DIAGNOSTIC METHOD AND DIAGNOSTIC MEANS USED IN CARRYING OUT SAID METHOD

Abstract: The present invention relates to a diagnostic method used to indicate the migration of a medicament through the digestive apparatus and its resorption during this migration, with the use of a negative MRI-contrast agent, e.g. Abdoscan, and a positive contrast substance, introduced into gelatin capsules. In accordance to the invention said gelatin capsules are arranged as inner capsules in a common outer capsule, which is provided with barium sulpate in such an amount, that the specific gravity of the filled outer capsule is higher than the specific gravity of the contents of the stomach, so that the capsule will be able to sink through the contents of the stomach and reach the small intestine without a substantial time-delay. The invention also relates to a diagnostic means used to carry out the diagnostic method.

Description: DIAGNOSTIC METHOD AND DIAGNOSTIC MEANS USED IN CARRYING OUT SAID METHOD The present invention relates to a diagnostic method of the type set forth in more detail in the preamble of claim 1. Also, the invention relates to a diagnostic means according to claim 3 used in carrying out the method according to claim 1 or 2. In certain circumstances it is desirable but difficult to prove the existence of a medicament in its surroundings in and on its way through the digestive apparatus. Conventional methods use capsules, which are labelled with isotopes. This certainly facilitates the finding of the capsule, but it subjects the examined person to radioactive radiation, which should be avoided. I have on my own tested another method, in which by means of magnetic resonance imaging (MRI) the existence of a tablet is proved by a negative contrast agent (iron oxide + barium) in the digestive apparatus, this tablet being shown as a black silhouette against a white background of the conventional liquid positive MRI-contrast agent Magnevist enteral. This method has a drawback, since even if it is easy to visualize this black tablet m the ventricle (stomach) in a white sea of liquid contrast agent, this very contrast agent, when being transferred to the small intestine, apparently is mixed with other digestive lnquids, which results n an uneven, streaked filling of the small intestine, the tablet also being dissolved too quickly. Thus, an indication of the existence of the tablet is not possible. Various efforts to make the positive contrast agent more paste-like have not yielded any satisfactory results. Examinations with Magnevist enteral and a negative contrast agent, i.e. an agent which is black in an MRI-display, require , that the stomach is purged before the examinations . US-A-3 939 259 teach how to fill a capsule with tablets and delay the release of medicaments by a layer of i.a. beeswax. Barium sulphate and iron oxide in a water solution are used as negative contrast agents according to US-A-5 323 780. WO 94/03210 relates to oils, used as positive contrast agents. Various useful and also advantageous details are individually Known through these publications, but they are not combined in a particular way m order to speed up a diagnose and make it more reliable and so clear and simple, that certain preparatory measures, such as purging, completely or partially can be dispensed w-d-ii Mso, no efforts apparently have been spent to develop a simple, variable construction, which it is easy to adapt to various diagnostic requirements and desires. Also, I have not been able to find, that so far there has been a generally expressed desire to design a capsule having tracer functions and which can be charged with an optional module, which contains a substance, which one wants to examine. The object of the present invention is to counteract and as far-reachingly as possible overcome the above-mentioned drawbacks. Additional objects comprise the development of the state of the art in this field in various respects. These objects are achieved in accordance to the invention by designing a diagnostic method of the type described in the introduction, mainly in the way set forth in the cnaracterizmg clause of claim 1. Said objects are also achieved according to the invention by designing a diagnostic means of the type described in the introduction, mainly n the way set forth in the characterizing clause of claim 3. Additional characterizing features and advantages of the invention are explained in the following description, reference being made to the enclosed drawings, which illustrate a process, chosen as an example, for the production of a diagnostic means according to the invention. A negative MRI-contrast agent Abdoscan is on the market. This agent is mixed with water to a water solution , which, when it has been swallowed , becomes pudding-like in consistency in the digestive apparatus and fills e.g. the small intestine relatively uniformly, which substantially facilitates the finding of the white signal capsule in this uniform black sea of contrast agent. Th s is an obvious advantage compared to said liquid positive , .e. white, contrast agents. The following problem appeared : to develop a capsule , which through a positive contrast agent filling is clearly visible in a negative contrast agent and which only in the lower part of the digestive apparatus releases the substance to be examined and also is not toxic. This substance , i.e. the cargo portion, is allowed to be dissolved depending on ts composition, which varies from substance to substance, in interaction with the biochemical environments in the body in various places along the movement path. I have found, that certain deep-sea fish oil capsules on the market yield an excellent positive contrast in MRI, i.e. gives a white picture. Other natural or synthetic organic non-toxic substances maybe can be used also. However, sucn capsules are dissolved too quickly, i.e. alreaαy in the stomach and also, they nave the negativ property in the stomach of being l gther than water. Thus, they float on top of the contents of the stomacn and αo not reacn the lower outlet of the stomach. Conseσuently, I have wrapped D two such capsules in a mixture of iron oxide + barium sulphate - powder in an empty gelatin capsule. I nave chosen two deep-sea fish oil capsules, since the signal picture, whicn only one capsule gives, may look like the body s own structures, e.g. fat. In case the MRI-picture shows the two inner capsules in front of each other, only a bright white point is visible. In order to decide, whether this is the capsule, the next picture is taken with a 90o angle in relation to the previous one and then in the same plane two bright white points having the same size are visible, obviously a picture of the capsule and not one of the body s own structures. In principle or alternatively it is of course possible to choose such a, e.g. an oblong and/or a rectangular and/or an oval, inner capsule shape, that, when said pictures are taken from different angles always at least one picture is obtained, which clearly differs from more common own structures of the body. In order as far as possible to avoid taking pictures from different angles in order to with great reliability and speed be able to identify the position of the capsule, it is also possible to give the capsule an asymmetrical shape as regards its contents in such a way, that one capsule side or end always tends to sink firstly, because this side or end contains substances having a larger weight and density respectively. Alternatively a small air inclusion can serve the same purpose. I have chosen iron oxide due to the fact, that this compound, because of its negative (black) MRI-picture, yields an increased contrast around tne positive (white) picture, which substantially facilitates the determination of its position. I have added barium sulphate, because this compound substantially facilitates the displacement of the capsule through the force of gravity through the stomach and into the small intestine during the time, when the patient between the picture takings is up and moves about. Tests without barium sulphate have shown, that the capsule then is too light-weight, flows on top of the contents in the stomach, and does not reach the small intestine within several hours. Also, barium sulphate has a negative contrast effect, i.e. it gives a blacK picture in MRI . Alternatively t is possible to put the signal substance in e.g. a gelatin capsule, which is wrapped up in a shell, which consists of a mixture of solid paraffin and barium sulphate. It was founα, that this funct oneα properly. An excellent contrast is seen between the two white oil capsules and the mixture of iron oxide and barium sulphate with ts negative (black) MRI-picture and between the positive substance ana the signal-negative snell respectively, which latter consists of paraffin plus barium sulphate. In the human body there are no structures, wnich yield such a or a similar signal pattern in MRI, which suostantially facilitates the finding of the capsule. Also, the capsule is now so heavy, that it finds its way by itself to the lower outlet of the stomacn. As regards the dissolution , which is too quick, I have considered using beeswax, which does not melt or is not dissolved at body temperatures. Thus, I have provided the dry gelatin capsule on its outer side with liquid beeswax and have let the wax cool. The capsule is, thanks to the included barium, still sufficiently heavy to sink. However, thanks to the wax it nas not even been dissolved, when it reaches the anal opening, which is perfect from the point of view, that it then also is not able to influence the examination of the substance, which is to be examined. Instead of beeswax it is possible to use a layer, which consists of a mixture of solid paraffin (paraffmum solidum) and barium sulphate m order to obtain a protection of the capsule, and at the same time the barium sulphate contributes to the necessary weight. The substance to be examined is wrapped up in or is mixed with solid paraffin (paraffmum solidum) . This solid paraffin portion constitutes the cargo portion itself, i.e. that portion, which is optional and can be united with the trace portion of the capsule. The release/dissolution takes place slowly or at a certain pH-value. It is done by coating the substance to be examined with a pH-sensitive substance. This method has been tested during several decades by the pharmaceutical industry and is used by routine n certain pharmacological preparations. Thus, the method allows a utilization of all this experience, how medicaments are to be mixed with paraffin in order to be released slowly and consequently in a careful way, or put in another way, intentionally during a longer time in orαer to provide the same medicament concentration during a long time. Instead of beeswax another non-toxic substance can be used, which melts or dissolves only at higher temperatures than tne temperatures of the body, e.g. at 40 - 50oC, and which at least during a sufficiently long time is able to resist the liquids in the body without αissolvmg in the wrong intestinal section and with that effect respectively, that it is dissolved in the proper intestinal section and also during a long time. My tests have shown, that it is possible to indicate the capsule all the way from the stomach and through the entire small intestine and also in the colon in its section close to the anal opening. The present invention is not limited to what has been stated above, which only is to be considereα a non-limiting embodiment, which can be modified and supplemented in an arbitrary fashion within the scope of the inventive idea and the following claims respectively. Instead of paraffin other substances can be used, e.g. waxes plus non-toxic substances heavier than water instead of barium sulphate. The substance to be examined can either be included in the outer capsule/the outer shell in the form of a separate capsule (the cargo capsule) or be mixed with the chemically inert substance of the shell. I have found, that a capsule according to the invention gives such a clear signal picture against the used contrast agent, that despite small amounts of substances remaining in the stomach and the intestines the otherwise mandatory purging before the examination is not required. This results not only in a substantial relief for the patient, who avoids the inconvenience of having at least one day lost due to the purging, but also in another advantage : A purging leads to an increased mobility in the intestines. This increased mobility is a substantial drawback during MRI-examinations, since the picture taking per se takes time (reminding one of the old-fashioned photographing, when it was necessary to stand absolutely still for a long time in order to obtain a sharp picture) . However, it is not possible to stop the movements of the intestines by sheer will-power. On the other hand the intestines hold substantially steady, if no purging s used and one keeps fasting from the evening before the examination and then in the morning swallows the contrast agent and the capsule, which provides excellently sharp pictures despite certain small remaining amounts of substances in the stomach/intestines . None of the other described diagnostic means has, according to what I as a physician know about it, had any substantial medical impact. None of them is said to be used commercially despite the fact, that these means have been known for several decaαes . The enclosed drawings show as a non-limiting illustrating embodiment a method of producing a diagnostic means 11 according to the invention. The drawings show in detail: a) an inner capsule i, wnicn contains a positive contrast substance ; b) a lower portion 2 ana upper portion 3 of a conventionel outer capsule. In this example only the lower portion is used as an outer capsule ; c) an otnerwise possible outer capsule, whicn consists of a lower portion + an upper portion ; d) on the oottom of the lower portion the application of a first αose 4 of a heavy suostance, e.g. barium sulphate, possibly barium sulphate ana iron oxide ; e) an inner capsule, inserted in the lower portion, prepared in this way, avoiding a r inclusions. Alternatively, it is in this case possible to form a possibly desirable small air inclusion in order to facilitate a vertical positioning of the means in e.g. the stomach ; f) a second dose 5 of a heavy substance, applied on top of the inserted inner capsule ; g) a lower portion 6 of a second outer capsule, inserted with forced fit into the first lower portion, air inclusions being avoided ; h) a third dose 7 of a heavy substance, inserted into the second lower portion ; l) a second inner capsule , inserted into the second lower portion, prepared j) a fourth dose 8 of a heavy substance, inserted into the second lower portion on top of the second inner capsule ; k) a thin layer 9 of liquid beeswax , applied to the outside of the construction, obtained in this way, and also to the inside of the from the outside available portion of the second lower portion and to the free outside of said fourth dose 8 ; 1) a cargo portion 10, which consists of or contains a substance, which is to be examined , which substance in a typical case is a drug substance, mixed with paraffin and is inserted into tne open end of the second lower portion to fill this and be joined with its outer paraffin portions with the wax, which is still liquid ; and m) the border area between the wax layer and said paraffin portions, fused together in a way similar to how thermoplastic materials fuse together. In this way some form of alloy or soldering together of adjacent portions is obtained and is it guaranteed in a far-reaching way, that this entire construction is kept together up to the end, i.e. until this means has left the body. In order to facilitate the swallowing of said means a part of the cargo portion , particularly the siαes, wnich are parallel to the lower portions, can be provided with a paraffin layer 12, a soft transition zone between wax layer 9 and cargo portion 10 being obtained. However, the rest of the outer side of the latter, particularly its outer free end 13, is not covered by the paraffin layer, a dissolution, a leaching or the like in relation to present liquids in the ooαy being possible. The present invention is not l miteα to the embodiments descπbeα aoove and/or shown in the accompanying drawings but can be modified and supplemented in an arbitrary fashion within the scope of the inventive idea and the following claims. Thus, barium sulphate and/or iron oxide are only to be regarded as examples. They can of course be replaced with other suitable substances, provided such substances are sufficiently heavy and satisfactorily function as contrasting agents respectively. Also, the term capsule and capsules respectively can be replaced with other forms of enclosing/limiting means, e.g. various forms of coating and/or treatment and filling respectively during a preferably fully automatic production process. By using a powdery substance or substance mixture the inner capsules will not be exposed to moisture. However, in case the material of the inner and outer capsules respectively is resistant to e.g. a water solution, which contains said heavy substance and contrast agent respectively, it is of course possible to use such a solution instead ot a powder.

Claims: CLAIMS 1. A diagnostic method to visualize the migration of a medicament through the digestive apparatus and how the medicament is resorbed during this migration by using a negative MRI-contrast agent, e.g. Abdoscan, and a positive contrast and signal substance, filled n one or several capsules made of e.g. gelatin , c h a r a c t e r i z e d in that said one or several capsules made of e.g. gelatin are inserted as inner capsules in a common outer capsule, which is provided with a heavy substance, preferably barium sulphate, in such an amount , that the specific gravity of the filled outer capsule is higher than the specific gravity of the contents of the stomach, this capsule being able to sink through the contents in the stomach and reach the small intestine without any substantial time-delay. 2. A diagnostic method according to claim 1, c h a r a c t e r i z e d in that iron oxide is inserted into the outer capsule to form a properly contrasting negative near zone in relation to and around the inner capsule and the inner capsules respectively, and/or n that said positive contrast and signal substance is a natural or synthetic organic non-toxic subtance, preferably a deep-sea fish oil and/or in that the dissolution of the outer capsule and possibly also the inner capsule or the inner capsules respectively is delayed or counter-acted, at least during a certain predetermined time, by a coating, known per se, with beeswax and/or another non-toxic substance, which melts or is dissolved only at higher tempertures than the temperatures of the body or when in contact with specific substances and/or during a certain minimal time in order to control the dissolution of the capsule and the release of an additional substance, which has been inserted into the outer capsule, and/or in that as a material for the outer capsule and/or the inner capsule and the inner capsules respectively a mixture is used, which consists of solid paraffin and beeswax and/or in that as a material for at least one of the capsules and as a heavy substance waxes are used and/or paraffin with non-toxic substances, and/or in that the outer capsule is provided with an additional substance, e.g. a substance to be examined, either by insertion into the outer capsule in the form av a separate capsule (cargo capsule) or by a mixing with the chemically inert substance of at least one of the capsules and/or in that the inner capsule and the inner capsules respectively are designed and arranged in such a way, that they at least, when they are viewed from a certain angle individually and jointly respectively yield a non-circular or non-single point-shaped contrast picture. 3. A diagnostic means (11) used to carry out the diagnostic method according to claim 1 or 2, designed to indicate the migration of a medicament through the digestive apparatus and its resorption during this migration , with the use of a negative MRI-contrast agent, e.g. Abdoscan, and a positive contrast and signal substance, introduced into one or several capsules (1) made of e.g. gelatin, c h a r a c t e r i z e d in that said one or several capsules (1) made of e.g. gelatin are arranged as inner capulses in a common outer capsule (2), which also contains a heavy substance, preferably barium sulphate, m such an amount, that the specific gravity of the filled outer capsule is higher than the specific gravity of the contents of the stomach in order to be able to sink through the contents of the stomach and to reach the small intestine without considerable time-delay. 4. A diagnostic means according to claim 3, c h a r a c t e r i z e d in that also iron oxide is introduced into the outer capsule (2) in order to form a satisfactorily contrasting negative near zone in relation to and around the inner capsule and the inner capsules (1) respectively. 5. A diagnostic means according to claim 3, c h a r a c t e r i z e d in that said positive contrast and signal substance is a natural or synthetic organic non-toxic substance, preferably a deep-sea fish oil. 6. A diagnostic means according to any of claims 3-5, c h a r a c t e - r i z e d in that the dissolution of the outer capsule (2) and possibly also the inner capsule or the inner capsules (1) respectively and one of the inner capsules respectively is designed to be delayed or counter-acted , at least during a certain predetermined time, by a coating, which is known per se, with beeswax and/or another non-toxic substance, which melts or is dissolved only at higher temperatures than the tempertures of the body or when contacted with specific substances and/or during a certain minimal time, the dissolution of the capsule (2) and the release respectively of an additional substance, carried along by the outer capsule (2), being controllable. 7. A diagnostic means according to claim 3, c h a r a c t e r i z e d in that the outer capsule (2) and/or the inner capsule and the inner capsules (1) respectively, consists of and/or contains a mixture of solid paraffin and barium sulphate. 8. A diagnostic means according to claim 3, c h a r a c t e r i z e d in that at least one of the capsules (1;2) contains said heavy substance, bound by or n waxes and/or paraffin. 9. A diagnostic means according to claim 3, c h a r a c t e r i z e d in that an additional substance , carried along by the outer capsule (2), e.g. a substance to be examined, either is inserted into the outer capsule (2) in the form of a separate capsule (cargo capsule) (6) or is mixed with the chemically inert substance, of which at least one of the capsules is made. 10. A diagnostic means according to any of claims 1-7, c h a r a c t e r i z e d in that the inner capsule or the inner capsules (1) respectively are designed and arranged in such a way, that they, at least when they are viewed from a certain angle, individually or jointly respectively , yield a non-circular or a non-single point-shaped contrast picture.

Inventors: POTTHOFF KLAUS, POTTHOFF, KLAUS
Applicants: POTTHOFF KLAUS, POTTHOFF, KLAUS
Application year: 1999
Main classification: A61K49
IPC codes: A61K49