throbber
(cid:38)(cid:68)(cid:83)(cid:86)(cid:88)(cid:74)(cid:72)(cid:79)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:20)(cid:19)(cid:21)(cid:26)
`
`Page 1 of 20
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`

`

`W001lfl36?6
`
`PCTI'G 3001’0261 6
`
`1
`
`r
`
`'tle1m ve
`
`'
`
`i
`
`l'
`
`il
`
`f th Inv
`
`'
`
`This 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.
`
`Backgmdtethelnxentinn
`
`Delivery capsules are well known and find particular application in the form of ingestible
`
`gelatin capsules
`
`for
`
`the delivery of accurately metered doses of pharmaceutical
`
`preparations and dietary supplements. Liquid preparations are typically encapsulated in
`
`soft gelatin capsules and particulate or powdered preparations are typically encapsulated in
`
`two part hard gelatin capsules. The capsules are designed to release their contents after
`
`ingestion, typically by solution of the capsule wall, and by use of suitable capsule material
`
`can thus provide a means of administering a dose of a preparation at a desired appropriate
`
`site in the body. The finished capsules offer protection to the contents yet solubility within
`
`the body.
`
`Other uses of delivery capsules include delivery of cosmetic ingredients, eg fragranced
`
`bath oils encapsulated in soft gelatin capsules for release into bath water, paint balls in the
`
`form of paint-containing capsules that rupture on impact etc.
`
`There are limitations on current capsules and encapsulation techniques. For example,
`
`because of differences in powder and liquid handling,
`
`the processing means for the
`
`encapsulation of powders and liquids within a gelatin capsule are quite distinct and
`
`incompatible.
`
`This situation renders impossible the provision of a gelatin capsule
`
`containing both powder and liquid that are kept separate.
`
`Page 2 of 20
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`Page 2 of 20
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`

`

`W0 le03676
`
`PCTIGBOOI'OZfilé
`
`The present invention seeks to address certain shortcomings and limitations of current
`
`2
`
`capsules and encapsulation techniques.
`
`Snmmanactthalnnentitm
`
`In one aspect the invention provides a delivery capsule having at
`
`least
`
`two separate
`
`chambers.
`
`The chambers of the capsule are completely discrete and separated from each other so that
`
`no communication between the chambers is possible. This means that the contents of the
`
`different chambers are kept separate from each other within the capsule until delivery.
`
`In most cases, different chambers of the capsule will contain different materials, possibly
`
`in different physical forms, eg liquid, solid (cg tablet, particulate, powdered), slurry etc,
`
`in a way that has not hitherto been possible. although it is also possible for the different
`
`chambers to contain separate doses of the same material.
`
`The capsule is preferably internally divided by a dividing wall or septum, conveniently in
`
`the form of a median wall symmetrically arranged to form two chambers of similar size
`
`and shape.
`
`One or more chambers of the capsule may be further divided if required, eg by inclusion
`
`in a chamber of a smaller delivery capsule, constituting a further separate chamber.
`
`The invention thus provides a compartmented capsule in a way that has not been done
`
`hitherto.
`
`Indeed,
`
`it is believed that this is not possible with known techniques for gelatin
`
`encapsulation.
`
`Instead of using gelatin for encapsulation,
`
`the present invention preferably uses a heat-
`
`sealable material
`
`that
`
`is capable of deforming plastically on heating (a thermoplastic
`
`material) andfor that
`
`is capable of deforming plastically when partially solvated by
`
`Page 3 of 20
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`Page 3 of 20
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`

`

`W0 01f03676
`
`PCTIGBBOIIJZISI 6
`
`3
`
`application of an appropriate solvent. Suitable materials include hydroxy propyl methyl
`
`cellulose
`
`(HPMC),
`
`pectin,
`
`polyethylene
`
`oxide,
`
`polyvinyl
`
`alcohol,
`
`alginate,
`
`polycaprolaetone, gelatinised starch-based materials etc. The material may be coated, eg
`
`with gum arabic, pectin, alginate eg sodium alginate etc to modify properties.
`
`For
`
`example, gum arabic, pectin and alginate all have a slight retarding effect on HPMC
`
`solubility, the extent of the effect varying according to coating thickness. Further, both
`
`pectin and alginate can be cross-linked, eg with calcium, this has the effect of making the
`
`material pH sensitive such that it will not dissolve in the mouth but will dissolve in the
`
`stomach where pH is lower. Multi-layer materials may also be used. Examples of
`
`suitable capsule materials and coatings are given in W0 978553? and WO 00127367. The
`
`capsule materials also have the advantage compared with gelatin of being non-animal
`
`derived, and so having no possibility of transmitting animal-related diseases such as bovine
`
`spongiform encepehalopathy (BSE). Such materials are commercially available, eg in the
`
`form of ribbon-like films or can be readily manufactured, eg by extrusion from solution.
`
`One currently favoured material is the thermOplastic material HPMC. in expanded or non-
`
`expanded form, with or without coatings. HPMC is suitable for ingestion by humans and
`
`so can be used for ingestible capsules as well as other uses, eg culinary, cosmetic etc.
`
`A compartmented capsule in accordance with the invention can be used simply to keep
`
`separate in the respective chambers two materials prior to delivery.
`
`This can be of
`
`advantage,
`
`for example, when delivering to the same site two materials which react
`
`together on admixture: by use of a compartmented capsule in accordance with the
`
`invention the two materials can be kept separate until the septum wall
`
`is dissolved on
`
`delivery. bringing the materials together. This approach is also useful, say, for delivery of
`
`two separate pharmaceutical preparations.
`
`For instance,
`
`this approach is relevant
`
`to
`
`delivery of certain mum-component cold remedies which are currently unable to get FDA
`
`approval due to concerns of possible chemical reactions prior to ingestion: by using a
`
`capsule in accordance with the invention to keep the components separate within the
`
`capsule prior to delivery such difficulties can be overcome. As a further example, there is
`
`a drug called Acctuane which is an effective treatment for acne but which can also cause
`
`birth defects.
`
`In order to ensure that this does not occur birth control drugs should be
`
`Page 4 of 20
`
`Page 4 of 20
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`

`

`WO 01103676
`
`PCT/GB00!02616
`
`4
`
`taken simultaneously with Acctuane by fertile female users. For safety reasons it would
`
`thus be far preferable if the birth control drug and the acne remedy were taken together,
`
`but kept separate until after
`
`ingestion.
`
`This can be readily achieved by use of a
`
`compartmented capsule in accordance with the invention.
`
`Furthermore, by using different materials (either in terms of thickness andror composition
`
`andfor coatings) defining the different chambers of the capsule, it is possible to arrange for
`
`release of the contents of the different chambers under different conditions, eg at different
`
`specific sites within the body. The contents of different compartments can thus be targeted
`
`to different specific areas within the body.
`
`For instance, use of a thicker material defining one compartment may result in slightly
`
`delayed release of material compared with that from a compartment defined by a thinner
`
`layer of similar material.
`
`Another example is the use of a pH sensitive coating on the material defining one chamber
`
`so that chamber contents are released at different delivery sites dependent upon pH. Use
`
`of enteric coatings such as cellulose acetate phthalate can also be used to target release, eg
`
`to within the stomach. Coatings such as ethyl cellulose can be used to retard solubility
`
`times. A further example is use of expanded HPMC defining one compartment and non-
`
`expanded HPMC defining another compartment. Expanded HPMC film releases rapidly in
`
`the month while standard, non-eXpanded film has sufficient resistance to dissolution to
`
`release only after it has been swallowed, providing that it is not kept in the mouth too
`
`long.
`
`It is also possible to coat a finished capsule after formation with materials such as sodium
`
`alginate to improve robustness or alter solubility.
`
`The capsule materials may include optional colourings, eg in the form of known food dyes
`
`such as FD and C yellow number 5, optional flavourings, textures etc.
`
`Page 5 of 20
`
`Page 5 of 20
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`

`

`W0 01!03676
`
`PCTi’GBflfli'026lfi
`
`5
`
`The capsules may have a range of different sizes and shapes as appropriate dependent on
`
`intended usage. Capsules are typically generally spherical, ovoid, cylindrical etc in shape.
`
`preferably incorporating a median septum as described above.
`
`Typical maximum
`
`dimensions of the capsule are in the range 3m to 20mm, but other sizes are possible.
`
`The capsules are conveniently made by a vacuum or pressure forming technique, that may
`
`be loosely based on the technique described in W0 9785537 but with very substantial
`
`modification.
`
`In a further aspect,
`
`the invention thus provides a method of encapsulation, comprising
`
`supplying two films of material capable of deforming plastically on heating andfor when
`
`partially soivated; heating the films andior applying solvent; forming the films into suitably
`
`shaped capsule portions; supplying respective substances to be encapsulated to capsule
`
`portions of each film; supplying a film of a dividing septum material to at least one of the
`
`filied capsule portions; sealing the capsule portions and septum material together to form a
`
`capsule having at least two separate chambers.
`
`The films are preferably formed into capsule portions by appiication of elevated pressure
`
`or vacuum (or reduced pressure).
`
`It is preferred to use two layers of film for producing the septum, with one film applied to
`
`each respective capsule portion, as handling including optional coating is easier.
`
`Adhesive material is preferably applied to the various fih'n materials to help secure the
`
`capsule portions and septum together. Capsule sealing is preferably accomplished by heat
`
`scaling,
`
`to fuse the films of material together, although other sealing methods may be
`
`used.
`
`Pre-formed films of material may be used. Alternatively, the films may be formed during
`
`the encapsulating process, eg by being cast from solution.
`
`Page 6 of 20
`
`Page 6 of 20
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`

`

`WO 01103676
`
`PCTIGBOOIGZISI 6
`
`6
`
`In a further aspect the invention provides encapsulation apparatus, comprising means for
`
`supplying two films of material to an encapsulation unit; means for plastically deforming
`
`each film to form suitably shaped capsule portions; means for supplying respective
`
`substances to be encapsulated to the respective capsule portions of each film; means for
`
`supplying a film of dividing septum material to at least one of the filled capsule portions;
`
`and means for sealing together the capsule portions and septum material to produce a
`
`capsule having at least two separate chambers.
`
`The apparatus typically also comprises reservoirs of the substances to be encapsulated,
`
`with associated supply arrangements adapted to supply a metered doses of the substance to
`
`the capsule portions at predetermined time intervals.
`
`The arrangement may employ
`
`syringe pumps or the like.
`
`The apparatus conveniently includes heater means for heating the capsule film material to
`
`enable thermoplastic deformation.
`
`The means for deforming the films conveniently comprises a pair of similar vacuum belts.
`
`The invention is applicable to encapsulation of a wide range of pharmaceutical, culinary,
`
`cosmetic etc ingredients, enabling delivery to different sites of different materials or
`
`delivery to the same site of materials that are desirably kept separate prior to delivery.
`
`Capsules described in this specification provide a delivery means with either at least two
`
`distinct liquid or solid, eg powder fills, or a combination of liquid and solids, eg powder.
`
`The materials can also be selected so as to exclude gelatin. The combination of materials
`
`used for the capsule wall and capsule dividing septum can be chosen to release either or
`
`both parts of the contents of capsule at specific sites within the body. These components
`
`can then address two different specific areas or act synergistically when mixed on release
`
`at the same site.
`
`In the latter example the capsule is serving to prevent the mixing of the
`
`two components prior to them reaching the correct site within the body as well as
`
`providing an accurate dose and blend of components for maximum efficacy.
`
`Page 7 of 20
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`Page 7 of 20
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`

`

`W0 01.103676
`
`PCTIGBIJIJIO2616
`
`The prCSent invention enables the encapsulation of both powders and liquids within discrete
`
`chambers in an ingestible capsule. Using pre-forrned rolls of film such as hydroxy propyl
`
`methyl cellulose capsules are formed with an outer shell and a dividing septum.
`
`In such a
`
`capsule two different materials which would react if brought together in a single chamber
`
`can be kept apart until the septum wall is dissolved.
`
`By the application of surface coatings to the forming rolls and the dividing layer prior or
`
`post capsule formation, or the use of different materials for the forming rolls, capsules can
`
`be formed which release their contents under different environmental conditions. An
`
`example of this is the application to pH sensitive coatings on the outer surface of the
`
`capsule wall and septum which causes the two distinct chambers to release their contents at
`
`different delivery sites dependent upon the pH of the surrounds.
`
`The capsules are produced on dedicated machinery employing the use of vacuum forming
`
`and heat sealing, and can be filled with liquids or powders.
`
`The invention will be further described, by way of illustration, with reference to the
`
`accompanying drawings in which:
`
`Figure 1
`
`is a schematic sectional view of a delivery capsule in accordance with the
`
`invention; and
`
`Figure 2 is a schematic representation of one embodiment of apparatus in accordance with
`
`the invention for producing a delivery capsule embodying the invention.
`
`£111.. Ell
`
`.
`
`Referring to the drawings, Figure 1
`
`illustrates schematically a generally ovoid delivery
`
`capsule 10 comprising at outer shell or wall in the form of two similar half shells 12 and
`
`14 each of generally semi-ovoid form, and a median dividing wall of septum 16 that
`
`Page 8 of 20
`
`Page 8 of 20
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`

`

`W0 011'03676
`
`PCTlGBODIflZfilfi
`
`8
`
`divides the capsule into two similar chambers or compartments 18 and 20 that are
`
`completely separate from each other. with no communication between the chambers 18 and
`
`20 being possible.
`
`Each chamber 18 and 20 contains a metered amount of a different material (not shown), eg
`
`with a powdered or particulate material in chamber 18 and a liquid material in chamber
`
`20, or visa versa, or with different liquid materials in each of the two chambers or with
`
`different powdered or particulate materials in each of the two chambers.
`
`The half shells 12 and 14 of the septum 16 may be made of similar or different materials,
`
`depending on the desired properties and intended use of the capsule.
`
`For example, where the function of the compartments is simply to keep two materials
`
`separate from each other until release at the same site of delivery, thus can be achieved by
`
`all of the capsule walls, half shells 12 and 14 and septum 16, being of the same material,
`
`eg HPMC (possibly coated as discussed above).
`
`However, where the capsule is designed to delivery the contents of chamber 18 and
`
`chamber 20 at different sites or under different conditions, eg at different sites in the body
`
`after ingestion, it is appropriate for the capsule walls to be of different material, eg with
`
`half shell 12 of a first material and half shell 14 and septum 16 of a second, different
`
`material, with the two different materials functioning to release the contents of the
`
`associated compartment under different conditions, eg under different conditions of pH, or
`
`after different time intervals etc. For example, the first material may comprise pectin and
`
`the second material may comprise HPMC. As a further example, the first material may
`
`comprise tin-coated HPMC and the second material may comprise a HPMC coated, eg
`
`with sodium alginate. Another possibility is for the first and second materials to have
`
`different coatings, eg of sodium alginate and gum arabic. A yet further possibility is for
`
`the first material to be expanded HPMC, with the second material being standard cast
`
`HPMC coated with sodium alginate.
`
`Page 9 of 20
`
`Page 9 of 20
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`

`

`WO 01103676
`
`PCTIGBOOIIJZfil 6
`
`9
`
`It is also possible for septum 16 to be of completely insoluble material that will. eg, pass
`
`through the body unchanged.
`
`The dimensions of capsule 10 may be varied to suit the intended purpose of the capsule.
`
`with the maximum dimension typically being in the range 3m to 20mm.
`
`Examples
`
`The following examples serve to give specific illustrations of this invention but they are
`
`not in any way intended to limit the scope of this invention.
`
`Example 1. A dual delivery capsule as showu in Figure 1 where the septum 16. and the
`
`capsule walls 12 and 14 are of like material, exampled by hydroxy propyl methyl
`
`cellulose.
`
`Example 2. A dual delivery capsule as shown in Figure 1 with one wall and dividing
`
`septum of like material, exampled by hydroxy propyl methyl cellulose, and the other wall
`
`of different material, exampled by pectin.
`
`Example 3. A dual delivery capsule as shown in Figure 1 with walls and dividing septum
`
`of like material, exampled by hydroxy propyl methyl cellulose with a coating on one half
`
`of the capsule and one side of the capsule dividing septum, exampled by sodium alginate.
`
`Example 4. A dual delivery capsule as shown in Figure 1 with walls and dividing septum
`
`of like material, exampled by hydroxy propyl methyl cellulose with the same coating on
`
`both sides of the capsule, exampled by sodium alginate.
`
`Example 5. A dual delivery capsule as shown in Figure 1 with walls 12 and 14 of like
`
`material exampled by hydroxy propyl methyl cellulose with different coatings on each
`
`exampled by sodium alginate and gum arabic and dividing septum 16 coated on the side
`
`closest to the wall bearing the alginate coating with gum arabic.
`
`Page 10 of 20
`
`Page 10 of 20
`
`

`

`WO 01103676
`
`PCTIG 1300392616
`
`10
`
`Example 6. A dual delivery capsule as shown in Figure 1 with a liquid fill contained in
`
`chamber 20 exampled by
`
`dextromethorphan and
`
`a powder
`
`filled example
`
`by
`
`chlopheniramine contained in chamber 18 between septum l6 and capsule wall 12.
`
`Example 7. A dual delivery capsule as shown in Figure l with two different liquid fills
`
`cxampled by cod liver oil and evening primrose oil contained in chamber 20 and chamber
`
`18, respectively.
`
`Figure 2 illustrates schematically one embodiment of apparatus for producing capsules in
`
`accordance with the invention.
`
`The illustrated encapsulation apparatus comprises two similar, aligned.
`
`side-by~side
`
`vacuum belts 40 and 42 each comprising a plurality of articulated segments of plastics-
`
`coated aluminium as represented by segment 44. Each segment has a width of about
`
`600mm, extending perpendicular to the plane of the sectional view of Figure 2. and is
`
`formed with a row of hemi-ovoid recesses running across its width, eg recess 46, only one
`
`such recess of each segment being visible in the drawing. Drive means (not shown) are
`
`provided for driving the two belts synchronously, with belt 40 being driven in a clockwise
`
`direction and belt 42 being driven in an anticlockwise direction, with the recesses of the
`
`two belts in registration with each other. Each recess includes a number of fine bore
`
`vacuum ports (not shown), each about 0.4mm in diameter, with vacuum means (not
`
`shown) arranged to apply a vacuum in the range -15 to -30 inches mercury. The vacuum
`
`may be applied only to the recesses in the segments when in the upper portion of travel of
`
`the belts.
`
`Four rolls of film material 50, 52, 54 and 56 are rotatably Supported on respective
`
`spindles, with the films being pulled from the spindles and over vacumn belts by a driven
`
`nip roller 58. The films pass around respective guide rollers 60, 62, 64, 66 to be brought
`
`into contact with the associated vacuum belt.
`
`Page 11 of 20
`
`Page 11 of 20
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`

`

`W0 [lli03676
`
`PCTIGBIIOIOZGIIS
`
`11
`
`Films 50 and 52 form the generally hemi-ovoid outer shell halves of a capsule. To this
`
`end, the films pass below respective infra red heaters 68 and 70 located near the outer end
`
`of each vacuum bed, which act to heat the film passing there below to a temperature at
`
`which it is capable of deforming plastically. The films then deform to take up the shape of
`
`the recesses in the vacuum belts, assisted by the vacuum applied to the belts.
`
`The films, moving with the vacuum bed, then pass below respective adhesive application
`
`stations 72, 74 in the form of rollers which apply adhesive to the surface of the films not
`
`within the recesses.
`
`The films then move past respective filling stations 76, 78 where metered doses of material
`
`are supplied to each outer shell half as it passes below the station.
`
`Suitable filling
`
`equipment for supplying metered doses of liquid materials (eg syringe pumps. peristaltic
`
`pumps etc) and for supplying metered doses of powdered or particulate materials are well
`
`known. Typical volume fills are in the range 0.1 to 3.0 mls per capsule half.
`
`The filled outer shell halves then move inwardly with the vacuum bed, past guide rollers
`
`64, 66 around which pass lengths of septum-forming films 54, 56. The septum-forming
`
`films adhere to the non—deformed parts of films 50 and 52 under the action of the
`
`previously applied adhesive, closing off the half capsules.
`
`The thus formed half capsules move inwardly with the vacuum belt past further adhesive
`
`stations 80, 82 which act to apply adhesive to the top surface of the septum-forming fihns.
`
`The capsule halves are brought together between adjacent sides of the vacuum belts and the
`
`two septums adhere together by adhesive action. At this point, the capsules are loosely
`
`stuck together.
`
`The films with arrays of capsules therebetween are fed to a sealing station cornprising two
`
`heater blocks 88, 90 mounted on pneumatic rams that reciprocate towards and away from
`
`each other in synchronism. The blocks act to heat and fully seal together the capsule
`
`Page 12 of 20
`
`Page 12 of 20
`
`

`

`W0 01.303676
`
`PCTfGBOOr‘flZfil 6
`
`12
`
`halves, forming compartmented capsules in accordance with the invention. A knife edge
`
`(not shown) is provided on one of the blocks to cut the capsules from the remaining
`
`material. The cut capsules are collected below and the remaining film web material
`
`is
`
`passed to waste.
`
`In a typical embodiment the films comprise HPMC having a thickness of about 120nm.
`
`Such material is readily available commercially. For example, HPMC is available from
`
`Dow Chemicals (USA) and is made into a film by Cast Film Technologies (USA).
`
`Optional coatings may be applied to the film material, eg upstream of the rollers.
`
`Different coatings may be applied to the different half-capsule forming films.
`
`When treating HPMC, the films should be heated at heating stations to a temperature of
`
`about 85 to 90°C so as to became thermoplastic and deformable.
`
`A suitable adhesive for use with HPMC is HPMC with 60% propylene glycol, which can
`
`be applied warm or cold. Other possible adhesivefplasticizer materials include triacetin.
`
`monoacetin and ethyl lactate.
`
`The adhesive formulation can also be applied before the forming heaters provided that it is
`
`of food grade and there is no reactiou with the capsule contents.
`
`In such a case there will
`
`be a continuous coating of the adhesive present inside the formed capsule half. This can
`
`help with adhesion of the septmn—forming film by causing a build up inside the seam.
`
`For sealing HPMC, the heating block should be heated to a temperature in the range 150
`
`to 170°C.
`
`When using PVA instead of HPMC, heater temperatures must be much higher, about
`
`150°C to produce a thermoplastic film, with the heater block typically being heated to a
`
`temperature in the range 160 to 200°C.
`
`Page 13 of 20
`
`Page 13 of 20
`
`

`

`W0 011'03676
`
`PCT16 3001'0261 6
`
`13
`
`The illustrated equipment can run at a rate capable of producing about 30,000 capsules per
`
`hour with a web width of about 600m.
`
`A typical embodiment uses expanded HPMC for one capsule half and standard cast HPMC
`
`coated with sodium alginate for the other capsule half. The standard cast HPMC has a
`
`thickness of about 120 micron with a coating of alginate in the range 2 to 10 microns
`
`thick.
`
`The application of the first adhesive is conveniently effected by rolling, extrusion or
`
`spraying, preferably by use of a roller, while application of the secoud adhesive is
`
`conveniently effected by a roller in contact with the film.
`
`The capsules produced by the apparatus of Figure 2 have a form generally corresponding
`
`to the capsule of Figure I, with septum 16 being constituted by two adhered together
`
`layers of film 54 and 56. The capsules include a short peripheral median flange (not
`
`shown in Figure I), aligned with and extending Outwardly from the position of septum 16,
`
`constituted by portions of the four films 50, 52, 54, 56 adhered together to seal
`
`the
`
`compartments and capsule.
`
`Page 14 of 20
`
`Page 14 of 20
`
`

`

`W0 01l03676
`
`PCTIGBOOIOZGIG
`
`14
`
`$1111.“:
`
`1. A delivery capsule having at least two separate chambers.
`
`2. A capsule according to claim 1, wherein each chamber contains a different material.
`
`3. A capsule according to claim 1 or 2, wherein each chamber contains a metered dose of
`
`a material.
`
`4. A capsule according to claim 1, 2 or 3, including a dividing wall or septum defining in
`
`part two separate chambers.
`
`5. A capsule according to claim 4, wherein the dividing wall or septum comprises two
`
`layers of material adhered together.
`
`6. A capsule according to claim 4 or 5, wherein the dividing wall or septum camprises a
`
`median wall symmetrically arranged to form two chambers of similar size and shape.
`
`7. A capsule according to any one of the preceding claims, formed from a heat-scalable
`
`material that is capable of deforming plastically on heating andlor when partially solvated.
`
`8. A capsule according to claim 6, wherein the capsule is formed from one or more
`
`materials selected from hydroxy propyl methyl cellulose, pectin. polyethylene oxide.
`
`polyvinyl alcohol, alginate, polycaprolactone, gelatinised starch basod materials.
`
`9. A capsule according to claim 8. wherein at least part of the capsule material carries a
`
`coating.
`
`10. A capsule according to any one of the preceding claims, wherein said at least two
`
`chambers are designed to release their contents under similar circumstances.
`
`Page 15 of 20
`
`Page 15 of 20
`
`

`

`W0 012'03676
`
`PCTIGBOOIGZ616
`
`15
`
`11. A capsule according to any one of claims 1 to 9, wherein said at least two chambers
`
`are designed to release their contents under different circumstances.
`
`12. A capsule according to claim 11, wherein different chambers of the capsule are
`
`defined at least in part by different materials.
`
`13. A capsule according to any one of the preceding claims. wherein the capsule is
`
`formed at least in part from hydroxy propyl methyl cellulose.
`
`14. A capsule according to claim 13, wherein at least part of the hydroxy prepyl methyl
`
`cellulose is coated with alginate.
`
`15. A method of encapsulation comprising supplying two films of material capable of
`
`deforming plastically on heating andfor when partially solvated; heating the films andfor
`
`applying solvent;
`
`forming the films into suitably shaped capsule portions; supplying
`
`respective substances to be encapsulated to capsule portions of each film; supplying a film
`
`of a dividing septum material to at least One of the filled capsule portions; sealing the
`
`capsule portions and septum material together to form a capsule having at
`
`least
`
`two
`
`separate chambers.
`
`16. Encapsulation apparatus comprising means for supplying two films of material to an
`
`encapsulation unit; means for plastically defamn'ng each film to form suitably shaped
`
`capsule portions; means for supplying respective substances to be encapsulated to the
`
`respective capsule portions of each film; means for supplying a film of dividing septum
`
`material to at least one of the filled capsule portions; and means for sealing together the
`
`capsule portions and septum material to produce a capsule having at least two separate
`
`chambers.
`
`Page 16 of 20
`
`Page 16 of 20
`
`

`

`W0 01l03676
`
`PCTIGBOIJIGZfilé
`
`1/1
`
`Fig.1.
`
`12
`
`18
`
`14
`
`16
`
`+10
`
`20
`
`>32
`Wo
`
`"Mr8
`
`90
`
`46
`
`\86
`
`..
`II
`
`0 0
`
`58 O.
`
`Page 17 of 20
`
`SUBSTITUTE SHEET (RULE 25)
`
`Page 17 of 20
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`imam ‘aIApplloetlonNo
`PCT/GB [JO/02616
`
`a. CLASSIFICATIONOF umac‘r lumen
`IPC 7
`A61K9 48
`A61J3/O7
`
`Accordhg to International Patent Classification “PC! or to both national classification and iPC
`
`Mirimum documentation searched tolewiiication system followed by classification symbols)
`IPC 7
`AGIK A61J
`
`Documentation searched other than minimu'n documentation to the extent that such documents are included in the fields searched
`
`Electronic data base cmwited during the intemational eeardt (name 01 data baae and. where pracfiwl. search terms used:
`
`NPI Data, PAJ, EPO-Internal
`
`
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation at comment, with indication. where appropriate. or H'ln relevant passages
`
`EP 0 211 079 A (FUJISAHA PHARMACEUTICAL
`00., LTD.) 25 February 1987 (1987—02-25)
`the whole document
`
`page 10,
`
`line 17 —page 11,
`
`line 5
`
`NO 97 3553? A (BIOPROGRESS TECHNOLOGY
`LIMITED) 2 October 1997 (1997-10-02)
`cited in the application
`claims 1,4
`
`NO 00 2736? A (BIOPROGRESS TECHNOLOGY
`INTERNATIONAL INCORPORATED)
`18 May 2000 (2000—05—18)
`cited in the application
`page 6,
`line 11 - line 1?
`
`1-1,
`1042,16
`
`3,9,13,
`14
`
`8.9.13
`
`El Further documents are listed in the confirmation ol' box 0.
`' Special catogonee' of cited documents :
`_
`_
`_
`.
`_
`A dommentdefinngll'togoneralatateoltho artwhlchtanot
`e
`do
`to
`otparlicularrei
`'E' ”flier document but publidtod on or ”a" "1° international
`filing date
`‘L' doc-tenant men may wow doubts on priority ciaimle) or
`W9“ ‘9 ““3" to wk“ the wbafimfim’ °f another
`citation or other 5mm] reason ('5 mm“)
`'0' document referring to an oral disclosure. use. exhibition or
`olhot' means
`‘P' doctment published prior to the lrrtemalional filing date but
`leter than the priority date claimed
`
`E Patent famin members are rated in annex.
`.
`to and not in conflict mth' the application but
`orprlority
`'1" later documgtt pthllehed alter the international filing date
`-
`-
`.
`.
`pinned firderatandd'teprmtplaortheory mderlylng the
`'X' document of particular :elevame: the claimed invention
`cannot be oortatd‘ered novel or cannot be cormtde'ted to
`involve an Inventive step when the document is taken alone
`'Y' domnem oi particuar relevance: the ctaimed lrwantion
`cannot be considered to involve an inventive step when the
`dome-non! is combined with one or more other such docu—
`meme. such combination being ohtn'oue to a person skilled
`"1 “‘3 “-
`'E' doom-pent member of the some patent family
`
`Date oi the acluai completion of the Hen-rational search
`
`Date of mailing of the lntematianal mm report
`
`11 October 2000
`
`Name and melting address oi the ISA
`European Patent Office. P3. 581 B Patentiann 2
`Ni. - 2230 Hv Fliiawiit
`
`17/10/2000
`
`Authorized officer
`
`Tel. (+3140) 340-2040. Tx. 31 651 epo nl.
`Fax: 9314013404015
`Form Pcmsmw [em-Id duet: {Jot}! 1992}
`Page 18 of 20
`
`B
`
`9112 s
`
`K
`
`page 1 of 2
`
`Page 18 of 20
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`0400mm DOCUMENTS CONSIDERED TO BE RELEVANT
`Citatim of document. with lmicafion.Mme appropriate. of tha m1 passages
`
`
`
`
`
`
`
`H0 00 28976 A (A. B. TECHNOLOGIES L. L. C. )
`25 May 2000 (2000——05—25)
`the whole document
`
` 1m al Amalie-flan Na
`
`PCT/EB [JO/02615
`
`
`
`
`
`
`Farm PCTHSAEW :mm 6 am ma] (July 1992}
`
`Page 19 Of 20
`
`page 2 of 2
`
`Page 19 of 20
`
`

`

`INTERNATIONAL SEARCH REPORT
`ImmflHanumllymm
`almumanbnuo
` Inunu
`PCT/GB 00/02616
`
`Patent document
`cited in search I’EDOH.
`
`Publication
`date
`
`Patent family
`ITIBI'I'IbeflS)
`
`Publication
`daie
`
`
`
`
`
`)-
`
`E? 211079
`A
`25-02-1987
`00
`8604501
`14-08-1986
`
`
`
` 2168597 A
`17-10-1997
`9708352 A
`04-01-2000
`BR
`
`
`CA
`2250397 A
`02-10-199?
`
`
`CZ
`9803079 A
`17-02-1999
`
`
`EP
`0889?10 A
`13-01~1999
`9844?2 A 28~09—1998
`
`
`
`
`
`3788800
`29-05-2000
`2343669
`1?—05-2000
`
`
`
`
`
`Form FC‘I‘IISAMO (want my mum [My 1N2}
`
`Page 20 of 20
`
`Page 20 of 20
`
`

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