Note: Descriptions are shown in the official language in which they were submitted.
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
PACK CONTAINING SOFT CAPSULES
The invention relates to a pack comprising a packaging material and soft
capsules, to a process for the stabilisation of soft capsules, and to a proc-
ess for the production of the pack.
Soft capsules are capsules which, owing to additions of softeners, such as,
for example, glycerol, sorbitol, maltitol and polyethylene glycols, present in
the capsule shell, have a certain elasticity and softness and are employed
for the administration of various substances, such as, for example, medi-
caments, food supplements and/or functional ingredients. Soft capsules
can be produced, for example, on the basis of gelatine or starch. Gelatine-
based soft capsules have long been known as soft gelatine capsules and
are commercially available from various suppliers. Starch-based soft cap-
sules are a relatively new development, an example thereof are soft cap-
sules marketed by Swiss Caps, Switzerland, under the trade name Vega-
Gels .
If liquid or semi-solid substances are to be administered by means of the
soft capsules, they can be encapsulated directly, solids are first dissolved
or suspended in liquid or semi-solid bases, such as, for example, fats, oils,
wax mixtures or polyethylene glycols, possibly in combination with emulsifi-
ers. Depending on the method of administration, such as, for example,
orally, rectally or vaginally, soft capsules can have various shapes, they can
be, for example, round, oval, oblong or torpedo-shaped. Soft capsules can
be produced by the processes known in the prior art, such as, for example,
by the Scherer process, the Accogel process or the droplet or blowing
process.
The softening action of the softener component present in the shells of soft
capsules is essentially based on the hygroscopicity thereof and the associ-
ated inclusion of water the capsule shell. At room temperature (22 C / 45 to
65% RH (RH = relative humidity)), soft capsules have a water content of
-1-
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
about 7 to 8% by weight. If the water content is significantly below this, for
example due to excessively dry storage or drying, this results in embrittle-
ment of the capsule shell, with the consequence of increased fragility of the
capsule wall and the formation of cracks. If the water content is
significantly
above this, for example due to excessively moist storage, swelling of the
capsule shell and sticking together of the soft capsules occur. Both exces-
sively dry and also excessively moist storage also result in unpredictable
effects on the substances to be administered and any further auxiliaries
present, meaning that the supply with the substances present therein that is
intended with the taking of soft capsules can no longer be ensured. Varying
environmental influences result in totally incalculable influences on the sta-
bility of soft capsules, meaning that their shelf life, i.e. the period over
which
the soft capsules are within the respective specifications applying to them
which have to be met in order that they can be taken as intended, can no
longer be predicted with the requisite certainty. This is unacceptable, in
particular also for safety reasons.
The object of the present invention was to find a simple and inexpensive
way of avoiding the losses in quality arising both with embrittlement of the
capsule shell and also due to swelling and sticking together and signifi-
cantly increasing the shelf life of soft capsules at high dryness, high atmos-
pheric humidity, possibly also together with high temperatures, as prevail,
for example, in climatic zones III and IV, and also in the case of strongly
varying atmospheric humidity.
The object has been achieved, surprisingly, by introducing the soft capsules
into a packaging material in the inside wall(s) of which an absorbent and at
least one channel former is embedded, at least over part of the area. The
invention thus relates to a pack comprising a resealable container in/on the
inside wall(s) of which at least one channel former is embedded, at least
over part of the area, together with at least one absorbent, and at least one
soft capsule, where the soft capsule(s) is (are) present in the container.
-2-
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
Surprisingly, the storage of the soft capsules results in an increase in the
shelf life, although the container with an absorbent an agent is present
which results in a drying action. This is because drying of soft capsules
results, via the removal of water, precisely in embrittlement and fragility of
the capsule shell or even cracking, i.e. precisely the state that is avoided
by
the invention.
According to an advantageous embodiment, the pack according to the inven-
tion contains soft gelatine capsules as soft capsules. The invention therefore
relates to a pack which is characterised in that the soft capsule(s) present
therein is (are) (a) soft gelatine capsule(s).
According to a further advantageous embodiment, the pack according to the
invention contains as starch-based soft capsules. The invention therefore
relates to a pack which is characterised in that the soft capsule(s) present
therein is (are) (a) starch-based soft capsule(s).
The container is resealable and can have any spatial shape, such as, for
example, that of a cylinder or cuboid, provided that it is sufficiently large
to
accommodate the soft capsules inside.
Resealable means that the container can be opened and re-closed repeat-
edly, i.e. at least once, preferably a number of times, particularly
preferably at
least as often as corresponds to the number of soft capsules present in the
container. The container is so tightly sealed after each opening and closing
operation that ingress of moisture and gases into the interior of the
container
is effectively prevented.
Opening and sealing of the container is carried out by a tightly sealing
closure
matched to the container. All types of closures can be employed so long as
they ensure that gases and/or moisture cannot penetrate into the interior of
the container in the closed state, or can only do so in extremely small
amounts, even after repeated opening and closing of the container.
-3-
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
According to an embodiment of the invention, lids are used as closure. Exam-
ples of lids are screw caps, caps which are inverted over the upper edge of
the vessels, or introduced into the interior of the vessel. In the case of
spatial
shapes which have corners, such as, for example, cuboids, the corners of the
opening and the matching lid may also be slightly rounded in order to increase
the tightness of the container against gases and moisture.
According to a preferred embodiment, the container has a cuboid-shaped
spatial shape, rounded corners and is readily stackable. An embodiment of
this type is depicted by way of example in Figure 1. The container comprises
walls (2) whose inward-facing sides contain, at least over part of the area,
at
least one channel former together with at least one absorbent, has rounded
corners (7) and has a lid (1) as closure.
The absorbents and channel formers present in the container may jointly
either be present directly in the inside wall(s) of the polymer forming the
con-
tainer or be applied as a layer to the inside wall(s) of the polymeric
container.
Likewise, absorbents and channel formers may be embedded in an inlay,
which is introduced into the container as insert, so that at least part of the
inside walls of the container are lined thereby.
Inside wall(s) is taken to mean the inward-facing surface of the wall/walls of
the container, i.e. the surface(s) of the container which is (are) in contact
with the soft capsule(s) present therein.
Suitable materials for the container are polymers. Polymers, which can be
employed in a mixture with absorbents and channel formers, are, in particular,
thermoplastics, such as, for example, polyolefins, such as polyethylene and/or
polypropylenes, polyisoprenes, polybutadienes, polybutenes, polysiloxanes,
polyamides, ethylene-vinyl acetate copolymers, ethylene-methacrylate copoly-
mers, polystyrenes, polyesters, polyanhydrides, polyacrylate nitriles,
polysulfo-
nates, polyester amides, polyacrylate esters, propylene-maleic anhydride,
polyethylene-maleic anhydride, polyethylene-urethanes, polyethylene-ethyl-
vinyl alcohols, polyethylene-nylon and/or polyurethanes. The walls provided
-4-
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
with absorbents and channel formers on their inside surface have, based on
the total weight of the mixture of polymer, channel formers and absorbents, a
content of polymer of 10 - 90% by weight.
Absorbents which may be present are in principle any type of desiccants, i.e.
moisture-binding binders. Three groups of desiccants come into consideration:
The first group contains chemical substances which form hydrates with
water. Examples of chemical substances of this type are anhydrous salts,
which tend to absorb water or moisture, and form a stable hydrate in the
process. The moisture is bound, and liberation thereof is prevented by a
chemical reaction.
The second group of desiccants contains substances which are reactive.
The substances react with water or moisture by forming a new substance.
The newly formed substances are normally stable at low temperatures,
which is only reversible with expenditure of high energy. Desiccants of this
type are used principally for drying solvents and as water-absorbent mate-
rial in polymers which themselves have to remain in a moisture-reduced
state.
The third group of desiccants binds the moisture by physical adsorption.
The desiccant contains particles having fine capillaries into which the
moisture is drawn. The pore size of the capillaries and the density thereof in
the desiccant determine the absorption properties. Examples of desiccants
of this type are molecular sieves, silica gels, certain synthetic polymers,
such as, for example, those which are used in babies' nappies, and
starches. Desiccants from the third group are preferably present in the
container since they are substantially inert and water-insoluble. Particular
preference is given here to molecular sieves having a pore size of 3 to
15 Angstrom and/or silica gels having a pore size of 24 Angstrom.
Suitable channel formers are hydrophilic substances, such as, for example,
polyglycols, ethylvinyl alcols, glycerol, polyvinyl alcohols,
polyvinylpyrrolidone,
-5-
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
vinylpyrrolidone, N-methylpyrrolidone, polysaccharides, saccharides and/or
sugar alcohols. Preferred polyglycols are polyethylene glycol and/or polypro-
pylene glycol. Saccharides which can be used are, for example, glucose,
mannose, galactose and/or fructose. Suitable sugar alcohols are, for example,
mannitol, sorbitol, hexitol, dulcitol, xylitol, ribitol and/or erythrol.
Polysaccha-
rides are taken to mean, for example, dextrins and/or hydrolysed starch.
In the inside walls provided with absorbents and channel formers, the channel
formers can have a proportion of 10 - 40% by weight, based on the total
weight of the mixture of polymer, channel formers and absorbents.
Absorbents and channel formers are embedded over part of the surface or
over the entire area in the inside wall(s) of the container. Over part of the
area means that at least part of the total area of the container forming the
inside wall(s) comprises absorbents and channel formers.
Over the entire area means that the entire area of the container forming the
inside walls comprises absorbents and channel formers. According to an
advantageous embodiment, absorbents and channel formers are present in
at least 10%, preferably in at least 50%, particularly preferably in at least
90%, of the inside walls, based on the total inside surface area of the con-
tainer.
Containers made from polymers which comprise absorbents and channel
formers and which are suitable as container for the pack according to the
invention are known in the prior art and are described, for example, in
WO 97/32663 Al, EP 1000873 A2 and WO 03/086900 Al, EP 1421991
Al. Containers which can be employed in the pack according to the inven-
tion are commercially available and are available, for example, from Capitol
Specialty Plastics Inc., 2039 McMillan Street Auburn, Alabama, USA, under
the trade name Activ-Vial or from Sud Chemie, Ostenrieder Str. 15, 85368
Moosburg, Germany, under the trade name 2 AP Multipolymer.
-6-
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
The pack according to the invention is produced by dispensing the soft cap-
sule(s) into a resealable container in/on the inside wall(s) of which at least
one
channel former is embedded, at least over part of the area, together with at
least one absorbent, and subsequently sealing the container. The present
invention therefore also relates to a process for the production of a pack,
which is characterised in that the soft capsule(s) is (are) introduced into a
re-
sealable container in/on the inside wall(s) of which at least one channel
former
is embedded, at least over part of the area, together with at least one absor-
bent, and the container is subsequently sealed.
The pack according to the invention results in an increase in the shelf life
of
the soft capsules present therein. The invention therefore also relates to a
process for increasing the shelf life of soft capsules, which is characterised
in
that they are introduced into a resealable container in/on the inside wall(s)
of
which at least one channel former is embedded, at least over part of the area,
together with at least one absorbent, and the container is subsequently
sealed.
The stabilising action of the pack according to the invention is based on the
influence of the container on the in soft capsule(s), which can consequently
be made available with a long shelf life. Achievement of the action accord-
ing to the invention thus requires that the soft capsule(s) is (are) present
in
the container, i.e. the soft capsule(s) and container are together in the form
of a pack.
Besides the stabilising action on the soft capsule shell, in the pack accord-
ing to the invention also results in stabilisation of the active compounds
and/or auxiliaries present therein, i.e. the entire formulation. This applies,
in
particular, if the active compounds and/or auxiliaries present are sensitive
to moisture. Examples of moisture-sensitive active compounds which are
thus preferably present in the soft capsules in the pack are many pharma-
ceutical active compounds, such as hormones or proteins, vitamins, cells,
such as, for example, probiotic cultures.
-7-
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
The examples explain the invention without being restricted thereto.
Example I
Investigation of the stability of soft capsules in the pack according to the
invention compared with soft capsules in conventional packaging materials
Multivitamin soft capsules (active-compound composition and capsule shell
as described below) are introduced individually into a thermoformed cavity
film made from PVC 250 pm + 40 g/m2 of PVDC and heat-sealed with alu-
minium foil (20 pm) and into a resealable container in/on the inside wall(s)
of which at least one channel former is embedded, at least over part of the
area, together with at least one absorbent (type: M-3006-16 Activ-Vial) in
the inside walls of which a molecular sieve having a capacity of 1.92 g is
embedded.
The blisters and containers containing the multivitamin soft capsules are
stored at 40 C and 75% relative humidity (RH), removed from storage after
predetermined times, assessed visually with respect to their appearance
and investigated analytically with respect to the amounts of active com-
pound present. The results are compiled in Tables 1 and 2.
Product Multivitamin soft capsule*
Batch 9018401
Packaging mate- PVC/PVDC-aluminium blister
rial
Storage condition 40 C/75% RH
Storage duration Start 3 months
Parameter mg/capsule % mg/capsule %
Ascorbic acid 209 100 159 76
Dexpanthenol 13.5 100 9.7 72
Thiamine*HCL 19.7 100 17.1 87
Cyanocobalamine 0.199 100 0.171 86
Folic acid 0.62 100 0.57 92
Table 1
* Composition of the soft capsule shell: gelatine 209.76 mg, glycerol 85%
-8-
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
65.83 mg, sorbitol solution 70% 44.21 mg, black iron oxide 1.22 mg, red iron
oxide 3.89 mg.
Product Multivitamin soft capsule*
Batch 9018802
Packaging mate- Container in the inside walls of which a channel former
rial and an absorbent are embedded
Storage condition 40 C/75%RH
Storage duration Start 6 months
Parameter mg/capsule % mg/capsule %
Ascorbic acid 213 100 210 99
Dexpanthenol 13.3 100 12.8 96
Thiamine*HCL 19.6 100 19.3 98
Cyanocobalamine 0.21 100 0.173 82
Folic acid 0.60 100 0.520 87
Table 2
* Composition of the soft capsule shell: gelatine 209.76 mg, glycerol 85%
65.83 mg, sorbitol solution 70% 44.21 mg, black iron oxide 1.22 mg, red iron
oxide 3.89 mg.
Example 2
Investigation of the stability of soft capsules in the pack according to the
invention
Multivitamin soft capsules (active-compound composition and capsule shell
as described below) are introduced into a resealable container in/on the
inside wall(s) of which at least one channel former is embedded, at least
over part of the area, together with at least one absorbent (type: M-3006-16
Activ-Vial) in the inside walls of which a molecular sieve having a capacity
of 1.92 g is embedded.
The the multivitamin soft capsules are stored at 30 C and 65% relative
humidity (RH), removed from storage after predetermined times, assessed
-9-
CA 02675892 2009-07-17
WO 2008/086852 PCT/EP2007/010743
visually with respect to their appearance and investigated analytically with
respect to the amounts of active compound present. The results are com-
piled in Table 3.
Product Multivitamin soft capsule*
Batch GD 06 0045
Packaging material Container in the inside walls of which a channel for-
mer and an absorbent are embedded
Storage condition 30 C/65%RH
Storage duration Start 6 months
Parameter m/ca sule % mg/capsule %
f3-Carotene 2.3 100 2.0 87
Thiamine nitrate 2.40 100 2.37 99
Riboflavin 2.09 100 2.23 107
Nicotinamide 20.6 100 20.1 98
Pyridoxine*HCL 3.60 100 3.39 94
Ascorbic acid 120.5 100 115.0 95
Tocopherol acetate 20.0 100 19.8 99
Folic acid 0.581 100 0.603 104
Biotin 0.176 100 0.185 105
Cyanocobalamine 0.0163 100 0.0158 97
Calcium panthote- 15.6 100 14.9 96
nate
Table 3
* Composition of the soft capsule shell: gelatine, glycerol 98-100%, sorbitol
solution 70%, water
-10-
