Note: Descriptions are shown in the official language in which they were submitted.
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HIPHASIC CAPSULE FORMULATION
This application is a division of Canadian Application
No. 2,179,041, filed on December 12, 1994.
'~!:e present invent=~n relates to improved capsule
~crmulations, in particular biphasic capsule
formulations.
WO-A-9206680 discloses biphasic release formulations for
i~DODflllc drugs comprising a C~2-CZ4 fatty acid and a
pharmaceutically act_ve substance. A portion of the
formulation is formu_ated 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.
I5 "'he formulations ire extremely effective for the
administration of __pophilic pharmaceutically active
substances greatly enhancing oral bioavailibility of
cropranolol. These results have been published (Barnwell
~:1, - "ant=~112d =~iease, 28, 306-309 :?994).', but it
20 has been discovered t'~at there are certain problems with
the stability of the compositions even when scored at
ambient Temperature.
after capsules contai::ina biphasic formulations such as
25 those described _n ;~0-A-9206680 have been stored for
periods cf greater t::an 3 months at ambient temperature,
t::ere is a decli.~.e -.. ' _~. vitro dissolution performance
compared with initia~ values. The level of propranolol
released from the formulation after 12 months' storage at
30 ambient temperature was found to be reduced by SO%
c~mpareci with initiate values. In contrast, arolonged
s~orage of capsules ~:,ntaining only the ~iquid rapid-
reiease chase and capsui2s containing only the solid
sustained release phase did not result in any change in
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GisSOlllti:.n profile. This unstable release profile is
~~erefcr_ a problem cniv ~.~ith biphasic Tormulations and
represents a serious drawback in the development of such
fcrmulat_ons since, clearly, a pharmaceutical formulation
S which is not stable under ambient storage conditions is
cf limited use in practice.
Or. investigation, it appeared that the deterioration in
the release profile had arisen because, unexpectedly, the
two phases oz the tormuiation had become mixed during the
storage of the capsules and the mixing of the phases had
caused the release characteristics of both harts of the
formulation to deteriorate. Deterioration was
characterised by a visible intermixing between the two
phases and a decline i.. in vitro dissolution performance.
The rate of intermixing between the liquid rapid and
solid sustained-release phases of the formulation was
accelerated at elevated storage temperatures, eg 37°C,
but much Yeduced a~ -'_°C.
':'herefore, in a ~irs~ aspect of the invention there is
provided a pharmaceutical formulation comprising a
capsule containing at least two fill compositions,
characterised in chat the compositions are prevented from
mixing with one another.
The capsule fill compositions may be compositions
comprising C~Z-CZ4 fatty acids such as those disclosed in
WO-A-9206680. The invention is particularly useful when
one of the fill compositions is a solid and one a liquid,
especially when ~he solid component also comprises
aiycerides, fcr example the GELUCIRET" mixture disclosed
is ~xampie 1 oz WO-A-9206680. In that case, the fatty
acids tend to dissolve the lower molecular weight lipids
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o= the solid composition so that they graduai'__r.mix with
t:-:e -iauic co:noosit_cn. The nregressive soiLb___sation
or the lower molecular weight glycerides into =a liquid
composition slows down the rapid release charac~eristics
of the liquid phase. It also leaves in the so~_id phase
only the higher molecular weight glyceride components
which do not easily erode to allow the release of the
remaining fatty acid and t:~e active material. .'-n example
of a modified capsule would be an adaptatica 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 coen ends.
This would allow two separate formulation comDOnents to
be filled, each end of the capsule being seai~d by the
usual potato starch cap. Thus .the sustained :eiease of
the active material from the solid component is retarded.
These changes in drug release may be monitored using an
in vitro dissolution method such as that described in
~xampie 2 below.
zowever, there may be other reasons for wishing to
separate the two fill compositions, for example they may
contain different active compounds or sifferent
zxcipients which interact in an unfavourable manner and
therefore the present invention is not li:.~.ited to
compositions such as those described in WO-A-9206680.
For example, with compositions such as those disclosed in
GB Application No 9417524.7 there is the possi~iiity of
unfavourable interaction of the active _ngredient,
carticularly _f ~= is a protein, and t:.e pH -:odifying
agent (for instance, carbonate or bicarbonate . Thus,
the present invention is particularly usefu: for such
Formulations.
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~~e simoiest method cf preventing phase mixing is to
=_=mulct= cctr of ~:e =;l_ compositions as sol_ds but of
curse this will not be possible in ail cases.
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
of the capsule walls and any barrier which has this
effect is of no use whatever.
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
caDSUle. his may ne achieved by manufacturing capsules
:~.aving two compartments and will be particularly
effective for hard Qeiatin capsules and starch capsules.
In some cases, it wil'_ 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 string enough to support a central barrier in
the capsule.
.a such cases a barrier must be introduced into the
capsule after manufacture and this will usually be done
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as c:~e capsule is filled. This will retain the avantage
~_ ltw m~arufactur=ag cost cf _::e capsules whi'~st still
separating the fill compositions and preventing t em from
mixing.
S
The choice of material for the barrier is important and
several factors must be taken into account. For _xample,
if hydrophobic fill compositions are used, it may be
desirable to use a hydrophilic material as a carrier
'0 between the fill composit_ons. On the other hand, if the
fill compositions are hydrophilic in nature, .hen a
hydrophobic material will be more suitable.
it is also highly desirable that the material used as a
15 barrier should have a melting point such that =t is a
solid at any likely storage temperature. Theref~=e, the
melting point should, at the least , be higher t an 25°C
':room temperature) but =t is much preferred _=at the
material should not begi.~.~. to melt until -t reac~es about
? 0 ? 7°C , body t emperature ) .
a barrier formed from suc:~. a material has the advantage
ef easy formation since the barrier material car. simply
be filled into the cansuies in a molten state at a
2~ temperature above its melt_ng point and then al:owed to
cool and form a solid barrier. The barrier mater:.al will
be added to the capsule after the first fill composition
has been put into the capsule but before the add_tion of
the second fill composition so as to form an e=Fective
30 barrier between the two ccmpositions.
T= the capsule is reQUired to contain. more than t:ao fill
comz~ositions then layers cf the barrier materia_ can be
added to the capsule between additions of the different
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i compositions.
_.-. addition, the barr=er material must, of course, be
::vsiolocricailv compat,ble since it is to be irciuded ir.
S a pharmaceutical formulation.
'.~'ateriais which have been found to be particularly useful
Gs barrier materials in capsules are glycerides having a
..=ansition temperature (melting point) above 37°C.
witable glycerides include di- and tri-glycerides, such
as many of the various GELUCIRE compounds, which are
hydrogenated fatty acid esters available from Gattefosse.
the word GELUCIRE is a trade mark.) Other trade marks
suitable giycerides include LABRAFIL and ~RECIROL.
..=LUCIRE compounds and other suitable compounds having
_=ansition temperatures of from 40°C to 70°C are
p=eferred. Specific examples of exemplary GELUCIRE
,.cmpounds, and their eauivalents include:
GELUCIRE 44/14
GELUCIRE 50/02
GELUCIRE 50/13
GELUCIRE 54/02 (also available as PRECIROL)
GELUCIRE 62/05 and
GELUCIRE 64/02 ;also available as PRECIROL WL 2155).
the First two digits in the numeric portion of the
G=LUCIRE name represent the liquid/solid phase transition
temperature in degrees centigrade and the second two
c'_gits represent the hydrophile/lipophile balance (HLB)
-: alue .
..ELUCIRE 44114 :has a high HLB value and is therefore
=_latively hydrophilic. This means that it is
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cart-cularlv useful as a barrier in capsules co~taininc
coo: ilic =__= comz~ositic:.s such as those desc=ibed in
~NU-r-9206630 since it will be immiscible with bot'.~.~. of the
'_ ccmDOSitions.
The other compounds are more suitable for use in capsules
with a hydrophilic fill since they are all relatively
_iaoprilic.
l0 A turt:~er 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
descr_beci in WO-A-9325192 together with a lipophilic drug
is the lipophilic delivery system described in WO-A-
~~06680. The advantage cf this arrangement is for the
_:~,orcvea aei_verv :f ~r;:as whicr. undergo bot:_ high
hepatic first-pass metabol_sm and enterohepatic recycling
?.g. haioperidol, chlorpromazine and morphine) or where
to non-membrane damaqincr bile acid can attenuate the
toxic effects of a. drug subject to high first-pass
metabolism and formulated as described in WO-A-9206680.
Conversely, where a iipophilic barrier is used to
separate hvdronhilic chases it may act as a reservoir for
a co-administered iipophilic drug.
Another way in which intermixing may be prevented with
the biphasic rapid and sustained-release formulations
_ described in WO-A-9206660 containing C~Z to CZ4 fatty
ac=ds, is to ensure that t:~e rapid-release phase =emains
a solid at normal storage temperature, e.g. below 30°C.
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T'_:is may be achieved by ~:ixina a hydrophobic Gelucire~
:~m~'.: a ~:e-_ting pci:.. above 30°C, exemplified by Gelucire
33/01, with the molten rabid release component before
_i~.lirg into caDSUles, the rapid-release phase
solidifying on ccoling and thus being unable to undergo
mixing with the resident solid sustained-release
Formulation component. An example of this formulation
approach is given below in Examr~ie 3.
l0 .~ is preTerred tat hard gelatin capsules are used and,
,~n that case, liquid fill 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 she stomach. Any convenient enteric
protection method may be used. Capsules containing the
~~rmulation may be coated with an enteric coat such as
hydroxvpropylmethyicelluiose 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
composir.ion, the barrier material and the second fill
composition seauentially into a suitable capsule.
Therefore, in a further aspect of the invention, there is
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provided a process for the preparation of a capsule
containing at least two fill 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.
In accordance with one aspect of the present invention
there is a pharmaceutical composition comprising a capsule
having a single compartment containing at least two fill
compositions, wherein each fill composition is
independently hydrophobic, hydrophilic, lipophobic, or
lipophilic, characterized in that the compositions are
prevented from mixing with one another by a physical
barrier, wherein the physical barrier comprises a further
fill composition of different material to that of the
capsule.
In accordance with another aspect of the present invention
there is a biphasic pharmaceutical formulation comprising a
solid rapid release phase and a solid sustained release
phase, wherein said rapid release phase remains solid at a
temperature below 30°C.
The invention will now be further described with reference
to the following examples which are not intended to be
limiting.
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Example 1 - Biphasic Propranolol Formulation with Phase
Barrier
The following example is a biphasic rapid and sustained-
release propranolol formulation similar to that described
in WO 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 mg/capsule
Propranolol 40.0
Oleic Acid BP 102.1
Colloidal silicon dioxide (Aerosil'M 200) 8.2
Polyoxyl-40-hydrogenated castor oil NF 27.2
(CremophorTM RH40)
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at::rated poiyQiycciysed glycerides ?h. F. 94.5
_.._vcir° 50/C2;
B. Phase Barrier
Saturated polygiycoiysed glycerides Ph.F.~ 150.0
lGelucire 44/14)
C. Rapid-Release Phase
Prooranolol base 40.0
Oleic acid BP 110.0
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 the propranolol base was fully
dissolved. ~inallv Aerosil was added while
stirring. A total of 272 mg of the formulation was
filled into size 0 hard gelatin capsules while hot
and hen allowed to solidify with cooling.
H. Phase Harrier
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.
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C. Rapid-Release Phase
oleic acid was heated wit: stirrincr at a5°C-50°C.
ProDranolol base was added and 3issoived with
stirring and allowed to ccol. A total of 150 mg of
the liquid rapid-release formulation was then filled
over the phase barrier. The resulting capsules
contained a solid sustained-release phase, solid
phase separation barrier end liquid rapid-release
phase. The capsules were then sealed by gelatin
banding. Following gelati~. banding, the capsules
may be enteric-coated as described in WO 92/06680.
EXAMPLE 2 Dissolution Studies With and Without Phase
Barrier Svstem
For evaluating the dispersion behaviour of the
experimental formulations, a ~est-method was devised
based ;:oon the USP XXII issoiution test =or tablets and
car~suies. The aim of the test :vas to subiect the samples
to an environment similar to .hat in the intestine.
Dispersion in 5 Pours was selected as a satisfactory
total release time for the test samples. This was based
en the understanding t:~at 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
deoxycholate, equilibrated to 37°C. The total volume of
buffer added to each dissolution vessel was 900 mi, with
a paddle rotation. sr~eed of '.'0 rn;~. The paddle height was
adiusted so that t:ne tcp edge o~ she blade was level with
t:~e surface of the liquid. The test sample was dropped
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into _::~ dissoiuticn medi;:m and the rotation of the
,:,addi= s=acted. 'he asst sample was allowed to float
rreeiv at the '_iquid sur=ace throughout the test. At
eacr. t'_me-point, a 5 mi aliauot of the dissolution medium
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 ~.M fine
filter. '~he absorbance of the filtered solution was then
determined at 290nm using a W at 290 nm using a W
spectrophotometer. "'he propranolol concentration in the
dissolution medium was calculated using a pre-determined
calibration curve for propranolol.
A = Examoie 1 with phase barrier.
B = Example 1 without phase barrier.
Table ~ - 30°C Storage
a Prooranolol Release
'"ime T_nitiai ~ Months 7 Months
(minutes)
A B A B A B
_.. 36 ~_4 39 30 34 23
30 41 =3 51 38 45 29
50 49 ~i0 57 47 50 35
120 59 ~4 54 61 55 43
300 77 71 79 71 69 59
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-~ab~e y _ _~o~ crcracre
% ProoranololRelease
Time Initial 1 Month
(minutes)
A B A B
15 36 44 26 15
30 41 53 44 25
60 49 60 48 37
120 58 64 51 45
300 77 71 62 54
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 :f cropranalol released, particularly _rom the
sustained =elease phase. The effect ci the barrier
-:creases with the iencrth of time for which the capsules
are stored.
EXAMPLE 3 - Hiphasic Propranolol Formulation with Solid
Raid-Release Phase
This is an example of a biphasic rapid and sustained-
release propranolol 'ormuiation based on that described
in WO-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
Gelucire~ 33/01, which melts on heating above 30°C
allowing (i) capsule filling to take place using
conventional mixing and pumping technology, and (ii)
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enables =aDid-release to tales place at normal
temz~era~v=a .
A. Sustained-Release Phase ma/capsule
S As .:.r Example 1 272.0
B. Solid Raid-Release Phase
20
Procranolol base 40.0
Oleic acid B.P. 110.0
Sat~.:rated polyglycolysed glycerides Ph.F. 150.0
(Ge~ucire~ 33/011
The modi~ied 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
complete_~r dissolved. The molten rapid-release phase was
maintained above 37°C until filled into capsules already
containi~~ the solid sustained-release phase described in
Examble -. A total of 300 ma of the modified sustained-
release phase containing Gelucire~ 33/01 was filled into
size 0 hard gelatin capsules while hot and then allowed
to solidi_'y with cooling. The capsules were then sealed
by gelat_n banding. Following gelatin banding,' the
capsules may be enteric-coated as described in WO-A-
9206680 and Burns et , International Journal of
Pharmaceutics, 110: 291-296 (19941.
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EXAMPLE 4 - Dissolution Studies Usina Solid Rapid-Release
Phase Svstem
The same dissolution method as described in Example 2 was
5 used to evaluate capsules containing the biphasic rapid
and sustained-release preparation described in Example 3.
Table ~ - 25°C Storage
o Propranolol Release
Time Initial Months 12 Months
2
(minutes)
32 26 23
'~5 30 52 49 50
60 60 61 64
120 65 67 71
300 75 83 82
Table - - .0°C Storage
~ Pro~ranolol
Release
Time Initial 1 Month ~
( min~~tes 2 Months 12 Months
)
=5 32 22 27 14
30 52 43 54 37
60 60 59 62 66
'_20 65 64 ~ 80 76
300 75 ~ 84 85 77
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The results in '"able 3 show that at 25°C the dissolution
prefi_e __ a ~,iphasic formuiatic:: is maintained for at
least '._2 ,:.onths. Table 4 shows that at 30°C, close to
the melti::g point of the modified rapid-release phase
S containing Gelucire~"' 33/01, there is a small
deterioration in initial release rate. However, the
overall biphasic release characteristics of the
formulation are maintained.
