WO2019073259A1

WO2019073259A1 - Methods of forming solid or liquid charged capsules

Info

Publication number: WO2019073259A1
Application number: PCT/GB2018/052942
Authority: WO
Inventors: Luca MARCIANI; Roy Harris; Kathryn MURRAY; Dave FAWKES; Mike Phillips; Bruce Renfrew; James Williamson
Original assignee: Nottingham University Hospitals Nhs Trust
Priority date: 2017-10-13
Filing date: 2018-10-12
Publication date: 2019-04-18
Also published as: GB201716851D0; GB2569266A

Abstract

A method of forming solid or liquid charged capsules for oral administration is disclosed. The method comprises the steps of providing a tube (510) of plastic material, at least partially charging said tube (510) with a solid or liquid material (520), and submitting the tube (510) to the action of heat and/or pressure by means of opposed cooperating dies (100,200) so as to divide the tube (510) into individual sealed capsules containing the solid or liquid material (520).

Description

Title - Methods of forming solid or liquid charged capsules

This invention relates to capsules useful in methods for the study of

gastrointestinal transit in a human or animal subject, and to methods of making such capsules.

Abnormalities of gastrointestinal (Gl) transit (both oro-coecal, small bowel and colonic transit) are a common underlying cause of gastrointestinal symptoms. The prevalence of functional Gl disorders in the general population is 25-40% and this accounts for up to 40% of Gl clinic consultations. Such patients often present with diffuse Gl motility disorder. In particular, constipation affects 12%-19% of the population with a general estimated annual cost of US$235m, which equates to US$7,522 per patient. Where a subject has an abnormality of Gl function it is often necessary to assess the time taken for matter (mostly food and bacterial matter) to pass through the subject's Gl tract (referred to as 'Gl transit time'). As well the transit time for the whole gut, small bowel transit (SBT), regional colonic transit and colonic transit may be of particular interest and relevance in the assessment of disease states. Direct assessment of Gl transit time is often required to establish an accurate diagnosis and direct therapy. In some cases, the outcome of the assessment may be surgery, including stomas to flush the bowel or resection of a part of the Gl tract that is not functioning properly. Current methods of assessing Gl transit are based on nuclear medicine

techniques which make use of ionising radiation, such as gamma scintigraphy and X-ray. Subjects are either fed a standard meal labelled with radioactive tracers or they ingest commercially available radio-opaque markers and undergo X-ray.

Such methods may be inconvenient or unpleasant for the subject, and the use of ionising radiation is generally undesirable and may be prohibited for certain groups of patients. In particular, disorders of the Gl tract are a significant problem amongst paediatric patients. Nine percent of children worldwide suffer from constipation at some point in their lives. Constipation becomes chronic in a third of these children with a great impact both on their and their families' well-being. Many are referred to hospital and some undergo surgery. In the hospital setting, paediatric constipation forms 3% of all referrals to paediatric practice and up to 25% to paediatric gastroenterologists. Functional constipation can markedly impair quality of life and results in repeated consultations, treatment attempts and various investigations. A recent U.S. study suggests that there is a great cost of health resources for children with constipation, estimated at $3.9 billion/year. In Britain, 34% of children aged 4-1 1 years are reported to have had constipation. Of these, 5% had complaints for more than 6 months. Managing these young patients is difficult. Direct and early assessment of Gl transit time can confirm the presence of slow transit, provide insight into the causes of disease, stratify the patients (e.g. slow-transit constipation and Irritable Bowel Syndrome-constipation), direct therapy and monitor responses. However, at present, this is not done routinely in children because of a lack of standardized methodology and concerns regarding the use of ionising radiation in this young population. In the UK, early use of X-ray and current transit studies are explicitly ruled out by NICE (National Institute for Health and Care Excellence) clinical guidelines and are only to be considered as a specialist service in cases of intractable constipation. Physicians therefore rely mostly on symptoms, often as reported by the child's parents. Uncertainty leads to repeated appointments and treatments, unhappiness with the results and waste of health service resources. Similar concerns apply to other groups for which the use of ionising radiation is precluded, eg pregnant women or women of child-bearing age.

Other minimally invasive methods include the breath test and radio-telemetry pills. In the breath test, a ¹³C tracer is ingested with a meal and its appearance later detected in the breath of the subjects. However, the ¹³C label needs to be metabolised first and variability is large. Radio-telemetry pills have recently appeared on the market and received FDA approval to measure Gl transit but their usefulness and reproducibility are still to be evaluated. Magnetic resonance imaging (MRI) is a non-invasive imaging technique which has become widely used in medicine due to its ability to produce high quality images without the use of ionising radiation. Conventional clinical MRI relies on the fact that hydrogen nuclei (¹H) present in the body (eg as water molecules) absorb and re-emit energy at a characteristic radio frequency when placed in a strong magnetic field. It is possible to detect the abundance of hydrogen nuclei present in the body, their location, and the type of tissue in which they are present using various well known MRI techniques. Contrast agents such as gadolinium are available which alter the appearance of a tissue in which they are present, making that tissue more visible to ¹ H MRI. Other nuclei such as, for example, sodium (²³Na), fluorine (¹⁹F) and carbon (¹³C) yield an MRI signal, though their use is far less developed than the use of hydrogen nuclei. MRI has also been used in experimental studies of Gl transit. Such studies have involved the ingestion by a patient of capsules containing MRI-detectable materials, typically gadolinium-doped water. In other studies, capsules also contained a fluorine-containing compound detectable by ¹⁹F (as opposed to ¹ H) MRI.

Whilst such studies have shown that MRI methods can in principle be used to monitor Gl transit, those methods hitherto proposed suffer from a number of disadvantages. The capsules that are used have necessarily been rather large, typically with dimensions of 20mm or more. This makes them relatively difficult to ingest, particularly for elderly or paediatric patients. More significantly, such large capsules may not pass through the Gl tract in a manner that is truly representative of Gl transit. In particular, the capsules may leave the stomach rather more slowly than food, but then pass through the rest of the Gl tract more quickly. In the case of methods involving more than one MRI nuclide (ie more than one MRI-detectable nucleus, eg ¹H and ¹⁹F), the methods may be difficult or impossible to carry out using standard MRI scanners, which are normally designed only for ¹H MRI. There is thus a need for improved non-invasive methods of monitoring Gl transit that accurately reflect the manner in which food is transported through the subject's Gl tract. It is particularly desirable that such methods should be applicable to elderly and paediatric patients.

According to a first aspect of the present invention, there is provided a method of forming solid or liquid charged capsules for oral administration, which method comprises the steps of

a) providing a tube of plastic material;

b) at least partially charging said tube with a solid or liquid material; and c) submitting the tube to the action of heat and/or pressure by means of

opposed cooperating dies so as to divide the tube into individual sealed capsules containing the solid or liquid material.

This method of forming solid or liquid charged capsules is particularly

advantageous because it allows charged capsules with significantly smaller dimensions than were previously possible to be manufactured in a straightforward manner. Charged capsules having small dimensions are very difficult to produce. The existing methods of charging capsules are either extremely fiddly when significantly reduced in size and therefore the manufacturing costs are too high or the methods are impractical to reduce in size, for example complete charging is often not possible which in the case of a very small capsule means that the volume of material encapsulated is too small to be detected. By forming the capsules from a pre-charged plastic tube, the problems involved in first forming a capsule and subsequently charging and then sealing the capsule are overcome.

In preferred embodiments, the tube is charged with sufficient solid or liquid material to charge a plurality of capsules, and the tube is subsequently submitted to the action of heat and/or pressure to divide the tube into individual sealed capsules containing the solid or liquid material, ie the tube is not charged in a dose-wise manner. The tube may be provided with a reservoir of the solid or liquid material at an open end of the tube to ensure that the tube remains charged as the capsules are formed. Alternatively, one or both ends of the tube may be sealed prior to formation of the capsules in order to ensure that the solid or liquid material remains inside the tube as the capsules are formed. In such an embodiment, a portion of the tube may be left uncharged in order to allow for movement of the solid or liquid material along the tube as the capsules are formed.

By "charged" is meant that the tube and/or capsule may contain other material, including gases. However, in presently preferred embodiments, the portion of the tube from which the capsules are formed is charged entirely, ie filled, with the solid or liquid material.

In preferred embodiments of the method, the plastic material is not soluble in water. This is advantageous because the capsule does not dissolve when administered orally. In particularly preferred embodiments, the plastic material, and therefore also the capsule itself, remains intact on gastrointestinal transit. The conditions of gastrointestinal transit can be harsh, especially the very acidic conditions in the stomach. Although enteric coatings for tablets and the like are known and used to protect pharmaceutical compounds from degradation by stomach acid, these systems are by definition only designed to survive passage through the stomach and are intended to dissolve after exiting the stomach, for example when the pH is no longer acidic.

The plastic tube material of the capsule should therefore preferably be such that it retains its integrity in the acid environment of the stomach and the alkaline conditions prevalent in the intestines.

In preferred embodiments, the plastic material is a thermoplastic material. A thermoplastic material allows the capsule to be readily formed from the plastic tube on application of heat and pressure. Hence, the method may comprise the step of submitting the tube to the action of heat and pressure by means of the opposed cooperating dies so as to divide the tube into individual sealed capsules containing the desired solid or liquid material. In particularly preferred embodiments, the plastic material is a synthetic

thermoplastic material. By synthetic is meant a thermoplastic material that is not naturally occurring. Preferred thermoplastic materials are cellulosic thermoplastics such as cellulose acetate butyrate, polypropylene, polyamides such as nylon 6,6, polyethylenes, in particular low density polyethylenes, and polyurethanes.

Currently preferred thermoplastics are polyamides, in particular nylon 12.

Preferably the thermoplastic is not polyvinyl chloride (PVC).

The plastic material of the tube is preferably a medical grade plastic.

Preferably the plastic material of the tube is substantially rigid. In particular, the plastic material is preferably sufficiently rigid to retain its shape when subjected to the forces of the gut which are commonly up to 1 -2N. The capsule preferably has sufficiently small dimensions that it may easily be ingested by the subject, even if the subject is an elderly person or a child.

Preferably, the largest dimension of the capsule does not exceed 10mm. More preferably, the largest dimension of the capsule does not exceed 5mm. The largest dimension of the capsule may be of the order of 1 mm or 2mm or 3mm. Thus, the capsule may have a maximum dimension of from 0.5mm to 10mm, or from 0.5mm to 5mm, or from 0.5mm to 3mm.

Preferably the cross-sectional diameter of the plastic tube is therefore between 0.5mm and 10mm, preferably the cross-sectional diameter of the plastic tube is approximately 4mm.

The thickness of the tubing wall is between 0.1 mm and 1 .0mm, preferably between 0.3mm and 0.5mm, preferably about 0.4mm. The capsule preferably has a volume of about 50 to 150μΙ, preferably 50 to 100μΙ, preferably 50 to 70μΙ, most preferably about 60 μΙ. The capsules of the invention are particularly useful in the assessment of Gl transit in paediatric patients, young patients (eg up to 21 years of age) and women of child-bearing age. In such patients, conventional use of X-rays is discouraged. MRI markers that are small are relatively easy to ingest and behave within the Gl tract in a manner that is representative of Gl transit in the subject.

The container may be spherical or non-spherical. Spherical containers may be preferred for reasons of manufacturing simplicity, particularly in the case of very small containers. However, non-spherical containers may be more readily discernible in MRI images and oblong containers may be easier to swallow than disk or spherical shapes. In presently preferred embodiments, the capsules comprise a cylindrical intermediate portion, with approximately hemispherical ends. The shape of the capsule can be selected by choosing an appropriately shaped set of opposing dies.

The step of dividing the tube into individual sealed capsules may comprise a single step process or a plurality of steps.

If the process is a single step process, the opposing dies are shaped to

correspond to at least part of, eg an end region of, the shape of the desired capsule, for example if the capsules to be formed are spherical or with

hemispherical ends, then each die may have a recess with at least part of a hemispherical profile. The parts of the opposing dies that are shaped to

correspond to the shape of the desired capsule may be those parts that require formation, relative to the original form of the tube of plastic material. For example, the parts of the opposing dies that are shaped to correspond to the shape of the desired capsule may represent end regions of the capsule, with an intermediate portion of the length of tube that forms each capsule not being deformed or pressed during manufacture.

By using a single step process, the process has a better procedural economy as one capsule is produced per step. However, by forming each capsule with a single set of dies in one process, the capsule is subjected to a more intense and concentrated heating procedure. The contents of the capsule may therefore get too hot if a single step process is utilised. A multistep process may therefore be preferred. In a multistep process, the dies may comprise two opposed open ended recesses in series such that, in each capsule forming step, the front end of one capsule and the back end of another capsule are formed concurrently. This process is advantageous because less heat is applied to each capsule at one time but also because it enables the size of the capsule to be varied by varying the distance that the tube is progressed through the apparatus between each application of the die. For example, if the tube is progressed further after the application of the die, the capsule produced is longer and therefore has a larger volume.

To reduce the effect of heat on the contents of the capsule, the method may also provide means of cooling the main body of the capsule as the capsule is formed by the dies. Portions of the dies themselves may be selectively cooled.

The dies may also be shaped such that they can cut the formed capsules into individual isolated capsules during the same step as forming the capsules. For example, the dies may comprise a sharp edge or blade at the points at which the opposing dies meet one another. Alternatively, the capsules may be cut away from the tube after they have been formed using a separate cutting means.

The tube may be progressed through the cooperating dies after a capsule has been formed or between steps of forming the capsule if the capsule is formed by a multistep process. The tube may be progressed by automatic means. The means may progress the tube by a predetermined distance each time a capsule is formed. Whatever the nature of the capsules, they preferably have a density that is comparable with that of the stomach contents, ie ingested food material and chyme, so that the capsules do not sink to the base of the stomach or float within the stomach, which could delay the passage of the capsule from the stomach. Thus, the capsule preferably has a density of 1 .0-1 .5 g/cm³, more preferably 1 .0- 1 .2 g/cm³.

The capsules are preferably charged with a material which is detectable by MRI.

The capsules may be charged with a solid or liquid material. Preferably the material is a liquid material. Using a liquid material enables the tube to be pre- charged with the relevant material more easily. The capsules may be charged with more than one liquid. The liquids are preferably contrasting and more preferably distinguishable from one another by MRI.

The first and second fluids are thus conveniently fluids that contain an abundance of the same nuclide, but in which that nuclide occupies different chemical environments such that the resonant frequencies of the nuclide in the two fluids differ sufficiently. Preferably, the fluids are also such that they are non-toxic and physiologically compatible, so that they do not present a risk to the subject if released from the container. A particularly convenient combination of first and second fluids is water (or a water-containing aqueous medium) and an oil. Typically, the first fluid is aqueous. Thus, the first fluid may be water or an aqueous solution, or as described below it may be the aqueous phase of an oil-in- water or water-in-oil emulsion. The first fluid may contain a solute that modifies the MRI properties of the first fluid. Such a solute may be a material that is known for use as a contrast agent in MRI. Such materials typically function by altering the magnetic resonance relaxation times of the first fluid, and include gadolinium salts and other paramagnetic ions. The nature of the first and second images, and hence of the composite image, may be optimised by appropriate choice of the concentration of the solute in the first fluid.

A wide variety of oils may be suitable for use as the second fluid. Typically, such oils include oils from vegetable, marine or animal sources. For instance, the oil may be selected from the group consisting of well-known and widely available oils such as olive oil, corn oil, soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seed oil, hempseed oil, herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose oil, and mixtures thereof.

Other forms of oil, such as mineral oils and silicone oils may also be suitable.

However, the use of an oil that is found in foodstuffs, and hence is known to be non-toxic in the event that it were to be released from the container within the subject's Gl tract, is preferred.

The first fluid and/or second fluid may have the form of a gel. The gel may be one that is relatively solid at ambient temperature, to facilitate manufacture, handling and administration to the subject, but which becomes fluid, and therefore easier to image by MRI, at body temperature.

The methods of the present invention may utilise the magnetic resonance properties of any nuclide. However, in the overwhelming majority of cases the nuclide of interest will be ¹H. Standard, commercially available MRI equipment is adapted for ¹ H imaging, and suitable fluids for use in the invention contain high proportions of ¹H nuclei (eg water and vegetable oils and the like). The first and second fluids may be intimately mixed. Hence, the first and second fluids may constitute distinct phases of a colloidal dispersion such as an emulsion. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.

According to a second aspect of the invention there is provided an apparatus for manufacturing solid or liquid charged capsules comprising opposing dies movable between open and closed positions, wherein the dies comprise recesses which in the closed position together form at least part of the shape of the desired capsule, and means of applying pressure and heat to the dies. Preferably the apparatus further comprises means for progressing, or indexing, a tube between the dies when the dies are in an open position. The opposed cooperating dies may be mounted for reciprocating motion, relative to each other. For example, one die may be stationary, and the other die may be mounted for reciprocating motion, eg drive by a reciprocating shaft. The surfaces of the dies that press the tube may be substantially flat, and the surfaces of the tube that form the walls of the capsule may be recesses in the substantially flat surfaces of the dies. The dies may be arranged to weld the walls of the tube together, between the capsules, through the action of heat and pressure.

One or both of the dies may include a heater, in order to provide the action of heat. The heater may be mounted to a surface of the die, eg within a bore extending through the die. The dies may also include a temperature sensor, such that an associated controller may determine the required temperature, which may be set according to the plastic material and/or solid or liquid material being used.

The apparatus may include a guide for the tube, as it is advanced through the cooperating dies. Preferably, the apparatus is for use in a method according to the first aspect of the invention. The dies and apparatus may have any of the preferred features of the method according to the first aspect of the invention.

According to a third aspect of the invention there is provided a capsule

manufactured by the method of the first aspect of the invention. It will be appreciated that any feature discussed above in relation to the first aspect of the invention applies equally to the third aspect of the invention where appropriate.

The invention further provides a method of assessing Gl transit in a human or animal subject, which subject has previously ingested a container formed by the method according to the first aspect of the invention containing a material that is detectable by MRI, which method comprises the steps of a) at a known time after ingestion by the subject of the container, forming a magnetic resonance image of at least a portion of the subject's Gl tract in which the container is located; and

b) identifying the location of the container within the subject's Gl tract at said time.

The in-phase and out-of-phase images may be formed directly, eg by double-echo imaging. Alternatively, the images may be formed indirectly, eg using double-echo or multi-echo imaging whereby the magnetizations of the first and second fluids are imaged using multiple echoes and combinations of these are formed by subsequent data processing.

Most commonly, steps a)-b) above will be repeated several times in order to track the progress of the container through the subject's Gl tract. Thus, the method may be repeated at intervals over a period of time sufficient to monitor the progress of the container through the Gl tract or a part thereof, and to enable a meaningful conclusion to be drawn in relation to the function of the Gl tract, or of selected segments of the Gl tract, in terms of transit time. Thus, images may be generated a number of times over the course of a time period that is long enough for the passage of the container through the subject's Gl tract to be tracked sufficiently for the required clinical assessment of Gl function to be possible. Such a time period may be up to 12 hours, or up to 24 hours, or up to 48 hours, or more. The number of times that images are generated during that period may be from 2 to 4, or up to 6, 8, 10, 12 or more.

In general, the method will involve the ingestion of a plurality of containers, not least in order to maximise the likelihood of at least one container being discernible in the MRI images. The number of containers that are ingested will depend on a number of factors, including the size of the containers. As described below, in some embodiments of the invention, the containers have dimensions of the order of a few millimetres. In such cases, the subject may typically ingest up to 24 containers or more, eg from 2 to 20, or from 2 to 10, or from 2 to 8, or from 2 to 6 containers. Containers may be ingested by the subject at more than one time. Thus, a first container (or a first plurality of containers) may be ingested at a first time, and a second container (or a second plurality of containers) may be ingested at a second, later time. Where containers are ingested at two or more time points, it may be desirable to distinguish those containers from each other. This may be achieved by various means. For instance, the containers may have different shapes that are discernible in the MRI images. Alternatively, one or both of the fluids in the different containers may be distinguishable on the basis of their MRI properties. For instance, one of the fluids may be water doped with differing concentrations of a contrast agent such as gadolinium, the effect of which is that the aqueous fluids in different containers have differing relaxation times, so that they can be distinguished from each other by appropriate choice of imaging parameters.

"Detectable by MRI" when applied to the first and second fluids in the context of the first aspect of the present invention means simply that the fluid contains nuclei that absorb and re-emit radiofrequency electromagnetic radiation in a manner that allows the generation of an image using standard MRI techniques. Typically, the fluid contains ¹ H nuclei, so that images may be generated using MRI equipment adapted, as most such equipment is, for the imaging of ¹H-containing material. The first and second fluids necessarily contain the same nuclide, most commonly H. "Distinguishable by MRI" when applied to the first and second fluids in the context of the first aspect of the present invention means that the nuclide of interest (most commonly ¹ H nuclei) has somewhat different nuclear magnetic resonance properties in one fluid than in the other. In general, this means that, at any given magnetic field strength, the nuclide of one of the fluids has a slightly different resonant frequency to the resonant frequency of the same nuclide in the other fluid. This is commonly referred to as one of the fluids having a slightly different chemical shift to that of the other fluid. An embodiment of the invention will be described in further detail below, by way of example only, with reference to the accompanying drawings, of which:

Figure 1 is an exploded perspective view of a first capsule formation stage of manufacturing apparatus according to the invention;

Figure 2 is an exploded front view of the first capsule formation apparatus of Figure 1 , which shows hidden detail; Figure 3 is a front view of the first capsule formation apparatus of Figures 1 and 2;

Figure 4a is a side view of the first capsule formation apparatus of Figures 1 to 3;

Figure 4b is a cross-sectional view of the first capsule formation apparatus of Figures 1 to 3;

Figure 5 is an enlarged fragmentary view of Figure 4b;

Figure 6 is an exploded perspective view of a second capsule formation stage of manufacturing apparatus according to the invention;

Figure 7 corresponds to the view of Figure 5, but for the second capsule formation apparatus of Figure 6; Figure 8 is a cross-sectional view of alternative die profiles, for use with the first capsule formation apparatus of Figures 1 to 5;

Figure 9 is a plan view of an intermediate capsule product; and Figure 10 is a plan view of a plurality of final capsule products.

A first capsule formation stage of manufacturing apparatus according to the invention is shown in Figures 1 to 5, which comprises an upper press 100 and a lower press 200, which cooperate, in use, to form an intermediate capsule product 500 from a plastics tube 510 precharged with liquid 520. This intermediate capsule product 500 is also shown in Figure 1 , as well as in Figure 9. The upper press 100 comprises a main body 1 10, which is a rectangular cuboid in shape, with generally square front and rear surfaces, and rectangular upper, lower and side surfaces. The upper surface of the main body 1 10 has an axially extending drive shaft, which is arranged for reciprocating motion, in use. The lower surface of the main body 1 10 has a die plate 1 12 co-extending therefrom.

The main body 1 10 of the upper press 100 also includes a cylindrical bore, which extends horizontally from the centre of a first side face to the centre of a second side face. The bore is open at each end, and accommodates a first cylindrical cartridge heater 130, with a close fit. The first cylindrical cartridge heater 130 projects a small distance from each end of the bore, and includes cables extending from one end of the heater 130 to power supply and control devices.

The die plate 1 12 includes formations that cooperate with corresponding formations on the lower press 200 to form the intermediate capsule product 500 from a plastics tube 510 precharged with liquid 520. These formations of the die plate 1 12 will be described in more detail below with reference to Figure 4b and 5. In addition, the die plate 1 12 includes a pair of cylindrical guide rods 1 14, which extend vertically downwards from each end region of the lower surface of the die plate 1 12.

The main body 1 10 of the upper press 100 also includes a ventilation passageway 1 16, which extends from an opening in the lower end of the front face of the main body 1 10, and extends partially, but not entirely, through the main body 1 10, with an open lower end that is in fluid communication with an opening 1 17 in the die plate 1 12.

The lower press 200 comprises an inner body 210, which is a rectangular cuboid in shape, with generally square front and rear surfaces, and rectangular upper, lower and side surfaces. The inner body 210 of the lower press 200 also includes a cylindrical bore, which extends horizontally from the centre of a first side face to the centre of a second side face. The bore is open at each end, and

accommodates a second cylindrical cartridge heater 230, with a close fit. The second cylindrical cartridge heater 230 projects a small distance from each end of the bore, and includes cables extending from one end of the heater 230 to power supply and control devices. The upper surface of the inner body 210 has a die plate 212 co-extending therefrom. The die plate 212 includes formations that cooperate with corresponding formations on the upper press 100 to form the intermediate capsule product 500 from a plastics tube 510 precharged with liquid 520. These formations of the die plate 212 will be described in more detail below with reference to Figures 4b and 5. In addition, the die plate 212 includes a pair of cylindrical guide openings 214, which extend vertically downwards from each end region of the upper surface of the die plate 212, and receive the guide rods 1 14 of the upper press 100.

The inner body 210 and die plate 212 are accommodated within a base

component 220, which comprises a rectangular base plate, and front and rear plates upstanding from each major side of the base plate, such that the base component 220 defines a rectangular channel within which the inner body 210 and die plate 212 of the lower press 200 are received. The two rectangular upper surfaces of the base component 220 each include a tube guide 222,224, which each comprises a hemi-cylindrical recess, and upstanding side walls, which together define a U-shaped channel. The tube guides 222,224 are aligned transversely across the upper surfaces of the base component 220 and the upper surface of the die plate 212, such that the tube 510 may be moved longitudinally through the guides 222,224, across the upper surface of the die plate 212, in use. The inner body 210 of the lower press 200 also includes a ventilation passageway 216, which extends from an opening in the upper end of the front face of the inner body 210, and extends partially, but not entirely, through the inner body 210, with an open upper end that is in fluid communication with an opening 217 in the die plate 212. The base component 220 also includes a ventilation passageway 226, which extends through the front plate of that component, and is aligned with the ventilation passageway 216 of the inner body 210 of the lower press 200. Referring particularly to Figure 4b and Figure 5, the lower surface of the die plate 1 12 of the upper press 100 comprises a concave recess 1 18, which leads to an opening 1 17 at the upper end of the recess, which extends with a uniform cross- section to the upper surface of the die plate 1 12, and defines a passageway therethrough. The surface of the concave recess 1 18 surrounding the opening 217 therefore has an annular form. The concave recess 1 18 of the die plate 1 12 is surrounded by a flat, horizontal portion of the lower surface of the die plate 1 12, which acts as a press on the tube 510, forming a pressed portion 512 of the tube 510, in use. In addition, on the lower surface of the die late 1 12, aligned with the concave recess 1 18 of the die plate 1 12 and the guides 222,224 of the base component 220, are depressions 1 19 adjacent to the edges of the die plate 1 12, adjacent to the guides 222, 224. These depressions 1 19 are flared and

accommodate the portion of the tube 510 adjacent to the pressed portion 512.

The upper surface of the die plate 212 of the lower press 200 has a similar form to the lower surface of the die plate 1 12 of the upper press 100, and comprises a concave recess 218, which leads to an opening 217 at the lower end of the recess, which extends with a uniform cross-section to the lower surface of the die plate 212, and defines a passageway therethrough. The surface of the concave recess 218 surrounding the opening 217 therefore has an annular form. The concave recess 218 of the die plate 212 is surrounded by a flat, horizontal portion of the upper surface of the die plate 212, which acts as a press on the tube 510, forming a pressed portion 512 of the tube 510, in use. In addition, on the lower surface of the die plate 212, aligned with the concave recess 218 of the die plate 212 and the guides 222,224 of the base component 220, are depressions 219 adjacent to the edges of the die plate 212, adjacent to the guides 222, 224. These depressions 219 are flared and accommodate the portion of the tube 510 adjacent to the pressed portion 512. During manufacture, the upper press 100 and the lower press 200 are disposed adjacent to each other, as shown in Figures 3, 4a and 4b, with the lower surface of the die plate 1 12 of the upper press 100 aligned with, and parallel to, the upper surface of the die plate 212 of the upper press 200. The upper press 100 is arranged for reciprocating motion between open position and closed positions. In the open position, the die plates 1 12,212 are separated by at least the diameter of the tube 510, such that the tube 510 may be moved longitudinally through the guides 222,224, between the die plates, without impingement. In the closed position, the lower surface of the die plate 1 12 of the upper press 100 and the upper surface of the die plate 212 of the upper press 200 are brought into near contact, such that the concave recesses 1 18,218 of the die plates 1 12,212 press the tube 510 to form the end regions of a capsule portion 514, and the flat, horizontal portions of the surfaces of the die plates 1 12,212, which act as a press on the tube 510, form the pressed portions 512 of the intermediate product 500, to the front and rear of the capsule portion 514.

The heat that is applied by the cartridge heaters 1 30,230 to the upper and lower presses 100,200 causes heat to also be applied to the tube, and particularly the pressed portions 512 of the intermediate product 500, to the front and rear of the capsule portion 514. This heat, in combination with the applied pressure, causes the tube 510 to become bonded to itself in the pressed portions 512, such that the pressed portions 512 form substantially unitary bodies of plastic material. The ventilation passageways 1 16,216,226 act to cool the capsule portion 514, and hence reduce the risk of damage to the liquid 520 and the wall of the capsule portion 514.

Once a capsule portion 514 has been formed in the intermediate product 500, the tube 510 is indexed forward, until a portion of tube 510 that has not been pressed is located between the die plates 1 12,212. The above pressing step is then repeated, the tube is indexed again, and so on, until a string of capsule portions 514 connected by pressed portions 512 are formed as an intermediate product 500. As the intermediate product 500 is formed, it is transferred to a second capsule formation stage of the manufacturing apparatus according to the invention.

The second capsule formation stage is shown in Figures 6 and 7, which comprises an upper press 1 100 and a lower press 1200, which cooperate, in use, to form a final capsule product 518 from the intermediate product 500. This final capsule product 518 is also shown in Figure 1 , as well as in Figure 10.

The upper press 1 100 and the lower press 1200 of the second capsule formation stage are almost identical to the upper press 100 and the lower press 200 of the first capsule formation stage, and hence only the differences are described below. In particular, although the upper press 1 100 and the lower press 1200 of the second capsule formation stage also apply heat and pressure, the principal difference is that the rims of the concave recesses 1 18,218 of the die plates 1 12,212, which are immediately adjacent to the flat, horizontal portions of the surfaces of the die plates 1 12,212, are formed with upstanding cutting formations, which are brought into contact, during use, to cut the final capsule products 518 from the pressed portions 512 of the intermediate product 500. Hence, during manufacture, the upper press 1 100 and the lower press 1200 of the second capsule formation stage are disposed adjacent to the upper press 100 and the lower press 200 of the first capsule formation stage, such that the final capsule products 518 are cut from the pressed portions 512 of the intermediate product 500, once the capsule portions 514 have been formed by the upper press 100 and the lower press 200 of the first capsule formation stage.

In the upper press 1 100 and the lower press 1200 of the second capsule formation stage, heat is also applied, which acts to facilitate the cutting action of the presses 1 100,1200, and also acts to smooth or remove any projecting plastics material, eg flash, at the cutting boundary.

Figure 8 is a cross-sectional view of alternative die profiles, for use with the first capsule formation apparatus of Figures 1 to 5. This alternative die profile comprises corresponding front recesses 314,315, central pressing portions

315,415, and rear recesses 316,416. The purpose of this die profile is to form only one pressed portion 512 of the tube 510 at a time, thereby reducing the heat that is applied to the tube 510 and the liquid contents 520, and hence reducing the risk of damage to the wall of the capsule portion 514 and its contents 520.

This alternative die profile is therefore arranged to form one pressed portion 512 at a time, as well as the rear end region of the leading capsule portion 514 of the intermediate product 500 and the front end region of the trailing capsule portion 514. The front recesses 314,414 are therefore concave for forming the rear end region of the leading capsule portion 514 and are open at the side wall of the die plates 1 12,212, through which the remainder of the leading capsule portion 514 extends. The rear recesses have an inner concave portion for forming the front end region of the trailing capsule portion 514, and are flared to accommodate the trailing remainder of the tube 510, which has not yet been pressed.

This method of forming solid or liquid charged capsules, and the associated apparatus, is particularly advantageous because it allows charged capsules with significantly smaller dimensions than were previously possible to be manufactured in a straightforward manner. Charged capsules having small dimensions are very difficult to produce. The existing methods of charging capsules are either extremely fiddly when significantly reduced in size and therefore the manufacturing costs are too high or the methods are impractical to reduce in size, for example complete charging is often not possible which in the case of a very small capsule means that the volume of material encapsulated is too small to be detected. By forming the capsules from a pre-charged plastic tube, the problems involved in first forming a capsule and subsequently charging and then sealing the capsule are overcome.

Claims

1 . A method of forming solid or liquid charged capsules for oral administration, which method comprises the steps of

a) providing a tube of plastic material;

b) at least partially charging said tube with a solid or liquid material; and c) submitting the tube to the action of heat and/or pressure by means of opposed cooperating dies so as to divide the tube into individual sealed capsules containing the solid or liquid material.

2. A method as claimed in Claim 1 , wherein the tube is charged with sufficient solid or liquid material to charge a plurality of capsules, and the tube is

subsequently submitted to the action of heat and/or pressure to divide the tube into individual sealed capsules containing the solid or liquid material.

3. A method as claimed in Claim 1 or Claim 2, wherein the tube is provided with a reservoir of the solid or liquid material at an open end of the tube to ensure that the tube remains charged as the capsules are formed.

4. A method as claimed in Claim 1 or Claim 2, wherein one or both ends of the tube are sealed prior to formation of the capsules in order to ensure that the solid or liquid material remains inside the tube as the capsules are formed.

5. A method as claimed in any preceding claim, wherein the plastic material is not soluble in water.

6. A method as claimed in any preceding claim, wherein the plastic material is a thermoplastic material.

7. A method as claimed in any preceding claim, wherein the tube is submitted to the action of heat and pressure by the opposed cooperating dies so as to divide the tube into individual sealed capsules containing the desired solid or liquid material.

8. A method as claimed in any preceding claim, wherein the plastic material of the tube is substantially rigid.

9. A method as claimed in any preceding claim, wherein the plastic material is sufficiently rigid to retain its shape when subjected to the forces of the gut which are commonly 1 -2N.

10. A method as claimed in any preceding claim, wherein the capsule has a maximum dimension of from 0.5mm to 10mm, or from 0.5mm to 5mm, or from 0.5mm to 3mm.

1 1 . A method as claimed in any preceding claim, wherein the cross-sectional diameter of the plastic tube is between 0.5mm and 10mm.

12. A method as claimed in any preceding claim, wherein the thickness of the tubing wall is between 0.1 mm and 1 .0mm, or between 0.3mm and 0.5mm.

13. A method as claimed in any preceding claim, wherein the capsule has a volume of about 50 to 150μΙ, or 50 to 100μΙ, or 50 to 70μΙ.

14. A method as claimed in any preceding claim, wherein the step of dividing the tube into individual sealed capsules comprises a single step process.

15. A method as claimed in Claim 14, wherein the opposing dies are shaped to correspond to at least part of the shape of the desired capsule, such that the parts of the opposing dies that are shaped to correspond to the shape of the desired capsule are those parts that require formation, relative to the original form of the tube of plastic material.

16. A method as claimed in Claim 15, wherein the parts of the opposing dies that are shaped to correspond to the shape of the desired capsule represent end regions of the capsule, with an intermediate portion of the length of tube that forms each capsule not being deformed or pressed during manufacture.

17. A method as claimed in any one of Claims 1 to 13, wherein the step of dividing the tube into individual sealed capsules comprises a plurality of steps.

18. A method as claimed in Claim 17, wherein the dies comprise two opposed open ended recesses in series such that, in each capsule forming step, the front end of one capsule and the back end of another capsule are formed concurrently.

19. A method as claimed in any preceding claim, wherein the method also provides means of cooling the main body of the capsule as the capsule is formed by the dies.

20. A method as claimed in any preceding claim, wherein the dies are shaped such that they cut the formed capsules into individual isolated capsules during the same step as forming the capsules, and hence also define cutting dies.

21 . A method as claimed in any preceding claim, wherein the capsules are cut away from the tube after they have been formed using separate cutting dies.

22. A method as claimed in Claim 20 or Claim 21 , wherein the cutting dies comprise a sharp edge or blade at points at which the opposing dies meet one another.

23. A method as claimed in any preceding claim, wherein the capsules may be charged with a solid or liquid material.

24. Apparatus for manufacturing solid or liquid charged capsules comprising opposing dies movable between open and closed positions, wherein the dies comprise recesses which in the closed position together form at least part of the shape of the desired capsule, and means of applying pressure and heat to the dies.

25. Apparatus as claimed in Claim 24, wherein the apparatus further comprises means for progressing a tube between the dies when the dies are in an open position.

26. A capsule manufactured by the method as claimed in any one of Claims 1 to 23.

27. A method of assessing Gl transit in a human or animal subject, which subject has previously ingested a container manufactured by the method as claimed in any one of Claims 1 to 23 containing a material that is detectable by MRI, which method comprises the steps of

a) at a known time after ingestion by the subject of the container, forming a magnetic resonance image of at least a portion of the subject's Gl tract in which the container is located; and