with gadolinium and add 15mM acetate. Add 1.10-phenan l-o1/(0.5 g) dissolved in t The mixture was stirred for 12 hours. Filter the clay and wash it with water and aliquots using the centrifugation method. It was washed and dried at 110°C. This sample contained 1.47% by weight Gd.

This modified t+! i The relaxivity of an aqueous suspension of soil is at a field of 40 MHz. It was measured as 6.578mM-'sec'.

Gadolinium exchanged by hecto-reih (: 0.5 g), iio 　’　Add to the melted phenan i. lorin (1 gram) with stirring. , 411! Stir for a while.

The modified clay was then extracted with acetone and water in a Soxhlet extractor. , - sample contained 68 tonicity 06 Gd. Aqueous suspension of this modified clay The gentle hitting velocity is 3.65mM -'sec-' in a 40MHz field. Measured.

1st Hectorite (0.5g), exchanged by Kadrigotsu 1, 175 °c″C melted bis(3-methoxysalicylaldehyl-)nee f ~ renizi ・Add amine (1 liter) with stirring and stir for 4 hours. . Next, the modified clay was first mixed with methylene chloride in the extractor. ``12 hours, then extracted with water for 12 hours. This sample is 1238 times ffi96 It contained Gd. The relaxation degree of this modified clay water t [suspension is 40MII 7.8mM in the Z field was measured.

150 mL of hectolytic acid (1 gram) exchanged with linium under force Suspended in deionized water/meth/-/l/(1:l, v/v), 120! Intermittent stirring Shite is ugly. , Bis(3-methoxydizate) dissolved in 30mL 9/-/L Add υ11 of ethylenediamine (0.25 grams 1,) and further Stirred for 12 hours. Filter the viscosity and use centrifugal separation to mix it with water, methanol, and alcohol. Washed and dried at 110°C. This sample contained 2.04 wt% Gd. .

The relaxation of the aqueous suspension of this modified clay was 5.　 It was measured as 08mM-'sec-1.

Hectorite (0.5 g) exchanged with gadolinium was added to 200 m of deionized water, stirred for 12 hours, then suspended in 100 mL of water/methanol. Add phthalic acid (1.25 grams) dissolved in (l:1, v/v) and add phthalic acid (1.25 grams) dissolved in Stirred for 2 hours. The clay was filtered and washed with water and methanol using the centrifugation method. , 110'C. This sample contained 6d of 1,48 tension 96 . The relaxivity of this modified viscosity-1 aqueous suspension is 1 in a 40 MHz field. 4. It was measured as 19mM-'sec-'.

150 m of hectorite (0.5 g) exchanged with gadolinium L of deionized water and stirred for 12 hours, then diluted with 30mM of di-ionized water. Picolinic acid (0.23 grams) was added and stirred for an additional 12 hours. filter the clay, It was washed with water and propatool using centrifugation and dried at 110'C. this The sample contained 0.165% by weight Gd. Aqueous suspension of this modified clay The slow 111 degrees is 7 in the 40MHz field.

It was measured as 97mM-lsee-'.

Hectolyl (0.5 g) exchanged by gadolinium was heated at 80 °C. 8-hydroxyquinoline (1 gram) melted at 100 ml and stirred for 1 hour. Next Next, the modified clay was subjected to Soxhlet extraction with toluene and water for 4 hours. this test The material contained 348% by weight. A 1'1 u suspension of water of this modified clay The sum degree is 5.5 in the 40 MHz field. Measured as 09mM -1sec-' It was done.

``Sal'' - The work of the craftsmanship, but the charcoal ``4'', the charcoal, ``YuweiX physical strength, and the on-the-spot formation~゛　 Hectoly 1- (1 gram) was suspended in 200 mL of deionized water, then 30 0,22 grams of ethylenediaminediacetic acid and gadolinium dissolved in mM water Mixed with 0.38 grams of mutrichloride and stirred for 12 hours. modified clay was washed with water using centrifugation and dried at 70°C. The sample was 2.15% G The relaxivity of this modified viscosity-L water 11-suspension containing d is 40 Mliz. F, yield is 15. It was 4mM 'see-'.

Hectorite (1 gram) was melted with IL deionized water at 75°C for 2.5 hours. 2 - Suspended in BipiIlsin (1 gram) and stirred for 4 hours. Next, the modified clay was subjected to Soxhlet extraction with acetone and water for 4 hours. The sample is 1. 425% by weight It contained Gd. The relaxivity of an aqueous suspension of this modified clay is 40 M) I 14 in the field of z. It was 83ml/g-'sec-1.

Gadolinium I set on montmorillonite replaced by Hl gadolinium Suspended montmorillonite (1 gram) in 80mM methanol and stirred for 4 hours. did. Next, 2.2°-bipyridine (0.2 ] grams) and gadolinium trichloride (0,438 grams) were added for another 12 hours. Stir 11 times. The clay was filtered and washed with water and acetone using the centrifugation method. Dry at 10°C. The modified clay was soaked in acetone and water for 4 hours. - Extracted. The sample was 0. It contained 376% by weight of Gd. This modified viscous The relaxivity of an aqueous suspension of soil is 135mM in a field of 4CJlIHz -'s It was ec-'.

The relaxivity values measured by T, relaxation time are the same for hectorite and montmorillonite. Gd(III) encapsulated in clay was measured. Tl! Japanese opening hours Gd measured as a function of content. Comparison with relaxation time of Gd encapsulated in zeolite Then, the T1 relaxation time of - encapsulated in clay is long, and therefore the image of comparable brightness is In order to obtain statues, it becomes possible to utilize the substances encapsulated in the clay of a small mouse.

Gd(III) or G encapsulated in hectorite or montmorillonite clay The aqueous suspension of the d(I[I) complex was stable for at least several hours.

Ka L 1 dog in town °゛ki Example 2 except that approximately 500 cc of a 1% suspension of aGdA was administered via nasogastric tube. Canine gastroenterography was performed according to the described experimental protocol. Figure 2Al , MRI scan obtained 1 hour after administration. Figure 2B is 3 hours after administration. This is an MHI scan obtained in .

ヱNext year femaleri This anticipated example outlines a method that the applicant considered useful for nozzle contrast imaging.

There is no risk of forgery. The patient has already been diagnosed with a blowhole. Delocalization of infection by injection of contrast fluid In general, there should be no signs of infection, as this can cause infection. appropriate In certain cases, 1% GaN suspended in a suitable vehicle such as EZpaque supernatant Inject the aX suspension into the nozzle. Inject 5-15cc depending on the size of the nozzle hole. . Next, contrast imaging was performed using standard MHI techniques to visualize the extent and location of the canal. conduct.

Eshiretsu [ This prospective example outlines a method that the applicant believes is useful for imaging the gastrointestinal tract in pediatric patients. It is something to do.

/) I MRI' in 1 patient. j／ Pediatric patients generally cannot tolerate the hyperosmotic iodine-containing contrast agents currently in use. Not possible. The following methods may be used in such patients. EZpaq to patient A 1% GaNaX solution suspended in ue supernatant or other suitable excipients was added to the pediatric oral cavity. Administer 100-150 cc via nasogastric tube. The administered suspension is hyperosmotic. It should not be. Images are obtained immediately after administration using standard MRI imaging techniques.

Expected Tagawa This prospective example outlines a method that the applicant believes would be useful for imaging surfaces on which prosthetics are used. It is something to do.

It was four. MRI of It is medically necessary to provide a suitable attachment surface for the limb to which the prosthesis will be attached. For this purpose, the attachment surface for the prosthesis is created using surgical techniques. Next, paint the surface Cover with a substance such as benzoin that promotes adhesion of the powder to be coated. As described in example 1 Gadolinium encapsulated in zeolite prepared by It can also be easily dispersed as an aerosol. Gas encapsulated in zeolite Gadolinium was found in the cleaning solution when tested using xylenol orange. Rinse thoroughly in water until determined to be clean before applying to the skin surface. . Applications can be made using aerosols, either as a dry powder or as a suspension in alcohol, water, etc. This is done by After the surface has been covered with a fine powder layer, it is examined using standard magnetic resonance imaging techniques. image. The resulting images will be used to design a custom prosthetic limb prosthesis.

The present invention is recognized by the inventors as constituting a desirable method of carrying out the invention. are stated in terms of specific examples. Those familiar with this technology will appreciate the perspective of this discovery. However, without departing from the intended scope of the invention, reference may be made to the specific examples illustrated. It will be understood that many modifications and changes are possible. For example, many Zeolites or molecular sieves can be used as encapsulation substrates, and many Any ionic species can be encapsulated within the zeolite. some kind of ze Olite is used to encapsulate the target ions in contrast examinations, such as trivalent gadolinium. It is also possible to modify the effects of Umu. These and obviously related modifications are: It is considered to be within the scope of the claims.

References The references listed below provide information on the methods, techniques and/or techniques used herein. references insofar as they supplement, explain, provide context, or teach the composition of This is included here as a reference document.

Braybrook, )1. )(, and Hall, L, D,, Dru g, Des, Deliv, i.

93-95 (1989).

Break, D, W,,' le u a S' v, Krieger Publishing Company, Malabar, FL, 198 4゜Bryant, R, G and Lishi 1n8k”/r σ, J,, U, S, Pa cent No.

4.927,624 (:L990).

C1aussen, Von C., ornmesser, W., Lan1ad o, M,.

Kaminsky, S., Hamm, B., and Fe1ix, R. ROFOk 匝, 683-689 f19B9).

+(ahn, P, F,, 5taark, D, D,, Lewis, J, M,, 　5aini, S.

Elizondo, G., Weissleder, R., Fretz, C. ,σ,andFerrucci,σ,T,, Radiology f5.69 5-700 (1990).

L6nnemark, M, HemmiHemmln, A, Bach- Gansmo, T.

Er1csson, A., Convex ksendal, A., Nyman, R., and M. oxnes, A.

Acja Radiol, 赳, 193-196 (1989).

Messina, C, A,, l7) k, B, M, and Flanigen, E ,M., ,U.S.

Patent No. 4,544,143 +19851゜Rankel, L. A, and Valyocaik, E, W,, U, S, Pasenj No.

4.388,285. June l, 1983, Wilson, M, J, λΩ A Handbook of DeeerminajiveMejhods n C1ay Mineralogy, M. J. Wilson, ed.

Chapman and Hall, New York, pp, S-6, 1 987° Wilson! 9. T, and Flanigen, E, M,, U, S, Parent No.

4.567.028 (1986).

Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN.

TD, TG), AT, AU, BB, BG, BR, CA.

CH, CZ, DE, DK, ES, FI, GB, HU, JP, KP , KR, LK, LU, MG, MN, MW, NL, NO, NZ, PL , PT, RO, RU, SD, SE.

SK, UA, VN

Claims (18)

[Claims] 1. Paramagnetic encapsulated in smectite clay useful as image brightening agent Aluminosilicate composition containing ions. 2. Claim 1, wherein the clay is hectorite or montmorillonite clay. Compositions as described in Section. 3. Consists of paramagnetic ions, free ions or complex ions encapsulated in the above clay. A composition according to claim 1. 4. The composition according to claim 3, wherein the complex ion is formed from a polydentate complex. thing. 5. Claim 1, wherein the paramagnetic ion is gadolinium (III). Composition. 6. Enclosed in clay in an amount effective as a contrast agent or image brightening agent A contrast imaging method comprising administering paramagnetic ions to an animal. 7. Claim 1, wherein the paramagnetic ion comprises a rare earth or transition metal element. The composition according to claim 6 or the method according to claim 6. 8. The paramagnetic ions are V+4, Cu+2, V+3, Ni+2, Cr+3, C o+2, Fe+2, Co+3, Mn+2, Gd+3, Dy+3 or Fe+3? A composition according to claim 1 or a method according to claim 6, comprising: 9. Phenanthroline, bipyridine, 8-hydroxyquinoline, anthranilic acid , picolinic acid, salicylic acid, phthalic acid, salicylamide, ethylene diamine selected from the group consisting of acetic acid and bis(salicylaldehyde)ethylenediamine. Claim 1, wherein the chelating agent and the paramagnetic ion form a complex. A composition or a method according to claim 6. 10. The paramagnetic ions encapsulated in the above clay are applied to the site of the fistula through the anus, vagina, or 7. The method of claim 6, wherein the method is administered by direct injection. 11. The paramagnetic ions encapsulated in the above clay may be administered enterally or intravascularly. The method described in item 6 of the scope of the request. 12. Claim 6, wherein the paramagnetic ions encapsulated in the clay are orally administered. How to put it on. 13. Claim No. 1, wherein the clay is hectorite or montmorillonite clay. The method described in Section 6. 14. The above contrast agent or image brightening agent is detected by magnetic resonance imaging. The method according to claim 6. 15. A pharmaceutically acceptable formulation containing divalent manganese encapsulated in clay. A method for imaging the gastrointestinal tract comprising oral administration and detection of the manganese by magnetic resonance imaging. 16. 16. The method of claim 15, wherein said manganese is chelated. 17. A framework or modified hectorite or is a stable aqueous pharmaceutical suspension composition consisting of montmorillonite clay. 18. Claim 17 wherein the lanthanide metal within the framework is gadolinium. Compositions as described.