CA2572498C - Biphasic capsule formulation - Google Patents

Abstract

Capsule formulations are provided containing at least two different fill compositions which are prevented from mixing either by providing both of the fill compositions as solids or by providing a physical barrier which separates the fill compositions so that they are prevented from mixing. The invention has the advantage that two different formulations can be provided in a single capsule without one of the formulations having an adverse effect on the other.

Description

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 Z
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 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.

~~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 S
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 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 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 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.

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 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.

9a 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) Z
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.

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 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 -~ab~e y _ _~o~ crcracre % ProoranololRelease Time Initial 1 Month (minutes) A B A B

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) l 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 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.

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 (minutes) '~5 30 52 49 50 Table - - .0°C Storage ~ Pro~ranolol Release Time Initial 1 Month ~
( min~~tes 2 Months 12 Months ) =5 32 22 27 14 '_20 65 64 ~ 80 76 300 75 ~ 84 85 77 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.

Claims (6)

1. 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.

2. The biphasic pharmaceutical formulation according to claim 16, wherein the rapid release phase comprises a pharmaceutically active substance and a glyceride having a melting point above 30°C.

3. The biphasic pharmaceutical formulation according to claim 17, wherein the glyceride is a saturated polyglycolyzed glyceride.

4. The biphasic pharmaceutical formulation according to claim 17, wherein the glyceride is a hydrogenated fatty acid ester.

5. The biphasic pharmaceutical formulation according to claim 17, wherein the rapid release phase and the sustained release phase comprise a C12-C24 fatty acid.

6. The biphasic pharmaceutical formulation according to claim 20, wherein the C12-C24 fatty acid is oleic acid.