(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:19)(cid:20)
`
`Page 1 of 27
`
`

`
`FOR ITHE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCI‘ on the front pages of pamphlets publishing inun-national
`appl.ica1:ion.s undcr the PCT.
`
`
`
`§;g§§:s:=§::a:w=aasa$a
`
`saaeadaaaaaasasazasaaga
`
`Austria
`Aumdja
`Buhdos
`
`AT
`AU
`BB
`Eli‘.
`IF
`IIG
`In
`HR
`BY
`CA
`CI?
`CG
`CB
`CI
`CM
`CN
`C8
`CZ
`DE
`DK
`
`BF
`
`I
`FR
`GA
`
`Page 2 of 27
`
`Page 2 of 27
`
`

`
`W0 9516438
`
`PCT.-‘GB94!02703
`
`Biphasi c capsul e formu1at.1 on
`
`The present
`
`invention relates
`
`to
`
`improved
`
`capsule
`
`formulations,
`formulations.
`
`in
`
`particular
`
`biphasic
`
`capsule
`
`W0-A-9206680 discloses biphasic release formulations for
`
`lipophilic drugs comprising a Cm-C3 fatty acid and a
`
`pharmaceutically' active substance.
`
`A. portion of
`
`the
`
`formulation is formulated for non—sustained release and
`
`is generally in liquid form and a portion is formulated
`
`for sustained release on non-parenteral administration
`
`and will generally be a solid.
`
`15
`
`The
`
`formulations
`
`11:
`
`re
`
`extremely
`
`effective
`
`for
`
`the
`
`20
`
`25
`
`30
`
`administration of
`
`lipophilic pharmaceutically active
`
`substances greatly enhancing oral bioavailibility of
`
`propranolol. These results have been published (Barnwell
`
`et al, J. Controlled Release, 28, 306-309 (1994)), but it
`
`has been discovered that there are Certain problems with
`
`the stability of
`
`the compositions even when stored at
`
`ambient
`
`temperature.
`
`After capsules containing biphasic formulations such as
`those described in
`NO—A—92066BO have "been stored for
`
`periods of greater than 3
`
`months at ambient temperature,
`
`there is a decline in in vitro dissolution performance
`
`compared with initial values.
`
`The level of propranolol
`
`released from the formulation after 12 months‘ storage at
`
`ambient
`
`temperature was
`
`found to be
`
`reduced by 50%
`
`compared with initial values.
`
`In contrast, prolonged
`
`storage of capsules containing only the liquid rapid-
`
`release phase and capsules containing only the solid
`
`sustained release phase did not result
`
`in any change in
`
`Page 3 of 27
`
`
`
`Page 3 of 27
`
`

`
`W0 95;‘ 16438
`
`PCTIGBSI4.-'02703
`
`l\)
`
`dissolution profile.
`
`This unstable release profile is
`
`therefore a problem only with biphasic formulations and
`
`represents a serious drawback in the development of such
`
`formulations since, clearly, a pharmaceutical formulation
`
`which is not stable under ambient storage conditions is
`
`of limited use in practice.
`
`On investigation,
`
`it appeared that
`
`the deterioration in
`the
`
`the release profile had arisen because. unexpectedly,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`two phases of the formulation had become mixed during the
`had
`
`storage of the capsules and the mixing of the phases
`
`caused the release characteristics of both parts of
`deteriorate.
`Deterioration
`formulation
`to
`
`the
`
`was
`
`characterised by a visible intermixing between the two
`
`phases and a decline in in giggg dissolution performance.
`
`The rate of
`
`intermixing between the liquid rapid and
`
`solid sustained—release phases of
`
`the formulation was
`
`accelerated at elevated storage temperatures,
`but much reduced at
`
`eg 37°C,
`
`Therefore,
`
`provided
`
`a
`
`the invention there is
`in a first aspect of
`formulation
`
`comprising
`
`a
`
`pharmaceutical
`
`capsule
`
`containing at
`
`least
`
`two
`
`fill
`
`compositions,
`
`characterised in that the compositions are prevented from
`
`mixing with one another.
`
`The
`
`capsule
`
`fill
`
`compositions may
`
`be
`
`compositions
`
`comprising Cm-Cu fatty acids such as those disclosed in
`W0-A-9206680.
`
`The invention is particularly useful when
`
`one of the fill compositions is a solid and one a liquid,
`
`especially
`
`when
`
`the
`
`solid
`
`component
`
`also comprises
`
`glycerides,
`
`in Example 1 of W0—A—9206680.
`
`for example the GELUCIREW mixture disclosed
`In that case,
`
`the fatty
`
`acids tend to dissolve the lower molecular weight lipids
`
`Page 4 of 27
`
`
`
`Page 4 of 27
`
`

`
`WO 93105438
`
`PCT:'GB94!02703
`
`h]
`
`of the solid composition so that they gradually mix with
`
`the liquid composition.
`
`The progressive solubilisation
`
`of the lower molecular weight glycerides into the liquid
`
`composition slows down the rapid release characteristics
`
`of
`
`the liquid phase.
`
`It also leaves in the solid phase
`
`only the higher molecular weight glyceride components
`
`which do not easily erode to allow the release of
`
`the
`
`remaining fatty acid and the active material. An example
`
`of
`
`a modified capsule would. be
`
`an adaptation. of
`
`the
`
`potato starch Capill® capsules manufactured by Capsugel
`
`Limited.
`
`In this case,
`
`the starch capsule would be
`
`manufactured with a central partition and two open ends.
`
`This would allow two separate formulation components to
`
`be filled,
`
`each end of
`
`usual potato starch cap.
`
`the capsule being sealed by the
`Thus the sustained release of
`
`the active material from the solid component is retarded.
`
`These changes in drug release may be monitored using an
`
`ig vitro dissolution method such as that described in
`'1
`J.
`
`Example
`
`below.
`
`However,
`
`there may be other
`
`reasons
`
`for wishing to
`
`separate the two fill compositions,
`
`for example they may
`
`contain
`
`different
`
`active
`
`compounds
`
`or
`
`different
`
`excipients which interact in an unfavourable manner and
`
`therefore
`
`the present
`
`invention is
`
`not
`
`limited to
`
`compositions such as those described in W0-A-9206680.
`
`For example. with compositions such as those disclosed in
`
`GB Application No 9417524.? there is the possibility of
`of
`the
`
`unfavourable
`
`interaction
`
`active
`
`ingredient,
`
`particularly i
`
`f
`
`is a protein,
`
`and the pH modifying
`
`agent {for
`
`instance, carbonate or bicarbonate
`
`the present
`formulations.
`
`invention is particularly useful
`
`Thus,
`
`for such
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Page 5 of 27
`
`
`
`Page 5 of 27
`
`

`
`W0 95! I 6438
`
`PCI‘.-'GB94:'02703
`
`|I"o
`
`The simplest method of preventing phase mixing is to
`both or the fi_l compositions as solids but of
`formulate
`will
`
`course
`
`this
`
`not
`
`be possible
`
`in
`
`all
`
`cases.
`
`U1
`
`10
`
`20
`
`25
`
`30
`
`Therefore,
`
`it is often desirable to provide some sort of
`
`physical barrier within the capsule to prevent mixing of
`
`the fill compositions.
`
`However,
`
`there are problems with this approach.
`
`One
`
`problem is that the placing of a physical barrier between
`
`two compositions in a capsule often leads to the collapse
`
`and any barrier which has
`the capsule walls
`of
`effect is of no use whatever.
`
`this
`
`Secondly,
`
`it
`
`is important
`
`to ensure that any material
`
`used as a physical barrier between fill compositions in
`
`a capsule does not
`
`interact with the fill compositions
`
`themselves. One solution which may overcome this problem
`
`is to provide a barrier of
`
`the same material as
`
`the
`
`capsule. This may be achieved by manufacturing capsules
`
`having
`
`two
`
`compartments
`
`and
`
`will
`
`be
`
`particularly
`
`effective for hard gelatin capsules and starch capsules.
`
`In some cases, it will not be possible to manufacture the
`
`barrier from the same material as
`
`the capsule shell.
`
`There may be a variety of reasons for this,
`
`for example
`
`the difficulties
`
`in manufacturing a
`
`two—compartment
`
`capsule and the weakness
`
`in the capsule wall which a
`
`central barrier within the capsule may introduce.
`
`In
`
`addition,
`
`for soft gelatin capsules,
`
`the capsule walls
`
`may not be strong enough to support a central barrier in
`
`the capsule.
`
`In such cases
`
`a barrier‘ must be
`
`introduced into the
`
`capsule after manufacture and this will usually be done
`
`Page 6 of 27
`
`
`
`Page 6 of 27
`
`

`
`W0 95!16438
`
`PCT.-"GB94.-'02703
`
`UI
`
`as the capsule is filled. This will retain the advantage
`
`of
`
`low manufacturing cost of
`
`the capsules whilst still
`
`separating the fill compositions and preventing them from
`
`mixing.
`
`The choice of material for the barrier is important and
`
`several factors must be taken into account. For example,
`
`if hydrophobic fill Compositions are used.
`
`it may’ be
`
`desirable to use a hydrophilic material as a barrier
`
`10
`
`between the fill compositions. On the other hand. if the
`
`fill compositions are hydrophilic in nature,
`
`than a
`
`hydrophobic material will be more suitable.
`
`It is also highly desirable that
`
`the material used as a
`is a
`
`barrier should have a melting point such that it
`
`solid at any likely storage temperature.
`
`Therefore,
`
`the
`
`melting point should, at
`
`the least.
`
`(room temperature) but
`
`it
`
`is much preferred
`
`be higher than 25°C
`that
`the
`
`material should not begin to melt until it reaches about
`
`20
`
`37°C {body temperature}.
`
`A barrier formed from such a material has the advantage
`
`of easy formation since the barrier material can simply
`be
`filled
`
`in a molten state at
`
`a
`
`into the capsules
`
`temperature above its melting point and then allowed to
`cool and form a solid barrier.
`The barrier material will
`
`be added to the capsule after the first fill composition
`
`has been put into the capsule but before the addition of
`
`the second fill composition so as to form an effective
`
`30
`
`barrier between the two compositions.
`
`If the capsule is required to contain more than_:wo fill
`
`compositions then layers of the barrier material can be
`
`added to the capsule between additions of the different
`
`Page 7 of 27
`
`
`
`Page 7 of 27
`
`

`
`WO 95316438
`
`PCT!GB94a"l]2'?03
`
`GI
`
`:."',
`
`compositions.
`
`In addition,
`
`the barrier material must, of course, be
`
`physiologically compatible since it is to be included in
`
`a pharmaceutical formulation.
`
`Materials which have been found to be particularly useful
`
`as barrier materials in capsules are glycerides having a
`37°C.
`
`transition temperature
`
`{melting
`
`point}
`
`above
`
`l0
`
`15
`
`Suitable glycerides include di— and tri—glycerides, such
`
`as many of
`
`the various GELUCIRE compounds, which are
`
`hydrogenated fatty acid esters available from Gattefosse.
`is a
`iThe word GELUCIRE
`trade mark.) Other trade marks
`
`cf suitable glycerides
`
`include LABRAFIL and PRECIROL.
`
`e;nUCIRE compounds
`
`and other suitable compounds having
`
`transition temperatures
`
`of
`
`from 40°C to
`
`70°C are
`
`preferred.
`
`Specific
`
`examples
`
`of
`
`exemplary GELUCIRE
`
`compounds. and their equivalents include:
`
`20
`
`GELUCIRE 44/14
`
`GELUCIRE 50/O2
`
`GELUCIRE 50/l3
`
`GELUCIRE S4/02 {also available as PRECIROLJ
`
`GELUCIRE 62305 and
`
`GELUCIRE 64/02 {also available as PRECIROL WL 2155}.
`
`.The first
`
`two
`
`digits
`
`in the numeric portion of
`
`the
`
`GELUCIRE name represent the liquid/solid phase transition
`
`temperature in degrees centigrade and the second two
`
`30
`
`digits represent
`value.
`
`the.hydrophile/lipophile balance (HLB}
`
`SELUCIRE -14/14 has a high I-ILB value and is therefore
`
`relatively hydrophilic.
`
`This means
`
`that
`
`it
`
`is
`
`Page 8 of 27
`
`
`
`Page 8 of 27
`
`

`
`W0 95.-16438
`
`PCTIGBQ4.-‘D2703
`
`particularly useful as a barrier in capsules containing
`
`lipophili
`
`fill compositions such as those described in
`
`WO~A-3206680 since it will be immiscible with both of the
`rn §I
`
`ll compositions.
`
`The other compounds are more suitable for use in capsules
`
`with a hydrophilic fill since they are all relatively
`
`lipophilic.
`
`A further use for the hydrophilic phase barrier may be to
`
`allow the formulation of
`
`a hydrophilic drug for co-
`
`administration with
`
`the
`
`lipophilic
`
`delivery system
`
`described
`
`in WO—A-9206680.
`
`An
`
`example
`
`of
`
`this
`
`application is the formulation and delivery of a non-
`
`membrane damaging bile acid (a hydrophilic material) as
`
`described in WO—A—9325l92 together with a lipophilic drug
`in the
`
`lipophilic delivery system described in WO-A-
`
`9206580.
`
`The advantage of
`
`this arrangement
`
`is for the
`
`improved delivery of drugs which undergo both
`
`high
`
`hepatic first—pass metabolism and enterohepatic recycling
`
`{e.g.
`
`haloperidol, chlorpromazine and morphine) or where
`
`the non—membrane damaging bile acid can attenuate the
`
`to high first-pass
`a drug subject
`toxic effects of
`metabolism and formulated as described in WO—A-9206680.
`
`Conversely, where
`
`a
`
`lipophilic barrier
`
`is
`
`used
`
`to
`
`separate hydrophilic phases it may act as a reservoir for
`
`a co-administered lipophilic drug.
`
`Another way in which intermixing may be prevented with
`
`the biphasic rapid and sustained-release formulations
`
`10
`
`15
`
`20
`
`25
`
`30
`
`described in WO—A—920668O containing Cu
`acids,
`
`to Ca
`
`fatty
`
`is to ensure that the rapid-release phase remains
`
`a solid at normal storage temperature,
`
`e.g. below 30°C.
`
`Page 9 of 27
`
`
`
`Page 9 of 27
`
`

`
`WO 95116438
`
`PCT:"GB94.-‘D2703
`
`{1}
`
`This may be achieved by mixing a hydrophobic Gelucire@
`
`melting point above 30°C, exemplified by Gelucire
`
`release component before
`with the molten rapid
`the
`
`into
`
`capsules,
`
`rapid-release
`
`phase
`
`I._: [1
`-ing
`
`solidifying on cooling and thus being unable to undergo
`solid
`
`mixing with
`
`the
`
`resident
`
`sustained-release
`
`formulation component.
`
`An example of
`
`this formulation
`
`approach is given below in Example 3.
`
`Ta-
`
`in
`
`is preferred that hard gelatin capsules are used and,
`that
`fill
`
`case,
`
`liquid
`
`compositions may contain
`
`gelatin softening agents such as those described in WO-A-
`9102520.
`
`Suitable gelatin softening agents can be found
`
`by
`
`reference to the art of manufacturing soft gelatin
`
`capsules where such materials are incorporated into the
`
`mix which forms the gelatin wall.
`
`Particularly suitable
`
`gelatin softening agents
`
`include glycerol, propylene
`
`glycol, glycerol mono—oleate and sorbitol.
`
`The capsules may be enteric coated or otherwise protected
`
`to ensure better survival of the pharmaceutically active
`
`compound through the stomach.
`
`Any convenient enteric
`
`protection method may be used. Capsules containing the
`
`formulation may be coated with an enteric coat such as
`
`hydroxypropylmethylcellulose
`
`phthalate
`
`or
`
`by
`
`the
`
`commercial coating process of Pharma—Vinci A/S {Denmark}.
`
`The formulations of the invention may be prepared by any
`
`suitable process but when a solid barrier material
`
`is
`
`used then the process may comprise filling the first fill
`
`composition,
`
`the barrier material and the second fill
`
`composition sequentially into a suitable capsule.
`
`Therefore,
`
`in a
`
`further aspect of the invention,
`
`there is
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Page 10 of 27
`
`
`
`Page 10 of 27
`
`

`
`W0 95.516438
`
`PCT:'GB94l02703
`
`Lfil
`
`provided a process
`
`for
`
`the preparation of
`
`a capsule
`
`containing at least two iii- compositions separated by a
`
`barrier material,
`
`the process comprising filling a first
`
`fill composition,
`
`the barrier material and a second fill
`
`composition sequentially into a suitable capsule.
`
`Preferred barrier materials are as described above.
`
`The capsule may be of any suitable material,
`
`for example
`
`hard gelatin capsules, soft gelatin capsules and starch
`
`capsules but gelatin capsules are preferred, particularly
`
`hard gelatin capsules.
`
`U1
`
`10
`
`The
`
`invention
`
`will
`
`now
`
`be
`
`further
`
`described with
`
`15
`
`reference
`
`to
`
`the
`
`following examples
`
`which
`
`are
`
`not
`
`intended to be limiting.
`
`20
`
`25
`
`30
`
`35
`
`EXAMPLE 1 - Biphasic Progranolol Formulation with Phase
`
`Bargier
`
`The following example is a biphasic rapid and sustained-
`
`release propranolol formulation similar to that described
`
`in
`
`W0 92/06680.
`
`Typically these materials melt upon
`
`heating,
`
`thereby allowing the use of conventional mixing
`
`and pumping technology for fluid filling.
`
`A.
`
`Sustained-Release Phase
`
`mggcagsule
`
`Propranolol
`
`Oleic Acid BP
`
`Colloidal silicon dioxide {Aerosil 200}
`
`Polyoxyl—40-hydrogenated castor oil NP
`icremophor RH40}
`
`40.0
`
`102.1
`
`8.2
`
`27.2
`
`Page 11 of 27
`
`
`
`Page 11 of 27
`
`

`
`VVO95.-‘I6-‘I38
`
`PCT."GB94!027l]3
`
`lycolysed glycerides Ph.F.
`}
`
`U‘!
`
`94.
`
`5
`
`E.
`
`Phase Barrier
`
`Saturated polyglycolysed glycerides Ph.F.
`(Gelucire 44/14}
`
`150.0
`
`10
`
`15
`
`C.
`
`RaQid—Re1ease Phase
`
`Propranolol base
`
`Oleic acid B?
`
`40.0
`
`110.0
`
`20
`
`A.
`
`Sustained—Release Phase
`
`The oleic acid, Gelucire 50/02 and Cremophor were
`heated to 50°C-55°C until
`a clear
`solution was
`
`obtained. Propranolol base was added with stirring,
`
`while maintaining the temperature of the mix at 50°C
`
`and continued until
`
`dissolved.
`
`Finally Aerosil was
`
`the propranolol base was fully
`added
`
`while
`
`stirring.
`
`A total of 272 mg of the formulation was
`
`filled into size 0 hard gelatin capsules while hot
`
`and then allowed to solidify with cooling.
`
`B.
`
`Phase Barrier
`
`The Gelucire 44/14 was heated until fully melted at
`
`45°C-55°C and 150 mg filled over
`
`the sustained-
`
`release phase, previously filled into size 0 hard
`
`gelatin capsules,
`
`and allowed to solidify with
`
`cooling.
`
`25
`
`30
`
`35
`
`40
`
`Page 12 of 27
`
`
`
`Page 12 of 27
`
`

`
`W0 95!l6438
`
`PCT:"GB94.-"D2703
`
`Rapid-Release Phase
`
`Oleic acid was heated with stirring at 45°C—50°C.
`
`Propranolol
`
`base was
`
`added
`
`and dissolved
`
`with
`
`stirring and allowed to cool.
`
`A total of 150 mg of
`
`the liquid rapid-release formulation was then filled
`OVEI
`
`the phase barrier.
`
`The
`
`resulting capsules
`solid
`
`contained a solid sustained-release phase,
`
`phase separation barrier
`
`and liquid rapid-release
`
`phase.
`
`The capsules were then sealed by gelatin
`
`banding.
`
`Following gelatin banding,
`
`the capsules
`
`may be enteric-coated as described in WO 92/06680.
`
`EXAMPLE 2
`
`— Dissolution Studies With and Without Ehase
`
`Barrier System
`
`For
`
`evaluating
`
`the
`
`experimental
`
`formulations,
`
`a
`
`dispersion
`:est—method was devised
`
`behaviour
`
`of
`
`the
`
`based upon the USP XXII dissolution test for tablets and
`
`capsules.
`an
`
`to
`
`The aim of the test was to subject the samples
`
`environment
`
`similar
`
`to :hat
`
`in the intestine.
`
`Dispersion in.
`
`5 hours was selected as as satisfactory
`
`total release time for the test samples. This was based
`
`on the understanding that
`
`lymphatic absorption occurs
`
`predominantly in the small intestine.
`
`The dissolution apparatus as specified by the USP XXII
`
`(apparatus 2) was used with Sorensens phosphate buffer,
`
`pH 6.8 containing 0.2% sodium cholate and 0.1% sodium
`The total volume of
`
`deoxycholate, equilibrated to 37°C.
`
`buffer added to each dissolution vessel was 900 ml, with
`
`a paddle rotation speed of 70 rpm.
`
`The paddle height was
`
`adjusted so that the top edge of the blade was level with
`
`the surfiace of the liquid.
`
`The test sample was dropped
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Page 13 of 27
`
`
`
`Page 13 of 27
`
`

`
`WO 95116438
`
`PCT/GB94/02703
`
`F.- f\)
`
`into :he dissolution medium and the rotation of
`
`the
`
`paddle started.
`
`The test
`
`sample was allowed to float
`
`freely at
`
`the liquid surface throughout
`
`the test.
`
`At
`
`.
`
`each time-point, a 5 ml aliquot of the dissolution medium
`
`5
`
`was
`
`removed and replaced with 5 ml of
`
`fresh buffer
`
`solution.
`
`Each 5 ml
`
`sample was
`
`initially filtered
`
`through a 1.2 uM coarse filter and subsequent 1.2 uM fine
`
`filter. The absorbance of the filtered solution was then
`
`determined at 290nm using a UV at 290 nm using a UV
`
`10
`
`spectrophotometer.
`
`The propranolol concentration in the
`
`dissolution medium was calculated using a pre-determined
`
`calibration curve for propranolol.
`
`A = Example 1 with phase barrier.
`
`15
`
`B = Example 1 without phase barrier.
`
`Table 1
`
`- 30°C Storage
`
`% Propranolol Release
`
`20
`
`25
`
`Page 14 of 27
`
`Page 14 of 27
`
`

`
`W0 95/16438
`
`PCT/GB94/02703
`
`U1
`
`l0
`
`l5
`
`20
`
`25
`
`30
`
`
`
`As is clear from the results shown in Tables 1 and 2 the
`
`presence of a barrier between the solid sustained release
`
`phase and the liquid phase improves considerably the
`
`amount of propranalol
`
`released, particularly from the
`
`sustained release phase.
`
`The effect of
`
`the barrier
`
`increases with the length of time for which the capsules
`are stored.
`
`EXAMPLE 3
`
`- Bighasic Progranolol Formulation with Solid
`
`Rapid-Release Phase
`
`This is an example of a biphasic rapid and sustained-
`
`release propranolol formulation based on that described
`
`in W0-A-9206680,
`
`except
`
`that
`
`phase
`
`intermixing
`
`is
`
`prevented by having a solid rapid-release phase.
`
`The
`
`rapid-release phase
`
`is formulated as
`
`a
`
`solid, using
`
`Gelucire3 33/O1, which melts
`
`on heating above
`
`30°C
`
`place
`filling to take
`capsule
`(i)
`allowing
`conventional mixing and pumping technology,
`and
`
`using
`(ii)
`
`Page 15 of 27
`
`
`
`Page 15 of 27
`
`

`
`W0 95.916438
`
`PCT:'GB94.~'02703
`
`"_ 4
`
`enables
`
`rapid—release
`
`to
`
`take
`
`place
`
`at
`
`normal
`
`temperature .
`
`A.
`
`Sustained-Release Phase
`
`5
`
`As for Example 1
`
`mggcapsule
`
`272.0
`
`10
`
`B.
`
`Solid Rapid-Release Phase
`
`Propranolol base
`
`_Oleic acid B.P.
`
`Saturated polyglycolysed glycerides Ph.F.
`(Gelucire® 33/01}
`
`40.0
`
`110.0
`
`150.0
`
`The modified.
`
`rapid-release phase was manufactured by
`
`heating cleic acid at 45-50°C with stirring. Propranolol
`
`base and Gelucire® 33/01 were added with stirring until
`
`completely dissolved. The molten rapid-release phase was
`maintained above 37°C until filled into capsules already
`
`containing the solid sustained-release phase described in
`
`Example 1.
`
`A total of 300 mg of the modified sustained-
`
`release phase containing Gelucires 33/01 was filled into
`
`size 0 hard gelatin capsules while hot and then allowed
`
`to solidify with cooling.
`
`The capsules were then sealed
`
`by gelatin banding.
`
`Following gelatin banding,
`
`the
`
`capsules may be enteric-coated as described in ‘W0-A-
`
`9206680
`
`and Burns
`
`et
`
`al.
`
`International
`
`Journal of
`
`Pharmaceutics, 110: 291-296 (1994).
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Page 16 of 27
`
`
`
`Page 16 of 27
`
`

`
`W0 95/16438
`
`PCT/GB94/02703
`
`*4 (H
`
`EXAMPLE 4 - Dissolution Studies Using Solid Rapid-Release
`
`Phase System
`
`The same dissolution method as described in Example 2 was
`
`used to evaluate capsules containing the biphasic rapid
`
`and sustained-release preparation described in Example 3.
`
`25°C Storaoe
`
`
`
`
`1I
`
`3
`
`°C Stora e
`
`
`
`
`% Propranolol Release
`
`Time
`(minutes)
`
`Initial
`
`2 Months
`
`12 Months
`
`E2
`
`13-1:
`
`10
`
`l5
`
`20
`
`30
`
`Page 17 of 27
`
`
`
`
`
`% Propranolol Release
`1 Month
`2 Months
`
`
`)
`
`12 Months
`
`.
`
`‘
`
`
`
`Time
`(minutes
`
`
`
`Page 17 of 27
`
`

`
`W0 95.-' 16438
`
`PCT.~'GB94:'02'703
`
`The results in Table 3 show that at 25°C the dissolution
`
`profile of
`
`a biphasic formulation is maintained for at
`
`least 12 months.
`
`Table 4 shows
`
`that at 30°C, close to
`
`the melting point of
`
`the modified rapid-release phase
`
`containing
`
`Gelucire®
`
`33/01,
`
`there
`
`is
`
`a
`
`small
`
`deterioration in initial
`
`release rate.
`
`However,
`
`the
`
`release
`oiphasio
`overall
`formulation are maintained.
`
`characteristics
`
`of
`
`the
`
`Page 18 of 27
`
`
`
`Page 18 of 27
`
`

`
`WO 95116438
`
`PCT."GB94f02703
`
`1 7
`
`CLAIMS
`
`5
`
`10
`
`1.
`
`A pharmaceutical
`
`formulation comprising a capsule
`
`containing at least two fill compositions, characterised
`
`in that the compositions are prevented from mixing with
`one another.
`
`2.
`
`A pharmaceutical formulation as claimed in claim 1,
`
`wherein both of the fill compositions are solid.
`
`3.
`
`A pharmaceutical formulation as claimed in claim 1,
`
`wherein the two fill compositions are separated by a
`
`physical barrier.
`
`15
`
`4.
`
`A formulation as claimed in claim 3, wherein the
`
`barrier is of the same material as the capsule.
`
`5.
`
`A formulation as claimed in claim 3, wherein the
`
`barrier
`
`comprises
`
`a material having a melting point
`
`20
`
`higher than 25°C.
`
`6.
`
`A formulation as claimed in claim 5, wherein the
`
`barrier comprises a material having a melting point of
`
`higher than 37°C.
`
`25
`
`7.
`
`A formulation as claimed in any one of claims 3
`
`to
`
`6, wherein the fill compositions
`
`are hydrophobic
`
`in
`
`nature and the barrier comprises a hydrophilic material.
`
`30
`
`8.
`
`A formulation as claimed in any one of claims 3
`
`to
`
`6, wherein the fill
`
`compositions are hydrophilic in
`
`nature and the barrier comprises a hydrophobic material-
`
`A pharmaceutical formulation as claimed in any one
`
`Page 19 of 27
`
`
`
`Page 19 of 27
`
`

`
`W0 95.316438
`
`PCT:'GB9-M12703
`
`of
`
`claims
`
`glyceride.
`
`3
`III
`
`:3 8, wherein the barrier comprises
`
`or
`
`example
`
`a
`
`di— or
`
`tri-glyceride, or
`
`a
`a
`
`mixture of glycerides.
`
`10.
`
`A composition as claimed in claim 9,
`
`wherein the
`
`barrier material comprises a hydrogenated fatty acid
`
`ester or a mixture of esters, available under one of the
`
`following trade marks:
`
`GELUCIRE 44 /14
`
`GELUCIRE E0/13
`
`GELUCIRE SO/02
`
`GELUCIRE 54/02 (also available as PRECIROLJ
`
`GELUCIRE 62/05 and
`
`GELUCIRE 64/02 {also available as PRECIROL WL 2155}.
`
`11.
`
`A formulation as claimed in any one of claims 3
`
`to
`
`10 comprising a first fill composition comprising a Cu—Cu
`
`fatty acid and a pharmaceutically active substance,
`
`formulated for non-sustained release on non—parenteral
`
`administration; and a second fill composition comprising
`
`a
`fatty acid and
`a pharmaceutically active
`C12'C2a
`substance formulated for sustained release of the active
`
`substance on non-parenteral administration.
`
`10
`
`15
`
`20
`
`25
`
`12.
`
`A formulation as claimed in claim 11,
`
`wherein the
`
`first and the second fill compositions are hydrophobic in
`nature and.
`the barrier
`is formed from a mixture of
`
`hydrogenated fatty acid esters sold under the trade mark
`
`30
`
`GELUCIRE 44/14.
`
`13.
`
`A formulation as claimed in any one of claims 1 to
`
`6 or any one of claims 8
`
`to 10 comprising a first fill
`
`composition comprising a biologically active material and
`
`Page20of27
`
`
`
`Page 20 of 27
`
`

`
`W0 95:‘ 16438
`
`PCTIGB9-#02703
`
`a bile acid salt and a second fill composition comprising
`
`an agent adapted to adjust
`value of from 7.5 to 9.
`
`the pH of
`
`:ne gut
`
`to a pH
`
`5
`
`14.
`
`A formulation as claimed in claim 13 wherein the
`
`biologically active material
`
`is
`
`a protein such
`
`as
`
`insulin, calcitonin, a growth hormone, an interferon, an
`
`interleukin or an active fragment of any of these.
`
`10
`
`15.
`
`A formulation as claimed in claim 13 or claim 14
`
`wherein the buffering agent comprises carbonate and/or
`bicarbonate ions.
`
`Page 21 of 27
`
`Page 21 of 27
`
`

`
`W0 95.’ I 6438
`
`20
`AMENDED CLAIMS
`
`PC'I'l‘GB94!02_'.’03
`
`[received by the International Bureau on 2 June 1995 (02.06.95);
`original claims 1 and 3 amended;
`original claim 2 unchanged;
`original claim 4 cancelled;
`original claims 5-15 renumbered
`into new claims 4-14.
`(3 pages)]
`
`1.
`
`A pharmaceutical
`
`formulation comprising a capsule
`
`having a single compartment containing at least two fill
`
`compositions, characterised in that the compositions are
`
`prevented from mixing with one another.
`
`2.
`
`A pharmaceutical formulation as claimed in claim 1,
`
`wherein both of the fill compositions are solid.
`
`3.
`
`A pharmaceutical formulation as claimed in claim 1,
`
`wherein the two fill compositions are separated.
`
`by’ a
`
`physical barrier comprising a further fill composition of
`
`a different material to that of the capsule.
`
`4.
`
`A formulation as claimed in claim 3, wherein the
`
`barrier comprises
`
`a material having a melting point
`
`higher than 25°C.
`
`10
`
`15
`
`20
`
`5.
`
`A formulation as claimed in claim 4,
`
`wherein the
`
`barrier comprises a material having a melting point of
`
`higher than 37°C.
`
`25
`
`30
`
`6.
`
`5.
`
`A formulation as claimed in any one of claims 3 to
`wherein the fill compositions are hydrophobic
`in
`
`nature and the barrier comprises a hydrophilic material.
`
`7.
`
`5,
`
`A formulation as claimed in any one of claims 3 to
`
`wherein the
`
`fill
`
`compositions are hydrophilic in
`
`nature and the barrier comprises a hydrophobic material.
`
`8.
`
`of
`
`A pharmaceutical formulation as claimed in any one
`claims
`
`comprises
`
`a
`
`3to 7,
`
`wherein the barrier
`
`glyceride,
`
`for‘ example
`
`a di-
`
`or
`
`tri—glyceride, or a
`
`Page 22 of 27
`
`
`
`AMENDED SHEET (ARTICLE 19)
`
`Page 22 of 27
`
`

`
`W0 95."l 6438
`
`PCT:'GB94I[}2703
`
`21
`
`mixture of glycerides.
`
`9.
`
`A composition as claimed in claim 8, wherein the
`
`barrier material comprises
`
`a hydrogenated fatty acid
`
`ester or a mixture of esters, available under one of the
`
`following trade marks:
`
`GELUCIRE.‘ 44/14
`
`GELUCIRE.‘ 50/13
`
`GELUCIRE 50/02
`
`10
`
`GELUCIRE 54/02 (also available as PRECIROL}
`
`GELUCIRE 62/05 and
`
`GELUCIRE 64/02 (also available as PREICIROL WL 2155).
`
`15
`
`10.
`
`A formulation as claimed in any one of claims 3
`
`to
`
`20
`
`25
`
`9 comprising a first fill composition
`
`comprising a C12—C,4
`
`fatty acid and a pharmaceutically active substance,
`
`formulated for non-sustained release on non—parenteral
`
`administration; and a second fill composition comprising
`
`a
`
`Cu-C2,,
`
`fatty
`
`acid and
`
`a pharmaceutically active
`
`substance formulated for sustained release of the active
`
`substance on non-parenteral administration.
`
`11.
`
`A formulation as claimed in claim 10,
`
`wherein the
`
`first and the second fill compositions are hydrophobic in
`nature and the barrier
`is formed from a mixture of
`
`hydrogenated fatty acid esters sold under the trade mark
`
`GELUCIRE 44/14.
`
`30
`
`12.
`
`A formulation as claimed in any one of claims 1 to
`
`5 or any one of claims 7
`
`to 9 comprising a first fill
`
`composition comprising a biologically active material and
`
`a bile acid salt and a second fill composition comprising
`
`an agent adapted to adjust
`
`the pH of
`
`the gut
`
`to a pH
`
`Page 23 of 27
`
`
`
`AMENDED SHEET (ARTICLE 19)
`
`Page 23 of 27
`
`

`
`WO 95116438
`
`PCT.-‘GB94:'02'703
`
`22
`
`value of from 7.5 to 9.
`
`13.
`
`A formulation as claimed in claim 12 wherein the
`
`biologically
`
`active
`
`material
`
`is
`
`a protein
`
`such
`
`as
`
`insulin, calcitonin, a growth hormone, an interferon, an
`
`interleukin or an active fragment of any of these.
`
`14.
`
`A formulation as claimed in claim 12 or claim 13
`
`10
`
`wherein the buffering agent comprises carbonate and/or
`bicarbonate ions.
`
`Page 24 of 27
`
`
`
`AMENDED SHEET (ARTICLE 19)
`
`Page 24 of 27
`
`

`
`INTERNATIONAL SEARCH REPORT
`
`an Application No
` Intern
`
`PCT/GB 94/02703
`ASSIFICATION OF SUBJECT MATTER.
`
`
`' E"6
`A61l(9/48
`P
`
`A I
`
`
`
`According to International Patent CIa5‘Sl.fiCfi.IIllJl1 (IPC) or to both nauonal claxiification and IPC
`B. FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by clasnficauon syinbols)
`IPC 6
`A61K
`
`
`
`
`
`Doctunentanon searched other than nnmmum docuinentatton to the extent that such documents are Included in the fields searched
`
`
`
`
`
`Electronic data base coristllted dunltg the Iriternauorial SCBICI1 (name of data base and. where practical, search terms used)
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document. with l.l'ld:l€-at|Ofl'I. where appropriate. ofthe relevant passages
`
`Rem’!-111 ID ¢lISI'I'l N0-
`
`
`
`
`
`
`
`
`
`
`
`
`
`DE,A,39 24 887 (KUBIN H.) 5 April 1990
`see the whole document
`
`EP.A,U 211 079 (FUJISAWA PHARMACEUTICAL CO
`LTD) 25 February 1987
`see page 2.
`line 15 - line 23
`see page 11,
`line 6 - line 21
`see page 13 — page 14; example 1
`see page 16; example 6
`
`EP,A,D 308 63? (STEPHAN D. ET AL) 29 March
`1989
`
`see page 2, column 1,
`column 2,
`line 27
`see page 3, column 3,
`
`line 54 - page 2,
`
`line 17 - line 31
`
`_/__
`
`
`
`E Further documents are listed in the continuation at box C.
`' S
`'
`l
`'
`:
`pun “Egon” of and docmmms
`.A. document defining the general mt: or me an which Is not
`considered to be of paructilar relevance
`‘E’ earlier document but pubtisl-ted on or otter the international
`rmn‘ dam
`1.,’ document which ri-my throw doubts on priority claim(s) or
`which is ulfld to establish the publication date Of another
`dun“ or other sped“ "awn (“ spanned)
`'0' document referring to an oral disclostite. use. exlubltion or
`other i-i-ieai-is
`‘P’ document ptilbliahed prior to the internatioi-ial filing date but
`later than the priority date claimed
`
`
`
`
`
`
`
`
`
`E Patent family meinben a.rc listed in annex.
`
`.
`'1" later document published alter the Imemauoi-ial llling date
`or pi-ionty date and noun confiict with the application but
`grgnéoogmdcnund the Pnncip" or mm” undcdymsme
`-x- dowmcm or particular relevance; the dmmd Inwnu-an
`cannot be oonsidered novel or cannot be comidered to
`involve an inventive step when the document is taken alone
`-1'» docmnent of Durham“. relevance: the claimed invention
`cannot be considered to involve an Inventive step when the
`document 15 combined with one or more other such docu-
`riieritt. such oornbinaoon being obvious to it person skilled
`“" tn‘ 5""
`‘at’ doetunent rncrntaer of the same patent farnily
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date of the actual completion oi the international search
`
`Date of mailing of the tnteiriational search report
`
`
` 10 April 1995
`Authorized officer
`Name and mailing address of the ISA
`
`Eumpean Patent Olficc. PB. 55! I! Patendaan 2
`
`NL - 2280 HV R.i]swrj|i:
`Tel. (-r 3|-'10) 34-0-2040. 1'2. 3| 651 epo 111.
`
`
`Fax: (+ 3130} 340-3016
`Boulois, D
`Fon'i1 'PCT.I'i5A,-F210 (second stint) {July 1992}
`
`25. 06. 95
`
`Page 25 of 27
`
`Page 1 01° 2
`
`Page 25 of 27
`
`

`
`INTERNATIONAL SEARCH REPORT
`
`lmnrn
`
`_:.1l Apphcauon No
`
`PCT/GB 94/02703
`
`C.(ConunuaI:Io11) DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category ‘ Cnanon of document. with indication. where approvpnata. of the re|eva.n1 passages
`
`Relevant to claim No.
`
`H0,A,92 06680 (CORTECS LTD) 30 Apri1 1992
`cited in the application
`see page 20, 1ine 10 - 1ine 22
`see page 21 - page 23; example 1
`
`H0,A.9O 12583 (CORTECS LTD)
`1990
`
`1 November
`
`see page 45; examp1e 51
`
`Form PCTIISAJIID [umtinultlon of ucnml sheet} [July 1992}
`
`Page 26 of 27
`
`P399 2 Of 3
`
`Page 26 of 27
`
`

`
`INTERNATIONAL SEARCH REPORT
`lnforrrmilon on palm! iarruly members
`
`Intern.
`
`.:aJ Apphcauon No
`
`PCT/GB 94/02703
`
`cited in search report
`
`date
`
`
`
`DE-A-392488?
`
`05-04-90
`
`——————-—-_————__—4—__--__———————______...__...——_———-—----————-.-—_—.——----—