FI ELD OF I NVENTION

The present invention relates to a composition and method for investi- gating alimentary functions .

BACKGROUND OF INVENTION

The methods most widely used today for investigating alimentary functions and visualization of the alimentary canal comprise the use of radioopaque contrast media. However, the use of radioopaque media with X-rays to determine gastric emptying time or intestinal transit time, or to monitor the passage of material th rough the alimentary canal will subject the patient to high energy radiation in amounts which are often undesi rable and fu rthermore offer only limited infor¬ mation on the functioning of the alimentary canal .

The radioopaque agent which is most often used for investigation of the gastrointestinal tract is barium sulphate, normally administered as a viscous suspension . Barium sulphate, however, has several disad¬ vantages for this purpose. I n particular, barium sulphate is known to change the movement of materials through the various parts of the intestines, which means that the results obtained by using barium sulphate can hardly be taken as an indication of the functional state of the intestinal system, resulting in inadequate or even faulty diag¬ nosis, which further results in inappropriate treatment.

It is also known to use soluble iodine compounds having a high radio- density, typically tri-iodinated substituted benzene compounds, as X- ray contrast media for investigation of the alimentary canal . How¬ ever, also with these agents, the patient will be subjected to undesi¬ rable amounts of high energy radiation .

Methods which do not rely upon the use of X-rays for the determina- tion of gastrointestinal transit time have used inert compounds such

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as carbon black and chromic oxide. I n these methods, however, the transit time is determined by determining the interval between the time of an oral dose and the time of appearance of the compound in feces, and this means that no visualization of the alimentary canal and no differential diagnosis of the functional state of the various regions of the gastro-intestinal tract are obtained.

it is known from US 4, 115,540 and US 4,243,652 that certain r-emit- ting radionuclides can be used in combination with certain carriers to provide multiple-units radiodϊagnostic agents for investigation of the alimentary canal by scintigraphy which is normally performed non- invasively by means of a suitable instrument such as a ' Y-camera or a rectilinear scanner, etc. It is also known to prepare single-unit

131 99m tablets labelled with e. g. I or Tc for investigating the beha¬ viour of pharmaceutical functions in the gastrointestinal tract.

BRI EF DISCLOSURE OF INVENTION

The present invention utilizes pharmaceutical formulation techniques to provide compositions and methods . for investigating alimentary func¬ tions, which compositions and methods are advantageous over the prior art compositions.

In one aspect, the invention relates to an enteraily administrable diagnostic composition for investigating alimentary functions compris¬ ing multiple units of a size of at the most 5 mm, each unit comprising a tracer-binding agent to which a diagnostically acceptable radioactive tracer substance with a half-life of at the most 5 days suitable for detection of the position of the unit in the alimentary system is asso¬ ciated . The tracer-binding agent is formulated with at least one pharmaceutically acceptable excipient in such a way that, when the composition is administered, the exposure of the gastrointestinal mucosa to the tracer-binding agent is reduced, and in such a way that the units do not disintegrate during their passage through the gastrointestinal tract. Other aspects of the invention relate to a method for making a labelled diagnostic composition, a composition designed to be labelled with tracer substance, and a method of inves¬ tigating alimentary functions as will be explained in the following .

The composition of the invention is a multiple units composition, i . e. a composition which is administered as a multiplicity of units, gene¬ rally at least 50 units, whereby they will distribute in the gastroin¬ testinal tract in a reproducible statistical manner, in contrast to the stochastical behaviour associated with single-unit compositions .

The tracer substances of the labelled units of the present invention are tracer substances with a half-life of at the most 5 days . I n con¬ trast to longer half-life tracer substances used in some of the known compositions, the tracer substances of the present invention minimize the risk of long term radiation injury for both the patient and the staff involved in the investigations .

The formulation with the pharmaceutically acceptable excipient pro¬ vides a number of advantages . Firstly, by formulating the tracer- binding agent with a pharmaceutically acceptable excipient, any prob- lems associated with the properties of the particular tracer-binding agent are minimized . Thus, for instance, tracer-binding agents which are not proven intoxic and therefore not approved by the health authorities for direct exposure to the gastrointestinal mucosa may nevertheless be used in the composition of the invention . This is especially an advantage as most tracer-binding agents, as will appear from the list later on, are substantially insoluble compounds for which , generally speaking, only local toxic effects caused by tracer- binding agent contact with the mucosa will have to be considered. Due to the formulation of the composition of the invention, such contact is substantially avoided. A fu rther advantage of formulating the tracer-binding agent with a pharmaceutically acceptable excipient in such a way that the exposure of the gastrointestinal mucosa to the tracer-binding agent is reduced is that this protects the gastrointes¬ tinal mucosa from local irritation by the tracer-binding substance. Another advantage is that the amount of the tracer-binding agent in the composition may be varied and thus optimally adapted to the particular tracer substance. One of the most important features of the composition of the invention is that by means of the pharmaceutical excipient or excipients, a number of parameters which are decisive to the transition behaviour of the units in the gastrointestinal tract, i . e.

size, size distribution , density, and surface properties, may be varied at will to provide compositions which are optimal for their particular diagnostic pu rposes, independent of the tracer-binding agent employed . Thus, in contrast to barium sulphate, the composi- tion of the invention can be formulated in such a way that it will neither coat nor adhere to the mucous membranes th roughout the ali¬ mentary canal .

As will appear from the following, a further advantageous feature of the composition of the invention is that it may easily be formulated in such a manner that the labelling of the composition by combining the tracer-binding agent with a radioactive tracer substance may be per¬ formed in a simple manner, even by unskilled staff, at the site of use whereby handling and transport of the labelled and hence radioactive composition is avoided . One advantage associated with this is that the amount of radioactivity administered with the units can be varied at the hospital or the laboratory, thus permitting optimization of the radioactivity for the particular investigation in question .

A still further important feature of the composition of the invention is that the formulation with one or several pharmaceutical excipients re- duces radioactive leaching from the units which would otherwise impair the scintigraphical detection . Thus, for instance, when the composition of the invention is used for determination of gastric emptying, a sufficiently low degree of leaching may be secured to significantly reduce or entirely obviate the systematic error which in the known art use of tracer-binding agent alone arises from leaching of free tracer substance. Thereby, it becomes possible i . e. to deter¬ mine a true solid phase gastric emptying and not a mixed gastric fluid/solid phase emptying.

Examples of conditions for which it has been found or is contemplated that they may be diagnosed by means of the composition of the in¬ vention are coionic functional diseases, sigmoid diseases, constipation, Crohn disease, diarrhea, duodenal diseases such as duodenal ulcer, ileal diseases, intestinal obstruction , malabsorption syndromes such as blind loop syndrome and tropical sprue, esophageal ulcer, esophageal

functional diseases such as esophageal reflux and esophageal stenosis, dumping syndrome, "Giesskannen" phenomenon (an apparently harm¬ less abnormality in the duodenum characterized by reduced mobility of the descending part of the duodenum) , stomach diseases such as pyloric stenosis and gastric ulcers, and functional effects of gastro¬ intestinal operations such as anastomosis, and various vagotomies, resections, ileostomies or colostomies .

The present invention permits the monitoring of the passage of the food-simulating units through the alimentary canal and makes it pos- sible not only to investigate the transit time through the entire ali¬ mentary canal, but also to investigate the transit time in segments of the alimentary canal individually. Thus, utilizing the composition of the present invention, the following transit times can be investigated and diagnosed, either individually or in combination :

Esophageal transit time, gastric emptying time, small intestine transit time, including the individual transit times in duodenum, jejunum, and ileu , and colonic transit time, including the individual transit times in the ascending, transverse and descending colon as well as in the sigmoid flexure or the rectum.

Further, the present invention makes it possible to investigate the mixing of the contents in the various parts of the gastrointestinal tract. An example is that it is possible to investigate the movement of stomach contents from the fundus to the antrum or investigate the effectivity of the mixing in the various parts of the small intestines or in the various parts of the large intestines .

This differentiation of the investigation and diagnosis of the alimen¬ tary canal transit times and mixing effectivity permit a very detailed and individualized diagnosis of the alimentary conditions mentioned above.

A special advantage of the present invention is that it allows co-admi¬ nistration of at least two formulations differing in their physical aspects such as size, su rface characteristics and/or density, the

different formulations being labelled with different tracer substances . This co-administration of the different formulations enables one to investigate the behaviour of each formulation separately without having to take the intrasubject variation into account as this variation will normally be so pronounced that no conclusions concerning the differences in the behaviour of the two formulations can be drawn . The co-administration is especially advantageous in view of the fact that the day-to-day variation of the transit time throughout the various parts of the gastrointestinal tract is known to be considerable and varies with conditions normally difficult to control such as the food ingested during the days prior to the investigation, the physical and mental activity level of the subjects and the emotional state of the subjects.

DETAI LED DESCRI PTION OF I NVENTION

Units

The composition of the invention when administered will normally be one which has a known behaviour with respect to passage through the alimentary canal of a reference animal, in particular a human . The behaviour of a particular composition with respect to passage through the alimentary canal of a reference animal, in particular a human, may be determined by means of scintigraphy as described herein .

The units employed in the diagnostic composition of the invention may be of various types . One example is units comprising the tracer- binding agent coated with a pharmaceutically acceptable coating which is substantially insoluble in gastrointestinal fluids, but which is of a type which permits diffusion of the tracer substance for binding with a tracer-binding agent. Alternatively, the units may comprise cores of one or more excipients and a tracer-binding agent combined in such a way that, when the composition is administered, the exposure of the gastrointestinal mucosa to the tracer-binding agent is reduced. I n this latter embodiment, the tracer-binding agent may either be applied to the su rface of the cores, optionally together with an adhesive to ensure that the tracer-binding agent is retained on the cores, in

. which case the cores are coated with a pharmaceutically acceptable coating as stated above or, according to a preferred embodiment, the cores may be cross-sectionally substantially homogeneous multi-compo¬ nent cores containing a tracer-binding agent granulated with one or more granulating excipients in such a way that, when the composition is administered, the exposure of the gastrointestinal mucosa to the tracer-binding agent is reduced, optionally coated with a pharmaceu¬ tically acceptable coating.

Although the granulating excipient or excipients incorporated in the core together with a tracer-binding agent may in themselves be suffi¬ cient to ensure that only a small number of the normally powdery particles of tracer-binding agent will actually be in touch with the mucosa, it is normally advantageous, depending on the type of or the amount of tracer-binding agent incorporated (particularly when the ratio of tracer-binding agent to the other ingredients is high) , to coat the cores with a coating as stated above in order to further reduce the exposure of the gastrointestinal mucosa to a tracer-binding agent causing local irritation .

Units comprising multi-component cores with incorporated tracer- binding agent may additionally comprise a tracer-binding agent and optionally an adhesive applied to the surface of the cores. In this case, the cores are necessarily coated as stated above.

It will be evident from what is stated above that one of the special advantages of the ^• multi-component -cores lies in their variability. Thus, it is possible to vary any one of the different parameters involved, such as the type and amount of tracer-binding agent, and the size, surface characteristics or density of the units, without concomitantly having to alter any other parameter. For instance, the units of the present invention have the advantage over the known radiodiagnostic compositions that they may comprise several tracer- binding agents in the same unit, each of which is adapted to associate with a different tracer substance. Such units may therefore be adap¬ ted to any desi red diagnostic pu rpose requiring isotopes of va rying half-lives, or different investigations which , with the known composi-

tions, would have to be performed successively, thus requiring re¬ peated dosages of radioactive substances, each dosage comprising a different isotope, as well as a prolonged investigation period, may be performed simultaneously by incorporating different isotopes in the same unit of the invention . This means that the production of the units may be standardized even though they may serve a variety of diagnostic purposes .

Alternatively or simultaneously, it may be desired to vary the size of the units .

The units may have a size in the range of between 0.05 and 5 mm, but for most of the normal purposes, the units will have a size be¬ tween 0.3 and 5 mm, preferably a size between 0.3 and 2 mm, and a size range which will often be preferred is one in which the indivi¬ dual units are between 0.5 and 1 .3 mm, in particular between 0.7 and 1 .0 mm. The units will often be administered in two size ranges according to their purpose, the units of each size range being label¬ led with different isotopes.

By means of the units of the present invention it has now been made possible to investigate the movement of particles of solid food through the gastrointestinal tract. This is in contrast to the known particles, the size of which was too small to permit any such investigation or which were leaching.

The size of any one of the types of units stated above may thus be varied, although it is easier to obtain size variations with the multi- component cores due to the method of their production .

I n accordance with a particular aspect of the invention, the density of the cores, and thus, the time of appearance of the cores in the predetermined segment of the intestine may be varied at will . (Bech- gaard, H & Ladefoged, K (1978) : "Distribution of Pellets in the Gastrointestinal Tract. The I nfluence of Transit Time Exerted by the Density or Diameter of Pellets" . J. Pharm. Set. 69, 1327-1330) .

The units of the composition can be varied with respect to their density by including various pharmaceutically acceptable excipients capable of giving the density in question . For most pu rposes, the units will have a density in the range of 0.5-2.5 g/ml, in particular 0.9-1 .7 g/ml . Examples of excipients which may be used to increase the density of the cores are described in US Patent No. 4 193 985 and include heavy particulate substances such as barium sulphate, titanium oxide, zinc oxides, and iron salts .

Through variations of the density of the units of the composition of the invention, it is possible to make the multiplicity of the units behave distinctively differently in the gastrointestinal system. Thus, when the units have a density of approximately 1 .0 g/ml, the units will float on top of the gastric fluids and thus be impeded from emp¬ tying for several hours, whereas units with a density of 1 .6 g/ml will sink down into the antru part of the stomach immediately upon administration, after which the units will empty very slowly. When co-administered, the two types of units will behave in a clearly diffe¬ rent way as can be seen from the examples .

A special advantage of the composition of the invention is that the surface characteristics of the units can be varied according to the pharmaceutical coating chosen . Further, the su rface characteristics can be varied by inclusion of surfactants or by inclusion of specifi¬ cally binding substrates in the coating composition .

Tracer-binding Agents and Tracer Substances

In contradistinction to the known radiodiagnostic compositions, it is not required that the association between the tracer-binding agent and the tracer substance be insoluble, as, even if the association dissolves within the unit, the composition can be formulated so that the components will not be released to the surrounding gastrointesti- nal environment due to the other components contained in the unit, either in the form of a coating or in the form of granulating exci¬ pients substantially compacting the association within the units . I n this way, the leaching of the radioactive tracer substance from the

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units is significantly reduced. (However, it is generally preferred that the tracer-binding agent be so selected that its association with the tracer substance in the units is a solid substance having a low degree of diff usability from the composition . ) Nor, as mentioned above, is it required that the tracer-binding agent be proven a non-toxic substance as, through the formulation with excipients, it can be ensured that only a minor amount of tracer-binding agent, preferably none, comes into contact with the gastrointestinal mucosa. Thus, a wider range of tracer-binding agents may be employed.

Tracer-binding agents which may be used for the purpose of the present invention are normally selected from the group consisting of ion exchangers, including ion exchange and synthetic resins, and hydroxyapatite, diphosphonates, anionic starch derivatives, sulphur colloids, phythate colloids, pyrophosp hates, organic phosphonates, organotin complexes, macroaggregated serum albumins, metal hydro¬ xide colloids, pyridoxals, phospholipids, diethylenetriaminepentaacetϊc acid, polyamine polymers formed from polystyrene and triethylene tetramine, and rose bengal . The tracer-binding agent is preferably an anionic ion exchange resin, the functional groups of which are secon- dary or tertiary aliphatic amines or quarternary ammonium groups with a pK value of the resin of more than 8, or a cationic ion ex- change resin, the functional groups of which are sulphonic acid or carboxylic acid groups with a pK value of the _. resin of less than 8. If the tracer-binding agent employed is a cationic ion exchange resin, it may be charged with, for instance, sodium ions or be in the acidic form.

The tracer-binding agents may be present in the units of the compo¬ sition of the invention in amounts ranging from as little as about 0.1% to as much as about 95% by weight, calculated on the units, depen- ding on the character of the tracer-binding agent, the construction of the units with respect to the position of the tracer-binding agent, etc. Normally, the tracer-binding agent will be present in amounts from about 2 to about 60% by weight, preferably 2-20% by weight, such as 2-10% by weight, in particular 5-10% by weight calculated on the units.

The tracer substance is preferably a substance having a high quan¬ tum yield of a relevant scintigraphically determinable radiation , such as a quantum yield of at least 25%, preferably a quantum yield of above 50%, more preferably a quantum yield of above 80% of the total radiation .

If the quantum yield is substantially lower than stated above, the necessary dose to the patient in order to obtain a sufficient scinti- graphical detection within a sufficiently short time would be so high that it will not be acceptable from a dosimetric point of view (which , for brevity, in the present specification and claims is included in the concept "diagnostically acceptable") .

Also, in order to meet the requirement of administering the minimum necessary radioactive dose in order to prevent radiation injury, the present invention provides compositions incorporating tracer substan- ces specifically chosen for their relatively short half-lives which are still compatible with the diagnostic pu rposes in question .

The dose (D) from an isotope depends in the following way on the to¬ tal administered activity (A) and the effective half-life of the isotope in the body (T., _{/2 ff} ) (Rocha AFG and Harbert JC (1978) : "Text- book of Nuclear Medicine: Basic Science", Lea & Febiger, Philadel¬ phia) . D - T _{1 /2 rff #} x A

^T 1/2 iso ^{x T} 1/2 bio

1/2 eff.

^T l/2 iso ^{x T} 1/2 bio

As seen from the expression , keeping in mind that the biological half-life of the isotope (T. ,„ _• - ) depends only on the total transit time (time from mouth to anus) , A and T should be kept as low as possible at the same time. However, in order to get good pictures

(sufficiently high counting rates) , a certain amount of activity is ne- cessary. I n order to investigate gastric conditions, an isotope with a

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half-life of a few hours, e.g. ^m l n ( ^ _{2 jso} ^{= "} • rl h) , will usually be sufficient. When the functioning of the intestines is to be investi¬ gated, e. g . small intestinal transit time, it may be necessary to use an isotope with a somewhat longer half-life such as Tc (T. ,~ : _so ⁼

129 6,03 h), and to determine the total transit time Cs (T- ,~ - ~ 32 h) or in I n (T. _/5 . = 67 h) is optimal . However, in no instance will it be necessary to use an isotope of a half-life of more than 5 days . The composition of the invention is thus distinguished from some of the known radiodiagnostic compositions which use isotopes, the half- lives of which are not shorter than 27 days (vide US 4, 107,283) , as these known art compositions are made by methods where the tracer substance is included in the composition by the manufacturer whereas in the composition of the invention, the tracer substance is applied at the site of use substantially immediately prior to use.

Examples of diagnostically acceptable tracer substances which fulfil the above criteria are well-known in clinical practice. Specific exam¬ ples of diagnostically acceptable tracer substances are substances, the active principle of which is selected from the group consisting of Tc, In, In , and Cs . An example of a tracer substance which, due to a too low quantum yield, is not diagnostically accep-

51 table is Cr, which has a quantum yield of about 8%.

It is an important advantage of the invention that the units of the invention can be formulated so that they are capable of binding the tracer substance to such an extent that the radioactive leaching from units is below the values which would tend to impair the scintigraphi- cal detection. Thus, for example, when the composition of the inven¬ tion is used for determination of gastric emptying, the leaching is so low that it significantly reduces or completely obviates the systematic error which in the known art use of associated tracer alone arises from the leaching of free tracer substance. Gastric emptying half time is normally of the order of from a few minutes to some hou rs, depen¬ ding upon whether the food is fluid or solid, and the leaching of radioactivity from the units during this time should be sufficiently low so that it does not significantly reduce the gastric emptying time measured. This aspect is especially critical with isotopes like ^m Tc

administered in the form of pertechnetate as the pertechnetate ab¬ sorbed from the lumen of the gastrointestinal tract would be secerned in the stomach or accumulated in the bladder or in the thyroid .

One particular advantage of the composition of the invention is that it may be formulated so that the leaching is sufficiently low even over prolonged periods to permit reliable investigations of the intestinal system where transit half times are of the order of several hours, and even reliable investigations of the colonic system where transit half times are of the order of more than 10 hours . Thus, as will appear from the results stated in the working examples, low leaching ratios have been measured on compositions of the invention even after very prolonged immersion in artificial intestinal fluid. As will further appear from the results in the working examples, leaching from the composition of the invention was not even detectable in vivo. Hence, the compositions of the invention constitute a new and reliable tool for scintigraphical determination of the functions of the alimentary canal.

A special advantage of the invention is that it permits a simple label¬ ling procedure at the site of use such as the laboratory or hospital, which procedure normally merely comprises immersing the units in a solution containing an effective concentration of the tracer substance for a period of time sufficient to bind an effective amount of tracer substance to the tracer-binding agent, for example for a few hours or simply overnight, . removing the solution from the labelled units, e. g . by means of a needle and syringe and simply rinsing excess tracer substance solution from- he -units with - ater or saline- solution: This means that when using the composition of the invention , the radioac¬ tive tracer-generating systems which are generally already available in hospitals or laboratories may be utilised for preparing the solution of tracer substance, thus avoiding transport and minimizing handling of the labelled and hence radioactive composition .

Furthermore, the simple labelling procedure reduces the radioactive doses to which the staff performing the labelling is exposed, to an absolute minimum.

The radioactivity of the labelled units will normally be in the range of

5-500 μCi, in particular about 50 μCi per dosage of the units to be administered.

Cores

In one embodiment, each unit comprises a core or a carrier material with tracer-binding substance applied to its surface. The carrier material may be a pharmaceutically acceptable natural or synthetic wax, e. g. paraffin wax, or a sugar in which case the core is a so-called "non-pareil" core. In a particular embodiment, the units are made from paraffin wax by breaking the paraffin wax into small par- tides, heating said particles to soften the surface and applying the tracer-binding substance by powdering.

These cores may, however, suffer from a number of disadvantages, mainly with respect to size and density variations which, in the "non-pareil" cores, are limited by the available standard cores .

Therefore, the most preferred embodiment is one in which a cross- sectionally substantially homogeneous multi-component core contains the tracer-binding agent granulated with one or more granulating excipients . In this type of core, mϊcroparticles of the tracer-binding agent are mixed with one or more excipients in such a way that, over a cross-section of the core body, the same type of composition is present.

The use of cross-sectionally substantially homogeneous cores offers several advantages.

Firstly, cross-sectionally substantially homogeneous cores are easy to produce on a large scale in reproducible manner in, e.g . , automatic equipment because the components therefor are normally simply mixed in the prescribed proportions, which means that the inter-core vari¬ ation in composition, e.g . , concentration of tracer binding agent, can be kept within narrow limits. Secondly, the concentration of tracer binding agent in the core can be varied within very wide limits (pre¬ ferably between 2 and 60% by weight) and thus variation in the

amount of tracer substance. Thi rdly, the size and density of the cores may be easily adjusted as desired .

The granulating excipients used to prepare the multi-component cores comprise one or more substances selected among carbohydrates and derivatives thereof such as sugars, e. g. lactose or sucrose, starch and starch derivatives, and microcrystalline cellulose, lubricants and fillers such as silicates, e. g . Bolus Alba or talc, or calcium stearate, binders such as cellulose derivatives including methylcellulose and hydroxypropylmethylceliulose, and polyethylene glycol, polyvinyl- pyrrolidone, agar or gelatin , and density-increasing substances such as barium sulphate, titanium oxide, zinc oxides and iron salts.

The cores are typically made by granulating particles of the tracer- binding agent together with excipients, including bulk agents such as carbohydrates and derivatives thereof such as starch and starch derivatives, including microcrystalline cellulose, binders such as cellulose derivatives, including methylcellulose or hydroxypropylme¬ thylceliulose, polyethylene glycol , polyvinylpyrrolidone, agar, or gelatin, such as by treatment in a high speed mixer (to directly obtain compact-shaped cores) , or by treatment in a planet mixer with subsequent extrusion of the mixture into strings of predetermined diameter close to the desired final cross-sectional dimension of the cores and treatment of the strings in a marumerizer or similar equip¬ ment to obtain compact-shaped cores.

When the cores are cross-sectionally substantially.. homogeneous. -coj-es, . the tracer binding agent is normally incorporated in the cores during the manufacturing of the cores as described above. Alternatively, or combined therewith, the tracer binding agent may be applied on the surface of the cores, optionally using an adhesive such as hydroxy¬ propylmethylceliulose.

Coating

When the tracer-binding agent is so situated that it is completely or partially exposed, it is necessary to provide the cores or particles of

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tracer-binding agent with -a coating which will protect the gastro¬ intestinal mucosa from local irritation caused by the tracer-binding agent. This is particularly necessary when the tracer-binding agent is an ion exchange resin, some of which would be local irritants if ingested without the protective coating . Even when the tracer-binding agent is contained within a multi-component core so that only a minor amount of it is exposed, it is, for the most purposes, preferred that the units of the composition of the invention be coated. The coating is a pharmaceutically acceptable coating which is substantially inso- luble in gastrointestinal fluids, and which is of a type which permits diffusion of the tracer substance for binding with a tracer-binding agent.

The basic ingredient of the coating is a film-forming excipient which is normally selected from cellulose derivatives, acrylic polymers and copolymers, vinyl polymers, and other high molecular polymer deriva¬ tives or synthetic polymers such as ethylcellulose, cellulose acetate, cellulose propionate, cellulose -butyrate, cellulose valerate, cellulose acetate propionate, polyvinyl acetate, polyvinyl formal, polyvinyl butyral, ladder polymer of sesquiphenyl siloxane, polymethyl meth- acrylate, polycarbonate, polystyrene, polyester, coumarone-indene polymer, polybutadiene, vinyl chloride-vinyl acetate copolymer, ethyl- ene-vinyl acetate copolymer and vinyl chloride-propylene-vinyl acetate copolymer or a combination thereof. Preferred film-forming excipients are ethyl cellulose or a polymerisate of acrylic acid ethyl ester and methacrylic acid methyl ester, e. g . the so-called Eudragit® coatings.

The coating may optionally comprise other pharmaceutically acceptable materials which improve the properties of the film-forming excipient such as plasticizers, anti-adhεsives, diffusion-accelerating substances or diffusion-retarding substances.

Often, it is preferred to plasticize the coating with a plasticizer such as a plasticizer selected from e. g. glyceryl triacetate, acetyltriethyl citrate, acetyl-tributyl citrate, propyleneglycol, polyethyleneglycol and castor oil . A coating which has been found to function well in practice is a coating comprising ethyl cellulose plasticized with acetyl- tributyl citrate.

The amount of coating applied on the units is normally in the range between about 1% and 50% by weight, calculated on the weight of the coated units, often preferably in the range from about 2% to about 20%, calculated on the same basis .

Generally, a thicker coating will necessitate a longer soaking period in the labelling solution, but will, on the other hand, reduce any leaching into the alimentary tract.

The techniques used in these methods, including the binders, lubri¬ cants, fillers, etc. , correspond to the techniques and excipients used in the normal pharmaceutical preparation of corresponding multiple units formulations .

I n another aspect, the invention relates to a diagnostic composition adapted to be labelled with a radioactive tracer substance, comprising multiple units of a size of at the most 5 mm, each unit comprising an ion exchange resin which is formulated with at least one pharma¬ ceutically acceptable granulating excipient in such a way that, when the composition is administered, the exposure of the gastrointestinal mucosa to the ion exchange resin is reduced, that the units do not disintegrate during their passage through the gastrointestinal tract, and further that at least part of the tracer-binding agent is acces¬ sible, by permeation, to a solution containing a tracer substance. The ion exchange resin is present in an amount of 2-60%, in particular 2-20%, by weight, calculated on the unit. The units are coated with a pharmaceutically acceptable coating which is substantially insolubl -in - gastro-intestinal fluids, but which permits diffusion of the tracer substance for binding with the tracer-binding agent.

I n particularly favourable embodiments of the composition of the invention, each unit contains a tracer-binding agent which is capable of binding at least two different tracer substances in the composition of the invention or at least two tracer-binding agents, each of which is capable of binding a different tracer substance, or the composition comprises two different types of unit each of which contains a diffe¬ rent tracer-binding agent capable of binding a different tracer sub-

stance. Optionally, the units may have different physical characte¬ ristics with respect to density, surface and/or size. These features, obtainable only by means of the present invention, have the advan¬ tage of providing compositions which may be used for simultaneous investigations of the alimentary system, thus eliminating the intraper- son variation occurring when two different types of units differing in said physical characteristics are compared, as described in detail above. The tracer substances are preferably selected from Tc,

113m, . I l l ,

In and In.

Similarly, the composition according to the invention can be in such a manner that the units are capable of binding at least three tracer substances, either due to each unit containing a multiplicity of tra¬ cer-binding agents, or due to the composition being a mixture of units each of which is capable of binding one or several tracer sub- stances, the units optionally having different physical characteristics with respect to density, surface and/or size. This aspect of the invention offers the same advantages as mentioned above, but in this case it will be possible to compare three different types of units, e.g. units with three different densities without having to take the intrasubject variation into account. The three tracer substances are se ,lect .ed . f ^, rom 99m- T-c, 113m. I n, I l l , I n and . 129 C-s . - T,-,he reason why * these tracer substances are selected is that their quantum yield is high (100%) , their half-lives are relatively short and they offer energy spectres which can be distinguished on the scintigraphic device in question, e. g. a Y-camera with two or more channels, by proper window setting of the channels eventually followed by mathematical calculations correcting for overlapping between the window setting for a tracer substance and the energy spectres of the other tracer sub¬ stances.

An aspect of the present invention is a method of investigating ali¬ mentary functions, comprising administering multiple units of a size of at the most 5 mm to an animal, in particular a human, and deter¬ mining the distribution or position of the units at intervals by a determination method utilizing the radioactive emission from the units . Each unit comprises a tracer-binding agent to which a diagnostically

acceptable radioactive tracer substance with a half life of at the most 5 days suitable for detection of the position of the unit in the alimen¬ tary system is associated, the tracer-binding agent being formulated with at least one pharmaceutically acceptable excipient in such a way that, when the composition is administered, the exposu re of the gastrointestinal mucosa to the tracer-binding agent is reduced, and in such a way that the units do not disintegrate during their passage through the gastrointestinal tract. The determination is usually per¬ formed by a scintigraphic method, such as by means of a T-camera or a scintillation counter. By means of this method, it is possible to perform individual investigations of one or several regions of the alimentary canal . Also, this method has the advantages of convenience to hospital or laboratory staff due to the simple labelling, and of safety, i . e. causing the staff and patients to be only minimally ex- posed to radiation as well as causing no local irritation of the pa¬ tient's gastrointestinal tract as discussed above.

A further aspect of the invention relates to a method of investigating alimentary functions, comprising administering at least two types of units which are labelled with different diagnostically acceptable radio- active tracer substances and which have different physical characte¬ ristics with respect to density, surface and/or size simultaneously or sequentially, and selectively determining the distribution or position of units of each type. This method makes it possible to investigate the influence of various factors, e. g . the physical characteristics of the pellets, on the transit time th rough or mixing of the iuminal content in various parts 'of the gastrointestinal tract. Such investiga¬ tions have hitherto been either extremely costly and time-consuming or simply impossible due to the intraperson variation . Th rough the elimination of intraperson variation obtained by this method of the present invention, such investigations have been made possible as will appear from the following examples .

BRI EF DESCRI PTION OF THE DRAWINGS

In the drawings, Fig . 1 illustrates the gastric emptying pattern of two formulations differing in density (open circles : density 1 .0 g/ml, closed circles: density 1 .6 g/ml) , labelled with two different isotopes and co-administered to a volunteer, and Fig . 2 illustrates the average gastric emptying pattern for 7 healthy volunteers (A) compared to the emptying from a person with the "Giesskannen" phenomenon (B) . The possibility of diagnosing the "Giesskannen" phenomenon and, on the whole, the reliability of the activity values in the range below 20% retained activity are particularly valuable features of the present invention such as described herein.

MATERIALS AND METHODS

In the examples, the following materials were used:

Barium sulphate Ph Eur Bolus Alba Ph Eur Microcrystalline cellulose BPC 79 Calcium stearate USP XX Talc Ph Eur

Purified water Ph Eur Ethyl cellulose NFXV Paraffin NFXV

Amberlite® CG400 Anion exchanger from Rohm & Haas,

75-150 ym, chloride form

Amberlite® CG 120 Cation exchanger from Rohm & Haas,

75-150 ym, sodium form Acetyltributylcitrate Citroflex® A-4; supplied by Pfizer A/S,

Copenhagen, Denmark

Iso ropanol BP 80

Polyvinylpyrrolidone BP 80 Add 81

99m-,. .

Tc generator Tecegen® from Hoechst (100 mCi) In solution Carrier-free indium trichloride, activity 4 mCi/ l, from Amersham

Mixobar® X-ray contrast agent: barium sulphate suspension, 0.6 g/ml, from Astra-Meditec

Density measurements: Were performed as Hg densitometry Scintillating counting: Was performed in a Nal(Tl) crystal counter (well type), BP 80

Dose calibration: Was performed in a Mediae® Dose cali¬ brator from Nuclear-Chicago.

Artificial stomach and intestinal fluids: Were prepared according to USP XX (excluding enzymes)

y-Camera I : I nternational General Electric MAXI I I having a 40 cm field and fitted with a 400 keV parallel hole collimator.

Z- Camera 11 : I nternational General Electric MAXI 161 having a 39 cm field and fitted with a low energy parallel hole collimator interfaced with a General Electric Star analysis syste .

Activity calculations: The counts were corrected for background, radioactive decay and dead time. (Parker, R P, Smith, P H S & Taylor, D M "Basic Science of Nuclear Medicine" (1978) ; Churchill Livingstone; Edinburgh)

EXAMPLE 1

QQm

Labelling of High Density Pellets with Tc and in vitro Testing of

Leaching

Preparation of Cores of Barium Sulphate with Incorporated Tracer Binding Agent

Cores were prepared from the following ingredients:

Barium sulphate 70.0%

Bolus Alba 10.0%

Talc 6.0%

Microcrystalline cellulose 7.0%

Calcium stearate 2.0%

Polyvinylpyrrolidone 2.0%

Ethylcellulose 0.5%

Amberlite® CG 400 2.5%

100.0%

A mixture of the above ingredients was moistened with isopropanol and purified water and mixed until the mixture was a tittle lumpy.

The moist mixture was extruded through a 0.75 mm sieve. The result¬ ing extrudate consisted of strings breaking off in lengths - of -a few cm.

The extruded strings were broken into small particles and formed into compact-shaped cores in a marumerizer.

Coating of Cores with Diffusion Coating

A diffusion coating suspension was prepared from the following ingre¬ dients:

MPI

Ethylcellulose 4.5%

Acetyltributylcitrate 0.5%

Isopropanol 95.0%

100.0%

The cores were coated with 5% of the coating material (calculated as w/w of dry ingredient in the coating suspension to dry ingredient in the cores) . The coating procedure was performed in a fluidized bed. Finally, the pellets were sieved (sieve fraction 0.71 - 1 .0 mm) .

Application of Gamma Emitter

QQm 99

Tc pertechnetate solution was prepared by eluting a Mo column

(Tecegeπ®) with a 0.9 N sodium chloride solution .

0.6 g of the pellets was soaked in 0.5 ml of the eluate having a radioactivity of approximately 1 .25 mCi/ml . The soaking was stopped by removing the solution by means of a needle and syringe, after which the pellets were rinsed in 1 ml of water.

In vitro Testing

Various samples of pellets were soaked for various soaking periods as appears from Table 1 . Some of the samples were tested for leaching of the radioactive substance by immersion in 5 ml of artificial gastric fluid, pH 1 .2, and 5 ml of artificial intestinal fluids, pH 7.5, respect¬ ively, while other samples were kept for later measurement of the radioactivity.

The radioactivity of the pellets, the soaking liquid, the rinsing li- quid, and the artificial fluids was measured by counting in a gamma scintillation well counter after a period of time sufficient for the radioactivity to be within the measuring range of the counter. Based upon the measurements, the activity of each of the samples at the elution time was calculated.

OMP

The results appear from Table 1

Table 1 Measurement of Radioactivity in yCi, Values Calculated for Elution Time

Radioactivity μCi

Experiment Soaking Soaking Rinsing Artificial Artificial Pellets

No. time Liquid Liquid gastric intestinal fluid fluid

1 1 h 40 min 208 60.4 _ _ 60.9

2 4 h 157 33.1 - - 99.4

3 21 h 58 12.4 2.40 ¹ 10.2 ² 237

4 21 h 73 40.0 2.99 ¹ 17.6 ³ 230

5 21 h 46.6 21 .4 - 24.6" 301

¹ = immersion 1 h

² = immersion 17 h

³ = immersion 44 h ^ft = immersion 66 h

It appears from Table 1 that it is possible to form an association be- tween the tracer-binding agent and the radioactive -tracer substance within reasonably short periods . Even a labelling period of 1 h 40 min results in a satisfactory activity of the pellets . It also appears that the release from the pellets in gastric fluid and intestinal fluid is relatively low, in view of the fact that even over a period of 66 hours in intestinal fluid, less than 10% of the radioactivity had leached.

EXAMPLE 2

Labelling of Low Density Pellets with Core-bound Tc and in vitro

Testing of Leaching

Preparation of Paraffin Cores with Incorporated Tracer Binding Agent

Paraffin was extruded through a 0.5 mm sieve. The resulting extru¬ date consisted of strings breaking off in lengths of about 10 cm.

The extruded strings were mixed with 2.5% of Amberlite® CG 400, calculated on the combined weight of the paraffin strings and the Amberlite®. Simultaneously with the mixing, the mixture was powdered with microcrystalline cellulose to avoid adhesion between the paraffin strings. The resulting mixture was extruded five times through a 0.5 mm sieve. Between the extrusions, the strings were powdered with microcrystalline cellulose.

The strings were immersed in water and mechanically broken into small particles by means of a stirrer.

The resulting cores were coated with a diffusion coating in the same manner as described in Example 1. The amount of coating applied was 5% of coating solids, calculated on the weight of the uncoated cores.

In vitro Testing

The resulting pellets were labelled with Tc and tested as descri¬ bed in Example 1 . The activity of the fluids and the pellets was mea¬ sured as described in Example 1 .

The results appear from Table 2.

Table 2 Measurement of Radioactivity in μCi, Values Calculated for Elution Time

Radioactivity μCi

Experiment Soaking Soaking Rinsing Artificial Artificial Pellets

No. time Liquid Liquid gastric intestinal fluid fluid

^r 1 1 h 40 min 111 88.8 _ _ 58.2

2 4 h 233 32.4 - - 42.9

3 21 h X 38.6 15.5 ¹ 9.5 ² 145

4 21 h no 7.64 4.2 ¹ 13.0 ³ 199

5 21 h 86.1 19.7 5.4 ¹ 15.1 * 254

¹ = immersion 1 h

² = immersion 17 h

³ = immersion 44 h * = immersion 66 h

X = the particles absorbed all the soaking liquid.

It appears from the data of Table 2 (Experiments 3, 4, and 5) that the reproducibility of the labelling is not quite satisfactory, which is believed to be due to trapping of labelling fluid between the paraffin microflakes formed during the extrusions .

EXAMPLE 3

Labelling of Low Density Pellets with Surface-bound ^m Tc and in vi¬ tro Testing of Leaching

Preparation of Cores of Paraffin with Tracer Binding Agent Applied on the Surface

Paraffin strings were made by extruding paraffin through a 0.5 mm sieve. The resulting extrudate consists of strings breaking off at lengths of about 10 cm.

The strings were immersed in water and mechanically broken into small particles by means of a stirrer. The water was removed, and the particles were heated to approximately 35°C. Thereby, the sur¬ face of the particles softened, and 10% by weight of Amberlite® CG 400 was added by powdering while stirring with a pestle. Thereby, about half of the Amberlite® adhered to the surface of the particles.

The resulting cores with Amberlite® applied at the surface were coated with a diffusion coating (5%, calculated on the weight of the cores) in the same manner as described in Example 1 .

In vitro Testing

The resulting pellets were labelled with Tc and tested in the same manner as described in Example 1 . The activity of the fluids and the pellets was measured as described in Example 1. The results appear from Table 3.

OMPI

Table 3 Measurement of Radioactivity in μCi, Values Calculated for Elution Time

Radioactivity μCi

Experiment I nterrup- Soaking Rinsing Artificial Artificial Pellet No. ted after Liquid Liquid gastric intestinal fluid fluid

1 1/2 h 12.6 - - 3.45

2 1 1/2 h 1.78 - - 12.0

3 24 h 1.03 0.380 0.337 ¹ - 10.8

4 24 h 1.08 0.162 0.303 ¹ 14.5

5 24 h 1.61 0.141 0.15 ² 9.45

¹ = immersion 24 h

² = immersion 49 h

It appears from these data that the reproducibility of the labelling is better than in Example 2. Also, it is seen that the stability of the labelling is satisfactory.

EXAMPLE 4

Labelling of Medium Density Pellets with Tc and in vitro Testing of Leaching from Whole and G round Pellets

Preparation of Cores with a density of 1 .3 g/ml

Cores were prepared from the following ingredients:

Lactose 30%

Microcrystalline cellulose 25%

Sucrose 25% Hydroxypropylmethyl cellulose 10%

Amberlite® CG400 10%

100%

The cores were prepared and coated with 2.5% coating suspension (per cent by weight calculated as dry matter on the weight of the cores) as described in Example 1 (except that only water was used as the moistening agent) . Finally, the cores were sieved, and the 1 .0- 1 .19 mm sieve fraction was selected .

In vitro Testing of Whole and Ground Pellets

Tc pertechnetate solution was prepared as described in Example 1 -

The eluate was diluted to give 0.7 μCi/ml . Four samples (each 0.60 g) were labelled with 1 ml of the Tc pertechnetate solution for 3 hours. The liquid was removed and the labelled pellets were rinsed in 4 ml isotonic NaCI solution .

Two of the samples were ground in an agate mortar, and the four samples were then placed in artificial gastric fluid (0.1 N HCI solu¬ tion) for 2 1/2 h . The fluid was removed from the pellets . The acti¬ vity of the pellets and the fluid were measu red in the dose calibrator in order to determine leaching from the pellets . The results appear from Table 4.

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Table 4 Leaching from Whole and Ground Pellets

Whole G round

Activity μCi pellets [9 275 242 232 Activity μCi fluid 4,54 4,51 3, 62 4,03 % Leaching 1 ,82 1 ,64 1,50 1 ,74

Average leaching in % 1 ,73 1 ,62

Thus, this formulation with effective granulating excipients resulted in low leaching. The coating was not observed to contribute further to the reduction of the leaching. The reason for this is probably that, due to the granulation, the resin particles are not exposed to the artificial gastrointestinal fluid to any significant extent even when ground .

EXAMPLE 5

In vitro Testing of the Effect of Coating upon Leaching from Tc- Labelled Ion Exchange Resins

Preparation of Uncoated and Coated Ion Exchange Resins

A diffusion coating suspension was prepared from the following ingre¬ dients:

Ethyl cellulose 2.5% Isopropanol 97.5%

100.0%

Two samples of an ion exchange . resin (Amberlite® CG 400) were

coated with 24% and 50%, respectively, of coating material (calculated as w/w of dry ingredient in the coating suspension to ion exchange resin) . The coating was performed in a fluidized bed .

Application of Gamma Emitter

99. 99 Tc pertechnetate solution was prepared by eluting a Mo column (Tecegen®) with a 0.9 N sodium chloride solution .

2 x 0.3 g of an uncoated and of each of the two coated samples of ion exchange resin were soaked in 1 .8 ml of the diluted eluate having a radioactivity of approximately 0.7 mCi/ml . The labelling was stopped after 3 hours by removing the solution, after which the pellets were rinsed in 4 ml isotonic NaCI solution .

In vitro Testing

The samples were tested for leaching of the radioactive substance by immersion in 5 ml of artificial gastric fluid, pH 1 .0, for 2 1/2 hours.

The fluid was removed from the resins by means of a needle and sy¬ ringe. The radioactivity of the resins and the fluid was measured in the dose calibrator.

The results appear from Table 5.

Table 5 Leaching from Uncoated and Coated Ion Exchange Resins

Uncoated ⁺ 24% ⁺ 50% coating coating

Activity μCϊ resin 282 290 333 337 320 355 Activity μCi fluid 7.0 5.3 1 .8 3.0 4.0 4.1

Average leaching, % 2. 17 0.72 1 .21

Thus, the effect of the coating is statistically significant on a 5% level as calculated by an analysis of variance.

EXAMPLE 6

In vivo Testing of the Leaching from Two Similar High Density For- mulations

Preparation of Pellets

Two batches of cores were prepared as described in Example 1 with 2.5% Amberlite® CG 120 and 2.5% Amberlite® CG 400, respectively, thus containing two different tracer-binding agents capable of binding two different isotopes ( I n and Tc) . The cores were coated with the same coating solution as in Example 1 , but using 20% by weight of coating solids, calculated on the weight of the uncoated cores. The two batches did not differ in their physical characteristics with res- pect to shape, size, density and surface.

111 A sample of each batch (0.80 g) were labelled with 0.22 mCi In

99m and 0.80 Ci Tc, respectively, for 21 hours as described in

Example 1 .

In Vivo Stability

The two samples were co-administered to a healthy volunteer (in¬ formed consent was obtained) . Anterior and posterior pictures (samp¬ ling time: 1 min . ) were recorded by means of Y-camera I . The subject was placed in front of the camera in a standing position .

The pictures were recorded using the "Dual isotope" facilities of the camera, thus making it possible to calculate the countings from each of the two isotopes separately. Regions of interest containing the whole of the stomach (including antrum) were drawn on the computer.

The geometric mean (of the anterior and posterior pictures) of the

countings for each isotope in the regions of interest was calculated and corrected for decay and background activity.

The corrected activity in the stomach as a function of time appears from Table 6:

5 Table 6

Corrected Activity in the Stomach as a Function of Time

99m-,- o *

Time (min. ) after Tc % of ^{1 1} lπ % of administration maximum value maximum value

10

3.00 97.91 98.62

19.00 100.00 98.55

44.00 96.70 100.00

60.00 87.27 96.67

15 - 8855..0000 7 744..7744 74.85

100.00 64.46 78.18

110.00 75.53 77.56

120.00 82.71 82.93

130.00 76.57 75.95

20 114477..0000 7 788..5555 80.00

Furthermore, pictures of thyroid and bladder were recorded, as any

^•» 99m -

Tc (in the form of TcO , ) leaching from the pellets would invari¬ ably be absorbed in the intestines and accumulated in these organs.

25 No activity, neither in the thyroid nor in the bladder, was detected in the course of the study.

Thus, no activity in detectable amounts was leaching from the ^m Tc- labelled pellets and, as the ^99m Tc- and ^{1 1 1} In-labelled pellets have the same physical characteristics and thus behave similarly in the gastro-

30 intestinal tract, it may be concluded that no detectable leaching of In was present either, as liquid I n would otherwise have emp¬ tied much faster from the stomach, which would have given rise to a

faster emptying of the decay- and background-corrected in I n activi¬ ty from the stomach compared to the emptying of the decay- and

99m background-corrected Tc activity.

EXAMPLE 7

Gastric Emptying of Low and High Density Pellets

Preparations

A sample (0.29 g) of pellets (density 1 .0 g/ml) prepared and labelled with ^m Tc as described in Example 3 and a sample (0.80 g) of

111 pellets (density 1 .6 g/ml) prepared and labelled with I n as de¬ scribed in Example 6 were tested in vivo. The two samples differed in their physical characteristics only with respect to the density as the same coating material and the same size of the individual pellets (the same sieve fraction) was used. Further, the compact shape of the individual pellets and the number of pellets in each sample were similar.

Administration

The samples were co-administered to a healthy volunteer (informed consent was obtained) , and the activity in the stomach was registered with a 7-camera as described in Example 6.

Results

99 The results appear from Fig . 1 . Curve A shows the activity of Tc in the stomach region representing the low density pellets . No activi¬ ty leaves the stomach for the first 3 hours because the low density pellets tend to float on top of the stomach fluid (which could easily be seen from the 7-camera picture) . But once the su rface of the stomach fluid passes below the smaller stomach wall cu rvatu re, the

111 emptying is quick. Curve B represents I n corresponding to high

OMPI

density pellets . Some activity leaves the stomach relatively fast (this is not leaching as was proven in Example 6) whereas the rest of the pellets _. was stuck in the antrum for a long time (which could also easily be seen from the T-camera pictu re) .

I n conclusion, the density has a significant effect upon the emptying pattern . Furthermore, the Y-camera pictu res distinctly show the difference and the separation between the two types of pellets .

EXAMPLE 8

Pellets as Solid Food Markers

Preparation of Cores with a Density of 1.3 glmt

Cores were prepared from the following ingredients :

Lactose 40%

Microcrystalline cellulose 25% Sucrose 25%

Hydroxypropylmethyl cellulose 5%

Amberlite® CG400 5%

100%

The cores where prepared and coated with 5% of coating suspension (per cent by weight calculated as dry matter on the weight of the cores) as described in Example 1 . -

Finally, the resulting pellets were sieved and the 0.71 -1 .0 mm sieve fraction was selected .

Study

A sample (0.6 g) of the pellets was labelled and administered to a

OMPI

person (informed consent was obtained) as described in Example 5. After an overnight fast, the person was given an "Amdrup beef" (consisting of 150 g tenderloin, 150 g potatoes and 15 g butter with¬ out salt and spices) and 100 ml of Mixobar®, which was ingestec? over 15 minutes . Then the pellets were administered on a spoon and the patient was further given a small amount of water. No smoking or eating was allowed du ring the study.

The patient was asked to lie down and turn 360° . Then the patient was asked to stand in front of the Y-camera . Anterior pictures were recorded every 15 minutes during the first 90 minutes and then every 30 minutes until no activity was left in the stomach.

Pictures were recorded with Y-camera I I . The pictures were recorded for 1 minute using the "Dynamic study" facilities of the camera. Regions of interest containing the whole of the stomach (including antrum) were drawn on the computer. The countings were corrected for decay and background activity. Furthermore, X-ray pictures were recorded.

After some hours, the Y-camera pictu res showed that only about 10% of the pellets were left in the stomach whereas the X-ray pictu res postulated a full stomach .

Gastroscopy

A gastroscopy was performed. nd two doctors independently estimated _* the volume of the remaining food bolus to be approximately 50 ml cor¬ responding to approximately 10-15% of the administered volume. At the same time, the gastroscopy revealed that the inside of the stomach was coated with BaSO , in spite of the fact that Mixobar® is acknow¬ ledged to be the least mucosa-coating BaSO . preparation available. Finally, a pellet-free sample of the bolus was aspirated through the gastroscope tube. The radioactivity of the aspirated sample was detected on the dose calibrator. No activity was detectable even though the lower detection limit of the dose calibrator is as low as 0.01 μCi, and the total dosis administered was 50 μCi .

OMPI

Conclusion

Thus, the radioactive pellets of the invention appear to be a far better solid food marker than is BaSO _* . The fact that no detectable leaching took place in vivo from the pellets of the invention shows that these may be used as reliable markers of the gastric emptying of the last 20% of a solid food bolus.

EXAMPLE 9

Diagnosing "Giesskannen" Phenomenon (Case Story)

Study

8 samples of the pellets prepared in Example 8 were labelled as de¬ scribed in Example 4 and administered to 8 fasted persons (informed consent was obtained) with 150 ml of water.

Pictures were recorded and data processed as described in Example 8.

The average emptying pattern observed in 7 of the 8 persons is represented by curve A in Fig. 2, whereas the last person showed the emptying pattern seen in curve B in Fig. 2.

X-ray anatomy studies of the gastro-intestinal tract of said last person showed a "Giesskannen" phenomenon .

Conclusion

Thus, due to their freedom from leaching and their associated ex¬ cellent capability of functioning as markers of also the last 20% of a solid food bolus, the pellets of the invention are useful as a diag¬ nostic tool to diagnose the "Giesskannen" phenomenon .

EXAMPLE 10

Pre-Anastomosis Diagnosis (Case Story)

Medical Background

A patient who had previously undergone a parietal cell vagotomy complained of abdominal pains and vomiting after meals . When the condition was investigated by traditional diagnostic techniques (X-ray and gastroscopy) no abnormalities were revealed. The initial diagnosis was therefore a possible retention and it was considered to perform an anastomosis . However, it was decided to first diagnose his condi¬ tion by means of the tracer substance-labelled pellets of the inven¬ tion .

Study

A sample (0.6 g) of the pellets prepared in Example 8 was labelled as described in Example 4. ^" The pellets were administered (with 100 ml of water instead of the Mixobar®) , the pictures recorded and the data processed as described in detail in Example 8.

Conclusion

The results showed that the patient had an unusually fast gastric emptying . As the anastomosis would have caused an even faster gastric emptying, it would probably in this case have caused the dumping syndrome to occur.

The reason why the fast gastric emptying had not been detected with the X-ray techniques is presumably that the mucosa had been coated by the Mixobar® used as contrast agent in the X-ray examination .

OMPI

EXAMPLE 11

Prepyloric Ulcer (Case Story)

Study

A patient with a prepyloric ulcer was tested to see whether his ga¬ stric emptying was disturbed.

A sample (0.6 g) of the pellets prepared in Example 8 was labelled as described in Example 4. The pellets were administered with 150 ml of water. Pictures were recorded as described in detail in Example 9.

During the gastric emptying, a small hot spot was clearly visible on the screen at the same place where the ulcer was located.

Conclusion

This is a remarkable phenomenon which indicates the usefulness of the composition of the invention for determining the position of ga- stric ulcers . Compared to the two other major methods available for determining the position of gastric ulcers, that is, administration of a BaSO , meal and X-ray determination, and gastroscopy, both of which are counterindicated when the patient is weak, the use of the compo¬ sition of the invention is highly preferred.