Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 6 PD 7005
0093Z
WARNER-LAMBERT COMPANY
Morris Plains/USA
Process for filling and sealing vessels with a non
locking mating
Background of the Invention
It is known that injection molding technique can be used
for producing pressure moldings from natural starch, or
from hydrophilic materials such as, for example, gelatin.
Vessels of this nature are produced because they are
preferred vehicles for filling with pharmaceutical
products, consumables, chemicals and the like, and they
~0 are, in particular, produced in the shape of pharma-
ceutical capsules for the dosed administration of
medicines. These vessels comprise a container part and a
closure part, at least one of the two parts, and often
both parts are generally provided with mating ridges and
grooves in such a way as to guarantee a snap effect, and
thus to guarantee that a good closure is obtained between
the two of them. Pharmaceutical capsules have relatively
small dimensions. In cases involving the filling of the
vessels with pharmaceutical agents, the snap effect is
particularly important because it must prevent the vessel
~rom being opened, either accidentally, or even if
opening is deliberately attempted. According to the
methods known at the present time, the snap closure is
obtained by providing a very precise undercut in the
container part, and/or in the closure part, such an
undercut being approximately 0.03 to 0.15 mm deep. A
smaller undercut results in a defective closure, while an
excessively Iarge one gives rise to cracking, especially
in the container part.
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Even if produced accurately, such snap-closures are
subject to various disadvantages. The wall thickness of a
pharmaceutical capsule must be kept as thin as possible.
In consequence, the wall thickness of the container part
will differ from that of the closure part. Because of
their different thicknesses, these two parts will exhibit
dissimilar dimensional behavior under non-steady-state
conditions, and this will cause the two parts to become
geometrically dissimilar, which will lead to the
generation of stresses, especially when the atmospheric
humidity is changing. Under some conditions, this can
cause the vessel to rupture, and if they have been fil-
led with powders or liquids their contents will then leak
out. In particular, difficulties can also arise in the
filling machine, especially during the operation of
closing the two parts.
Moreover, such snap-closures are also technically
complicated to produce. In particular, sliding,
carriage-type molds or split-follower molds are
~0 necessary, and the moving mold parts leave markings which
then appear as uneven areas on the surface of the
molding. As a result of the need for sliding carriages or
followers, the molds possess more sliding parts, suffer
more wear, operate at higher pressures or with higher
~5 locking forces, as the case may be, and exhibit greater
susceptibility to faults, which manifest themselves
through longer downtimes and increased plant costs.
Furthermore, sliding carriages destabilize the mold to a
certain extent. In particular, moreover, fewer cavities
can be installed per available area, and this
considerably redu~es t~e outpL-.
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Summary of the Invention
It has now been found that all the abovementioned
disadvantages can be eliminated when pressure-molded
parts with a non locking mating are utilized, and when
these parts are sealed in the manner according to the
invention, as will be described later in this disclosure.
These parts preferably form a vessel with an essentially
continuous outer surface.
The present invention relates to a process for filling
and sealing vessels with a non-locking mating which have
been produced by pressure molding and preferably by
injection molding starch or at least one other
hydrophilic material, or a mixture of compounds of this
nature, and which comprise a container part and a closure
part, said vessels being preferably of the shape of
pharmaceutical capsules, the said filling and sealing
process being one wherein
a) the product constituting the filling is introduced
into a vessel of the abovementioned type, this vessel
being snap-lock free,
2~ b) a sealing liquid is brought into contact either with
the whole of that mating area of the closure part
which touches the mating area of the container part
when the vessel is in the closed state, or with an
element of that area of the closure part, and/or with
the whole of that mating area of the container part
which touches the mating area of the closure part
when the vessel is in the closed state, or with an
element of that area of the container part, and
c) the container part and the closure part are
subsequently united in order to form the irrevocably
sealed vessel.
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Detailed_Description of the Invention and_Drawings
The term ~starch~ is to be understood as meaning carbo-
hydrates of natural, vegetable origin, composed mainly of
amylose and amylopectin. It is extracted from various
plants, examples being potatoes, rice 7 tapioca, corn, and
cereals such as rye, oats and wheat. By applying pressure
and at the same time raising the temperature, starch of
this nature can be formed into dense molded articles
exhibiting a high degree of precision. The production
technique for the pressure-molding operation,
particularly for the injection-molding operation which is
performed under pressure and at an elevated temperature,
is described in European Patent Application No.
84 300 940.8 (Publ. No. 118 240), and also applies for
the present invention, this published description
specifying the process conditions and including
information regarding the possible additives, such as
extenders, lubricants, plasticizers and/or coloring
agents (also re
~0 preferred temperatures, pressures and moisture level
contents).
The expression "other hydrophilic materials" is to be
understoPd as meaning those hydrophilic materials which
are suitable for the production of the vessels according
~5 to the invention, and which are especially suitable for
the production of vessels of the shape of pharmaceutical
capsules.
"Other hydrophilic materials" are polymers such as, for
example, gelatin, vegetable proteins such as:
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sunflower protein, soybean proteins, cotton seed
proteins, peanut proteins, rape seed proteins,
blood proteins, egg proteins, acrylated
proteins; water-soluble polysaccharides such as:
S alginates, carrageenans, guar gum, agar-agar, gum arabic
and related gums (gum ghatti, gum karaya, gum tragacauth),
pectin; water-soluble derivatives of cellulose:
alkylcelluloses hydroxyalkylcelluloses and hydroxyalkyl-
alkylcelluloses, such as: methylcellulose, hydroxy-
methylcellulose, hydroxyethylcellulose, hydroxypropyl-
cellulose, hydroxyethylmethylcellulose, hydroxpropyl-
methylcellulose, hydroxybutylmethylcellulose,
celluloseesters and hydroxyalkylcelluloseesters such as:
celluloseacetylphthalate (CAP), hydroxypropyl-
1~ methylcellulose (HPMCP); carboxyalkylcelluloses,
carboxyalkylalkylcelluloses, carboxyalkylcelluloseesters
such as: carboxymethylcellulose and their
alkalimetalsalts; water-soluble synthetic polymers such
as: polyacrylic acids and polyacrylicacidesters,
polymethacrylic acids and polymethacrylicacidesters,
polyvinylacetates, polyvinylalcohols, polyvinyl-
acetatephthalates-(PVAP), polyvinylpyrrolidone,
polycrotonic acids; suitable are also phthalated gelatin,
gelatin succinate, crosslinked gelatin, shellac, water
soluble chemical derivatives of starch, cationically
modified acrylates and methacrylates possessing, for
example, a tertiary or quaternary amino group, such as
the diethylaminoethyl group, which may be quaternized if
desired; and other similar polymers. Gelatin is preferred.
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The production techniques for the pressure-molding of
other hydrophilic materials, of the types just mentioned,
and particularly for the injection-molding operation
which is performed under pressure and at an elevated
temperature, are described in European Patent Application
No. 83 301 643.9 (Publ. No. 090 600), which specifies the
process conditions and includes information regarding the
possible additives, such as extenders~ lubricants,
plasticizers and/or coloring agents
(incl. preferred
temperatures, pressures and moisture level contents).
Such hydrophilic materials are described e.g. in Robert
~. Davidson, Handbook of Water-Soluble Gums and Resins,
McGraw-Hill Book Company.
The details described in the two European Patent Applica-
tions cited above, Nos. 84 300 940.8 and ~3 301 643.9,
relating to the production of pressure-molded vessels of
the type in question, and especially to the production of
pressure-molded pharmaceutical capsules, preferably by
~0 injection molding, also apply in the case of the present
invention.`
The present invention utilizes pressure-molded and
preferably injection molded vessels which can be
obtained in this way, these vessels preferably being of
the shape pharmaceutical capsules.
It is within the scope of this invention to blend or
combine the various hydrophilic materials listed. To the
above mentioned materials may be added inorganic fillers,
such as the oxides of magnesium, aluminum, silicon,
titanium, etc. Extender concentrations of up to 5û % are
indicated, but they should preferably range from 3 to 10
%, based on the weight of all the components forming the
vessel wall.
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Examples of plasticizers which may be added include
polyalkylene oxides, such as polyethylene glycols,
polypropylene glycols, polyethylene-propylene glycols;
organic plasticizers with low molecular weights, such as
glycerol, glycerol monoacetate, diacetate or triacetate;
propylene glycol, sorbitol, sodium diethylsulfosuccinate,
triethyl citrate, tributyl citrate, etc., added in
concentrations ranging from 0.5 to 15 %, preferably
ranging from 0.5 to 5 % based on the weight of all the
~0 components.
Examples of coloring agents include known azo dyes,
o~ganic or inorganic pigments, or coloring agents of
natural origin. Inorganic pigments are preferred, such as
the oxides of iron or titanium, these oxides, known per
~5 se, being added in concentrations ranging from 0.001 to
10 %, preferably 0.5 to 3 %, based on the weight of all
the companents forming the vessel wall.
The vessels molded from starch, and/or from the other
hydrophilic materials, have a water content of 10 to 20
%, but preferably 12 to 19 %, and especially 14 to 18 %,
based on the weight of all the components forming the
vessel wall.
The sum of the plasticizer and water contents should
preferably not exceed 25 %, and should most preferably
2S not exceed 2û %, based on the weight of all the
components forming the vessel wall.
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While this invention is described with reference to
capsule forms it is understood -that the invention is
meant to cover all containers which are essentially
hollow, susceptible of being made from the hydrophilic
materials mentioned above and form a disposable, sealed
vessel. The vessel is further characterized as having
preferably an essentially continuous outer surface.
In comparison with European Patent documents
84 300 940.8 (118 240) and 83 301 643.9 (090 600), the
1~ special feature of the vessels according to the present
invention is that the closure part and the container part
of the vessel exhibit no snap-lock ridges or grooves and
also, in consequence of this, possess no snap-closure
arrangements of any kind. The preferred type of vessels
is one in which the container part and the closure part
can be united without any deformation. Vessels of this
type are novel, and are the subject of the present
invention. After being closed, the vessels according to
the present invention preferably possess virtually the
same wall thickness overall, thus avoiding the generation
of stresses as a result of dissimilar dimensional
behavior under non-steady-state conditions.
Vessels according to the present invention are uncom-
plicated to produce, as well as being easy to fill and
2~ close. However, because no snap-closure is now provided,
they can be opened easily, or they will open of their own
accord during subsequent handling, especially as the
container part and closure part are mated without any
deformation, even if this mating operation is performed
in a highly precise manner. The area elements which are
pushed together, one inside the other, are generally only
0.5 to 2 mm high, the latter value being a maximum.
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Accordingly, it was surprising to discover that the
containers do not open if a sealing liquid is brought
into contact with at least one of those areas of the
container part and/or closure part which touch one
` another, thus permitting high speed filling; this
operation being performed before the capsules are
irrevocably closed.
This sealing liquid preferably contains water. This
liquid is preferably a mixture of water and an alcohol,
preferably one with l to 4 carbon atoms, preferably
ethanol, propyl alcohols or butyl alcohols, and
` particularly preferably ethanol or isopropyl alcohol, and
most preferably ethanol, the water/alcohol ratio ranging
from 95:5 to 40:60, but preferably ranging from approxi-
l~ mately 80:20 to 60:40, and most preferably approximately
to 7û:3û.
Further aqueous sealing agents include, for example,aqueous solutions of sucrose, starch, monosaccharides,
oligosaccharides and polysaccharides, glycerol and other
polyols, glycol, polyethylene glycols and/or polypropyl-
ene glycols, surface-active agents which are known per
se, and which my be anionic, cationic or amphoteric,
gelatin, polyvinyl alcohols, water-soluble acrylic poly-
- mers which may be anionic or cationic, in a concentration
~S of 0~5 to lO percent by weight, and preferably l to 4
percent by weight, based on the total weight of the
sealing liquid.
The abovementioned water-ethanol mixture is preferred.
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On its own, water, for example, gives rise to excessive
wetting, or to wetting which is imprecisely distributed,
and this causes damage to the capsule, or degradation of
its contents. Because the outer capsule wall is sensitive
to water, the sealing liquid must permit the wetting to
be subject to precise control, with regard both to its
positioning and to the quantity of liquid applied.
A certain time must, of course, elapse before a sealing
effect begins to occur. This being so, it was surprising
to discover that the closed vessels according to the
invention can be subjected to further processing, and to
packaging, without the occurrence of any phenomena which
would indicate that they are opening or being damaged.
As a resuit of the precisely controlled manner in which
1~ the sealing liquid is applied, with regard both to its
positioning and to the quantity which is fed out, an
accurately closed vessel is obtained, which is impervious
to liquids. Once sealed, the vessels can be opened only
by destroying it.
In order to accelerate the sealing process, it is also
possible to heat the closed vessel, or the mating zone,
as appropriate. Any heat source which does not damage the
vessel or its contents may be utilized, examples of such
sources including heat which is applied by convection,
~5 such as by means of heated air, electromagnetic radiation
at a suitable frequency, such as microwaves or infrared
radiation, and ultrasonic energy, the temperature thus
generated being non-critical provided that no damage is
caused to the capsule or its contents. However, there is
normally no need to accelerate the sealing process by
resorting to additional measures of this kind. Heating to
3û to 50C generally suffices. Heating can also occur
~2952~ PD 7005
in whole or in part by the use of sealing fluid
maintained at a temperature between ~0C and 100C.
The product constituting the filling can be solid, pasty,
or liquid. The substances which are dispensed in pharma-
ceutical vessels are known per se, and are here
substances which are compatible with the vessel wall, and
which are conventionally dispensed in hard gelatin pharma-
ceutical vessels.
In addition to eliminating the disadvantages mentioned in
the introductory paragraphs, further advantages, which
were not expected, follow from the utilization of the
vessel according to the present invention, and from the
manner in which they are sealed. It is thus feasible to
reduce the vessel wall thickness by a large amount, since
the mechanical stresses generated by the snap closure
have been eliminated. This results in a significant
decrease in the time which the vessel takes to open and
dissolve in the gastric or intestinal juices, as well as
in a saving of material and improved utilization of the
~0 vessel volume.
The invention may be more readily understood by reference
to the drawings in which:
Fig. 1 shows a vessel according to the invention, in
side view,
~5 Fig. 2 shows a vessel according to the invention, in
longitudinal section along the line II-II in
Figure 1,
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Figs. 3a - 3u show cross sectional views of various
embodiments of the stressfree joint of the container part
to the closure part, corresponding to the indication III
in Fig. 2,
Fig~ 4 shows a plan view of a filling/sealing machine
for the vessels according to the invention.
Fig. 5 shows the wetting and sealing station which is
associated with the filling/sealing machine,
this station being represented in section along
the line V-V in Fig. 4, and
Fig. 6 shows a perspective illustration of a filling
machine, namely a machine of the design shown
in Fig. 4, equipped with a wetting station.
A vessel 20 having a container 22 and a closure part 21
with a powdered fill component l9 is shown after sealing
having the stress free configuration represented in
Figures l and 2. As can be seen, an essentially
continuous surface is formed on the outer surface of the
capsule after the container mating portion 24 is
positioned adjacent seal mating portion 23. Figures 3a -
3u show differing configurations of the mating unit III
In each of these figures, it can be seen that a smooth
essentially continuous outer surface of the vessel 20 is
formed at the areaIII of the mating unit. Fig. 4 shows
~5 the design of a filling machine in horizontal
cross-section, this machine being equipped with a sealing
station. In this machine, the magazine l is connected to
a continously vibrating conveying channel, 2, which
guides the container parts to the container part feed
station 3.
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In this container part feed station 3, the container
parts, with their openings facing upwards, are pressed
into the container part holders, 5, by means of the ram
3a. The container part holders 5 are fixedly installed on
the rotary table 4. The container parts are now conveyed
to the filling station 6, in a sequence of timed steps
which are defined by the stepping rotation of the rotary
table, in which filling station each container part
receives a metered quantity of a powder 19, or of a paste
or liquid, the product in question being supplied from a
stock container 6a.
The container part, thus filled, then moves to the
closing station 7, likewise in successive, timed steps.
In this closing station 7, the closure parts, fed in from
the closure part magazine 10 by means of vibration, via
the conveying channel 9, are transferred onto a piece of
felt 12a, which wets them, and are then placed on the
container parts, these operations being effected by means
of the star rotor 8 and the closure part holder 8a. After
being conveyed further, likewise in successive, timed
steps, the closed vessel - shaped like a pharmaceutical
capsule in the present case - is ejected from the
container part holder 5 on arrival at the ejection
station 11. Fig. 5 shows a sealing station in horizontal
~5 cross-section. The closure parts 21 are located within
the conveying channel 9, whence they are acquired by the
closure part holder 8a, this being effected by means of a
vacuum, after which they are transferred to the
positioning and wetting unit 12 as a result of a combined
3~ rotational and vertical movement. Vertical movement of
the closure part holder 8a causes the closure part 21 to
be pressed onto the felt 12a, which is impregnated with
sealing liquid 13.
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At the same time, the closure part 21 is aligned, and its
overlap zone is wetted with sealing liquid. The sealing
liquid is supplied from the container 14, and is drawn
into the felt 12a by capillarity, the liquid level in the
container 14 being kept constant by means of a dropper 15
and an overflow 16. Subsequent rotation of the closure
part holder 8a, combined with a vertical movement, brings
the closure part 21 to the seal station 7, in which it is
pressed onto the container part 22 as a result of a
1~ vertical movement of the closure part holder 8 a. Of
course, any other suitable wetting technique can be used.
At the same time, the vacuum is removed - this vacuum
having been holding the closure part 21 in the closure
part holder 8a. The closure part holder 8a now executes a
lS combined rotational and vertical movement which advances
it to the vibrating channel 9, in order to acquire a
fresh closure part 21.
Both the closing machine, as described, and the sealing
station are novel, and each forms part of the invention.
Whereas hard gelatin pharmaceutical capsules are conven-
tionally pre-closed before being supplied to the closing
machine, the invention enables the closure part 21 and
the container part 22 to be loaded in separate magazines,
lO and l, and to be conveyed to the closing station 7
~S independently of one another. It is thus possible, in
addition, to wet the parts independently, prior to the
closing operation.
The invention is illustrated by the following Examples:
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Example 1
The lip (mating part according to Fig. 3a) of the closure
part (21) of a vessel having the shape shown in Fig. 1
- was pressed onto a piece of fine felt, to a depth of
1.5 mm, this felt having been impregnated with a sealing
liquid containing 70 % by volume of water and 30 % by
volume of ethanol, so that the thin lip of this closure
part was completely wetted, the vessel in question having
been injection-molded from natural wheat starch according
1~ to the conditions specified in EP document 84 300 940.8
~118 240), Example 8 (water content: 12.7 %). This
closure part was thereafter united with the container
part, which fitted it, no stresses being generated as a
result of this closing operation.
After 10 minutes, the vessel could no longer be opened.
The same result was obtained when the vessel had
previously been filled with solid, pasty or liquid
pharmaceutical compositions, sealed vessels dld not leak.
Example 2
The procedure described in the context of Example 1 was
repeated, but with the addition of an operation wherein
the vessel was exposed, without delay, to one of the
following heat sources:
(i) air which had been heated to 35C: 3 minutes,
(ii) infrared radiation: 2 1/2 minutes,
(iii) ultrasonic energy: 2 seconds.
Thereafter, the vessel could no longer be opened, and
were impervious to liquids.
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Example 3
The lip (according to Fig. 3 1) of the closure part (21)
of a gelatin capsule having the shape shown in the Fig. 1
' relating to the present invention was placed on a plate
carrying a film of liquid, 1.0 mm deep, this liquid being
an 80 20 mixture of water and ethanol, while the capsule
itself had been produced in accordance with the
conditions specified in EP document 83 301 643.9 (090
60û), Example 2 B-2 (water content 14.6 %). The closure
part was thereafter united with the container part, no
de~ormation occurring during this closing operation.
After a 15-minute holding period, at room temperature,
the vessel could no longer be opened. When, thereafter,
one of the heat sources mentioned in the context of
Example 2 was utilized, the shorter welding times cited
therein ~ere obtained.
In no case could the vessel be opened after completion of
the sealing process, without destroying it at the same
time.
~o Example 4
The procedures described in the context of Example 1, 2
and 3 were repeated, employing sealing liquids of the
following compositions:
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No. Water Ethanol Other additions
%
1 95 5
2 85 15
3 60 40
4 50 50
98 - SLS* 2 %
6 98 - Glucose 1%, SLS 1%
7 89 10 SLS 1 %
8 60 38 SLS 2 %
9 70 20 Glucose 5 %, SLS 5%
16 Glycerol 4 %
*SLS = sodium lauryl sulfate
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