Note: Descriptions are shown in the official language in which they were submitted.
WO 95/16438 217 9 0 41 P~~GB94/02703
1
Biphasic capsule formulation
The present invention relates to improved capsule
formulations, in particular -biphasic capsule
formulations.
WO-A-9206680 discloses biphasic~release formulations for
lipophilic drugs comprising a C~z-Czy fatty acid and a
pharmaceutically act'_ve substance. A portion of the
10- formulation is formu'_~ted for non-sustained release and
is generally in liauid form and a portion is formulated
for sustained release on non-parenteral administration
and will generally be a solid.
. The formulations a==_ extremely effective for the
administration of lipophilic pharmaceutically active
substances greatly enhancing oral bioavailibility of
propranolol. These results have beenpublished (Barnwell
al, S. Controlled Felease, 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 contair.ina biphasic formulations such as
those described in WO-A-920668D have been stored for
periods or greater than 3 months at ambient temperature,
there is a decline in is vitro dissolution performance
compared with initial values. The level of propranolol
released from the formulation after 12 months' storage at
ambient -temperature was ~ouhd- 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
WO 95116438 217 9 0 41 pCTlGB94102703
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dissolution profile. This unstable release Drofile is.
_ _ ,
therefore a prcbiem- only with biphasic faraiulations and
represents a serious drawback in the development of such
fcrmulatioris since, clearly, a pharmaceutical fornulation
which is not stable under ambient storage conditions is
of limited use in practice:
On investigation, it appeared that the deterioration in
the release profile had arisen because, unexpectedly, the
two phases of the formulation had become mixed during the-
storage of the capsules and the mixing of the phases had
caused the release characteristics of both parts of the
formulation to deteriorate. Deterioration was
characterised by a visible intermixing between the two
IS phases and a decline ir. iri vitro-dissolution performance.
The rate of ,ntermixing between the liquid rapid and
solid sustained-release phases of the formulation was
accelerated at elevated storage temperatures, eg 37°C,
but much reduced at _°C.
Therefore, in a fi=st aspect of the invention there is
provided a pharmaceutical formulation comprising a
capsule containing at least two fill compositions,
characterised in that the compositions are prevented from
mixing with ane another.
The capsule fill compositions may- be compositions
comprising Ciz-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 the solid component also comprises
glycerides;- for example the GELUCIRETM mixture disclosed
in Example 1 of WO-A-9206580.- In that case, the fatty ,
acids tend to dissolve the lower molecular weight lipids
WO 95/16438 ~ 217 9 0 41 PCT/GB94/02703
z
of the solid composition so that they gradually mix with
the liquid composition. The progressive solu:._lisation
of the lower molecular weight glycerides into to 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. rn example
ofa 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 cDen ends.
This would allow two separate formulation comDOnents to
be filled, each end of the capsule--being sealed by the
- ' usual potato starch cap. Thus the sustained release of
the active material from the solid component is retarded.
These changes in drug release may be monitored using an
vitro dissolution method such as that described in
Example 2 below.
However, there may be other reasons for wishing to
separate thetwo fill compositions, for example they may
contain different active compounds or different
excipients which interact in an unfavourable ~anner and
therefore the .present invention is not li.-.sited to
compositions such as those described in WO-A-X206680.
For example, with compositions such as those disclosed in
GB Application No 9417524.7 there is the possibility of
unfavourable interaction of the active, i-gredient,
particul rly if i.. is a protein, and ti:e pH -:.~.odifying
agent (for instance, carbonate or bicarbonate.. Thus,
the present ir_vention is particularly useful for such
.
formulations.
R'O 95/16438 217 9 0 4 l P~~GB94/02703
c
~-he simpiest.method- cf preventing phase mixing is to
o=mulace boLr--cf she ~i11 compositions as solids put of
course this- will not be possible in -all cases.
Therefore, it is often desirable to provide some sort of
physical barrier within the-capsule to prevent mixing of
the fill compositions.
~?owever, 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
efiect_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.~f 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 wil'_ not be possible to manufacture the
barrier.-from the same material as the capsule shell.-
There may be a varietyof -reasons for this, for example
the difficulties- iri 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.
T_n such cases a-barrier :must be introduced into the
capsule after manufacture=and this will usually be done
O 95!16438 217 9 0 41 PCTlGB94/02703
as the capsule is filled. ;his will retai:. the ad vantage
c. low manufacturing cost of to capsules whilst stii'_
separating the fill compositions and preventing tem from
mixincr .
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
between the fill compositions. On the other hand, if the
fill compositions are hydrophilic in nature, then a
hydrophobic material will be more suitable.
It is also highly desirable that the material used as a
barrier should have a melting point such that i_ is a
solid at any likely storage temperature. Therefore, the
melting point should, at the least, be higher t=an 25°C
(room temperature) but i_ is much preferred teat the
material should not begin to melt until a reaches about
37°C ;body temperature).
A barrier formed from such a material has the advantage
of easy formation since the barriermaterial can simply
be filled into the capsules in a molten state at a
temperature above its melting point and then al-owed to
cool and form a solid barrier. The barrier mater_al will
be added to the caDSUle 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
barrier between the two compositions.
If the capsule is recruired to contain more than t:ao fill
compositions then layers of the barrier material can be
added to the capsule between additions of the different
WO 95/16438 217 9 0 41 PCT/GB94/02703
___1 comaositions.
_.. addition, the barrier ;aaterial must, of course, be
~ysiologically compatiple since it is to be included in
a aharmaceuticai formulation.
:~!ateriais which have been found to be particularly useful
as barrier materials in capsules are glycerides having a
transition temperature (melting point) above 37°C.
Suitable 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
c. suitable glycerides include LABRAFIL and PRECIROL-.
GELUCIRE 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 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).
he first two digits in -the- numeric portion of the
GELUCIRE name represent the ~iquid/solid phase transition
temperature in degrees centigrade and the second two
digits represent the hydrophile/lipophile balance (HLB)
value. ,
GELUCIAE 44/14 has a high HT-R value and is therefore
relatively hydrophilic. This means that it is
~WO 95/16438 ~ 217 9 0 41 PCTlGB94102703
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cart-cularly useful as a barr_er -in capsules containing
=_conhi~_ic f-11 compositicas such as those described in
WO-A-9ZD6680 since it W l.i be immiscible with both of the
-ill ccmpositions.
The other compounds are more suitable for use in capsules
with a hydrophilic fill since they are all -relatively
liaophilic:-
A °urther use for the hydrophilic chase 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-9325192 together-with a lipophiiic drug
is the lipophilic delivery system described .a WO-A-
9206680. The advantage cf this arrangement is for the
improved delivery- of 3rags which -undergo both high
hepatic first-pass metabolism and enterohepatic recycling
ue.g. haloperidol, chlorpromazine and morphine) or where
the non-membrane damaging 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 hydrophilic phases it may act as a reservoir for
a co-administered iipophilic drug.
Another way in which intermixing may be prevented with
tae biphasic rapid and sustained-release formulations
described in WO-A-9206680 ccntaining CiZ to CZ~ fatty
- acids, a to ensure that the rapid-release phase remains
a solid at normal storage temperature, e.g. below 30°C_
WO 95/16438 ~ 217 9 0 41 PCTlGB94102703
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This may be achieved by mixing a hydrophobic Gelucire~
with a melt_ng poi.~.: above 30°C, exemplified by Gelucire
33/01, with the molten rapid release component before
filling into capsules, the rapid-release phase
solidifying on cooling 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 Example 3.-
=t is preferred that hard-gelatin capsules are used and,
in that case, liquid fill compositions may contain
gelatin softening agents such as those described in w0-A-
9102520. Suitable gelatin softening agents can be found
by reference to the art of manufacturing soft gelatin
capsules wheresuch materials are incorporated into the
mix which forms the gelatin-wall. Particularly suitable
gelatin-- softening agents include glycerol; propylene
glycol, glycerol mono-bieate 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 eateric
protection method may be used. Capsules containing the
formulation may be coated with an-enteric :coat such as
hydroxypropylmethyice11u1ose - 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 info a suitable cagsule.
Therefore, in a further aspect of the invention, there is
CA 02179041 2005-07-12
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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.
CA 02179041 2005-07-12
9a
Example 1 - Biphasic Propranolol Formulation v~tith 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 (AerosilT"" 200) 8.2
Polyoxyl-40-hydrogenated castor oil NF 27.2
( CremophorT"" RH4 0 )
WO 95/16438 , 217 9 0 41 p~~Gg94102703
1D
Sat::rated polygiycciysed glycerides Ph.F. 94.5 ,
Gcl;:cire 50/02)
B. Phase Barrier
Saturated polyglycolysed glycerides Ph.F. 150.0
(Gelucire 44/14)
1D
C. Rapid-Release Phase
Propranoloi base 40.0
Oleic acid BP - 110.0
A. Sustained-Release Phase
The oleic acid, Gelucire 50/02 and Cremophor were
heated to SO°C-55°C until a clear- solution was
obtained. Propranolol base was added with stirring,
while mainta3riing the temperature of the mix at 50°C
and continued until the propranolol base was fully
dissolved. Finally Aerosil was added vihile
stirring. A total of 272 mg of the formulation was
filled into size D-hard gelatin capsules while hot
and :.hen 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.
O 95!16438 217 9 0 41 PCT/CB94/02703
,,
C. Rapid-Relea a Phase
Olsic acid was heated wit: stirring at 45°C-50°C.
Prcpranolol base- was added and dissolved with
S stirring and allowed to cool. 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 and liquid rapid-release
1o 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 S dire With and Without Phase
15 Barrier Svatem
For evaluating the dispersion behaviour of the
experimental formulations, a test-method was devised
based upon the USP XXII dissolution test-for tablets and
20 capsules. The aim of the test cans to subject the samples
to an environment similar to that in the intestine.
Dispersion in 5 hours was selected as a satisfactory
total release time for the test samples. This was based
or_ the understanding that lymphatic absorption occurs
25 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 0.1s sodium
30 deoxycholate, equilibrated to 37°C. The total volume of
buffer added to each dissolution vessel was 900 mi, with
a paddle rotation speed of 70 =-p;~. The paddle height was
adjusted so that the tcp edge of the blade was level with
tae surface of the liquid. The test sample was dropped
WO 95/16438 217 9 0 41 PCTIGB94102703
12
into the dissoiutiori-medium and the rotation of the
paddle started. The test camp-~e was allowed to Moat
freely at the liquid surface throughout the test. At
each time-point, a 5 ml aliauot of the dissolution medium
was removed and replaced: with 5 ml of fresh buffer
solution. Each 5 ml sample was initially fil~ered
through a 1.2 ~M coarse filter and subsequent 1.2 uM fine
filter. The absorbance of 'he 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 = Example 1 with phase barrier.
B = Example 1 without phase barrier.-
Table 1 - 30°C Storacre
o Proprano lol
Release
Time I Initial 3 Months 7 Months
(minutes ~
)
A B A B A B
-5 36 a4 39 30 34 23
30 41 53 51 38 45 29
5D 49 50 57 47 50 35
120 58 64 54 61 55 43
30D 77 71 78 71 69 59
W O 95116438 217 9 0 41 PCT/GB94/02703
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ssble 2 37°~ Storage
% Propranolol ase
Rele
Time Initial 1 Month
(minutes)
/: B A B
36 44 26 I5
10 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 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.
_E~CAMPLE 3 - Hiphasi Pronraaolol Formulation with Solid
Rapid-Release Phase
This is an example of a biphasic rapid and sustained-
reiease propranoiol formulation based on that described
in WO-A-920668D, 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)
WO 95116438 217 9 0 41 PCTlGB94/02703
14
enables rapid-release to tak°_ place- at normal
temperaL~re. - _. .._.__
A. Sustained-Release Phase _ _ ma/canaule
As .or Example I - ~ 272.0
B. Solid Rabid-Release Phase
20
Prouranolol base 40.0
Oleic acid g.P. 11D.0
Saturated polyglycolyaed glycerides Ph.F. 150.0
(Gelucirea 33J01)
The moth=led rapid-release-- phase -was manufactured by
heating oleic 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
containi=g the solid sustained-release phase described in
Example =. -Atotal of 3D0 mg of the modified sustained-
release phase containing Gelucire~ 33/01 was filled into
sizes 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 WO-A-
92D6680 and Burns et al, rnrPrnational Journal of
Pharmaca~rLics, 110: 291_-296= (1994).
WO 95116438 217 9 0 41 PCT/GB94/02703
EXAMPLE 4 - Dissolution Studies Usina Solid Rspid 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 S oraq~
to
a Propranoloi
Release
Time Initial 12 Months
(minutes) 2 Months
15 32 26 23
15 30 52 49 50
60 60 61 64
120 65 67 71
300 75 83 82
ao
T~le = - 30°C Storage
% Pronranolol Release
Time Initial 1 Month 2 12 Months
(mimeses) Months
_5 32 22 27 14
30 52 43 54 37
60 60 59 62 66
120 65 64 80 76
300 75 84 85 77
VI'O 95116438 217 9 0 41 pCTIGB94102703
16
The results in Table 3 show that at 25°C the dissolution
profile c_' a biphasic formiiiaticn 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
overall biphasicrelease characteristics of the
formulaticn are maintained.
