WO2001060340A1

WO2001060340A1 - Delivery capsules

Info

Publication number: WO2001060340A1
Application number: PCT/GB2001/000558
Authority: WO
Inventors: Malcolm David Brown
Original assignee: Bioprogress Technology International Inc.
Priority date: 2000-02-16
Filing date: 2001-02-13
Publication date: 2001-08-23
Also published as: GB0411917D0; GB2398499B; AU2001232068A1; GB2398499A

Abstract

The present invention provides a delivery capsule comprising an enclosing wall, the enclosing wall comprising an inner layer of a first material and an outer layer of a second material, the first and second materials having different solubility properties, with one or more portions of the inner layer constituting part of the outer surface of the capsule. When capsules in accordance with the present invention are added to an appropriate solvent, the solvent contacts both the inner layer and the outer layer of the conclosing wall of the capsule which may behave differently under the same conditions. It is thus possible to exploit the differential solubility effect which exists between the inner layer and the outer layer to control e.g. the rate of release of the contents of the capsule and/or the temperature at which said contents are released.

Description

Title: Delivery Capsules

Field of the Invention

The present invention relates to a delivery capsule, that is, a capsule designed to retain and protect its contents until an intended site of delivery or conditions of delivery are encountered, at which point the capsule contents are released.

Background of the Invention

Delivery capsules are well known as a convenient means for conveying doses of a substance. As such, they find particular application in numerous and disparate fields including the delivery of accurately metered doses of pharmaceutical and dietary supplements, and doses of cosmetic preparations e.g. fragranced oils encapsulated within a soft water soluble film material.

Conventionally, the capsule walls of delivery capsules have been formed from animal derived gelatin. However, in view of animal welfare concerns and the fear of animal related diseases such as Bovine Spongiform Encephalopathy (BSE), the popularity of water-soluble gelatin substitute materials, which are non-animal derived, is increasing.

WO 97/35537 describes capsules produced from non- animal derived materials including water soluble films such as polyvinyl alcohol (PVA). The capsules described in this document dissolve and release their contents according to the solubility of the film material of the capsule wall i.e. if a hot water soluble film is used, the capsules will only dissolve and release their contents in hot water. The capsules of WO 97/35537 are formed from two films of like material with each film forming a capsule half, and with two halves being sealed together to form a complete capsule. ftnmmarv of the Invention

According to one aspect of the present invention, there is provided a delivery capsule comprising an enclosing wall, the enclosing wall comprising an inner layer of a first material and an outer layer of a second material, the first and second materials having different solubility properties, with one or more portions of the inner layer constituting part of the outer surface of the capsule.

The inner layer and the outer layer of the enclosing wall together form a complete enclosure around the contents of the capsule.

The capsule may contain a wide range of materials in the form of gels, liquids, solids (e.g. particulates, powders etc.), and mixtures thereof e.g. slurries. Examples of suitable materials for use in the capsules described herein include drugs, vitamins, powders, oils, cosmetic preparations, drug delivery systems, domestic and household preparations etc.

The outer surface of the capsule is comprised in part by the inner layer of the first material and in part by the outer layer of the second material, the two materials having different solubility properties. One or more portions of the inner layer thus constitute part of the outer surface of the capsule. This means that the outer layer of the enclosing wall is incomplete. Therefore, regions of the inner layer are exposed to the external environmental conditions experienced by the capsule.

In use, when capsules in accordance with the present invention are brought into contact with an appropriate solvent (e.g. by being added to an appropriate solvent), typically water (although other solvents may be usefully employed e.g. alcohols, aqueous alcoholic mixtures, digestive juices etc.), the solvent contacts both the inner layer and the outer layer of the enclosing wall of the capsule. The first and second materials of the inner layer and the outer layer respectively may behave differently under the same conditions due to their different solubility properties. Thus, it is possible to exploit the differential solubility effect which exists between the inner layer and the outer layer to control e.g. the rate of release of the contents of the capsule and/or the temperature at which the contents are released. Moreover, as the outer surface of the capsule is comprised in part by the inner layer of the first material and in part by the outer layer of the second material, different geometries of capsule are possible.

As has been discussed herein above, the outer layer of the enclosing wall is incomplete. In contrast, the inner layer of the enclosing wall may be incomplete or complete, and preferably is complete. In simple cases the inner layer is approximately spherical or ovoid, and may be formed from two similar halves of an appropriate shape conveniently joined together by a circumferential flange at their periphery.

In one preferred embodiment herein the capsule is of a generally spherical or oval shape, having a circumferential flange extending from its outer surface. The capsule thus comprises two similar hemispherical or hemiovoid halves having at their periphery a circumferential flange, each half including a superimposed inner layer and outer layer with the two halves being sealed together via the flanges to form the complete capsule. In this particular embodiment of a preferred capsule in accordance with the present invention, the inner layer constitutes part of the outer surface of the capsule at the inner or central region of the flange periphery.

Such capsules may be conveniently made by the technique and apparatus described in WO 97/35537 with possible minor modification. The materials of the inner layer and/or outer layer may be supplied in the form of ribbon-like films, or alternatively can be readily manufactured e.g. by extrusion from solution. In a currently preferred method, the inner layer of a first material is applied to the outer layer formed from two ribbon-like films in the form of a viscous solution via extrusion, generally employing extruder bars modified with fine applicator controls for accuracy. The viscous solution should be applied to the outer layer in an appropriate amount. The amount of viscous solution applied is generally controlled to prevent complete dissolution of the outer layer and/or the formation of a film of insufficient strength to process into a complete capsule: this amount can be readily determined by experiment. In order to obtain good adhesion between the inner layer and the outer layer and form a bond between the layers of acceptable strength, desirably the amount of viscous solution applied to the outer layer is such that the outer layer softens and partial dissolution thereof is effected. Conveniently, this effect also facilitates the formation of a capsule of a desirable shape. Typically, the first material of the inner layer is applied as a 12% solution in water to each film forming the outer layer at a thickness of about 25 to about 50 g/m , preferably 35 g/m . The outer layer generally absorbs a proportion of the solvent, typically water, from the solution. Additionally, some of the solvent will evaporate under manufacturing conditions. This results in the formation of a discrete, superimposed inner layer. In order to seal the two halves of the capsule together, it is desirable that not all of the solvent from the solution is absorbed by the outer layer or is evaporated prior to encapsulation, so that an inner layer remains partially solvated and tacky. The capsule halves can thus be sealed because of the adhesive effect of the partially solvated inner layer. Typically therefore, means for applying solvent described in WO 97/35537 are replaced with means for applying a solution of an inner layer of a first material to the upper surface presented by the outer layer of a second material, preferably at an appropriate location upstream of the encapsulation unit.

In an alternative embodiment of a capsule according to the present invention, the capsule comprises a complete inner layer of a first material bearing an incomplete outer layer comprising one or more portions of a second material including one or more apertures, gaps or spaces. The inner layer thus constitutes part of the outer surface of the capsule in the region of the apertures, gaps or spaces.

The inner layer of the first material and the outer layer of the second material may be chemically alike but may not be identical in terms of grade, or alternatively, the materials may be chemically different.

The thickness of the outer layer of the enclosing wall may depend upon a number of factors including the nature of the contents, the intended use and purpose of a particular capsule and its size. Typically, the thickness of the outer layer may vary between the range 50 microns to about 150 microns, and is preferably about 100 microns. Typically, the thickness of the inner layer will be chosen so as to control the rate at which the contents of the capsule are released, but generally varies between about 5 microns to about 30 microns.

Typically, for practical purposes, the first and second materials of the inner layer and the outer layer respectively, have different solubility properties from one another in an appropriate solvent, generally water, although for certain applications other solvents e.g. alcohols may be appropriate.

Preferred materials for the first material and second material of the enclosing wall herein are cold water soluble, warm water soluble or hot water soluble. The term "cold water soluble" as used herein means a material which dissolves at a temperature in the range from about 0°C to about 30°C. The term "warm water soluble" as used herein means a material which dissolves at a temperature in the range from about 30°C to about 60°C and the term "hot water soluble" as used herein means a material which dissolves at a temperature greater than 60°C.

Suitable examples of materials soluble in water (hot, warm or cold) include polyvinyl alcohol (PVA), alginates, hydroxypropyl methyl cellulose and polyethylene oxide, or mixtures thereof.

Any of the above described materials may be suitable for use as the outer layer of a capsule. Further suitable materials for the outer layer of capsules herein include non-water soluble materials such as polycaprolactone and gelatinised starch based materials.

A suitable material for the inner layer is PVA which is possibly admixed with polyethylene oxide and optionally plasticised e.g. with glycerin.

The preferred material for both the inner layer and the outer layer of a capsule herein is PVA, which is available in a range of grades, types, e.g. several different grades forming a blend or one grade in isolation, solubilities and thicknesses. Additionally, such materials are commercially available e.g. in the form of ribbon-like films or can be readily manufactured e.g. by extrusion from solution. An appropriate material in the form of a film or solution can be readily selected having regard to the intended use, capsule contents and desired capsule properties.

Examples of suitable first materials for the inner layer of a capsule herein include:

1. 12% aqueous solution of Mowiol 28:99 hot water soluble, fully hydrolysed PVA commercially available from Hoechst, Germany, optionally comprising oil, typically vegetable oil.

2. 12% aqueous solution of Mowiol 30:92 warm water soluble, partially hydrolysed PVA commercially available from Hoechst, Germany.

3. 12% aqueous solution of Gohsenol GL05 cold water soluble, partially hydrolysed PVA (Nippon Goshei) commercially available from British Traders and Shippers, 429 Rainham Road, South Dagenham, Essex, UK.

4. 12%) aqueous solution of Gohsenol GH20, partially hydrolysed PVA (Nippon Goshei).

5. 12% aqueous solution of Gohsenol GL05 (as above), plasticised with glycerin.

6. 12% aqueous solution of cold water soluble resin 70:30 Mowiol 28:99 and Gohsenol GL05.

7. A solution of 80:20 w/w PVA resin and polyethylene oxide, prepared by dissolving up the PVA resin and polyethylene oxide together to produce a solution which will generally form a homogeneous inner layer with consistent solubility properties throughout.

Suitable second materials for the outer layer of capsules herein include PVA film material commercially available for example from Chris Craft, 407 County Line Road, Gary, Indiana, USA; Nippon Goshei from British Traders and Shippers as above; Aichello, Japan; and Cast Film Technology Incorporated, 910 East Burnett Road, Island Lake, Illinois, USA. Suitable films are available in a range of grades (containing a single type of PVA or blends of PVA resins), thicknesses and having differing speeds of solubility. An appropriate film can be readily selected having regard to the capsule type and desired capsule size. For example, PVA films of a thickness ranging between 70 microns and 120 microns are typically used. Non-limiting examples of suitable films for use herein include the Monosol range available from Chris Craft (Monosol is a Trade Mark) as exemplified by Monosol M7030 and Monosol M8630 and the Hi-Selon range available from Nippon Goshei (Hi-Selon is a Trade Mark) as exemplified by cold water soluble Hi-Selon C200.

By using an inner layer of a first material and an outer layer of a second material having different solubility properties, it is possible to arrange for release of the contents of the capsule under different conditions. Generally, at least one of the materials of the inner layer or outer layer of the enclosing wall is chosen so as to be substantially insoluble, when for example, the delivery capsule is immersed in a solvent, particularly water, of a particular temperature or exposed to digestive juices. Thus, in order to facilitate release of the contents of the capsule, the at least one other material of the enclosing wall is chosen having an appropriate solubility which will cause it to dissolve when the delivery capsule is exposed to the same conditions. Therefore, any particular delivery capsule will be formed from at least two such materials of differential solubility.

The inner layer of a first material may be less soluble than the outer layer of a second material, e.g. which may enable a capsule to be produced having an enclosing wall which dissolves at a different rate across its thickness.

For instance, exposure to cold water of a finished capsule comprising an inner layer of hot water soluble Mowiol 28:99 ((1) above) and an outer layer of cold water soluble Hi-Selon C200 film in cold water, will result in the outer layer of the enclosing wall of the capsule being dissolved leaving the inner layer intact. Typically, use of a thin (e.g. 5 micron to about 30 micron) hot water soluble inner layer, is likely to result in the inner layer rupturing under the weight of the contents of the capsule, thereby releasing said contents. Following rupture, the hot water soluble inner layer generally remains substantially intact. Alternatively, the addition of a proportion of cold water soluble resin such as a blend of 70:30 Mowiol 28:99 and Gohsenol GL05 ((6) above) to Mowiol 28:99, will produce an inner layer which upon rupture, fragments instead of remaining substantially intact. Depending on the intended use of a capsule, it is also possible to release the contents of the capsule from an inner layer of a first material which is more soluble than the outer layer of a second material. Thus, in a preferred embodiment herein, the inner layer of the first material is more soluble than the outer layer of the second material.

Advantageously therefore, the present invention facilitates the provision of capsules designed to be more stable and robust than has hitherto been possible, and which conveniently prevent premature release of the contents of the capsule upon handling, storage, manufacturing and packaging. Capsules which release their contents in cold or warm water are generally more sensitive to dissolution upon handling. Hence minimal handling of these capsules before use is preferable, as incidental contact with solvent such as sweat on the hands can cause premature release of the contents. Manufacture, storage, packaging and handling of soluble capsules is therefore difficult to achieve if the thickness of the capsule wall and its solubility are the only determining factors in the rate of release of the capsule contents (i.e. solubility rate). Depending on the intended use of a capsule, it is thus possible to obviate these difficulties and provide a capsule which is typically water soluble and displays greater resistance to degradation of the outer layer of the enclosing wall of the capsule upon contact with solvent of an appropriate temperature e.g. upon handling or upon incidental contact with moisture, yet controllably (e.g. at a desired rate) releases its contents under appropriate conditions of temperature e.g. in cold or warm water.

This may be achieved to good effect by employing an outer layer of warm water soluble PVA film and an inner layer of cold water soluble material such as Gohsenol GL05 ((3) above). Use of Mowiol 30:92 ((2) above) as the inner layer of an enclosing wall instead of Gohsenol GL05, will produce an inner layer of a capsule which is more resistant to dissolution in cold water than Gohsenol GL05, but less resistant than an inner layer of Mowiol 28:99 ((1) above). Alternatively, use of Gohsenol GH20 ((4) above) as the inner layer will produce an inner layer which is less soluble than an inner layer of Gohsenol GL05.

One currently favoured material for the inner layer of a capsule, designed to release its contents upon exposure to cold water yet resist handling, is a cold water soluble 70:30 blend of Mowiol 28:99 high hydrolysis level PVA resin from Hoechst, Germany and Gohsenol GL05 PVA resin from Nippon Goshei, Japan. This enables the manufacture of robust capsules (in preferred embodiments of a capsule herein), which may be readily sealed to good effect, the seal typically being constituted by the inner layers of two similar halves which have been joined together to form a complete capsule. The seal generally has a thickness of about 10 microns.

The inner layer of a first material and/or the outer layer of a second material may be coloured with any suitable colouring agent e.g. for aesthetic or barrier purposes. An inner layer and outer layer may be the same colour or different colours.

In a preferred aspect, a capsule in accordance with the present invention comprises two similar halves, each half having at its periphery a circumferential flange together with a superimposed inner layer of a first material which is more soluble (typically in water) than an outer layer of a second material, the two halves being sealed together via the flanges to form a complete capsule.

The present invention thus provides a water soluble capsule comprising two similar halves, each half including an inner layer of a water soluble first material or blend of materials (i.e. a controlled release layer) superimposed upon an outer layer, with the inner layer determining the release of the contents of the capsule, e.g. rate of release and/or temperature of release, independently of the outer layer. This may be achieved by careful selection of the formulation of the inner layer and the thickness at which it is applied. Typically, the materials of the two halves of the capsule are sufficiently adhesive to produce robust capsules when sealed together to form a complete capsule. Thus, capsules may be designed which are more resistant to incidental exposure to water and rough handling, yet are sensitive to the external conditions to which they are exposed.

In use, when such a capsule is added to a suitable solvent, typically water, of an appropriate temperature to the solubility of the inner layer of the first material, the capsule releases its contents upon partial or complete dissolution of the inner or central region of the flange periphery constituted by the inner layers i.e. susceptibility of the capsule to dissolution is effectively built into the seal. The outer layers of the capsule remain substantially intact, despite the release of the con ents of the capsule. This may be advantageous in certain applications, where dispersior of the outer layer into several smaller fragments is not desirable.

Generally, it is undesirable to employ optional ingredients in the inner layer which may prevent efficient sealing thereof. Such ingredients are readily determined by a person skilled in the art. However, it has also been found that the nature of the contents to be encapsulated within the enclosing wall may also affect the ability to seal the inner layer at its periphery and thus form a complete capsule. For example, contents which favour attachment to the hydrophilic sites presented by PVA, particularly fully hydrolysed PVA, coat PVA typically preventing sealing of the inner layer and thus formation of a complete capsule. Oils e.g. vegetable oil in varying proportions may thus be added to PVA to prevent the contents forming attachments therewith and enabling the inner layer to be sealed at its periphery.

In a further aspect of the present invention, a different formulation of material for the inner layer i.e. controlled release layer is applied to each half of the two similar halves comprising the outer layer.

The capsules may have a variety of different shapes and sizes, usually determined by the shape of the mould employed and or the desired application. Generally, the capsules are spherical or oval, but more elaborate forms e.g. based on fruit, flowers or abstract shapes may be produced. Typically, the size and thus the dimensions of the capsule may be varied to suit the intended purpose of the capsule, with a typical diameter of a capsule being in the range from about 10mm to about 40mm and preferably about 26mm.

The capsules of the present invention find numerous applications with, for example, a typical cosmetic or personal application being the encapsulation of bath oils to produce capsules intended to be used in the bath having improved handling and rapid dissolution. Further, a typical household or domestic application is the encapsulation of a dose of domestic or household product. The invention will be further described, by way of illustration, with reference to the accompanying drawing, in which:

Figure 1 is a schematic sectional view of a delivery capsule in accordance with the present invention.

Detailed Description of the Drawing

Referring to the drawing, Figure 1 illustrates schematically a generally ovoid delivery capsule 10 comprising an enclosing wall 12 in the form of two similar half shells 14 and 16 each of generally hemi-ovoid form.

The half shells 14 and 16 of the enclosing wall 12 each comprise an inner layer 30 of a first material and an outer layer 40 of a second material. The inner layer 30 and outer layer 40 of the enclosing wall 12 together form a complete enclosure around the contents 20 of capsule 10. The first and second materials have different solubility properties from one another, with one or more portions of the inner layer 30 constituting part of the outer surface of the capsule 10 at flange 18 in the inner region of the flange periphery.

The half shells 14 and 16 are sealed together to form a complete capsule 10 at seal 50 on flange 18 which extends circumferentially from the generally ovoid delivery capsule 10.

The outer layer 40 of a second material and the inner layer 30 of a first material of the enclosing wall 12 may be chemically alike but may not be the same in terms of grade, or alternatively, the materials may be chemically different, depending on the desired properties and intended use of the capsule. However, each layer has different solubility properties from the other. This requirement may be exploited when it is desirable to formulate a capsule 10 which is generally robust, and capable of for example, being handled and stored to prevent premature release of the contents 20. A capsule demonstrating these properties can be provided when the outer layer 40 is less soluble than the inner layer 30. For example, the outer layer 40 comprises a polyvinyl alcohol material which is soluble in aqueous solution at temperatures above 30°C and the inner layer 30 comprises a polyvinyl alcohol resin which dissolves in aqueous solution at temperatures above 5°C.

Generally, delivery capsule 10 may be designed to release its contents 20 in-use under different conditions and after different time intervals. For example, contents 20 may be released through seal 50 when the capsule is added to a suitable solvent, typically water, upon dissolution of all or part of the inner layer 30. Alternatively, seal 50 may release the contents 20 when the outer layer 40 dissolves upon the capsule being added to a suitable solvent and the seal ruptures as a result of not being able to support the weight of contents 20 within the comparatively thin inner layer 30.

Example

The following example serves to give a specific illustration of this invention but it is not in any way intended to limit the scope of the invention.

A good quality delivery capsule containing an aqueous and oil fill was prepared as shown in Figure 1 using the method and apparatus substantially as described in WO 97/35537. The delivery capsules so produced generally resisted release of their contents upon exposure to incidental moisture and sweat during handling, yet rapidly released their contents upon exposure to a volume of water having a temperature above 5°C.

The outer layer of the capsule was formed from two films of lOOμm warm water soluble polyvinyl alcohol, soluble in water at temperatures above 40°C. To the films at positions 28 and 30 illustrated in Figure 1 of WO 97/35537 i.e. to the inner surface of each film, was applied via extrusion, using cold adhesive extruder bars modified with fine applicator controls for accuracy, (such as those provided by Valco, Cincinnati, USA), a viscous solution prepared as described below:

A 12% solution of a 70:30 blend of Mowiol 28-99 PVA resin available from Hoechst, Germany and Gohsenol GLO5 PVA resin available from Nippon Goshei, Japan was prepared in hot water with frequent stirring. When the solution became clear, the heat was removed and the blend allowed to cool.

The viscous solution is applied to the films in an appropriate amount to cause softening and partial dissolution of the films. Typically, the solution was applied to the films forming the outer layer of a capsule at a thickness of about 35 g/m². The applied solution i.e. resin thus forms the inner layer of the capsule which partially dissolves in water down to a temperature of about 5°C at the inner or central region of the flange periphery typically releasing the contents of the capsule.

The films with viscous solution applied to the surface, having allowed some of the water to evaporate, were then supplied to an encapsulation unit, typically as described in WO 97/35537, where doses of an aqueous and oil fill to be encapsulated were injected between the inner layers. The outer layers of the film materials having superimposed thereon an inner layer were formed into opposed capsule halves containing the aqueous and oil fill. The capsule halves were then brought together and sealed, the seal being created by the adhesive effect of the partially solvated inner layer applied to the outer layer. The finished capsules were then cut from the films and air dried or force dried to remove any excess water, before being packaged.

When capsules prepared as described above, were placed in water at a temperature of about 20°C, the aqueous and oil fill was released from the capsules within about 60 seconds, following the ingress of water into the capsule seal formed by the inner layer at the inner or central region of the flange periphery. The outer layer of the capsule remains substantially undissolved in solution.

Capsules are thus provided, which rapidly release their contents under desired and appropriate conditions, e.g. in cold or warm water, yet which are less susceptible to degradation through handling or exposure to incidental moisture.

Claims

1. A delivery capsule comprising an enclosing wall, the enclosing wall comprising an inner layer of a first material and an outer layer of a second material, the first and second materials having different solubility properties, with one or more portions of the inner layer constituting part of the outer surface of the capsule.

2. A delivery capsule according to claim 1, wherein the inner layer of the enclosing wall is complete and the outer layer of the enclosing wall is incomplete.

3. A delivery capsule according to claim 1 or 2, wherein the capsule comprises two similar shaped halves having at their periphery a circumferential flange, each half including a superimposed inner layer and outer layer with the two halves being sealed together via the flanges to form the complete capsule.

4. A delivery capsule according to claim 3, wherein the two similar shaped halves are hemispherical or hemiovoid.

5. A delivery capsule according to claim 1 or 2, wherein the capsule comprises a complete inner layer of a first material bearing an incomplete outer layer comprising one or more portions of a second material including one or more apertures, gaps or spaces.

6. A delivery capsule according to any one of the preceding claims, wherein the inner layer of a first material and the outer layer of a second material are chemically alike but not identical in terms of grade.

7. A delivery capsule according to any one of the preceding claims, wherein the inner layer of a first material and the outer layer of a second material are chemically different.

8. A delivery capsule according to any one of the preceding claims, wherein the first and second materials have different solubility properties from one another in water.

9. A delivery capsule according to any one of the preceding claims, wherein the enclosing wall comprises an inner layer of polyvinyl alcohol, optionally admixed with polyethylene oxide or glycerin, and mixtures thereof.

10. A delivery capsule according to any one of the preceding claims, wherein the enclosing wall comprises an outer layer of a second material selected from polyvinyl alcohol, alginates, hydroxypropyl methyl cellulose and polyethylene oxide, or mixtures thereof.

11. A delivery capsule according to claim 10, wherein the enclosing wall comprises an outer layer of polyvinyl alcohol.

12. A delivery capsule according to any one of the preceding claims, wherein the inner layer of polyvinyl alcohol is less soluble than the outer layer of polyvinyl alcohol.

13. A delivery capsule according to any one of claims 1 to 1 1 , wherein the inner layer of polyvinyl alcohol is more soluble than the outer layer of polyvinyl alcohol.