CA2179041C - Biphasic capsule formulation - Google Patents
Biphasic capsule formulation Download PDFInfo
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- CA2179041C CA2179041C CA002179041A CA2179041A CA2179041C CA 2179041 C CA2179041 C CA 2179041C CA 002179041 A CA002179041 A CA 002179041A CA 2179041 A CA2179041 A CA 2179041A CA 2179041 C CA2179041 C CA 2179041C
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- formulation
- fill
- barrier
- compositions
- hydrophobic
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Abstract
Capsule formulations are provided containing at least two different fill com positions 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 t hey are prevented from mixing. The invention has the advantage that two different fo rmulations can be provided in a single capsule without o ne of the formulations having an adverse effect on the other.
Description
WO 95/16438 217 9 0 41 P~~GB94/02703 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 G
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 ___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 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 , 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 a 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 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 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 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) 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 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 ssble 2 37°~ Storage % Propranolol ase Rele Time Initial 1 Month (minutes) /: 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 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 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 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).
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 ao T~le = - 30°C Storage % Pronranolol Release Time Initial 1 Month 2 12 Months (mimeses) Months _5 32 22 27 14 VI'O 95116438 217 9 0 41 pCTIGB94102703 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.
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 G
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 ___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 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 , 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 a 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 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 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 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) 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 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 ssble 2 37°~ Storage % Propranolol ase Rele Time Initial 1 Month (minutes) /: 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 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 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 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).
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 ao T~le = - 30°C Storage % Pronranolol Release Time Initial 1 Month 2 12 Months (mimeses) Months _5 32 22 27 14 VI'O 95116438 217 9 0 41 pCTIGB94102703 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.
Claims (16)
1. 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.
2. The formulation as claimed in claim 1, wherein both of the fill compositions are solids.
3. The formulation as claimed in claim 1 or 2, wherein the barrier comprises a material having a melting point higher than 25°C.
4. The formulation as claimed in claim 3, wherein the barrier comprises a material having a melting point of higher than 37°C.
5. The formulation as claimed in any one of claims 1, 3 and 5, wherein the fill compositions are hydrophobic or lipophilic in nature and the barrier comprises a hydrophilic or lipophobic material.
6. The formulation as claimed in any one of claims 1, 3 and 4, wherein the fill compositions are hydrophilic or lipophobic in nature and the barrier comprises a hydrophobic or lipophilic material.
7. The formulation as claimed in any one of claims 1 and 3 to 6, wherein the barrier comprises a glyceride.
8. the formulation as claimed in claim 7, wherein the glyceride is a di- or tri- glyceride, or a mixture of glycerides.
9. The formulation as claimed in claim 8, wherein the barrier material comprises a hydrogenated fatty acid ester of mixture of esters, available under one of the following trademarks:
GELUCIRE 54/02 (also available as PRECIROL) GELUCIRE 64/02 (also available as PRECIROL WL 2155).
GELUCIRE 54/02 (also available as PRECIROL) GELUCIRE 64/02 (also available as PRECIROL WL 2155).
10. The formulation as claimed in any one of claims 1 and 4 to 9, comprising a first fill composition comprising a C12-C24 fatty acid and a pharmaceutically active substance, formulated for non-sustained release on non-parenteral administration; and a second fill composition comprising a C12-C24 fatty acid and a pharmaceutically active substance, formulated for sustained release on non-parenteral administration.
11. The 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 trademark GELUCIRE 44/14.
12. The 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 value of 7.5 to 9.
13. The formulation as claimed in claim 12, wherein the biologically active material is a protein.
14. The formulation as claimed in claim 13, wherein the protein is insulin, calcitonin, a growth hormone, an interferon, and interleukin or an active fragment of any of these.
15. The formulation as claimed in any one of claims 12 to 14, wherein the buffering agent comprises carbonate and/or bicarbonate ions.
16. The formulation as claimed in any one of claims 1, 3 and 4, wherein the first fill composition is hydrophobic or lipophilic in nature, and second fill composition is hydrophilic or lipophobic in nature, and the barrier comprises a material that is hydrophobic, hydrophilic, lipophobic, or lipophilic in nature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2572498A CA2572498C (en) | 1993-12-13 | 1994-12-12 | Biphasic capsule formulation |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB939325445A GB9325445D0 (en) | 1993-12-13 | 1993-12-13 | Pharmaceutical formulations |
| GB9325445.6 | 1993-12-13 | ||
| PCT/GB1994/002703 WO1995016438A1 (en) | 1993-12-13 | 1994-12-12 | Biphasic capsule formulation |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2572498A Division CA2572498C (en) | 1993-12-13 | 1994-12-12 | Biphasic capsule formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2179041A1 CA2179041A1 (en) | 1995-06-22 |
| CA2179041C true CA2179041C (en) | 2007-04-10 |
Family
ID=38007157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002179041A Expired - Fee Related CA2179041C (en) | 1993-12-13 | 1994-12-12 | Biphasic capsule formulation |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2179041C (en) |
-
1994
- 1994-12-12 CA CA002179041A patent/CA2179041C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2179041A1 (en) | 1995-06-22 |
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