Note: Descriptions are shown in the official language in which they were submitted.
WO 95/00123 216 5 7 a 3 PCT/GB94/01361
SOFT GELATIN CAPSULE SHELL COM1~OSITIONS
This invention relates to compositions for the use
in comestible and other soft gelatin capsules, of the
type used in oral drug delivery systems and in food
products and food additives.
It is known to encapsulate medicinal and food
products using capsule material which is itself
comestible. The shell materia_1 for such capsules is-
normally gelatin based, and as a consequence largely
void of flavour, odour and colour. While such capsules
have been used with great success, gelatin based shell
materials can be relatively slow in 3isintegrating, and
particularly where an encapsulated product for oral use
is intended to be released in the mouth, faster
disintegration rates are desirable.
Examples of gelatin based capsules are described in
the following Patent Specifications to which reference
is directed:
EP -A- 0 233 231 & US -A- 4,804,542
EP-A- 0 199 034
EP -A- 0 120 248 & US -A- 4,744,988
US-A- 2 580 863
Shell materials of the~above type normally comprise
Gelatin and a physiologically acceptable plasticises
such as Glycerol, the Gelatin forming a matrix for the
plasticises. The relative quantities of these
components is important to ensure reliable
encapsulation, and storage characteristics. However, we
have found that the amount of Gelatin can be reduced if
a further component is included which forms a secondary
matrix for the plasticises. According to the invention
therefore, a composition for use in the shell of a
capsule comprises Gelatin and a plasticises, the Gelatin
forming a primary matrix for the plasticises; and a
further component compatible with the Gelatin, which
component forms a secondary matrix for the plasticises.
WO 95/00123 ~ PCT/GB94/01361
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Typically, the composition includes 18 to 30% by weight
of Gelatin and 30 to 45% by weight of the plasticiser.
The further component is normally a potato starch
acetate, another starch derivative, starch itself or
mixtures thereof.
The invention also provides chewable compositions
formulated according to the above criteria, and
comestible capsules with shells comprising such
compositions. Additionally disclosed herein is a
process for the preparation of a composition according
to the invention comprising the steps of mixing the
further component with water and the plasticiser;
adding the gelatin to the mixture: allowing the mixture
to crumb; heating the mixture; leaving the heated mass
to stand; and deaerating the mass with minimum water
loss.
In preferred compositions according to the
invention the amount of the further component does not
exceed 25%, and is normally no more than 12% by weight.
The preferred further component is unbleached starch
acetate, most preferably derived from potato, and a
suitable product is available under the Trade Name
PERFECTAMYL GEL MB from Avebe BA. Another suitable
potato starch acetate is available from Roquette Freres,
under the Trade Name CLEARAM.
A typical amount of the further component is up to
12% by weight. While higher levels result in a more
chewable product, solubility is likely to deteriorate.
Additionally, examination of capsules formed from
selected compositions using higher levels of starch
acetate as the further component, showed that some
starch aggregation was taking place. A preferred
maximum level is 10%; 8% is particularly preferred.
The quantities of gelatin specified above are
substantially less than is normally used in known
gelatin based capsule shell compositions. Similarly,
the amount of plasticiser is relatively increased. This
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is made possible by the presence of the further
component which reduces the effect of the plasticiser on
the gelatine which might otherwise result in a
composition which does not form a structure of strength
sufficient for encapsulation and storage. In effect,
the further component forms a secondary compatible
matrix, typically in the range 20° to 60°C, for the
plasticiser within the primary gelatine matrix which does
not adversely effect the function of the plasticiser,
but reduces its tendency to form an adherent surface on
the eventual product. It will be appreciated that a
certain quantity of the further component is always
required in the composition, and a typical minimum level
would be 3% by weight.
The plasticiser is usually Glycerol, but suitable
alternatives are Xylitol, Sorbitol, Polyglycerol, non-
crystalising solutions of Soribtol, glucose, fructrose
and glucose syrups with different equivalents. One
preferred alternative is ANIDRISORB° (a proprietary
mixture of Sorbitol, Sorbitans, Maltitol and Mannitol,
available from Roquette Freres). These may be used
alone or in combination. In a combination of
plasticizers including Glycerol, the Glycerol typically
comprises at least 30% by weight of the combination,
normally in the range 30% to 70% by weight. The
inclusion of Glycerol provides a more "chewable"
product. Using an alternative plasticiser or
plasticiser component produces a less "chewable"
product, but one which does disintegrate more quickly
than known formuations.
The chewability of compositions according to the
invention can be enhanced by the inclusion of an oil
such as fractionated coconut oil. Up to 15%, preferably
no more than 10%, can be included in the composition,
but at high levels, the resultant product appears
cloudy. A preferred quantity is around 3% to 7%,
typically 5% by weight. Oil disperses within the shell
WO 95/00123 2 ~ PCT/GB94/01361
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structure as microscopic droplets. These prevent some
of the gelatin bonds forming, and hence act in a similar
way to the plasticiser. However, the plasticiser can
allow a formation of hydrogen bonds across the
interstitial spaces of the gel matrix and some of the
liquid in the spaces is removed as the gel dries. As a
result more gelatin links form, stiffening the matrix.
The oil inhibits the formation of these additional
gelatin links resulting in a more chewable product,
although the pressure exerted by the gelatin causes some
droplets to coalesce.
Preferred embodiments of the invention also include
a bleached starch acetate, normally derived from potato,
and typically in an amount up to 12% by weight,
preferably 6% to 100. A suitable such potato starch
derivative is also available from Avebe BA under the
Trade Name PERFECTAMYL GEL 45. This starch derivative
is soluble in the manufacture of compositions according
to the invention, and therefore remains in solution
until the composition dries. At this stage the bleached
starch acetate forms a film, thus acting as a bulking
agent. It causes a degree of stickiness in the
composition as it sets, which is counteracted by the
setting of the gelatin and the preferred further
component; unbleached starch acetate. A combination of
both starches was found to replace higher levels of
gelatin than the unbleached acetate alone. Similar
effects can be achieved by using a variety of soluble
materials.
Capsules may be formed using compositions according
to the invention by any suitable technique. Two such
techniques are the concentric cylinder and the rotary
dye methods. The latter has been used for many years by
R.P. Scherer Corporation and its associated companies, .
and is described in the September 1985 edition of
Pharmaceutical Technology, to which reference is
directed. Briefly,~the composition in a liquid state is
WO 95/00123 , PCT/GB94I01361
X165783
spread on a suitably prepared and cooled drum upon which
the gel mass sets to a non-sticky film. Where two
similar films merge on encapsulation, seals are formed
which become stronger as the mass dries. The further
5 component makes a significant contribution to film
strength at this stage, and in this respect its
selection is important. The preferred component is
potato starch acetate which adds structure to the gel
matrix by the association of starch molecules to form a
starch gel inside the gelatin matrix.
The use of bleached starch in addition to the
unbleached starch results in improved suitability for
chewing because the starches swell at a different rate
to gelatin without substantial cross-bonding.
Consequently, they are readily separable on chewing.
Compositions embodying the invention and a known
composition, will now be described by way of example.
Details of the compositions are as follows.
Formulations used in which the plasticiser is Glycerol
Material Formulation
Number
o by Weight 1 2 3 4 5 6
Gelatin 26 26 24 28 26 38.4
Glycerol 35 35 40 39 36 29.2
Water 27 22 20 25 22 32.4
Potato Starch Acetate 12 10 6 3 6 -
Bleached Potato - 7 10 - 10 -
Starch Acetate
Oil - - - 5 - -
Example S1 (using formulation 1)
A gelatin decoction was prepared by blending the
Potato Starch Acetate with the water and glycerol to
form a slurry. After addition of the gelatin with
stirring, and allowing the mixture to 'crumb' under
vacuum for ten minutes, the decoction was prepared in a
WO 95/00123 PCTIGB94/01361
21b78~
6
per se known manner using a waterbath with circulator in
which to heat the vessel containing the mixture to 90°C
and leaving to stand for 35 minutes. The gel mass is
then deaerated using a vacuum pump while minimising
water loss.
Capsules were readily made with a flavoured placebo
paste formulation for fill, which were easily chewable.
Example S2 (using formulation 2)
A gelatin decoction was prepared by blending both
starch derivatives with the water and glycerol to form a
slurry. After addition of the gelatin, the decoction
was prepared in a per se known manner.
Capsules were readily made with a flavoured placebo
paste formulation for fill, which were very easily
chewable.
Example S3 (using formulation 3)
A gelatin decoction was prepared as described in
example S2. To this was added colours and flavours
totalling 6.0% of the gelatin mass using a high speed
blender.
Capsules were readily made with a flavoured placebo
formulation for fill. These capsules were very easily
chewable.
Example S4 (using formulation 3)
The gelatin decoction described was blended to
colour and flavour and used to make capsules with an oil
fill material. Disintegration testing in distilled
water at 70°C gave results of capsule rupture and full
shell disintegration approximately 40-50% faster for the
capsules using the invention than the known shell
formulation (6). ,
Example S5 (using formulation 4)
A gelatin decoction was prepared as described in
WO 95/00123 216 5 7 8 3 pCT/GB94/01361
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example S2 with the component of formulation 4 excluding
the oil. To this decoction was added colours and
flavours identical to example S3 and vegetable oil 3%
(flavour oil level was 2o making a total oil content of
5%).
Capsules were readily made with a flavoured placebo
paste fill which were soft and easily chewable.
Examples S6, S7 and S8 (using formulation 5)
Gelatin decoctions were prepared as described in
example S2.
These were blended to different colours and
flavours with a range of additions of 3-7.2% of the
gelatin decoction used.
Capsules with flavoured paste fills containing
active vitamin compositions were readily made. All were
easily chewable with a very notable improvement compared
to the same recipes using formulation 6 as the base
shell formulation.
Example S9 (using formulation 5)
A gelatin decoction was prepared in two stages.
First, the Potato Starch derivatives were blended with
1~ times their own weight of glycerol from the
formulation. This slurry was heated to 50-60°C and added
to a gelatin decoction made from all remaining materials
in a per se known manner. The mixture was stirred on a
high speed blender until a temperature of 60-65°C was
attained. This mixture was then further blended with
colours and flavours totalling 6.25% of the mixture
weight.
Capsules with flavoured paste fill containing
active vitamin components were readily made and were
identical in chewability to the same formulation of
capsules made in Example S7.
Example S10 (prior art, using formulation 6)
WO 95/00123 ~ ~ ~, 5 7 8 3 PCT/GB94/01361
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A standard shell was prepared in a per se known
manner and blended to the same colour and flavour and
used to make capsules with the same fill formulation. ,
These capsules had a very tough chewing characteristic
requiring approximately twice the time (60-65 secs) to
chew before swallowing. A slippery, slimy mouth feel
was also noted for these capsules.
Formulations used including alternative plasticisers
Material Formulation
Number
% by weight 7 8 9 10 11
Gelatin 195 Bloom Acid 25 25 25 25
processed
Gelatin Succinated 34
Glycerol 24 20 24 12
Sorbitol 70% 12 10 24
Anidrisorb 85/70 12
Polyglycerol 36
Purified Water 23 29 23 23
Potato Starch Acetate 6 3 6 6 6
Bleached Potato Starch Acetate 10 4 10 10 10
Examules S11 to S14
Gelatin decoctions were prepared using formulations
7 to 11, by first blending the starch derivatives with
the water and plasticiser components (Glycerol,
Sorbitol, Andrisorb, Polyglycerol) to form a slurry, to '
which the Gelatin was added as in Example S2. Capsules
made according to these examples exhibit short
disintegration times on contact with water, but are less-
readily chewable than those made according to Examples
S1 to S9.
WO 95/00123 b PCT/GB94I01361
9
From experimental work conducted using the above
examples it appears that any plasticises normally used
in soft gelatin capsules can be used in compositions
embodying this invention. The matrix formed by the
lower Gelatin content, modified starch components, and
high plasticises contact give faster disintegration
times than those exhibited by known formulations,
although improvement in chewability was clearly most
apparent in the formulations which used Glycerol as the
plasticises and/or'an oil.
As will be apparent from Examples S1 to S10 above,
the material in capsules of the present invention of the
wall can itself contain significant components
contributing to its overall properties. This is of
particular value where two component elements are to be
kept separate prior to use and they may, of course, be
kept separate between the capsule material and the
encapsulated product.
Products provided in liquid form for encapsulation
in capsules of the invention typically incorporate
hydrophobic or hydrophilic carrier media or a
combination of both. Examples of hydrophilic solvents
or carrier media include: Polyethylene Glycols (PEGs),
particularly PEG 400 and PEG 600; Glycofurol:
Polyglycerols; propylene Glycol: Ethanol: Water:
Glycerol: transcutol, polysorbate and propylene
carbonate.
Hydrophobic solvent/carrier media also include
hydrogenated natural oils, synthetic oils such as
polymethylsiloxane (dimethicone), neutral oils such as
fractionated coconut oil, mineral oils, triacetin, ethyl
oleate, and other natural oils such as: Soyabean Oil:
Arachis Oil; Corn Oil: Sesame Oil: Olive Oil; Rapeseed
Oil; Sunflower Oil and Safflower Oil. Thickened fill
products with high viscosities are preferred as they
disperse less rapidly and improve palatability. They
also reduce the contrast between the shell and the fill
CA 02165783 2004-08-27
materials.
Capsules embodying the invention can include
flavouring and aromatic components, in either the
encapsulated contents, or in the capsule shell material
5 itself. Suitable components include essential oils such
as lemon, orange and peppermint oils; fruit flavours;
aniseed; liquorice; caramel; honey; cream; various
spices and combinations of these and other flavours.
Such components are available from International
10 Flavours & Fragrances, IFF (GB) Ltd. of Haverhill,
Suffolk, CB9 8LG ENGLAND. Natural or artificial
sweeteners can also be used, such as:
Aspartame, Saccharin, Acesulphame K, Neohesperidine
hydrochloride, Mannitol, Xylitol, and Maltitol;
-taste-masking ingredients such as sodium
bicarbonate, ion exchange resins, cyclodextrine and
adsorbates;
-suspending agents such as beeswax, hydrogenated
vegetable oils, glycerol monostearate or glycerol
palmitate, and high molecular weight PEGS; e.g.1500 to
6000.
where the encapsulated contents include particles
in suspension, the particles may be separately coated,
typically with suitably sweetened or flavoured coatings,
such as those referred to above. Such a coating can
serve as either or both of a taste-masking agent and a
stabiliser in the suspension.
My way of further illustration some contents
formulations will be given by way of example.
Example CL
Fractionated Coconut Oil BP/PhEur 75%
Gelucire° 42/12 * 70
Span 20~ ** 3%
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Mannitol BP 9%
Aspartame US NF XVII 1%
Flavour 5%
100%
* Glycerides and polyglycides of fatty acids of
vegetable origin.
** Sorbitan fatty acid esters (BP 1980)
Example C2
Imwitor~ 742 * 80%
Tween~ 80 ** 14%
Aspartame US NF XVII 1%
Flavour 5%
100%
* Caprylic/Capric mono-di & tri-glycerides
(Medium chain partial glycerides US OF XVII)
** Polysorbate 80 BP
Example C3
Polyethylene Glycol 400 BP 56%
Glycerol BP 8%
Water, Purified BP 5%
Mannitol BP 25%
Aspartame US NF XVII 1%
Flavour 5%
100%
Example C4
Lycasin 80/55 * 88.5%
Aerosil~ 200 ** 1.5%
Glycerol BP 5%
Flavour 5%
100%
* Hydrogenated Glucose Syrup
** Colloidal Silicon Dioxide
Example C5
Fractionated Coconut Oil BP 58%
Tween~ 80 * 25%
Mannitol BP 10%
Sodium Saccharin BP 2%
Flavour 5%
PCT/GB94/01361
WO 95/00123 2 ~ 6 5 l 8
...-
12
100%
* Polysorbate 80 BP
Example C6
Fractionated Coconut Oil BP 95% '
Flavour 5%
100%
Example C7
Fractionated Coconut Oil BP/Ph Eur 75%
Gelucire 42/12 7%
Span 20 3%
Mannitol BP 9%
Peppermint Oil BP 6%
100%
Example C8
Fractionated Coconut Oil BP/Ph Eur 75%
Gelucire 42/12 7%
Span 20 3%
Mannitol BP 9%
Aspartame US NF XVII 1%
Peppermint Oil BP 5%
100%
Examt~le C9
Polyethylene Glycol 400 BP 53.3%
Glycerol BP 7.6%
Water Purified BP 4.8%
Paracetamol BP 28.6%
Aspartame US NF XVII 1.0%
Lemon Flavour 17.42.7201 4.8%
100%
Example C10
Polyethylene Glycol 400 BP 53.3%
Glycerol BP 7.6%
Water Purif ied BP 4 . 8 %
Paracetamol BP 28.6%
Saccharin, Sodium BP 1.0%
WO 95/00123 PCTIGB94/01361
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Lemon Flavour 17.42.7201 4.8%
100%
