GB2357488A - Capsules by injection moulding - Google Patents

Abstract

One or more of a range of thermoplastic materials, typically a soluble polyvinylalcohol, are used to make, by an injection-moulding technique, a capsule that will at least in part dissolve in the body. Most preferably the capsule has raised or incuse portions moulded into its external surface, which patterns may define a code or simply be rib-like, either to reduce its apparent surface area or to assist in its partial dissolution. The injection-mouldable material can contain one or more particulate hydrophobic solid in order to both reduce the surface tackiness and also increase the density of the capsule, or can contain one or more particulate solid in order to accelerate the rate of dissolution of the capsule, for example in the different conditions of pH which exist in the gastro-intestinal tract. It can also be made from materials that will not hold a static charge.

Description

2357488 Capsules This invention is concerned with capsules, and relates in

particular to capsules that may be utilised for the delivery into Man or other animals of substances such as ingestible ingredients like pharmaceutically- or nutritionally-active materials, that dissolve or disperse within the gastro-intestinal tract.

There are numerous forms of systems used in the delivery of medical preparations in the market place today. The two most dominant in relation to oral routes are capsules made from hard gelatine, and tablets - the socalled solid dose formulations. Both of these presentations have remained virtually unchanged for decades. Gelatine capsules are made by a dipping process, building up successive layers, while tablets are formed by compressing a powder or fine granules.

The gelatine capsules currently employed are used extensively throughout the world to deliver thousands of prescribed and over-the-counter meditations and nutritional formulations. Unfortunately, they have a number of highly significant limitations, these including: their inability easily to be formed into a shape that facilitates the optimum delivery of their ingredients into the Patient; the fact that gelatine is animal-based; and the substantial likelihood of them sticking in the Patient's oesophagus when they are swallowed. In recent years these and other limitations - see below - have been acknowledged, and efforts have been made to overcome them by finding and using a number of materials as alternatives to gelatine, but in most 2 - cases the materials are even more brittle, more difficult to shape, and significantly more expensive than gelatine and other conventional solid dose delivery systems, and therefore they have not thus far been used successfully for this purpose which leaves the problem of the hard gelatine capsule, and its disadvantages, still to be solved. Some of these disadvantages are as follows.

As noted above, gelatine is animal-based, being extracted from bones and hides, and as such it carries the risk - or, at least, the perceived risk - of being linked with Creutzfeldt-Jakob disease. The manufacturing process used to make hard gelatine capsules involves a so-called dipping process, which makes thickness parameters difficult to control. More significantly, the process does not lend itself to the more complex shapes, sizes and chemical characteristics now required within the pharmaceutical and nutraceutical industries, wore specifically when controlled release is desirable. Hard gelatine capsules also have an inherent problem of attracting a static charge, which makes their handling during manufacture an additional problem, while the gelatine itself has a tendency to undergo detrimental physical and chemical changes during long-term storage.

As also pointed out above, gelatine capsule may be rather hard to swallow properly, for they can all too easily stick in the oesophagus. Now, this may seem trivial, but in fact whilst the most frequent cause of accidents to Patients in hospitals is falling out of bed, the second most frequent cause is capsules or tablets sticking in the Patient's oesophagus! Very few Patients are able to swallow a capsule when lying down, and when a gelatine capsule sticks in the oesophagus it - 3 can be extraordinarily difficult to dislodge. Indeed, it has been shown that drinking liquids such as water fails to move such a stuck capsule even when taking large amounts, and on occasion even eating food fails to overcome the adhesion. Part of the problem may be that a filled gelatine capsule will float if its contents are not dense (as is often the case), and will have a tendency to remain in the mouth, after the initial mouthful of water has been swallowed. This allows stickiness rapidly to develop on the surface of the capsule, which in turn increases the probability that the capsule will stick in the oesophagus when finally swallowed.

Until recently, there were no synthetic materials suitable as candidates for gelatine replacement for capsule manufacture. However, a range of PVOH polyvinylalcohol - polymer materials has now become available not only in grades and qualities that can safely be ingested by both human and other animals but also in forms that can relatively easily be injectionmoulded (a moulding method in which 4 thermoplastic mouldable material, in a warm, flowable form, is injected into a closed mould defining the required shape, which mould on cooling to "set" the thermoplastic can be opened up to reveal the removable moulded article). These PVOH polymers are quite different from the gelatine used to make hard capsules, and the ability to injection-mould them provides many advantages.

In one aspect, therefore, this invention provides a capsule that may be utilised for the, delivery of some active ingredient or device into the human or animal body, which capsule is made of a material that can be injection-moulded and will at least in part dissolve in the body.

The invention provides a capsule that is to say, a small container for the relevant ingredients, which container is in at least two parts (a body part and a cap part) which fit tightly, and preferably sealingly and inseparably, together to form a compartment in which is stored the ingredient to be delivered. As an alternative, the capsule may have three parts - a body, a first cap, and then a second cap to fit over the closed end of either the body or the first cap, so as to result in a capsule with two separate compartments. And where there are three such parts (or more; four parts a body and three caps - make three compartments, and so on), then naturally the ingredients in each compartment may be the same or they may be different.

By using capsule cap/body parts of different thicknesses, or of different polymers, or both, this invention enables enhanced control over the release of different active ingredients at different times or in different positions within the gastro-intestinal tract, which control ability is of utility in the developing science of chrono-biology.

The capsule is most conveniently of the standard shape - an elongate tubular package with closed, rounded ends. Moreover, although it is possible to have the several parts of much the same sizes, it is usual that there will be a long body with a shorter cap (the cap may be half or a quarter the length of the body). Typically, a capsule has an overall closed length of 10-25mm (about 0.4-lin) and an external diameter of 51Omm (about 0.2-0.4in).

The invention's capsule is intended to be utilised for the delivery of some active ingredient or device into the human or animal body. The delivery may be by any appropriate route; for most active ingredients the oral route is preferred - and it is when the capsule is administered orally that its advantages are most apparent - but rectal or vaginal routes may of course be employed if appropriate. Regardless of the nature of the route, however, it is clearly necessary that the material f rom which the capsule is made - the material that can be injection-moulded should of course be safe for delivery into the target organism (which may be a Human or some other animal). PVOH - polyvinylalcohol is such a material; not only is it not-toxic but it is available in food-quality grades, and it is very much preferred.

PVOH - or more specifically PVOH-based formulations - is presently the most convenient injection-mouldable, water-soluble or water-dispersible, material, and of the various commercially-available PVOH formulations one particularly-preferred variety is that range of materials sold (in the f orm of granules) under the name CP1210TO5 by Soltec Developpement SA of Paris, France In general, PVOH polymers are synthetic materials capable, when appropriately formulated with other adjuvants - such as plasticisers, particularly glycerine (but other glycols and polyglycols may be used depending upon their acceptability for ingestion), and solids such as talc, stearic acid, magnesium stearate, silicon dioxide, zinc stearate, and colloidal silica - of being moulded at temperatures between 180-2200C, depending upon the formulation selected and the melt flow index. required, into capsule bodies and caps of the appropriate hardness, texture and solubility characteristics required of a pharmaceutical or like capsule.

PVOH materialst unlike gelatine, can be modified to dissolve at different rates under varying conditions (including the pH of the aqueous medium such as the interior parts of the target organism's body - into which they are introduced). Capsules made from PVOH materials can therefore be formulated to release their contents in the stomach, the upper or lower small intestine, or the colon, as considered desirable.

Furthermore, PVOH formulations generally do not interact with many organic solvents or oils of the type used in pharmaceutical or nutritional compositions, while the aqueous gels often utilised in such compositions can be formulated to resist interaction with PVOH, so that capsules made from PVOH can be used to contain such materials.

The invention provides a capsule which is in at least two parts (a body part and a cap part) which fit tightly, and preferably sealingly and inseparably, together. The actual joining of the parts can be carried out in any convenient way, but advantage can be taken of the very nature of the capsule material - the fact that it is one that can be injectionmoulded (it is a thermoplastic). Thus, the preferred joining method is welding - either heat welding, by melting the parts when they are in contact, and allowing them to "run" into each other and then cool and solidify to become an integral device, or solvent welding, where much the same effect is achieved by partially dissolving the adjacent portions of the capsule and letting them again run into each other and then solidify to form a whole. Heat welding is much the preferred way.

7 Indeed, in one of its several aspects the invention specifically provides an injection-moullded capsule (suitable for use in the delivery of some active ingredient or device) having a cap portion and a body portion which, after filling, are welded together into a single indivisible unit (so sealing in and preventing subsequent access to the contents, and thus ensuring containment of the contents, whether granular, liquid, gel or suspension presentations).

PVOR materials are particularly!suited to thermal welding, a convenient variety of this technique being laser welding, though any suitable method can be used providing it does indeed make a permanent weld with the polymer used to form the capsule. Some other common methods are infra-red (IR), radio frequency (RF), and ultrasonic welding.

Some of these methods may require the addition of other items or processes to ensure their correct operation. For example, RF welding may require the use of a metal (normally aluminium) conductor in contact with the capsule surface. Laser welding will normally require the top surface to be transparent to the laser used, and the lower surface to be opaque to it. This can be achieved by avoiding opaque coatings and fillers on the outer surface of the capsule pap and by their application to the outer surface of the capsule body. For example, a circumferential line of a suitable material can be printed around the body at the required joining point to facilitate the weld at that point.

Of the various methods, the laser weld is preferred as there is no direct contact required, and it can achieve the very high production speeds required.

After placing the intended contents in the capsule body, and putting the cap on the body, the two portions - 8 of the capsule can be welded - by means of a laser beam, say - into a single unit which cannot thereafter readily and without leaving visible traces be separated into body and cap in order to gain access to the contents. Accordingly, any attempt to tamper with the contents would be clearly obvious, unlike the situation with a hard gelatine capsule.

The two parts of the capsule that are to be welded together are made.so that the open end of one will pass into the open end of the other with the smallest gap that can be practically achieved to allow easy assembly. Normally, but not necessarily, the capsule is designed with a stop on one or other component so that the entry of one into the other cannot overrun and stops at the same fixed position in every case.

The two halves or shells are in the closed position when the entire periphery of the open end of one is overlapped by the periphery of the open end of the other. The closed capsule is then ready for welding, and this is done by bringing the capsule into close proximity to the welding head. This distance will vary with the method of welding chosen. The welder is operated, and forms a weld between the two layers in contact in the form of a line of weld in a closed loop around the periphery of the capsule. This can be achieved either by having the welding heads in the form of a ring (which may be continuous or made up of a number of discrete heads), or by rotating one or other of the capsule and the head around the other. The exact method will depend on the welding technology chosen.

It is also possible.to use solvent welding - that is, using a solvent for the chosen injection-mouldable material so as to soften and render flowable the surface layers of the material where the two parts are in contact. In the MH case the solvent is conveniently water or an aqueous electrolyte solution (typically using an alkali metal halide such as lithium chloride as the electrolyte). This technique, however, requires another stage to the welding process,'in which the solvent is applied to one of the surfaces to be in contact before the two shells are closed. This method is not preferred, however, as it is likely to be comparatively slow, and the addition of water and solute may well be detrimental to the active ingredient or other preparations contained within the capsule.

The weldability of the two parts (body and cap) of the injection-moulded capsule of the invention into a single unit which cannot subsequently be separated into its two parts without visibly destroying the capsule is in contrast to the nature of the known hard gelatine capsule parts, which cannot be so welded. Thus, the integrity of the contents can be pro t ected by the invention's capsule in a way which cannot take place using capsule parts made of gelatine. i Due to the integrity of the welded seal, the capsule can be filled with any appropriate liquid, gel, or oil.

The invention provides a capsult made of a material that can be injectionmoulded. The injection-moulding process allows controlled variationslin the thickness of the walls and domed ends of either or both halves of the capsule, thereby allowing the release characteristics to be infinitely varied. The use of such moulded capsule shells permits the development of capsule formulations containing controlled-release beads or granules - of a drug, say - which can determine where the contents art released so that the system as a whole can be made to deliver drugs at the desired position, rate and period of release irrespective of differing physico-chemical properties of the drug. This also enables the delivery system to be used to protect the drug against adverse conditions in other parts of the organism - the gastrointestinal tract, for example - before absorption occurs.

There are many advantages in the production of capsules using injectionmoulding as compared with the traditional dip-coating methods, and it is worth setting out a few here.

Dip-coating of gelatine is the traditional method for the production of capsule shells. One of the principal properties of a capsule is the rate at which the shell material dissolves or disperses to release the contained ingredients. Using the dipping process there is only a limited control over the final thickness of the capsule shell. The principal advantage of using the injection-moulding process is that there is much greater versatility over the final component form, for example:

a) The thickness of the wall sections can be more closely controlled, and hence may be varied inter alia to obtain the appropriate dissolution rate of the capsule.

b) Reduced wall thickness possible with injection moulded capsule shells will result in increased production rates.

c) The surface form (smoothness) of both inner and outer capsule surfaces can be more closely controlled for moulded as compared with dipping, which latter only allows control of the inner surface form.

d) The degree (tightness) of fit between the two capsule halves can be more closely controlled with moulding.

e) Injection-moulding permits the addition of sectional variation around the rim of either or both of the capsule halves, so that features for final capsule assembly, such as ultrasonic or laser welding, can be included in the basic component design.

f) If both capsule halves are moulded simultaneously, in the same injection-mould tool. the capsule halves can be assembled automatically as a post moulding operation carried out immediately the tool halves open (with benefits for cleanliness and quality assurance). i g) There are no requirements for further trimming or sizing operations. i The invention provides a capsule,for the delivery into the human or animal body of an active ingredient or device. For the most part the ingredient will, as suggested hereinbefore, be a drug - a, pharmaceuticallyactive substance or perhaps some sort of nutritionally- active material - a "neptraceuticallyactive" material - such as a vitamin or a f ood supplement. However, it is not impossible for this capsule to be used for the delivery of quite a different sort of "ingredient" - for example, a, measuring or sampling device, or machine, as might, be required in some forms of medicine or surgery.

In its broadest aspect this invention provides a capsule made of a material that can be injectionmoulded. This injection-moulding concept has several unexpected consequences, as does the choice of a polymer of the MH type for this purpose. Specifically, an injection-moulded capsule can be moulded in almost any shape that might be useful (as might have been inferred from what has been said above). In particular, it can be given external raised (or lowered) areas - this has the advantage that, for the preferred orally delivery route, it significantly reduces the surface area of the capsule that is able to come into contact with the walls of the oesophagus as the capsule is being swallowed, and thereby reduces the risk of the capsule sticking in the oesophagus, and thus facilitates the passage of the capsule down into the stomach.

In another aspect, therefore, the invention provides an injection-moulded capsule (suitable for use in the delivery of some active ingredient or device) having raised portions moulded into its external surface.

The raised portions - for the most part they are referred to hereinafter as "raised", though obviously the effect of a raised part can be achieved by lowering the other parts - can be in the form of short, small pimplelike projections, or they can be ribs that extend wholly or partially either around or along the capsule. The portions may be designed to include or act as markings allowing identification of the capsule and its contents either visually, by the sighted, or tactilely, by the visuallyimpaired, or even by a machine. Thus, a code can be moulded into the surface so that a filled capsule can be identified at all stages of its life - by the manufacturer for quality assurance and quality control, by a pharmacist in dispensing, and by the patient before use, particularly those with vision impairment.

The surface of the capsule needs no pre-treatment prior to printing.

- 13 By suitable cutting of the moulds used, any required pattern can be moulded into the surface, either raised or incuse. Both raised and incuse variants bring different properties to the capsules,jand the benefits of each are described hereinafter. The complexity of the pattern is limited only by the practical limitations on mould making.

The use of an incuse pattern has a number of interesting possibilities. ' For example, for sparinglysoluble drugs delivered orally, the g4strointestinal transit from mouth to rectum is often too short to allow the active ingredient of some orally-aelivered medicament to be absorbed, with the consequence that most of the drug is excreted, and so wasted. However, incuse moulding in a suitable pattern provides a way of converting the capsule - in, say, the acidic conditions prevailing in the stomach - from an integral, sealed, container to a perforate container from which the contents of the capsule can readily escape as a solution or suspension (rather like a tea bag, or a metal tea infuser).

Such an incuse pattern design ma y include a capsule of standard form but with relatively thick walls. Around the centre section of the caps ule base is moulded an array of thin-walled incuse panels. Once the capsule has reached the stomach, the thin-wal: led panels in the capsule body quickly dissolve, leaving the capsule with a grid structure of holes. These hol es can be small enough to prevent the internal contents leaving the capsule, but large enough to allow the dissolving medium to enter and make contact with the contents of the capsule. As has been described earler, PVOH materials can, due to variations in molecular weight and extent of hydrolysis, be selected to dissolve at different speeds and at different temperatures in aqueous conditions. Hence, by varying the thickness and the dissolution characteristics of the injection- moulded capsule materials, the body of the capsule may be designed to dissolve or break up at a chosen rate in the stomach. Once the capsule has dissolved or broken up, the beads or granules are released but only after being retained in the stomach for an extended period of up to 12 hours. As long as such capsules with holes remain intact, they do not pass through the pyloric sphincter into the duodenum until the housekeeper wave is in operation.

Another possibility is to mould a capsule in a relatively sparinglysoluble polymer material - such as a high molecular weight PVOH having a high degree of hydrolysis - with a similar array of holes (rather than thin-walled soluble panels), and then in a separate process, after filling and capping, to cover the area containing the holes with a relatively soluble polymer either by spraying or by shrinking or gluing a soluble sleeve thereover. It should be noted that in use such a llcoveredll perforate capsule may either break up in the gastro- intestinal tract after being swept from the stomach, thereby releasing its ingredients, or it may carry on to leave the body in the faeces while still containing the active-ingredient-carrying beads or granules (though these have by then been relieved of most of the active-ingredient content). The relativelysparingly soluble polymer used in this case could even be an insoluble polymer - provided, of course, that it is both injection-mouldable and tolerated by the body.

By this means, such a capsule of outer diameter between 3 and 6 mm may contain, for example, a plurality of beads slightly larger than the holes which will be formed in the capsule and on which the finely-divided sparingly-soluble drug is layered. The drug dissolves - 15 only slowly in the acid conditions prevailing in the stomach. The capsule, because of itsIsize, can be retained in the stomach and thus allow the release in solution form of the drug for absorption in the stomach and gastro-intestinal tract. In thisiway, the absorption of the sparingly soluble drug in the gastro-intestinal tract will be increased as the beads are held f or a longer time in the stomach than they would be if released from a gelatine capsule that rapidly dissolves with the result that the beads pass quickly from the stomach into the small intestine. In the "fed state", units of dimensions greater than 3mm do not pass through the pyloric sphincteX into the duodenum as long as there are contents in the stomach. Thus, if such a PVOH capsule is taken with thel breakfast meal, it will be retained in the stomach until after the evening meal if a normal midday meal was taken. If the capsule has not dissolved or broken up in the stomach, it will be swept f rom the stomach into the large intestine where C it may either dissolve or break up or be eliminated from the body in the faeces. The overalliresult is an increased transit time of the drug delivery system from mouth to faeces, and thus increased bio-availability for sparingly-soluble drugs.

The capsule which either contains or develops holes while keeping its integrity can alsobe used advantageously to retain in the stomach beads containing soluble drugs and possessing controlled-release membranes programmed to take advantage of the better absorption of such drugs in the small intestine rather than the large intestine, and thereby to give a constant rate of systemic drug input.

These hole-containing or hole-developing capsules can be used to release two or more dugs at designated regions each at a controlled relative rate even if the drugs in conventional form have different rates of drug absorption or metabolism in different regions of the gastro-intestinal tract.

Whilst the oral route is preferred for may of the drug applications envisaged using the capsules of the invention, the rectal and vaginal routes, particularly those utilising perforate capsules which produce holes in vivo, are also important.

The oral route is suitable generally for sparinglysoluble drugs, and for good control of drug input and activation location.

The rectal route is particularly appropriate for use with perforate capsules that produce holes in vivo, together with controlled-release drug-carrying beads or granules. This allows the avoidance of "first pass metabolism" - some drugs are especially sensitive to this when administered orally. The perforate capsule can deliver the drug at a controlled rate via its location in the rectum so that the drug, unlike the delivery from a suppository, is released locally from the beads or granules in the capsule to give a steady, localised, input into the lower haemorrhoidal vein (unlike the higher medium and upper haemorrhoidal veins, which deliver blood to the liver, this allows systemic delivery without "first pass metabolism" by the liver). If they were not contained in the capsule, the beads would move upwards into the descending colon, and so would supply their drug content mainly to the medial and upper haemorrhoidal veins. Thus, using the rectal route with a perforate capsule, a drug can be delivered to a Patient in a similar but more acceptable manner to that achieved by intravenous infusion.

The vaginal route with a perforate capsule facilitates drug delivery at a constant rate followed by - 17 cessation when the system is withdrawn from the body aperture at the designated time.

From the above examples, other more selective approaches can be developed to maximise and control the rate of drug input by the chosen route of product use, thereby offering solutions to many current problems of drug delivery in man and other animals.

Another consequence of using an tnjection-moulding method is that the mouldable materiaLmay easily include one or more additional substance that has some effect on the way the capsule behaves in use - for instance, on its surface properties (and specifically on its tackiness, or stickiness), or on its rate of dissolution. 1 Thus, in yet another aspect the invention provides an injection-moulded capsule (suitable for use in the oral delivery of some active ingredient or device) that is made from an injection-mouldable material that contains one or more particulate hydrophobic solid in order to both reduce the surface tackiness and also increase the density of the capsule, Which effects will reduce the risk of the capsule sticking in the oesophagus. i This meets one of the problems of current hard gelatine capsules - and of those made of any other watersoluble polymer - namely that upon insertion in the mouth the capsule comes in contact with water, which will begin the softening process prior to dissolving and lead to a stickiness of the surface Which can cause problems and interruptions (sometime$ leading to release of its contents in the oesophagus) on the capsule's path through the oesophagus to the stomach- As noted, reduction of this stickiness can acheved by modifying the mouldable polymer formulation by the addition of inert solids in powder form though naturally the added solids have to be approved for ingestion, and must be compatible with the medical preparation contained within the capsule.

This use of added solids provides a more rigid capsule shell with a surface less immediately affected by the aqueous content of the mouth or oesophagus, thereby reducing surface tackiness during the initial swallowing.

In this aspect - the incorporation of a particulate solid to influence tackiness - the solid is very preferably extremely finely divided, typical particle sizes being in the range 1-50 micron, and preferably 510 micron. The upper limit is generally a practical one for the moulding process, but with increasing solid particle size the capsule surface will be to a greater extent made up of the insoluble solid ingredient and to a lesser extent the polymer (which will be partially concealed below the contact surface with the oesophagus).

Materials that can be utilised to reduce the capsule's surface tackiness are most preferably insoluble and preferably hydrophobic. Substances suitable for this purpose are talc, stearic acid, magnesium stearate, zinc stearate, sodium stearate, colloidal silica and magnesium trisilicate, with talc and magnesium stearate being especially preferred.

And in still another aspect the invention provides an injection-moulded capsule (suitable for use in the oral delivery of some active ingredient or device) that is made from an injection-mouldable material that contains one or more particulate solid in order to accelerate the rate of dissolution of the capsule, for example in the different conditions of pH which exist in the gastro- intestinal tract.

Unlike gelatine capsules, which sometimes release their contents prematurely (especially in elderly patients) when they stick in the oesophagus and open, capsules of PVOH (in particular) can he formulated so that they do not open in the oesophagus but release their contents only where necessary -lie, when they reach the relevant target area.

The particulate solid incorporated into the injection mix may be a material that is barely affected in a non-acidic medium but dissolves relatively rapidly in an acidic environment, so as to allow the capsule to release its contents in the stomach. Alternatively, the solid material may be one that is relatively insoluble in an acidic medium but relatively soluble in a neutral environment, so as to allow release of the capsule's contents in the lower small intestineand in the colon.

The simple dissolution of the solid in the chosen medium is sufficient to cause a signi ' ficant acceleration in the capsule break-up, particularlyso when a gas is also generated, when the physical agitation caused will result in the virtually immediate release of the contents from the capsule.

Such solids are of course subject to the same limitations of approval and compatibility as before. The most obvious solids for this purpose are the bicarbonate and carbonate salts of the alkali and alkaline-earth metals, typically sodium, potassium, magnesium and calcium, all of which Salts liberate carbon dioxide gas on contact with stomach acid.

The solid is very preferably extremely finely divided, typical particle sizes being in the range 1-25 micron, and preferably 5-10 micron.

- 20 Materials that can be utilised to affect the capsule's dissolution rate in a non-acid medium (the lower intestine or the colon, say) but without being affected by an acid medium (the stomach, say) are most preferably solid acidic substances with carboxylic or sulphonic acid groups or salts thereof. Substances suitable for this purpose are cinnamic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, malic acid, pamoic acid, citric acid, and naphthalene disulphonic acid, as free acids or as their alkali or alkaline-earth metal salts, with tartaric acid, citric acid, and cinnamic acid in the form of acids or their alkali metal salts being especially preferred.

One of the great practical problems of current hard gelatine capsules is their ability to hold a static electrical charge. Such capsules in production rapidly pick up a high static charge which has the effect of making them not only stick to each other and to all other non-polar surfaces but also making them attract particles of foreign material from their surroundings. It also means that the capsules are hard to fill, and that their surfaces must be treated immediately prior to printing. This phenomenon is common to some mouldable polymers, but not to PVOH, which is not only soluble, ingestible, mouldable and weldable, but in addition will not support a static charge capable of causing the problems described above. So, yet another consequence of using an injection- moulding method is that the mouldable material may be chosen having regard to its ability to pick up and retain a static charge - or may include one or more additional substance that has some effect on the way the capsule behaves in this respect'.

Thus, in a still further aspect this invention provides an injectionmoulded capsule (suitable for use - 21 in the delivery of an active ingredient or device into the human or animal body) being made trom materials that will not hold a static charge.

The capsule of the invention is One that, utilised for the delivery of some active ingredient or device into the human or animal body, dissolves in the body to release its contents therein. The term "dissolve" is used herein in a fairly general sense. to indicate that the capsule crumbles, decomposes, distntegrates or disperses; it need not actually dissolve, although most often it will.

i Various embodiments of the invention are now described, though by way of illustration only, with reference to the following Examples (and Test Results) and also with reference to the accompanying diagrammatic Drawings in which:

Figures 1A & B show longitudinal cross-sections of a capsule of the invention in its open and closed states respectively; Figure 2 shows the closed capsule of Figure 1B but in see-through perspective; Figures 3A & B show longitudinal cross-sections of two- and three- compartment capsules of the invention; Figures 4A & B show respectively longitudinal and transverse cross- sections of another two-compartment capsule of the invention; Figure 5 shows a section through the wall of a solidfilled polymer capsule of the invention; Figures 6A6 show various different forms of moulding on and in the surface of capsules of the invention.

Figure 1 shows a two-part, one-compartment capsule of the invention in its open and its closed form.

The body (11) and cap (12) are to be welded together, and are made so that the open end (11a) of one will pass into the open end (12a)',of the other with the smallest gap that can be practically achieved to allow easy assembly. There is a "stop" - a bump (11b) running all round outside of the body 11 that co-operates with a dent (12b) runningiall round the inside of the cap 12 - so that the entry of one into the other cannot overrun, and stops at the same fixed position in every case.

When the two halves or shells 11,,12 are in the closed position (as in Figure 1B), with the entire periphery of the open end 11a of the body 11 overlapped by the periphery of the open end 12a,of the cap 12, the capsule is ready for welding. The welder (not shown) forms a weld line (13) between the two layers all round the periphery of the capsule.

Figures 3 and 4 show different sorts of multi-compartment capsule according to the invention.

In Figure 3 the capsule is made,in two or more parts (three in Figure 3A, four are shown in Figure 3B, but there could be more) - in each c se there is a single cap portion (32) and a plurality of body portions (as 31). The outer of the body portions 31 is much the same as an "ordinary" body portion (as in Figure 1), but each inner one is shaped at its "out:r" end (as 31c) so that it will fit tightly inside the ?pen mouth of the next body portion, much like in Figure 1 the body 11 fits inside the cap 12.

As shown (in Figure 3A), when te first (outer) body part 31 has been filled with product A, it may then be closed by the second (inner) body part 31 within it.

That second body part 31 may then be;filled with product B, the cap 32 placed in position, and the three parts welded together simultaneously.

Figure 4 shows a capsule with body (41) and cap (42) two compartments side-by-side (Figure 4B shows a transverse section on the line A-A in Figure 4A). The two compartments can of course hold different products (A and B).

There is theoretically no limit to the number of separate chambers that can be produced either linearly (as in Figure 3) or side by side within the body portion (as in Figure 4). Of course, limitations will be set by practical problems of manufacture and swallowing! In Figure 5 there is shown a section through the wall of a solid-filled polymer capsule of the invention.

Inert solids in powder form have been added to the polymer formulation prior to moulding. This provides a more rigid capsule shell with a surface less immediately affected by the aqueous content of the mouth or oesophagus, thereby reducing surface tackiness during the initial swallowing. The capsule surface is to a significant extent made up of the particulate insoluble solid ingredient (as 54); the soluble polymer (55) is partially concealed below the contact surface (56).

Figure 6 etc show various different forms of moulding on the surface of capsules of the invention, some in the form of crosssections.

These are self-evident, and need little comment. Figure 6A,F, for example, shows a capsule with longitudinal raised ribs, while Figure 6B shows one with lateral (or circumferential) raised ribs and Figure 6E shows one with helical ribs. Figure 6C,H shows a capsule with raised pimples, while Figure 6D,I shows one with raised identification coding pat terns. Figures 6G,J,K,L and M show variants analogous to some of the others, but with incuse ratherthan raised portions.

Examples

Example 1: The manufacture of capsules by injection moulding and laser weldiq The moulding stage Capsules according to the invention were made by the injection moulding method utilising an Arborg 220D (35 tonne) injection moulding machin6.

The injection cavities were in a two-impression (cap/body) composite water-cooled stainless-steel mould. The PVOH had a material melt flow index of 10-20 grams per 10 mins (DIN 53735).

Injection temperatures were 1750 i C, 1800C, 1800C and 1850C in the feed, zone 2 and 3, and Nozzle areas. The first stage injection pressure was 4010psi and the hold stage pressure was 270psi The pressure well time was 3 secs in thelfirst stage and secs in the hold stage. Tool temperatures were between ambient and 400C. i The moulding pressures were justsufficient to fill the cavities on the first pressure stage and then sufficient packing pressure to hold on the second stage. Mould open and close rates were as fast as possible.

As noted, the mould layout was divided into two halves, one half moulding capsule bases and the other half capsule caps. After the mould o pening sequencet' two robotically controlled loading plates pneumatically picked up each capsule half from each tool face. With i - 26 identical cavity pitch centres, these loading plates were brought together so that each capsule half was located resulting in the usual temporary location of the pair ready for automatic filling.

The filling stage For test purposes the capsules were filled by hand with various test materials (see below).

The welding stage The closed capsule is introduced into a transparent tube with an internal diameter not more than 20% greater than the external diameter of the capsule. An array of diodes is located circumferentially around the outside of the tube. As the capsule passes by the diode array, a weld is formed. The velocity of the capsule and the power of the IR emitted by the diode array provide the necessary control over the melting process. The IR emission is either continuous or discontinuous. In the case of discontinuous emission, this is achieved by synchronisation of switching depending on the form of weld required and the sensitivity of the contents of the capsule to the IR.

If the characteristics of the material contained within the capsule are such that they absorb the IR, switching of the laser is necessary such that exposure to the IR is limited to the area of the join. This is effected by means of electrical switching or, in a further embodiment, by a form of optical switching using a lens/prism arrangement. In order to overcome the difficulty of synchronisation, again optical fibre delivery of the IR is used to restrict the area of exposure.

Example 2: The manufacture of capsules using laser welding In an alternative laser welding stage, the laser or - 27 other IR source is arranged to focus on the area of the join. This does not create a full circumferential weld but generates a spot weld. Again, the laser is continuously emitting. By forcing the!: filled capsules to roll (by mechanical means) whilst exposed to the laser, a full circumferential weld results.:Alternatively, an optical fibre is used to deliver the: iR to the join. Test Results PVOH capsules made in the manner: described in Example 1 above were filled with either sugar or tea leaves. They were designed to have a cap portion that would dissolve sooner than the body, and thus open the capsule progressively.

Similarly, a number of conventio 1 gal gelatine capsules were also prepared and so filled.

In the Test, a capsule was placed in each Test Subject's mouth (in the buccal cavity), and the Subject was asked to note when he/she became aware of the taste of the contents - thus, when the capsule "opened" and then when the capsule had completely dissolved.

There were two Test Subjects, and each Test was carried out twelve times (for each filling).

The conventional gelatine capsues opened in 3-4 minutes, and dissolved completely in 5-8 minutes. The sugar-filled PVOH capsules of the invention opened in 8-12 minutes, while the tea-filled ones took longer 14-18 minutes. Complete dissolution took 30-40 minutes in each case.

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Claims (18)

Claims

1. A capsule that may be utilised for the delivery of some active ingredient or device into the human or animal body, which capsule is in at least two parts which fit tightly together, and which is made of a material that can be injection-moulded and will at least in part dissolve in the body.

2. A capsule as claimed in Claim 1, which has three parts a body, a first cap, and then a second cap to fit over the closed end of either the body or the first cap, so as to result in a capsule with two separate compartments.

3. A capsule as claimed in either of the preceding Claims which is made of polyvinylalcohol.

4. A capsule as claimed in any of the preceding Claims, wherein the several parts are welded together.

5. A capsule as claimed in any of the preceding Claims, wherein the thickness of the walls and domed ends of the body and cap portions are adjusted during moulding to achieve the desired contents release characteristics.

6. A capsule as claimed in any of the preceding Claims, which capsule has relatively-raised portions moulded into its external surface.

7. A capsule as claimed in Claim 6, wherein the raised portions are in the form of short, small pimple-like projections, of ribs that extend wholly or partially - 29 either around or along the capsule, ad/or of markings allowing identification of the capsule and its contents.

8. A capsule as claimed in either of Claims 6 and 7, wherein the relatively-raised portions provide an incuse pattern design on a capsule of stand form but with relatively thick walls, so forming around the centre section of the capsule base an array of thin-walled incuse panels such that in use the thin-walled panels quickly dissolve, leaving the capsulewith a grid structure of holes.

9. A capsule as claimed in any of Claims 6 to 8, which is moulded in a relatively sparingly- oluble, or even insoluble, polymer material with an aray of holes, and then, after filling and capping the cipsule, the area containing the holes is covered with a relatively soluble polymer.

10. A capsule as claimed in any of the preceding Claims, which capsule for oral use and is made from an injection-mouldable material that contains one or more particulate hydrophobic solid in order to both reduce the surface tackiness and also incre4 se the density of the capsule, which effects will reduce the risk of the capsule sticking in the oesophagus.

11. A capsule as claimed in Claim 19, wherein the particulate solid has particle sizesl:in the range 5-10 micron.

12. A capsule as claimed in either Of Claims 10 and 11, wherein the particulate hydrophobic solid is talc or magnesium stearate.

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13. A capsule as claimed in any of the preceding Claims, which capsule is for oral use and is made from an injection-mouldable material that contains one or more particulate solid in order to accelerate the rate of dissolution of the capsule.

14. A capsule as claimed in Claim 13, wherein the particulate solid has particle sizes in the range 5-10 micron.

15. A capsule as claimed in either of Claims 13 and 15, wherein the particulate sodium, potassium, magnesium or carbonate or bicarbonate, or is tartaric acid, citric acid, and cinnamic acid in the form of the acid or an alkali metal salt thereof.

16. A capsule as claimed in any of the preceding Claims, which capsule is made from materials that will not hold a static charge.

17. A capsule as claimed in any of the preceding Claims and substantially as described hereinbefore.

18. A method of making a capsule as claimed in any of the preceding Claims, which method is substantially as described hereinbefore.