WO1997040822A2

WO1997040822A2 - Delivery device

Info

Publication number: WO1997040822A2
Application number: PCT/GB1997/001192
Authority: WO
Inventors: Neil Bonnette Graham
Original assignee: University Of Strathclyde
Priority date: 1996-05-01
Filing date: 1997-04-30
Publication date: 1997-11-06
Also published as: EP0910347A2; WO1997040822A3; GB9609094D0

Abstract

A delivery device under osmotic control when in contact with a liquid comprising an enclosure having an enclosure wall and at least an aperture through the wall, wherein the osmotically active material is present within the enclosure, and the apertures being sized such that when the device is in contact with liquid, osmotically controlled flow of solution from the enclosure through the aperture occurs.

Description

DELIVERY DEVICE

Background

The present invention relates to a delivery device for delivering a substance into a liquid at a substantially constant rate. The device is particularly, though not exclusively, applicable to the release of pharmaceutical or veterinary substances, but may also be used in a more general context where controlled release is required.

Controlled release devices are known which comprise a tablet coated with a semi-permeable membrane, which allows the passage of water therethrough, having an aperture punched therethrough. The tablet contains an osmotic agent mixed with a drug. When the tablet is introduced into an aqueous environment, water is driven through the semi-permeable membrane into the tablet due to the difference in osmotic pressure. A balancing flow of aqueous solution of drug which has dissolved in the water passes outwardly through the aperture in the semi- permeable membrane under hydraulic pressure. This is alleged to provide a reasonably constant drug delivery over a period of around 24 hours.

The art is replete with other suggestions for constant rate drug delivery devices.

It is an object of the present invention to provide a related delivery device in a particularly simple and cost effective manner. Statement of Invention

Thus, the present invention provides a delivery device for delivery under osmotic control when in contact with a liquid, which comprises: an enclosure having an enclosure wall and an aperture through the wall; an osmotically active material being present within the enclosure, the material being soluble in the liquid to form a solution; the aperture being sized such that, when the device is in contact with the liquid, osmotically controlled flow of said solution from the enclosure through the aperture occurs.

Thus, it has been surprisingly found that osmotically controlled flow can be achieved through a simple aperture without the need for any semi-permeable membrane. The delivery device of the present invention allows the achievement of a substantially constant rate of delivery in a particularly simple manner. Generally speaking, the rate of delivery is substantially constant until no more osmotically active material is left undissolved within the enclosure. It is surprising that a single aperture is sufficient to allow both the incoming flow (into the enclosure) of liquid and also the outgoing flow of delivered solution.

The term "osmotic control" as used herein means that delivery is determined by the difference in chemical potential (i.e. the partial molar free energy difference) between the solution inside the enclosure and the liquid outside the enclosure. Depending on various parameters including the orientation of the device and density differentials, delivery may be with or without an additional effect due to gravity.

The enclosure may be a self-supporting enclosure, such as a bottle, capsule, bag etc., or may be a coating applied onto a solid osmotically active material. The enclosure wall will not include a semi-permeable membrane.

The osmotically active material is present in the enclosure in a liquid or solid form, which then dissolves in the liquid. The presence of undissolved osmotically active material helps maintain a solution of substantially constant concentration (e.g. substantially saturated) within the enclosure. A solid osmotically active material may be provided in a suitable solid form, such as a tablet, granule, suppository, pessary etc. Coated granules may be filled into a capsule, such as a hard gelatin capsule, for ease of handling. A larger solid form may be prepared by compaction, such as in a tablet making machine, by moulding a molten or extruded formulation or by other means known in the art.

When the enclosure is in the form of a coating, the coating is preferably formed of a polymeric material including homopolymers and/or copolymers, such as a suitably hydrophobic cellulosic polymer, an acrylate, a polyvinyl ester, a polyamide, a polysulphone, a polycarbonate, a polyalkane (such as polyethylene or polypropylene) , a copolymer of ethylene and vinyl acetate, a silicone, or natural or synthetic rubber (such as a homopolymer or copolymer of isoprene or butadiene, or polyisobutene) , or other coating material known in the art. The coating material should, of course, be substantially insoluble in the liquid into which the delivery device is to be brought into contact, and substantially impervious thereto.

A liquid osmotically active agent (e.g. glycerol) will generally be soluble in the liquid in all proportions or in limited proportions. Measures may need to be taken to prevent the liquid osmotically active agent from flowing out of the aperture in the enclosure wall. Thus, the device will generally be arranged such that the liquid osmotically active agent is kept away from the aperture; such as by providing the aperture at the top of the device when the osmotically active agent is denser than the solution (or at the bottom when it is less dense than the solution) . The aperture in the enclosure wall is typically a circular aperture of diameter 0.01 to 5mm, preferably 0.1 to 1mm. The aperture may be made in any convenient way, such as by drilling or using a laser.

However, in an alternative embodiment, a plurality of apertures are formed in the enclosure wall. In a particular embodiment, at least a portion of the enclosure wall is in the form of a microporous membrane comprising a multiplicity of apertures and having a pore size which is typically in the range 0.2 to 5 microns. Such microporous membranes are to be distinguished from the semi-permeable membranes employed in the prior art which typically have pores of the order of a molecular size, for example in the region 1-20 nanometers. Microporous membranes are well known in the art and are typically formed from polymeric materials, such as celluloses, polyamides, polysulphones, polycarbonates, polypropylene, polyethylene, polystyrene, polyurethane, polytetrafluoroethylene, polyvinylidenefluoride; and alumina. Typically, in one technique microporous membranes are produced by stretching a crystalline polymer film or on a film which has been embossed with a pattern of raised and depressed areas such that pores are formed in the stretched product. Stretching may be uniaxial or biaxial. Other processes involve phase inversion providing pores during membrane formation, and the production of cylindrical pores by radiation track etching.

The osmotically active material is delivered from the device under osmotic control. Such osmotically active materials will be present in solid form or liquid form within the enclosure but will be soluble in the liquid to form a solution. Where the device is intended to be used in an aqueous medium, such as a body fluid, the osmotically active material will be water soluble. However, the device may be designed to operate within other liquids or solutions, including organic or inorganic liquids, in which case the osmotically active material would be chosen to have a suitable solubility in the chosen liquid. The osmotically active agent may, for example, be a salt of a heavy metal ion, such as silver, gold or copper, which may be used for sterilisation purposes. Other sterilisation applications include the treatment of water tanks in air conditioning units to prevent multiplication of bacteria, and the purification of drinking water in remote areas, countries and conditions where the quality of the water supply is questionable. Peroxides and bleaches for water sterilisation purposes may also be delivered. Swimming pools may be treated. Sustained release of copper ions may be useful in marine anti-fouling applications. Complexing agents and acids such as citric acid, sodium citrate, polyphosphoric acid, and polyacrylic acid may be used for descaling or maintaining clean surfaces in hard water areas. The device may also be arranged to deliver dyes, surfactants, scents or fluorescers. Thus, the delivery device may be in the form of a toilet block intended to release a dye and/or a disinfecting agent at a substantially constant rate. In an agricultural or horticultural context, the device may be arranged to provide a controlled release of fertiliser, nutrient or trace elements at a controlled rate. In the commercial or laboratory preparation of micro-organisms, the regulated supply of selected nutrients to improve growth is an important need which may be met by the simple device of the present invention.

The osmotically active material may or may not be the material which it is desired to deliver. The osmotically active material may also function as a vehicle for delivering a different active material, which may be soluble or insoluble in the liquid. Thus, the osmotically active material may be a substantially inert material, such as a salt or a sugar whose function is to deliver the different active material within the outgoing solution. In a pharmaceutical context, such a delivery device may be useful for delivering high molecular weight species such as proteins which are difficult to deliver by simple prior art diffusion devices since the diffusion co-efficient decreases dramatically with increasing molecular weight. This type of device may be used to deliver living or dead organisms, or suspended drug particles or other insoluble materials. The insoluble material is generally distributed uniformly throughout the osmotically active material such that it forms a fine dispersion in the liquid as the osmotically active material dissolves. Thus, a pigment dispersion in the osmotically active material will be carried by the hydraulic flow of the solution into the external liquid. A finely divided water insoluble drug can be delivered in a similar manner.

The osmotically active material may comprise a mixture of such materials where the materials have different solubilities in the liquid, particular delivery characteristics may be provided. For example, a first more soluble material may be delivered first, followed by a second less soluble material. Pulsed or delayed delivery devices may be provided in this way. It is an important feature of the present invention that the delivery (usually in a substantially linear manner) of osmotically active material occurs under osmotic control, that is to say is controlled by the difference in chemical potential of the osmotically active material between the solution inside the enclosure and the liquid outside. Generally speaking, the liquid outside the enclosure is present in a large excess, such that its chemical potential remains essentially constant and is essentially unchanged by the solution passing through the aperture in the enclosure wall. Notwithstanding this, the rate of delivery may also be effected by gravity, where the density of the solution inside the enclosure is different to that of the liquid outside the enclosure; or by diffusion. However, the effect of gravity will depend on the orientation of the delivery device and in many orientations it will be a secondary effect.

The size of the aperture will be chosen by simple experimentation in order to provide the desired delivery rate over the chosen period of time. Thus, delivery times may be chosen to be substantially constant over a period of hours, days, weeks or even months. The size of the aperture may also depend upon the solubility of the osmotically active material in the liquid. The size of the aperture and the particle size of a solid osmotically active material will be chosen such that the solid osmotically active material is retained within the enclosure and cannot accidentally pass through the aperture prior to dissolution.

Embodiments of the present invention will now be described by way of example only in conjunction with the attached drawings wherein;

Figure 1 shows release profiles from coated tablets having different sized apertures according to Example 1; Figure 2 shows release profile for sodium chloride passing through a microporous membrane;

Figure 3 shows a glucose release profile; and Figure 4 shows a surfactant (sodium lauryl ether sulphate) release profile.

EXAMPLE 1 (apertured coated tablets)

Tablets of etamiphylline camsylate (lOOmg) containing conventional excipients were obtained (with and without a red sugar gelatine coating) from Dale's Pharmaceuticals Ltd. along with a sample of the pure drug. The latter, which is highly water soluble, was used to prepare standard aqueous solutions for absorbance callibration and to confirm peak absorbance at wavelength 274 nm. A quarter of a coated tablet dissolved in 10 ml of water and when diluted one hundred fold gave an absorbance reading of 0.622, which represents a drug concentration of 34 micromole/ml . The red coating did not affect the peak absorbance value.

Six of each type of tablet had a hole 1.5 mm deep drilled in the centre of one convex surface thereof with a 0.35 mm drill, into which was fitted a short length of 0.35 mm diameter nichrome wire. Tetrachloromethane (in which the tablets were insoluble) was used to make a 10% solution of Cariflex (trademark) polymer. Cariflex is a thermoplastic elastomer made by Shell and is believed to be a block copolymer of butadiene and styrene. The tablets, held by the wires, were dipped five times into the solution. The wire enabled the tablets to be held for dipping and to be supported in cork for drying (10-15 minutes at room temperature) to allow evaporation of the solvent after each dip. The wire was then carefully removed from each tablet. The holes left when the wire was removed were measured under the microscope and found to be fairly consistently 0.39 mm in diameter. The coating was seen to be complete although not entirely free of small bubbles.

A tablet of each type was stirred in a litre of water at 37°C and absorbance readings taken half-hourly for 24 hours. To ensure that the tablets turned over regularly to avoid gravity effects, a stirring speed of 240 rpm was required. In this time the bath concentration of etamiphylline camsylate reached only about 1 microgram/ml, a release of well below 10%. The holes in another pair of Cariflex coated tablets were enlarged with a 1.5 mm drill but the resulting holes were very irregular, and that in the plain white (non- coated) tablet was at least four times the cross sectional area of that in the red (sugar coated) tablet. Each was stirred in a litre of water for 24 hours with absorbance readings being taken hourly, while the previous samples continued to be stirred. The white tablet bath reached a concentration of about 20 micromole/ml, releasing at a steady rate. The red tablet disintegrated shortly after the trial started and its results are omitted.

The stirring speed was reduced to the 60 rpm after about 50 hours without any apparent effect on the release rate. The stirrer for the original white tablet failed at about 100 hours and a subsequent lower release rate can be observed.

The results are shown in Figure 1.

The rate of drug release from the tablets is linear and dependent on the size of the hole in the impervious coating but is little affected by the red sugar coating.

EXAMPLE 2

Vials of 5ml capacity were filled with a known weight of solid osmotically active material and then topped up with a saturated aqueous solution thereof. The vials were then sealed with Duropore (trademark) 0.45 microporous membrane. The membrane has a nominal stated pore size of 0.45 microns. Duropore is a hydrophilic vinylidene difluoride microporous membrane supplied by Millipore. Each vial was initially weighed and then placed in water, either in an upright position with the microporous membrane uppermost, in an inverted position, or in a horizontal position. Delivery of osmotically active material was monitored by removing the vials from the water daily, followed by drying and weighing. In some cases the vial was weighed more frequently. In each case the time was noted at which all the remaining solid had dissolved. Enough water was available around the vial so that the concentration of osmotically active material therein never rose higher than 5% by weight.

Figure 2 shows the results using sodium chloride as the osmotically active material. The upper three traces show release profiles for sodium chloride with the vial upright in water, the third trace including the presence of a dye mixed with the sodium chloride. The lower three traces show the release profiles for inverted vials.

Figure 3 shows release rates for glucose as the osmotically active material both for upright and inverted vials in water.

Figure 4 shows the release profile for sodium lauryl ether sulphate surfactant from vials in the upright, horizontal and inverted positions.

It may be seen that the rate of release of osmotically active material is substantially constant in all cases up until the last remaining solid material has dissolved. The orientation of the vial has an effect on the actual release rate, due to a contribution from gravity, owing to the density of the solution within the enclosure being higher than that of the surrounding liquid

Claims

1. A delivery device under osmotic control when in contact with a liquid, which comprises:

(1) an enclosure having an enclosure wall and an aperture through the wall;

(2) an osmotically active material being present within the enclosure, the material being soluble in the liquid to form a solution;

(3) the aperture being sized such that when the device is in contact with the liquid, osmotically controlled flow of the said solution from the enclosure through the aperture occurs.

2. A device according to claim 1 wherein the osmotically active material is present in liquid or solid form.

3. A device according to claim 1 or claim 2 wherein the solid osmotically active material is present as a tablet, granule, suppository or pessary.

4. A device according to any of claims 1-3 wherein the enclosure is a self-supporting enclosure.

5. A device according to any one of claims 1-3 wherein the enclosure is in the form of a coating applied onto a solid osmotically active material.

6. A device according to claim 5 wherein the coating is formed of a polymeric material including homopolymer and/or copolymers.

7. A device according to claim 6 wherein the polymeric material is substantially insoluble in the liquid into which the delivery device is placed in contact and substantially impervious thereto and is formed of homopolymers and/or copolymers selected from a suitably hydrophobic cellulosic polymer, an acrylate, a polyvinyl ester, a polyamide, a polysulphone, a polycarbonate, a polyalkane, a copolymer of ethylene and vinyl acetate, a silicone or a natural or synthetic rubber.

8. A device according to claim 6 or claim 7 wherein the polyalkane is selected from polyethylene or polypropylene.

9. A device according to claim 6 or claim 7 wherein the synthetic rubber is a homopolymer or copolymer of isoprene or butadiene or polyisobutene.

10. A device according to any preceding claim wherein the aperture in the enclosure wall has a diameter of 0.01 - 5.00mm.

11. A device according to claim 10 wherein the aperture in the enclosure wall is from 0.1 - 1.00mm.

12. A device according to claim 10 or claim 11 wherein the aperture is circular.

13. A device according to any of the preceding claims wherein the device comprises a plurality of apertures formed in the enclosure wall.

14. A device according to claim 13 wherein at least a portion of the enclosure wall is in the form of a microporous membrane comprising a multiplicity of apertures and having a pore size in the range of 0.2 -5 microns.

15. A device according to claim 14, wherein the microprous membrane is formed from a polymeric material selected from polymeric materials, such as celluloses, polyamides, polysulphones, polycarbonates, polypropylene, polyethylene, p o l y s t y r e n e , p o l y u r e t h a n e , polytetrafluoroethylene, polyvinylidenefluoride, and alumina.