EP1638533A1

EP1638533A1 - Controlled release devices with lumens

Info

Publication number: EP1638533A1
Application number: EP04742958A
Authority: EP
Inventors: John Michael Newton; Roy Edward Carter
Original assignee: Individual
Current assignee: Individual
Priority date: 2003-06-18
Filing date: 2004-06-18
Publication date: 2006-03-29
Also published as: WO2004112755B1; WO2004112755A1

Abstract

A device for controlled delivery of biologically active agent into a liquid environment comprises an extruded cylindrical core (1) of matrix material in which the agent is dispersed, which either has several lumens (5, 6) extending generally axially between the two ends (3, 4) or has one lumen extending between the two ends, but spaced from the axis of the core, where the core is erodible. The external cylindrical wall (2) may have an insoluble and impermeable coating, whereby release of active agent takes place only by passage of liquid through the lumen(s). Selection of the diameter and length of the lumens and of the matrix material and any coatings allows for control of the release rate of the agent. The device is of particular utility as an orally administrable drug delivery device.

Description

CONTROLLED RELEASE DEVICES WITH LUMENS

The present invention relates to controlled release devices for delivery of biologically active agents, particularly pharmaceutical agents. The device is formed by a process involving extrusion of a material to form a cylindrical core having multiple axially extending lumens, which generally allow for passage of a liquid medium into which the biologically active is to be released.

Some materials can be made extrudable either by raising the temperature of the mass to one that ensures that it can flow from the large cross-section through the smaller cross-section of a die (often referred to as melt or thermoplastic extrusion) or by the addition of fluid to provide the appropriate consistency, for example forming a paste or dough. The final shape achieved is controlled by the configuration of the smaller cross- section (the die) and cooling, removal of the fluid, or cross-linking. Melt extrusion is associated mainly with polymers, while fluid/solid systems are associated mainly with ceramics, nuclear, high-energy materials, animal feed and foods. In the latter industry, a combination of both heat and fluid addition are employed in "extrusion cooking".

Extrusion processes are applied within the pharmaceutical industry to produce a variety of dosage forms such as suppositories, pessaries, tablets, pills, implants and granules. The most important application of extrusion in this industry is in the preparation of granules or pellets of uniform size, shape and density containing one or more drugs by extrusion spheronisation. A wet mixture of the active material and excipient is extruded to form short cylindrical rods which are subsequently spheronised and, usually, coated. The spheres may be filled into capsules or subsequently compressed with other materials to form tablets. The coatings on the spheres may be selected so to provide a controlled release over a period of time, or in a particular location in the digestive tract. Implants are usually prepared by the "melt extrusion" process and involve drugs mixed with a polymer. Extrusion is used in the manufacture of high energy propel lants, for instance which are filled into ammunition cartridges. The propellants are formed by the process in a wide variety of geometric shapes including multitubular granules to precisely controlled dimensional tolerances allowing 5 consistent combustion characteristics. The mixture may comprise nitrocellulose and nitroglycerine, optionally with crystalline picrite (nitroguanidine or guanidine nitrate) and/or other particulate fillers with adequate liquid processing aids and stabilisers, for safety.

An important characteristic of the extrusion process is the ability to 0 prepare structures of complex shape.

In GB-A-2249957, a process is described for extruding a wet mixture of an active material and excipient to produce a core which may be in the form of a hollow tube. The exterior of the core is coated with a water insoluble coating. The wall of the lumen may be coated or uncoated, so as 5 to control dissolution of active into the lumen for delivery in the target location.

US 3113076 discloses medicament in a solid or tablet form wherein upon disintegration, release of the active medicament into the body is controlled. The tablet has at least one aperture and the total area of inner to o outer surfaces of the tablets remains relatively constant during disintegration. No details are given of a composition which would be suitable for extrusion.

US 4,601 ,893 describes a laminate comprising at least one core sheet which comprises at least one active agent in a polymeric matrix and 5 the sheets are interposed between coextensive inert polymeric films which are substantially impermeable to the active agent.

Cleave investigated the best theoretical design of a tablet to achieve a uniform release rate in J. Pharm. Pharmacol. (1965), 17, 698-702. The configuration modelled is a square/rectangular geometry and the studies are o based on an erosion model only. Kim et al, in Eur. J. Pharm. Sci. 7 (1999) 237-242 investigated the release kinetics of water soluble drugs from annular tablets having various coatings and various geometries. Variations in the geometry were in respect of the diameter of the hole, the external diameter and the length of the tablets. The tablets were made by compressing a tableting mixture in a regular tablet punch, with the hole being drilled in a subsequent process step.

In a first aspect of the present invention there is provided a novel orally administrable device a pessary or a suppository for controlled release of a biologically active agent in the body comprising a cylindrical core having multiple lumens extending generally parallel to the cylinder axis between the ends of the cylinder, the core being an extrudate of a mixture of an excipient material which forms a matrix and a biologically active agent distributed through the matrix, or in filling material filled into the lumens the device substantially retaining its integrity during the period and in the environment of the intended controlled release.

The device should retain its integrity in the sense that matrix and biological active should remain integral as the device in the target location in the liquid medium environment for delivery of the active. The device should not be intended to be reconfigured before it reaches the target location for instance as would be the expected fate of a food product which is chewed before being swallowed.

Although the invention is of particular relevance for formulating pharmaceutical or diagnostically active agents including prophylactic agents as well as therapeutic agents, it may also be of use for formulating nutrients for administration to animals including humans or for controlled delivery of pesticides, herbicides or alternatively nutrients, to plants in horticulture or agriculture. In such uses, the liquid into which the biologically active agent is released is generally water, for instance rain or other precipitation, or water used for irrigation or a body liquid including gastric fluid. The invention is of most use where the device is an orally administrable device for delivering pharmaceuticals, diagnostic agents or nutrients to animals, especially humans. Release of the biologically active agents may be targeted to any location in the gastrointestinal tract, for instance the stomach or the upper or lower intestine, including the colon. The matrix material in the extrudate may be selected so as to confer suitable mechanical characteristics as well as release characteristics for the biologically active agent. It is possible to control the release of the biologically active agent at the target site by selection of suitable materials having appropriate swellability, permeability and/or erodibility (e.g. solubility, digestibility and/or degradability) to allow release of the intimately mixed biologically active agent over the desired delivery period. The device may be provided with coatings to confer additional mechanical stability, or release characteristics.

As well as being useful when coated on the outside of the pellet, the coating is not essential, but is another variable available in the design of the desired release profile. Similarly, a coating may be applied to the walls of the lumens, or the lumens may be filled with a composition of dissimilar dissolution or release properties to the matrix. For an erodible matrix, whereas the diameters and thus the exposed surface area of the internal lumens will increase with time and therefore will increase the rate of release of the active agent, the external diameter will progressively decrease with time, giving a decreasing rate of release; the overall release profile may be controlled by careful selection of the number and size of the lumens, the outside diameter, the length of the core, the characteristics of the matrix, the properties of any coating and the scope of application of such coating. For a non-eroding matrix, a similar argument applies except that it is the shape of the concentration profile within the matrix which changes as the active agent is released.

The invention is of particular utility where the outer wall of the cylindrical core is provided with a coating which is substantially impermeable to the biologically active agent at the target site. The coating should be selected so as to be resistant to the environment to which the device is exposed before it reaches the location at which release of the active is desired. For instance, where the device is a pharmaceutical device, for delivery of an active agent to locations beyond the stomach in the Gl tract, the coating should be resistant to gastric juices as well as being impermeable to the active agent in the target environment for delivery of the agent. In such a device, the agent will be released through the end walls of the device which are not provided with the same coating. The active agent should be released through the axially extending lumens and out through the end walls. In another embodiment the device is coated across the ends which may, where the lumen contains gas, result in the device having a bulk specific gravity less than the liquid so that it may float in aqueous systems.

By choice of lumen size, device length, and the disposition and number of lumens, the release rate of the biologically active agent from the device may be controlled.

Although the device may have an external shape other than circular, such as polygonal, especially hexagonal, and even including exterior surfaces which have concavities for instance being ribbed, we have found that it is most convenient for the cross section of the device (perpendicular to the axis) to be circular. Although the lumens may have a cross section which is other than circular (perpendicular to the axis), it is most convenient for the lumens to be circular. The lumens within the device may have different diameters, but it is most convenient for all the lumens to have substantially the same diameters. Thus the term cylindrical in the present specification is not restricted to circular cylindrical but covers a shape generated by a straight line remaining parallel moving around a closed curve (which curve may include rectilinear portions as well as convex sections).

The number of lumens within the device is generally at least 3, preferably at least 7. For devices which are for oral administration to animals, particularly humans, the maximum size of the device may confer limitations on the maximum number of lumens which may be formed. For such devices it may not be possible to achieve more than about 50 lumens.

Preferably the lumens are arranged in a regular pattern within the cylindrical device. In one preferred embodiment one of the lumens will be substantially central in the cylinder. In another embodiment a number of lumens in the range 21 or more may be arranged equally around a circle concentric with the core axis with no centrally located lumen. The distance between the lumens and their distance from the external surface of the core may be selected for desired release characteristics. Generally the maximum external diameter of the device is 13 mm, where the device is for oral delivery to humans. Devices for animals may have larger or smaller external diameters, depending on the species. The axial length of the cylinder may be 5 to 20 mm, preferably 5 to 15 mm, where the device is for oral delivery to a human. The diameter of the lumens may be in the range 0.3 to 5 mm, preferably in the range 0.5 to 2.0 mm. Preferably the lumens are open, so that air may pass through the device from one end to the other.

We have found that particularly interesting release profiles for devices with erodible matrices may be achieved by ensuring that the thickness of the wall provided by the matrix around the or each lumen varies around the periphery of the lumen. According to a preferred embodiment of the invention the lumens are surrounded by walls, and the device is characterised in that the thickness of the wall surrounding the or each lumen varies around the perimeter of the lumen, and the matrix is erodible into the liquid environment whereby at least in part, release of the active takes place. The thickness of the wall is the shortest distance from the periphery of the lumen at that part through the matrix to the external surface of the core, or to the periphery of an adjacent lumen if that is shorter.

Where, as is preferred, the external surface of the core is circular cylindrical, the wall thickness requirement will inevitably be met as can most easily be appreciated by considering the sketch of a radial section through the core (C) forming Figure 4. The wall thickness around the perimeter of the left hand lumen is represented at various parts by arrows.

There is also provided in the present invention a novel process comprising forming an extrudable mass of matrix material and a biologically active agent and extruding the mass to form an extrudate having a substantially cylindrical exterior surface and comprising one or more lumens as required for the novel devices extending continuously in a generally axial direction, at least one of said lumens being eccentric relative to the exterior surface of the core, and solidifying the extrudate. The process may further involve cutting the extrudate to desired lengths, for instance before or after the solidifying step. The process may further involve providing the dried extrudate with a coating, on the exterior walls, and optionally on the end walls of cut lengths of extrudate and/or on the luminal surfaces. The coating should preferably be as described above. The extrusion may be carried out in an extruder, which may additionally be used to blend the particulate matrix material, the biologically active agent and the wetting liquid. The extruder may be a ram extruder, a gear pump extruder or a screw extruder, for instance a twin screw extruder, which is useful for mixing as well as moulding. The extruder may use gas or liquid (eg water or oil) pressure rather than mechanical pressure, such as in a hydrostatic extruder.

The extrusion parameters for an extruder may be selected by a person skilled in the art so as to achieve an appropriate rate of extrusion, strength of product and smooth exterior surfaces, as well as to control the release rate of the biologically active agent. Extruders may be controlled in respect of the die diameter, the length-to-radius ratio of the die (L/R) and extrusion rate. We have found that a suitable value for the L/R for a ram extruder is in the range 5:1 to 20:1 , preferably at least 10:1.

Generally where the materials are particulate, blenders in which matrix material and the active agent are premixed, for instance in blenders generally used for forming extrusion spheronisation mixtures, may be useful. Where the active and matrix material are particulate, the matrix particles and the active particles are premixed before addition of a wetting liquid. Where the biologically active agent is a liquid, it may be sprayed onto a moving mass of matrix particles. Where the active agent is soluble and the matrix is particulate, the active may be dissolved in a suitable liquid and sprayed onto a moving mass of particles of matrix material. Where the solvent is suitable for acting as the wetting liquid, it need not be removed prior to forming the extrudable mass.

The extrudable mixture may alternatively be a melt. The matrix material should thus soften at raised temperatures. Suitable materials are waxes, thermoplastic polymers, fats etc. Such materials may require the presence of plasticisers and/or other additives to control the viscosity of the melt and thus the temperature, solidification, in such processes involves cooling to a temperature below the softening temperature. The lumens are generally formed by providing the extrusion die with pins (mandrels) located in the appropriate position. The pins may be solid, or preferably, are tubular, with their interior passageway being vented. Alternatively, the pins may be tubular and may be used as exits for extrusion of a different material which is coextruded to fill or partially fill the lumens or to partially coat the surface of the lumens.

Coextruded material filled into the lumens may, for instance, comprise a second biologically active agent, or an additional portion of the same biologically active agent as is dispersed in the matrix of the core. For instance, the material may be formulated with a matrix material conferring desired release characteristics for providing a release profile of utility to give pulse of biologically active upon initial administration. Preferably biologically active material and/or any matrix within the lumen should be selected such that the lumen filling is delivered from the lumens to a target location over a period to leave empty lumens. In this way the device will thereafter have lumens allowing passage of liquid for release of biologically active agent from the matrix in the core of the device at the target location. As an alternative embodiment the materials may be selected so that the core erodes more quickly than the lumen to leave free-floating cylinders which continue to release active.

The process of the invention may, as mentioned above, involve steps for providing the device with a coating. The coating may be coextruded onto the external cylindrical surfaces, for instance by feeding suitable coating material to the extrusion die having an exit adapted to provide an overall external coating as the extrudate is formed. The coating may be applied in a separate step, before or after the extrudate has been solidified. If it is desired that all surfaces of the extrudate be coated, then it is preferable if not essential that the coating is carried out after cutting. If it is desired that only the outer surface is coated, then it is preferable that the coating is carried out before cutting. Coating may be complete or partial, and may be carried out for example by a printing, spraying, dipping or tumbling process, using a coating composition. Such a composition may be a solid, such as a powder or a liquid curable resin, but is preferably a liquid comprising a vehicle in which a coating material is suspended or dissolved. A coating step using a liquid is preferably followed by a drying step in which liquid is removed and/or optionally a curing step. The end walls of the device may be coated in a separate step after the devices have been cut to the desired length. Coating may, again, be by dipping, spraying or a printing type process, for instance by roller coating, brushing, ink jet spraying or other procedure. The coating need not be continuous and may, for example, take the form of axial stripes, annular bands, a helix or patches, depending upon the effect desired.

Where it is desired to coat the luminal surfaces, this may be carried out before or after the external cylindrical surfaces are coated. For instance, a coating applied to the luminal surfaces may be applied by immersing the entire device in a coating solution under conditions whereby solution penetrates through the lumens, and also coats the external cylindrical surfaces. Additionally or alternatively the lumens may be substantially filled with a liquid which cures to leave solid blocked lumens, the liquid for instance including a therapeutically active component. Subsequently, the external surfaces may be overcoated with a suitable, different, coating material by use of conventional coating processes, such as fluid bed and/or rotating pans.

The applicant believes it is the first time it has been suggested to fill a lumen through an extruded core with pharmaceutically active compound. According to a further aspect of the invention there is provided a device for controlled release of a biologically active agent into a liquid environment comprising a cylindrical core and at least one lumen extending generally parallel to the cylinder axis, between the ends of the cylindrical core, in which the core is an extrudate of a mixture of matrix-forming excipient material, characterised in that the biologically active compound is present in a solid filling material which is located in the lumens. This aspect of the invention also comprises a method of making the device in which the core is extruded and simultaneously or in a subsequent step a filling composition comprising the biologically active compound and filler is filled into the lumens. The filling composition may be coextruded and solidified with the core material. The filling composition may alternatively be injected into the lumens for instance after cutting the devices to length after the extrusion, in liquid form and then solidified. In this aspect, additional biologically active, which is the same or different, may or may not be present in the core material.

Suitable material for forming the matrix comprises a particulate inorganic water-insoluble compound such as a clay. The matrix additionally preferably comprises synthetic or natural polymer or derivatives as binding agents. Such polymers may be mixed with other ingredients which may be particulate, liquid or in solution. The extrudable mixture may additionally comprise other components, such as swelling agents, lubricating agents, biodegradable components, water soluble components, preservatives, flavourings, dies, fragrances, hydrophobic agents, binding assistants, fillers, stabilisers and anti-static agents.

We have found that a particularly useful matrix is formed of a mixture of particulate microcrystalline cellulose and a clay, especially a swelling clay such as bentonite, or kaolin, in combination with a soluble polymer such as polyvinyl pyrrolidone. Microcrystalline cellulose is preferably used in an amount of at least 20% by weight, preferably more than 30% by weight, for instance up to 80% by weight, preferably no more than 50% by weight. The clay is generally used in an amount of at least 1 % by weight, preferably in the range 2 to 20% by weight, for instance in the range 5 to 15% by weight. The polymer may be present in an amount of at least 1 % by weight, preferably in the range 2 to 20% by weight, for instance in the range 3 to 10% by weight.

The level of biologically active agent depends on the activity of the agent and the desired release profile. It may be present in an amount in the range 0.001 to 80% by weight, preferably in the range 0.1 to 50% by weight.

The invention further includes a controlled release process in which a device comprising a cylindrical core having one or more lumens extending generally parallel to the cylinder axis between the ends of the cylinder, the core being an extrudate of a mixture of an excipient material which forms a matrix and a biologically active agent distributed through the matrix, is positioned in a liquid containing environment comprising a target for the biologically active agent, whereby active agent is released from the core to the environment via the lumen(s) to act upon the target, provided that at least one of the lumens is eccentric in the core.

In this process, the matrix is preferably erodible and the active is released as the matrix is eroded.

The environment may be within an animal, e.g. human, body. Alternatively the environment is non-animal, for instance agricultural or horticultural. The invention is of utility for delivering a wide range of biologically active agents to a range of locations. Where the active agent is a pharmaceutically active compound, it is preferably designed for administration to the G.I. tract, for instance orally, or for making pessaries and suppositories. Suitable classes of pharmaceuticals for which the invention is particularly useful are those where it is required to maintain plasma levels above a minimum effective level, yet prevent plasma levels exceeding those which produce untoward systemic side effects: those drugs which can produce local gastro-intestinal side effects if present in high concentrations and those drugs of which the half life of elimination is such that the frequency of dose required is impractical or inconvenient.

The coating material for the device may be selected amongst materials approved for this purpose, designed for delivery of the active agent to a target area, for instance from an orally delivered product. Suitable coatings may be applied on exterior and luminal surfaces to confer pH- dependent resistance, permeability and/or solubility, to control the release location of the active. Suitable gastric-resistant coating materials are, for instance, ethyl cellulose and acrylic polymers. Suitable coating materials which are resistant to gastric juices, but soluble in or degraded in the environment pertaining in the upper or lower intestine are, for instance, cellulose acetate phthalate, polyvinyl acetate phthalate and acrylic polymers. Multiple coatings may be applied to confer a suitable combination of resistance and permeability. Suitable vehicles for coating compositions are aqueous or organic, with suitable organic vehicles including esters, ethers and alcohols, particularly alcohols. Mixtures of solvents may be used as vehicles.

The drawings illustrate the method and the products and comprise Figure 1 and 2 showing perspective views of two cores, each having a circular cylindrical outer surface, and comprising multiple lumens, figure 1 having seven lumens and figure 2 having nineteen lumens; Figure 3 shows a perspective view of a core having a hexagonal cylindrical outer surface, and comprising thirty one lumens;

Figure 4 is a section through a core having a circular cylindrical outer surface and comprising two lumens; Figures 5a to c illustrate a die suitable for forming a core having a circular cylindrical outer surface and nineteen lumens, figure 5 a representing a view of the inlet side of the die, figure 5b representing an axial cross section through the centre of the die, and figure 5c representing a view of the outlet side of the die; Figures 6 to 10 show the results of the experiments, with figures 6 and 7 illustrating the effect of changing the length of a core, for a seven lumen system, figure 7 showing the effect of the length of the core for a nineteen hole embodiment, figures 8 and 9 showing the effect of changing the number of lumens on drug release for two different length cylinders; and figure 10 showing the effect of changing the concentration of the coating composition on drug release, for cores with lumens and without lumens;

Figure 11 shows the cross-section through a core with 7 lumens as it is progressively eroded;

Figure 12 shows a cross-section through a coated device the core of which has 7 lumens as it is progressively eroded;

Figure 13 shows the cross-section through a device comprising a core with two asymmetrically arranged lumens as the device is progressively eroded;

Figure 14 shows the cross-section through a coated device comprising a core with two asymmetrically arranged lumens as the core is progressively eroded;

Figure 15 shows the calculated drug release profile from the devices illustrated in figures 11 to 14;

Figure 16 shows the cross-section through a device comprising a core having 12 lumens as the device is progressively eroded; and Figure 17 shows the calculated drug release profile from the device of figure 16 and a coated version thereof.

Figure 1 shows a device according to the first aspect of the invention comprising a cylindrical core (1 ) having a circular cylindrical outer surface (2) and two ends (3 and 4). Extending parallel to the axis from one end to the other are seven lumens, consisting of a central lumen (5) and 6 peripheral lumens (6). Each lumen has the same diameter. The lumens may, as described above, be empty, or may be filled by a matrix material, in which biologically active agent is dispersed. The lumen surface (5, 6), outer surface (2) and/or ends (3, 4) may be provided with coatings for controlled release.

Figure 2 shows an alternative embodiment of the first aspect of the invention comprising a device consisting of a core (11) having an outer circular cylindrical surface (12), ends (13, 14), a central lumen (15), a series of six lumens (16) surrounding the central lumen, and a series of twelve peripheral lumens (17) arranged around the periphery of the core. Again the lumens (15, 16 and 17) all have the same internal diameter.

Figure 3 shows an alternative embodiment of the first aspect of the invention. A device comprises a core (21 ) having a generally hexagonal cylindrical outer surface (22) and ends (23, 24). Extending between the ends are several lumens, comprising a central lumen (25), six lumens surrounding the centre (26), a third series of twelve lumens (27) surrounding the lumens (26), and a peripheral series of twelve lumens (28) arranged around the periphery of the core. Figure 4 illustrates both first and second aspects of the invention. It is useful in particular to illustrate the second aspect of the invention. A section through a core falling within the second embodiment, comprises a core (31 ), and two lumens (32 and 33). Surrounding the left hand lumen, (32), is a series of arrows indicating the wall thickness t_θ, of the wall. Thus t₀ represents the wall thickness at the point on the circumference at angle 0°, where the distance to the nearest adjacent lumen is t₀. The thickness at the diametrically opposed point on the circumference, which represents the distance from the edge of the lumen to the outer surface (34) of the core, is t₁₈₀. At a point further around the periphery, at about 240° from the initial point, the thickness of the wall is no longer perpendicular to the lumen wall at that point, but rather at an angle, as illustrated as t₂₄₀. Further around the periphery of the lumen, at an angle of 270°, the distance is represented by t₂₇₀ being the shortest distance to the external wall of the core (34). Further round, the closest distance from the lumen (32) to another lumen or the external surface is in fact to the right hand lumen (33). This distance is represented by t₃₁₅.

Figures 5a to c represent views of the die which is suitable for forming a core having 19 lumens. The product would have an appearance similar to that of the product shown in figure 2. Figure 5a represents a plan view of the inlet side of the die. Figure 5b represents an axial section through the centre of the die, whilst figure 5c represents a plan view of the outlet side of the die. The die consists of an outer sizing member (40) and a pin support mandrel (41). The pin support mandrel (41) generally comprises a plate having an outer annular flange, (43) and central portion (44). Through the outer section are a series of conduit ports, (45) for flow of material from the ram or screw portion of the extruder towards the exit of the die. The conduit ports in this embodiment are circular, but could be another shape.

The outer sizing member (40) comprises a first section (46) which abuts the pin support mandrel at its outer flange portion (43). The inner surface of the portion (46) is a generally conical wall (47) which directs the material being extruded towards the exit whereby the separate flows through ports (45) are reconnected. The downstream portion of the outer sizing member (48) forms a circular cylindrical passage (49), through which the extrudate is forced. Within the circular cylindrical chamber (49) formed from the downstream part of the outer sizing member, there are located a series of hollow pins (50). The material being extruded flows around these pins, whereby the extrudate has a series of lumens coinciding with the pins, extending axially through the core. The pins are hollow and form a fluid conduit with the gallery (51 ) formed between the central portion (44) of the pin support mandrel and a disk (52) forming a wall of the mixing chamber, and a tube (53), exiting through the outer sizing member at its top outer portion (46).

In some circumstances, the conduit represented by the tube (53) and gallery (51 ) through the hollow pins (50), may merely vent to the atmosphere. It may allow for gas to enter or exit from the die. In other circumstances, the conduit may be used to direct a flow of coextruded material or a liquid material for coating the internal lumen walls.

The apparatus further comprises components not shown including a ram screw or other pumping device for forcing the material through the die, as well as take-up devices, for collecting the extrudate, cutting the extrudate and solidifying the extrudate with optional coating steps. Such components are known.

The following examples illustrate the invention.

Example 1

Propanolol hydrochloride 20g

Microcrystalline cellulose 63g Kaolin 11g

Polyvinyl pyrollidone 8g

Eudragit RL 30 D 20g

(30% aqueous polymer dispersion)

Water 70g The above ingredients are mixed in a planetary mixer, extruded through 10 mm diameter circular die with either 7 or 19 pins with a capillary extrusion rheometer (Acer 2000, Polymer Labs, Loughborough, UK). The extrudate is dried at room temperature and cut to known lengths. The pins are sized to give lumen diameters of 660 μm for the 7 lumen extrudate and 285 μm for the 19 lumen extrudate. The cut lengths of some of the cylinders are coated by one or two applications of a 3% solution of ethyl cellulose in ethanol to the external surface to give a known increase in weight.

Example 2

The coated cylinders of example 1 are tested to compare the release 5 profiles for propanolol, by the standard British Pharmacopoeia beaker method. The stirring rate was 50 rpm, temperature 37°C, and volume of water 1000 ml.

The results are shown in Figures 6 to 10. Figures 6 and 7 show the release profile comparing release rates for core lengths in the range 5 to 10 0 mm. Figure 7 shows the effect for a seven hole die, whilst figure 7 shows the effect for the 19 hole die. The core does not erode during the release tests.

Comparing these results the release of the drug can be influenced by both the length of the cylinder and the number of holes in the cylinder. In 5 general the longer the cylinder the slower the release and the greater the number of holes of the same diameter, the faster the release.

Figures 8 and 9 compare the effect of die geometry on drug release. The comparison is between cylinders having the same length (7.5 mm long in Figure 8 and 15 mm long in Figure 9) provided with seven or nineteen o compared to solid cores with the same outer diameter of lengths to give approximately the same drug content 15 mm for figure 8 and 10 min in figure

9).

Comparing these results, it can be seen that introduction of holes into the cylinders increases drug release and there is a slight advantage with 5 fewer larger diameter holes.

Figure 10 shows the effect of providing additional coating on drug release. The tests are carried out on cores having no lumens, and cores having 7 lumens, in each case being 10 mm long. Coating is provided on external cylindrical walls, but not end walls. The cylinders with holes lost o their shape at 80 mins for 1 % and 90 mins for 2%. The solid cylinder did not change shape. Example 3 - Release rates for erodible matrices

A model was devised to show theoretical drug release rates for a series of core designs. The model uses a graphical technique, in that the program draws on the computer screen in a distinct colour and to scale the overall end profile/cross-section which forms the matrix; the holes (lumens) are then drawn upon the end profile in the appropriate positions using another colour. The model allows the presence or not of a central lumen, allows one or more pitch circles of a selectable number of lumens, and allows pitch circle to be offset by a user-selectable angle with respect to a reference diameter. Each pitch circle may contain holes of different diameter to those in other pitch circles. It is possible to make dies with such variables. The computer is then instructed to scan the picture pixel by pixel and to count the number of pixels that are in the "matrix" colour. The exact area of the initial geometry may be calculated exactly, and so a calibration of number of pixels per unit area may be derived from the initial scan. Using a nominal rate of erosion from the surface, the decrease in outside diameter and the increase in internal (lumen) diameter may be computed, and so we can clear the screen, draw the new outside diameter in the "matrix" colour and superimpose the new lumen diameters, then scan again. Selection of the time intervals between scans and the distance moved to sample the screen colour during each scan point define the resolution of the experiment. To simulate an external coating, the outside diameter is not reduced from the original value. This model assumes that there is no substantial release by diffusion from the matrix to the surface, nor that corners are eroded more quickly than flat surfaces, such factors could, however, be brought into the simulation using the relevant parameters, of the matrix, the active and any coating, as well as the environment.

After each sequential scan, the software calculates the surface area of the matrix remaining, makes an adjustment for erosion via the end faces (at the same rate of erosion), and computes the volume of matrix remaining. Knowing the original volume of the pellet, the percentage of material that has been lost may be calculated, and thus the percentage of active ingredient that has been released.

The progressive sequences of erosion of various cores are shown in figures 11 to 14 and 16. The timescale progresses from left to right, then from top to bottom. As well as the change in cross-sectional area, the length of the pellet will also be decreasing as material is dissolved from the end faces. In figures 11 and 12 the core has an outside diameter of 10.0 mm and length of 10.0 mm and a central lumen and six lumens on a pitch circle having diameter 50 mm each lumen having a diameter of 1.0 mm. The device of figure 12 is provided with a non-erodible, water impermeable coating ("coated 7-hole"). The time scale of erosion in Figure 12 is twice that of Figure 11 ("uncoated 7-hole").

Figures 13 and 14 show similar progressions to those of Figures 11 and 12, but for a core with two lumens, arranged asymmetrically. Each lumen has a diameter of 1.0 mm and the outer diameter and length of the core are both 10.0 mm. One lumen is centred is 4.0 mm from the centre of the core and the other is centred 2.0 mm from the core and they are diametrically opposed. In Figure 14 ("coated 2-hole") the core is provided with an insoluble and impermeable coating and the total timescale for the erosion progression is twice that for the uncoated core ("uncoated 2-hole"). Figure 15 shows the projected percentage release profile for the four cores of Figures 11 to 14.

The total volume of active ingredient that has been released at any given time may be calculated by computing the volume of the granule remaining at that time (cross-sectional area at time t multiplied by length at time t). The rate of release may be estimated by simply noting the change in volume between sequential time points. The assumption is made for the sake of these models that a constant linear rate of dissolution prevails throughout the time-frame of the experiment, and this is considered to be reasonable given that we are considering the behaviour of a small pellet in a relatively large volume of solvent (eg the stomach). Considering the two uncoated pellets (Figures 11 and 13), as dissolution progresses, the outer diameter is progressively reduced and the diameters of the lumens are progressively increased; at the same time, the overall length of the core is reduced due to erosion from the end faces. The amount of active ingredient available for instantaneous release into the solvent at any given time may be estimated from the total surface area of the loaded matrix in contact with the solvent at that time. Considering the 7-hole symmetrical pellet (Figures 11 and 12), it can be seen that the inner holes open quite quickly, providing a rapidly increasing surface area and thus an increasing rate of release. After the dissolution of the inner structure, the rate of change in surface area changes as the outer structure is eroded. This process takes longer for the coated pellet (Figure 12), as the outside surface of the core is not available to the solvent. Note that the timescales are arbitrary, but that the diagrams for the coated cores represent double the time elapsed than for the uncoated cores. Application of a coating (Figures 2 and 4) prevents erosion from the outer surface of the pellet and gives different release profiles over an extended timescale, all other things being equal.

Figures 13 and 14 illustrate the change in cross-section as a core with two lumens located asymmetrically is eroded. As can be seen, the change in cross sectional profile with time follows a different pattern than the 7-hole symmetrical symmetry. By judicious selection of the geometry of the pellet and by the selection of the nature and location of an optional coating, the profile of the rate of release of the active ingredient into the liquid medium may be controlled. Figure 15 shows the computed rate of release (ie rate of erosion) of the geometries shown in Figures 11 to 14. As can be seen the selection of geometry and the presence of a coating has a considerable effect on the duration and on the profile of the release. For example, in Figure 15, the trace for the coated 2-hole pellet shows two distinct rates of release (ie as shown by the slope of the line), with a smooth transition between the two rates. This is more clearly seen in Figures 16 and 17. Figure 16 which shows the change in cross-section with time as a pellet with 12 symmetrical lumens is eroded (same length and outer diameter and lumen diameter as in the devices in Figures 11 to 14, and lumens centred on a circle of diameter 6.0 mm). The dimensions have been chosen such that, as erosion progresses, the centre section becomes detached from the outer hollow cylindrical section. The centre section may, of course, be configured with a central hole so that two perforated pipe sections are produced. As can be seen from the projected rate of release graph, Figure 17, there is a sharp change in the rate of release, corresponding to the external components being fully consumed and the residual release being due to the central cylinder. Thus, by careful design of the pellet geometry and judicious selection of the matrix and (where applicable) the coating material, it is possible to engineer a release profile whereby the rate of release of the active agent may change after a certain amount of erosion has occurred.

Claims

I . An orally administrable device a pessary or a suppository for controlled release of a biologically active agent in the body comprising a cylindrical core having multiple lumens extending generally parallel to the cylinder axis between the ends of the cylinder, the core being an extrudate of a mixture of an excipient material which forms a matrix and a biologically active agent distributed through the matrix, or in filling material filled into the lumens the device substantially retaining its integrity during the period and in the environment of the intended controlled release.

2. A device according to claim 1 having 2 to 50 lumens, preferably 7 to 19 lumens.

3. A device according to claim 1 or claim 2 in which the matrix is erodible.

4. A device according to any preceding claim characterised in that the thickness of the wall surrounding the or each lumen varies around the perimeter of the lumen, and the matrix is erodible into the liquid environment whereby, at least in part, release of the active takes place.

5. A device according to claim 4 which has one lumen only.

6. A device according to claim 5 in which the axis of the lumen is parallel to but spaced from the axis of the outer surface of the core.

7. A device according to claim 4 which has two or more lumens.

8. A device according to any preceding claim in which the core has a right circular cylindrical outer surface.

9. A device according to any preceding claim in which the or each lumen is circular in cross-section.

10. A device according to any preceding claim which is an orally administrable device for delivering pharmaceuticals, diagnostic agents or nutrients to animals, especially humans.

I I . A device according to any preceding claim in which the outer cylindrical wall is provided with a coating which is substantially impermeable to the biologically active agent at the target site.

12. A device according to claim 11 in which the solubility or permeability of the coating is pH-dependant.

13. A device according to any preceding claim which has an axial length of no more than 30 mm, preferably in the range 5-20 mm, more preferably 5 to 15 mm, and a diameter no more than 10 mm, preferably no more than 8 mm.

14. A device according to any preceding claim in which the or each lumen has a diameter in the range 0.5 to 2 mm.

15. A device according to any preceding claim in which the excipient material comprises a particulate water-insoluble inorganic compound and at least one organic polymer.

16. A process for forming a device according to claim 1 comprising forming a wet extrudable mass of matrix-forming excipient material and a biologically active agent and extruding the mass through a die to form an extrudate having a substantially cylindrical exterior surface and comprising one or more lumens extending continuously in a generally axial direction, and solidifying the extrudate.

17. A process according to claim 16 in which the extrudate is cut to predetermined lengths before or after the solidifying.

18. A process according to claim 16 or claim 17 comprising the step of providing the solidified extrudate with a coating on the exterior walls, and optionally on the end walls of cut lengths of extrudate and/or on the luminal surfaces.

19. A process according to any of claims 14 to 18 in which the extrusion is carried out in a screw gear pump, hydrostatic or ram extruder.

20. A process according to any of claims 16 to 19 in which the extrudable mass is formed by mixing dry particulate starting materials together and then adding and mixing in a wetting liquid to form the extrudable mass, in a separate vessel to the extruder.

21. Use of a device according to any of claims 1 to 15 in the manufacture of a medicament or a diagnostic or nutrient product for administration to an animal for use in a method in which the biologically active compound is released in a controlled manner at the target site in the body of said animal.

22. A controlled release process in which a device comprising a cylindrical core having one or more lumens extending generally parallel to the cylinder axis between the ends of the cylinder, the core being an extrudate of a mixture of an excipient material which forms a matrix and a biologically active agent distributed through the matrix, is positioned in a liquid-containing environment comprising a target for the biologically active agent, whereby active agent is released from the core to the environment via the lumen(s) to act upon the target, provided that at least one of the lumens is eccentric in the core.

23. A process according to claim 22 which is not a method of treatment of an animal by therapy nor a diagnostic method practised on an animal body.

24. A process according to claim 22 or 23 in which the matrix is erodible and the active is released as the matrix is eroded.

25. A process according to claim 22 in which the device has multiple lumens, preferably 2 to 50.