Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
This invention relates to sealed capsules.
This is a division of copending Canadian Patent
Application Serial ~o. ~38,716, filed October 11, 1983.
The capsules sealed by utilizing the present
invention are hard shell, telescopically joined capsules,
having coaxial cap and body parts. The capsules are made
of gelatin or other materials whose properties are pharmaceuti-
cally acceptable.
In this application, when the term "yelatin"
is used it is also understood to include gelatin combined
with other hydrophilic polymers.
Capsules were sealed having a cap and/or body
part made from a gelatin foam. In addition, capsules were
sealed by sealing fluids.
Hard shell gelatin capsules have a disadvantage
when compared with other dosage forms, in that the cap and
body parts can be opened and rejoined without the disruption
becoming externally visible or tamper-evident. Therefore,
the consumer has no real guarantee that the contents of a
capsule have not been tampered with.
Telescopically joined, hard shell gelatin capsules
have an overlap of the cap side wall over the body side wall
which impedes gripping and withdrawal of the body, thereby
making separation difficult. The present invention uses
sealing fluid and/or thermal energy applied to the overlap
of the cap side wall over the body side wall to secure tamper-
proofing by spot or complete sealing of the overlap of the
capsule parts. With the use of a complete sealing, the capsules
are also tight against leakage of liquid contents.
Prior art for capsule sealing is contained in
the following United States Patents:
. . I
' ',.
. '
. : . . .
9;~
1. Number 3,071,513 issued Jan. 1, 1963 to
H.R. De Boer, et al. which discloses a sealing fluid comprising
a dispersion of an air-drying hydrophilic, film-forming polymer
in an organic solvent. The application of the sealing fluid
was by dipping the capsules.
2. Number 3,159,546 issued December 1, 1974
to J.R. Kane discloses a liquid sealant consisting of three
components containing by weight from about 1 to 4 ~ parts,
preferably 3 to 4 ~ parts, of acetone; from about 1 ~ to 2
parts, and preferable 1 ~ to 2 parks, of water; and from about
3/4 to 2 ~ parts, and preferably about 3/4 of a part, of ethyl
acetate. The application of the liquid solvent was by drop
application.
According to the present invention there is provided
a hard gelatin capsule provided cap and body parts which have
been telescopically joined with the wall of one part over-
lapping a wall of the other part. In the region of overlap,
the parts are sealed together by raising the temperature of
the gelatin within the overlapping section above its melting
point by applying thermal energy in the presence of a sealing
fluid.
-
In a specific embodiment of the invention, thesealing fluid is a mixture including an aliphatic monohydric
alcohol having from 1 to 4 carbon atoms. The aliphatic
monohydric alcohol may be in the range of about 60~ to about
90~ of the mixture.
- 2 -
:" ,;
BRI:EF DESCRIPTION OF THE DRAWINGS
The manner of manufacturing the present invention
is illustrated in the accompanying drawings in which:
Figure 1 is a schematic view of an apparatus
for making the capsules of the present invention;
Figure 2 is a cross-sectional view through a
portion of the apparatus of Figure 1 but showing an alternative
arrangement;
Figure 3 is yet another view in the form of a
cross section view through the apparatus showing yet another
embodiment of the apparatus for making the present invention;
- Figure 4 shows the capsule of the present invention
before the capsule is telescopically joined and illustrating
the application of its sealing fluid; and
Figure 5 is a view showing the capsule of the
present invention telescopically joined and wherein the sealing
fluid is being sprayed onto it.
In Figure 1 a continuous conveyor is shown at
1 having net or wire mesh baskets 2. A capsule filling machine
3 ejects filled and telescopically joined hard shell gelatin
capsules 4 through a funnel 5 into the mesh baskets 2 which
pass beneath the funnel 5. The capsules 4 are randomly oriented
in the mesh baskets 2, which capsules 4 are then dipped into
a sealing fluid 6 contained in a dipping tank 7. It is essential
that the overlap of the cap and body slde walls of each capsule
4 come into contact with the sealing
~ 3 -
.
.: ,
.
:
~2~
;fluid 6 ~hereafter, the capsules 4 are conveyed through
a drying stream of conditioned air 8 from a blower 9 located
above or below the capsules 4 in order to remove excess sealing
fluid 6 from the surface of the capsules 4 so as to avoid
deformation and sticking together of the capsules 4. However,
the sealing fluid is removed only from the surface, and not
~rom within the overlapping seal of each capsule. The surface
dried capsules 4 are then heated by a specific energy source
15 applying a defined quantity of thermal energy, located
after the dryer 10 or at the ejection of capsules 4 from
the conveyor 1. The dryer 10 may be a kiln; an oven; a tumbler
dryer; etc. Thereafter, the capsules 4 are conveyed to and
ejected into a capsule container 11 for further processing
and shipment. A cover 14 is provided over the mesh baskets
2 to prevent floating-away or blowing-away of thecapsules
4 during processing between the funnel 5 and the dryer lO;
In Figure 2, an alternative embodiment of the
present invention is shown wherein the filled and telescopically
joined capsules 4 are oriented and held with the cap part
upright while the overlap of the cap and body part side walls
o each capsule 4 are contacted by the sealing fluid 6 within
the dipping tank 7.
_ In Figure 3 there is shown another embodiment
of the present invention wherein the filled and telescopically
joined capsules 4 are conveyed through a spray chamber 12
wherein sealing fluid 6 is sprayed by nozzle 13 so as to
contact the sealing fluid 6 with the overlap of the cap and
body 15 part side walls of each capsule 4.
Figure 4 shows another embodiment of the present
invention wherein the sealing fluid 6, or a steam thereof,
is sprayed before the capsule 4 is teIescopically joined,
by a spray nozzle 13 which sprays the sealing fluid 6, or
a steam thereof, into the open end 15 and/or onto the inside
ofthe side walls 16 of the cap part 17 of the capsule 4.
Alternatively, the sealing fluid or a steam thereof is sprayed
into the open end and or onto the outside of the side walls of
. -- 4 --
J~ ~ ~
:
:'
~ ir2~
~the body part 19 of the capsule 4. This embodiment of the
present invention mav be connected to a capsule filling machine.
.
The embodiment of the present invention shown
in Figure 5, the sealing fluid 6 is sprayed after the capsule
4 is telescopically joined. The capsule 4 is sealed by spraying
the sealing fluid 6 or a steam thereof onto the seam 16 of
the overlap of the cap and body paxt side walls of the capsule
4. This embodiment of the present invention may be connected
to a capsule sealing machine or used separately.
OPERATION OF THE APPARATUS FOR SEALING CAPSULES
The sealing of capsules in the present invention
is accomplished as ollows:
The sealing fluid is evenly distributed between
the overlap of the cap and body side walls of the gelatin
capsule by capillary effect. This effect is achieved when
the contact angle between a drop of the sealing fluid and
~0 the gelatin film is small, e.g. if the wettability of the
gelatin film is high, the contact angle can be reduced by
the addition o~ surfac~ants.
The mechanism of the capillary efect is described
by Walter J. Moore in Physical Chemistry, 4th ~dition, pages
479-481, Longman-Edition, London, England, (1978) as follows:
"Whether a liquid rises in a glass capillary depends on the
relative magnitude of the forces of adhesion between the
liquid molecules themselves, and the forces of adhesion between
the liquid and the walls of the tube. These forces determine
the contact angle, which the liquid makes with the tube walls.
If this angle is less than 90 degree, the liquid is sai~
to web the surface and aconcave meniscus is formed."
The wettability of gelatin films is measured as
"adhesional wetting" where a liquid not originally in contact
with a substrate makes contact with that substrate and adheres to it.
The contact angles between gelatin films and solvents
were measured for a number of sealing fluids of the present
invention by use of a microscope fitted with agoniometer eyepiece.
-- 5 --
~ 7
~ 92~
, , ' The tests were performed on a gelatin film whereby
. the contact angle W25 measured 20 seconds after deposit-
- ing a drop of sealing fluid on the gelatin film. ~he
following Table I shows contact angles of sealing fluids
-~ 5 of the present invention:
TABLE I
- Sealing ~luids Mean Contact Angles
- Water 83 + 6
- 75% aqueous ethyl alcohol 3.5 ~ 1
solution
- 7s% ethyl alcohol near to 0
solution mixed with an (not detectable)
aqueous solution of
0.5M CaCl2 and 1M RI
- 90~ aqueous methanol near to 0
solution (not detectable)
. - ~iater containing 0.1% 51
sodium lauryl sulfate
- Water containing 0.5% 66
of a hydrolyzed
gelatin and 0.1% of ---
sodium lauryl sulfate
- Water containing 0.2 M 43
Na2SO4 and 0.1%
sodium lauryl sulfate
- ~iater containing 1~ 64
polyvinylpyrrolidone
and 0.1~ of sodium
lauryl sulfate
The sealing fluid dissolves the amorphous part of
the gelatin between the overlap of the cap side walls
over the body side walls of the capsules by lowering
the glass transition temperature of the gelatin.
~urthermore, the sealing fluid may partially depress
the melting point of the crystalline part of the
gelatin. The melting point of the crystalline part of
the gelatin
. .
... . .
. .
.
...
` , . l~g%~4 t-............ i
may, however, mainly be depressed below room tempera-
ture by solvents, which are known as hydrogen bond
breakers. These solvents are, however, not edible
_ - (urea, formamide, N-methylformamide, dimethylformamide).
In order to achieve better sealing the melting of the
crystalline part of the gelatin may be af'ected by
raising the temperature of the gelatin above its
melting point. This may be achieved by the input of
thermal energy. Another importznt effect, due to the
application of thermal energy, preferably with con-
vection heat, is the shrinkage of the overlap of the
cap with the body of the capsule, resulting in a com-
plete contact of the peptizized wall surface of the
overlap, thus achieving a better seam. The reason for
- 15 this is that the gelatin changes its specific volume
_ during the abovementioned process~ The input of
ther~al energy can be accomplished by conduction due to
~- contactins the overlapping seam with the warm surface
of a solid, i.e. by metal coated with te lon, heated to
120 to 1~0C; or circulatiny a warm gas at a tempera-
. .
ture of about 70 to 140c, around the capsule; or by
putting the capsules in the field of electromagnetic
irradiation preferentially in the infrared or microwave
range of the frequency spectrum. The input of energy
may be localized to the part of the capsule i.e. the
overlapping seam, ~7here the sealing is taking place.
This can be achieved by irradiating electrornagnetic
energy at a frequency range whereby the sealing fluid
preferentially absorbs this energy in the form of
heat. One embodiment to realize this is to irradiate
electromagnetic energy at 2.4 GHz in the presence of
water as a sealing fluid. However, the dry gelatin
swells in the presence of water in much too short a
time to be applicable otherwise than locally at the
overlap of cap and body parts of the capsule ~o
circumvent this, one dips the capsules in various
aqueous and/or organic sealing fluids and blows off the
.. . .. . .
.
.. . .
~21~2~4 !......... -
excess sealing fluid from the surface of the capsules;
leaving the fluid only between the overlap of the body
and the cap parts of the cz?sule. Another embodiment
to localize the thermal energy at the overlapping seam
- 5 can be achieved by the ap?lication of energy throush a
slit of an insulating plate under which the capsule is
positioned and axially rotated in a way that only the
overlapping seam part is exposed to the thermal energy.
Sources of energy can be radiation (microwaves or
infrared) or convection heating. Organic solvents,
which are suf,iciently miscible with water but reduce
- -the swelling ability of water to a proper degree are
given in the following groups of sealing fluids:
In general, the sealing lluids used in the present
-15 invention contain a considerable amount of water. A
denaturation and peptization of the gelatin is a
necessary effect ~or the present invention. This
.. ` effect can be achieved by the application of a local-
ized thermal energy source to following 4 Groups of
sealing fluids to the capsule seam:
s
-- Sealing fluids of organic solvents having a
solubility para~eter between about 10 to about-23.4;
and being sufficiently miscible with water at a pH
range between 1 to 13 are given in TABLE 2 belou, based
on the following References-
- J. Brandrupp and ~. H. I~mergut, Pol~mer
Handbook, 1st Edition, pages I~ 356-358, John ~liley
~.Y. (1966)
- J. Bello et al, J. Phys. Chem 60, page 1299,
(1956)
' -
- ` ~2~92~
.,.. ,...................... ~.:.:
TABL~_2
~cal/ce)l/2 Organic Solvent
10.0 amyl alcohol (iso)
10.0 carbon disulfide
- 5 10.0 dichlorobenzene (ortho)
10.0 diethyl phthalate
10.0 dimethyll-2,2-butanediol-1.3
10.0 dioxane-1,4 - -
10.0 dipropylene glycol
10.0 ethylamine
10.0 ethylene glycol diacetat.e
10.0 ethyl lactate
10.0 methyl isobutyl carbinol
10.0 nitrobenzene
10.0 propionic anhydride
10.1 acetic acid
10.1 caprolactone
.- . 10.1 dibromoethylene-1,2
10.1 propylene glycol methyl ether
10.2 cresol (meta)
10.2 diethylene slycol ~onoethyl ~ther
. 10.2 dioxolane-1,3
10.2 . methyl formate
10.2 methyl iodine
10,3 acetaldehyde
10.3 acetic anhydride
10.3 aniline
10~3 butyric acid (iso)
10.3 hexanediol-2,5
10.3 methyl-2-pentanediol-1,3
10.3 nitro-l-propane
10.3 octyl alcohol (normal)
10.4 cyclopentanone
10.4 dibromoethane-1,2
35 - 10.5 acrylonitrile
10.5 butyl alcohol (iso)
10.5 butyric acid (normal3
.
,
.
~.
.. 10
. . 10.5 butyronitrile
10.5 ethyl-2-butanol-1
--. 10.5 ethylene glycol monoethyl.e.ther
10.5 hexamethylphosphoramide
_ 10.5 methyl benzoate
10.6 bromonapthalene
10.6 butyl alcohol (tert.)
10.6 diethylfor~amide (N,N)
10.6 heptyl alcohol (normal)
10.6 methyl salicylate
10.7 dimethyl phthalate
-10.7 hexyl alcohol (normal~
10.7 pyridine
10.7 triethylene glycol
10.8 butyl alcohol (secondary).
.10.8 dimethylacetamide (N,N)
10.8 pentanediol-2,4
.. - 10.8 propionitrile
10.8 quinoline
10.9 amyl alcohol (normal)
- . 11.0 ~ cyclobutanedione
11.0 dichloroacetic acid
11.0 dimethyl malonate -.
11.0 dimethyl oxalate
. 11.0 ethyl cyanoacetate
11.0 neopentyl glycol
11.1 butanediol-2,3
11.1 ethylene oxide
11.1 , nitroethane
ll.Z acetylpiperidine (N)
11.2 dimethyl-2,2-butanediol~1,2
(Isobutylene glycol)
11.2 urfural
11.2 methacrylic acid ..
~ 11.2 methylamine ..
11.3 dlpropyl sulfone
.. .. . ..
. .
.
.
2~ f. j.
, . . . .
11
3 methylpyrrolidone-2 ~N)
11.4 . acetylpyrrolidine (N)
11.4 butyl alcohol (normal)
11.4 cyclohexanol
11.4 ethylene glycol monomethyl ether
11.4 tetramethyloxamide
11.5 formylpiperidine (N)
11.5 pentanediol-1,5
11.5 propyl alcohol (iso)
11.6 acetylmorpholine (}I)
11.6 butanediol-1,3
11.8 allyl~aicohol
11.8 methylene iOa ide
11.9 acetonitrile
11.9 propyl~alcohol (normal)
11.9 Santicizer 8
12.0 acrylic acid
... 12.0 dimethyl sulfoxide
12.1 benæyl alcohol
12.1 butanediol-1,4
12.1 butylene-2,3 carbonate
12.1 diethylene glycol --
12.1 .dimethylformamide (I~
12.1 dimethyltetramethylene sulfone
12.1 formic acid
12.1 hydrogen cyanide
12.2 ethylene chlorohydrin
12.3 ethylacetamide (N)
12.4 diethyl sulfone
12.4 methylene glycolate
12.5 dimethyl phosphite .
12~S urfuryl alcohol
12.5 meth~l propyl sulfone
12.6 butyrolactone
. .
12.6 chloroacetonitrile
12.6 propylene glycol
12.7 caprolactam (epsilon)
.
.: . ,. ~ . .
~,
' ' ' 12
~ 12.7 ethyl alcohol
12.7 nitromethane
- 12.9 methyltetramethylene sulfone
. -13.0 formylmorpholine (N)
- 5 13.1 dimethylnitroamine (~,N)
13.3 propiolactone
13.3 propylene-1,2 carbonate
13.4 methyl ethyl sulfone
13.4 pyrone (gamma)
13.4 tetramethylene sulfone
13.6 maleic anhydride
13.6 piperidone
13.7 diacetylpiperazine (N,N)
13.9 ethylfo,rmamide (~I)
14.5 methanol
14.5 dimethyl sulfone
14.6 ethylene glycol
~ 14.6 methylacetamide (~)
: 14.7 ethylene carbonate
14.7 pyrrolidone (alpha)
15.1- diformyl~iperazine (N,N)
15.4 ., succinic anhydride ,_,
16.1 methylformamide (N)
16.3 ammonia
16~3 glycerol
19.2 formamide,
23.4 water
The above organic solvents with a solubility
parameter below about 10, which are miscible with
water, can be used at low concentrations in combinatlon
, with solvents having a solubility parameter, above about
10 ~ (cal/cc)l/2
For the sealing of pharmaceutical gelatin capsules,
only pharmaceutically accepted organic solvents are used.
- 2. Solutions of Salts
Sealing fluids of an aqueous solution of salts or
an aqueous' organic solution (Organic so.lvents from
.. :,. . . .
.
.:, . , .;
. "., ~.
- .
. ~:. .", , :,, : , ,,
92
r
13
.~ ' 'TABLE 2 above) of salts, as well as the corresponding
acids and/or bases of the salts, are also effective.
The water in these sealing fluids may be at a pH range
- between l and 13. The effect of cations and anions of .
these salts is to depress the melting point of gelatin,
as stated by K. ~. ~ustavson, ~he Chemistry and
Reactivity of Collagen, Academic Press, N~Y. (1956) and
may be explained as follows:
a) Cations like Ca~+ and Al++ are extremely
efficient if their share is high and their radius small,
which yields a strong polarization according to the
~~~- ~ ~ Hofmeisters seri~s. ..
b) Anions like SCN- and I- must possess a
large electron cloud in order to have a strong polari-
-- 15 zability.
- For the sealing of pharmaceutical gelatin capsules,
only pharmaceuticallv acceptable salts are usea.
3. W2ter
Water at a p~ range between l and 13 is effective
as a sealing ~luid when thermal energy is applied
specifically to the sealing fluid between the body and
~cap overlap. --
4. Polymer Solu~ions or Emulsions In addition tothe above embodiments the present invention may also
include the following polymer solutions or emulsion~-
. a. Polyalkylenes such as polyethylene,
polypropylene and.the like;
b. Cellulose, its microcrystalline orform, and derivatives thereof, including cellulose
esters such as cellulose acetate, hydroxypropyl-
.methylcellulose-phthalate, hydroxypropyl-
methylcellulose, celluloseacetate-phthalatei cellulose
ethers such as lower alkyl cellulose, wherein the lower
: alkyl yroup contains from 1 to 3 carbon atoms as for
example ethyl cellulose, methylcellulose, other
. ~
,
.
~ .
14
. .derivatives such as sodium-carboxymethyl-cellulose, and
- lower hydroxy-alkyl-cellulose wherein the lower alkyl
has from 1 to 4 carbon atoms;
c. Waxes such as carnauba wax;
~ 5 d. Polyvinylpyrrolidone;
e. Polymers and copolymers of acrylic acids
and methacrylic acids and salts and esters thereof;
f. Carbohydrates including mono-, di-, and
polysaccharides such as glucos~, suc-ose, starch, agar,
polydextrose, mucopolysaccharides, as well as derivatives
of those carbohydrates and the like;
g. Proteins such as gelatin and hydrolyz~d
gelatin, with derivatives thereof, soy bean proteins,
sunLlower proteins, and the like (in addition a protein
1~ may be used that has enzymatic activity on the gelatin
like protase, preferably collogenase, papain, pepsin,
and the likerwhich causes an enzymatic degradation of
~: the gelatin which results in a seal of the overlap of
the cap on body parts);
h. Shellac;
- ~ i. Rubber;
-- j. Polyvinyl-acetates;
k. Polyuronic acids like alginates and
its derivatives;
1. Polyvinylalcohol;
m. Cyanoacrylate-monomer; and
n. Related materials and combinations of
the above.
The concentrations of the polymer solutions or
emulsions may ~ary widely and are preferably used as
ollows: .
- For dipping 2 - 50% by weight
- For spraying/jetting 2 - 70% by weight
In addition to the polymer solutions or emulsions
~listed above, the following softeners may also be used:
a. Poly-hydroxy-alcohols like glycerol,
sorbitol, mannitol, and the like;
. , .
'~ ~
~ ~9~L4
.-. .
....... ......
b.~ Dialkylphthalates preferably where alkyl is
~utyl;
c. Lower alkyl citrates wherein lower alkyl has
1 - 6 carbon atoms;
- 5 d. Polyglycols such as polyethyleneglycol and
methoxy-propylene-glycol, and 1,2- propyleneglycol;
e. Esters of polyhydroxy~alcohols such as mono-,
di- and tri-acetate of glycerol and the like;
f. Reocineoleic acid and esters thereo~;
g. Related materials and mixtures of the above.
The above softeners are used in a concentration
range of 0.1 - 20% by weight based on the polymer
solutions or emulsions listed above.
In addition to the polymers and the softeners
listed above any solvent may also be used that is non-
toxic for pharmaceutical capsules and is compatible with
the capsule composition. Examples of such solvents
: include:
a. Organic solvents such as:
1) Lower alkyl ethers wherein lower alkyl
has 1-4 carbon atoms;
-- 2) Lower alkyl ketones wherein lower alkyl
has 1 8 carbon atoms;
- 3) Methyleneglycol;
4) Lower alkyl esters of lower alkyl
carboxylic acids wherein the lower alkyl has more than
1-4 carbon atoms; and
5) Related materials of the above and lower
alkyl alcohols such as ethanol and isopropanol.
b. ~7ater; and
c. Related materials and combinations of the a~ove.
In Groups 1-4 of the above described sealing fluids.
surfactants like sodium lauryl sulfate at a concentratiOn
within a range of 0.1 to 5% may be added in order to
-obtain the smallest possible contact angle between the
sealing fluid and the capsule material and thus leading
to a maximal wettability. Furthermore, the addition of
2~L9Z~
. ...
16
.softeners such as glycerol, sorbitol and the like is
preferred in some cases in order to get a more flexible
seam between body nd cap overlap. Furthermore,
combinations of the sealing fluids described in groups
_ 5 1 - 4 may be used at various mixing ratios.
Methods for the Application of Sealing ~luids to Capsules
Various methods were used for the application of
the above sealing fluids for ~elatin capsules:
1. Dipping of the entire capsule into a bath of
the sealing fluid as shown in FIG. 1 for a time period
of 1 to 5 seconds at a temperature range from between
about 5 to 70CC followed by removing of the excess
fluid from the capsule surface by a strong air jet.
Thereafter, the capsules were dried.
2. Dipping of the capsules in an-upright position
as shown in FI~. 2 so that the cap is on ~op and the
overlap o~ the capsule is in contact with the sealing
- fluid. The sealing conditions were the same as in
p2rasraph 1 above.
3. Spraying of the capsules with a sealing ~luid
as shown in FIG. 3. TXe sealing fluid was used at a
te.?erature ranse between about 5 to 70C. After
spraying the excess fluid was removed from the capsule
surface by a strong air jet (followed by capsule
drying, if necessary to remove the sealing fluid from
the surfaces of the capsules).
4. ~pplication of a sealing fluid to the capsules
by using a high fre~uency pressure pulse jet nozzle as
shown in FIGS. 4 and 5 with an accurate monitoring of
droplet delivery and deflection. Only minor surface
drying was necessary. The sites of application of the
sealing fluid were as follows: -
- into and/or onto the open end of the cap part
~ beore capsule joining on a filling machine;
~ - onto the outside of the side walls of the open
end of the body part before capsule joining on
a filling machine;
.
,. ' ,,': .'~,. :'
.
2~
.
17
, ~ onto the ovezlap of the cap and body parts
after capsule joining and filling.
5. Application of a steam of the sealing fluids
by a jet nozzle 25 shown in FIGS. 4 and 5. On~y minor
5 surface drying was necessary. The sites of application
were ~he same as in paragraph 4 above.
Capsule sealing by a steam of the sealing fluids
selected was also accomplished by exposing the capsules
in a combined s'eam vacuum chamber.
, ,
. . .
.
The sealing of capsules by the present invention
can be used o~ hard shell gelatin capsules which have
been telescopically joined and have the following
contents:
a. Em t ~
- b. Powde~s;
- c. Pastes;
d. Table.s, pelletsj granules, microcapsules, etc.
e. Liaulds-(the sealing o the present invention
was zlso successful in preventing leakage of
oil ~rom within the gelatin capsule; and
f. Liquids and solids.
For the sealing of gelatin capsules fil~ed with oils,
it was noted that an inverse capillary effect driving
the oil between the overlap of the body and cap parts
of the yelatin capsules may occur, especially when the
filled gelatin capsules are held in a cap part down
position. For rape seed oil, having a viscosity of
above about 90 centipoises, a contact angle between the
gelatin film and the oil was measured which means that
the capillary forces of oil are much lower than the
~- capillary forces of the sealing fluids. Therefore, if
35- the gelatin capsules are sealed within a Eew minutes
a~ter filling with an oil, the oily capsule content
- - .
~ _ .
.
..
-. , '.;~ . :
:L.'~,~.~2~
...... .
..........
1~ '
,
' does not enter between the overlap of the body and the
cap of the gelatin capsule. Hence, the capsules can be
sealed by the sealing fluids of the present invention.
_ If liquids or oils wi~h low viscosities below
abou~ 90 centipoises and small contact angles are used,
the following ~easures accomplished a complete sealing
- ~ by the present invention:
- sealing the gelatin capsules within a few
seconds after ejection from the filling machine.
- holding the gelatin capsule in an upright
position with the cap part on top during the
sealing process, as shown in FIG. 2.
- cooling the liquid contents prior to filling
- ~ into the gelatin capsule in order to increase
the viscosity and the contact angle between
_ _ the gelatin film and the li~uid.
- - adding a thickening agent to the liquid
contents prior to the filling process.
The best results were obtained without capsule
deformation; with sealing fluids having a high degree
of peptization, such as an a~ueous solvent of 75%
ethanol in water, and also with an aqueous solvent of
90~ methanol in water.
The sealing of the overlap of the capsule side
walls is accomplished in the present invention as
follows:
Gelatin used in the production of capsules contain
chains of peptides in the amorphous and the crystalline
states. In the crystalline state there is scarcely any
translational movement of the center of energy of the
chains of peptides. The non-crystallized molecules
retain a slight mobility of their chains above the glass
transition temperature.
The addition of sealing fluid by capillary action
between the side walls of the capsule lowers the melting
point of the gelatin or other hydrophilic polymer
material. This initiates the movement of the chains of
~................................. . .
,
. .. . .
;. . : :,
. .. :
.
:
'
. lg
' ~ 'peptides within the overlapping side walls of the
capsule a~d results in a physical bond or seal therein
By the addition of thermal energy to the ~hains of
peptides in the presence of sealing fluid within the
~ 5 overlapping seam of the capsule the chains of peptides
have an increased Brownian movement, resulting in a
denaturation of the gelatin or other hydrophilic polymer
therein. Upon cooling of the seam the denatured gelatin
or other hydrophilic polymer becomes gelatinated or
solidified, so as to form a physical bond or seal
between the overlappiny side walls or seam of the
capsule.,
In the present invention the preferred manner of
adding thermal energy is by electromagnetic irradiation ~;
of the chains of peptides in the presence of sealing
fluid within the overlapping seal of the capsule. The
electromagnetic irradiation found to be ~ost effective
was at fre~uencies of about 2.4 G~z for an exposure of
about 1 to 5 seconds with a strength of field in the
range of 200 V/cm. It was observed that microwaves of
this strength of field and time caused efficient
- peptization and'~dena~uration of the material within the
overlapping seam and resulted in gelatination of the
material so as to make a strong physical bond or seal
~herein.
It was also noted that 'the use of microwaves at
such levels did not deform the capsules. This is
explained in that the average water content of capsules
is in the range of about 10 to 15~. Such water content
is too low to cause a peptization of the gelatin, so as
to result in deformation of the entire caps,ule. At
this water content, the melting point of the
crystalline chains is not achieved below about 120C.
This temperature is not exceeded by the application of
the thermal energy in the present invention.
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Al~ernatively, the addi,ion of thermal eneroy to
the sealing fluid in the overlapping seam can be
accomplished by other ranges of frequency of electro-
magnetic irradiation such as infrared heatingi~or by
_ 5 convection such as by hot gas or by steam heating; or
by conventional conduction heating means such as by
electric or by hot water heat directly and locally
applied to the overlapping seam of the capsule. A
method of conduction heating i~ to apply a metal stamp
or bar, heated in a range of about 120C to 185C
directly to all or part of the overlapping seam for
about 1 to 3 seconds. In order to avoid sticking of
the metal stamp to the seam, the metal stamp may be
coated with a non stick-ing material such as a tetra-
fluoroethylene fluorocarbon resin sold under thetrademark: TEFLON~; trademark o~ned and material
supplied by The DuPont Company, Wilmington, Delaware;
: or a dimethyl silicone sold under the trademark:
SILICO~IE~; trademark owned and material supplied by the
General Electric Company, Schenectady, New York.
In the present invention it W2S found that an
-acceptable bond or sealing of the overlap could be
obtained without the application of a sealing fluid
thereto, provided the ther~al energy is locally applied
to the overlap, in any of the following ways:
1. Electromagnetic irradiation at frequencies in
the infrared range, preferably applied by laser source.
2. Convectionrsuch as by hot gas or by steam
heating of approx. 160C.
3. Conductionrsuch as by contacting with a metal
stamp or bar heated to approx. 180C.
4. Friction~such as by ultrasonic vibration.
The application of thermal energy to the overlap
at the above high levels, without the use of a sealing
3~ -fluid, must be closely controlled in order to avoid any
deformation of the capsule.
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.
21
' Example 1
Gelatin capsules, empty and filled with contents
as described on page 17 b to e above, and tele--
_ scopically joined, ~ere sealed by the apparatus shown
in FIG. 1 with a sealing fluid of 75% ethanol in water,at room temperature.
No sealing fluid was observed to enter the interior
of the telescopically joined capsules during the dipping
time of 1 to 5 seconds, and thereafter.
After the elimination of the excess fluid from
their surfaces, the capsules were heated with air at a
temperature of 70C for 60 seconds.
~ ue to the additional supply of energy through hot
air, the inner surface of the cap and the outer surface
of the bodies at the overlapping seams of the capsules
were completely touching (shrinking of cap part) thus
the peptizized surfaces formed a hi~h quality capsule
sezm.
The capsules were tested and found to be all
tamper-proof. The capsules with contents as described
on page i7 c and e above showed no leakage. ~
ExamPle 2
100 capsules, size 2 (imprinted~, were rilled with
rape seed oil, joined and put on a sieve (diameter 20
cm), the latter being covered by another sieve. The
capsules were dipped by a complete immersion of the
sieves, during 3 seconds, at room temperature, into a
sealing 1uid of 60% ethanol and 40% water.
The sealing fluid contained 0.1% of sodium lauryl
sulfate as a surfactant decreasing the contact angle
between the fluid and the gelatin wall. I~mediateiy
after removal from the sealing fluid, the sieve was
shaken and together with a strong air jet, the excess
fluid was removed from the capsule surface uithin about
10 seconds. The capsules where then positioned in a
hot air drier at 70C for 60 seconds.
The capsules were not deformed nor was the imprint
faded.
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22
The quality of the capsule seam was tested after 24
hours storage at room temperature and 40% of rel~tive
humidity~ All capsules tested could not be separated
without destroying. Furthermore, no liquid content ~as
~ 5 leaking from the capsules.
Example 3
50 capsules, size 2I were filled with lactose,
joined and put on a sieve (diameter 20 cm), the latter
being covered by another sieve. The capsules were
completely immersed for 3 seconds at room temperature
into a sealing ~luid of 60~ ethanol and 40~ water con-
taining 0.1% sodium lauryl~~sulfate. The excess fluid
was removed from the capsule surface within lO seconds
by shaking the sieves and air jetting the capsules,
followed by a drying of about 60 seconds under an air
flow at 20C and 30% relative humidity. Then the
capsules were placed on a rolling conveyor which axially
- aligned the capsules. The capsules were then heated by
an infrared lamp for 90 seconds at a temperature of
60C.
The quality of the capsules and of the capsule
seams was similar to,the results obtained in example 2.
Ex~m~le 4
100 capsules, size 2, were filled with rape seed
oil, joined and placed in a sieve, the latter being
covered by another sieve. The capsules were completely
i~mersed for 3 seconds into a sealing fluid consisting
of 60% ethanol, 40% water and ~ sodium lauryl sulfate
at 5C. The excess fluid was removed from the capsule
surface within 10 seconds by a strong air jet at room
temperature. ; .
The capsules were then placed on a conveyor system
with plastic rolls and moved in an axially vertical
position. A wood plate, having a slit o~ 3mm, covered
the capsules at a distance of about 2 c~ whereby the
slit was positioned perpendicularly to the axis of,
and over, the body and cap overlap.
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23
An infrared source was placed over the wood plate
', , . ,in ~ vertical position over the slit~ With this
procedure, the body and cap overlap were heated to
about 80C for 90 seconds resulting in a completely
^ - 5 liquid tight and tamper proof'capsule.
The local application of thermal energy at the
capsule overlap (without affecting the rest of the
capsule) is required for liquid contents which show
heat expansion of the contents resulting in an air
escape between body and cap during the sealing process.
Exam~le 5
50 capsules, si~e 2, were filled with lactose,
joined and placed in a sieve, the latter being covered
by a second sieve. The capsules were completely
immersed for 3 seconds into a sealing fluid consisting
of water and 0.1% sodium lauryl sulfate at 5C. The
excess fluid was removed from the capsule surface by a
strong air jet at room temperature and 20% relative
hu~idity for 90 seconds.
In order to form an optimal seal at the overlap,
the capsules were irradiated for 3 seconds with
electromagnetic energy at 2.4 G~z at a field s~rength
! - of 171 V/cm. The microwaves of this intensity caused
efficient pe~tization and denaturation of the material
within the overlapping seam and resulted in
gelatination of the material so as to give a strong
physical bond.
Exam~le 6
50 capsules, size 2, were filled with rape seed
oil, joined and put in a sieve. The capsules were
sprayed with a sealing fluid consisting of, water con-
taining 0.1% sodium lauryl sulfate at 5C. After ,
spraying, the siéve was covered by another sieve. 'The
excess fluid from the surfaces were removed by an air
jet' at room temperature and 20% relative humidity for
90 seconds. For the formation of a strong bond at the
body and cap overlap, the capsules were irradiated for,
4 seconds with electromagnetic energy ~microwaves) at
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. 24
2.4 GHz at a field strength of 171 V/cm. All capsules
proved to be liquid-tight and tamper-proof.
Exam~le 7 1
. .
_ 100 capsules, size 2, were filled with rape seed
~ 5 oil, joined and placed in a sieve with a diameter of 20
cm, the latter being covered by another si~ve. ~he
- capsules were completely immersed for 3 seconds into a
sealing fluid consisting of water containing 0.2 M
sodium sulfate and 0.1% of sodium lauryl sulfate at
5C.
The excess fluid was removed from the capsule
sur~ace by a strong air jet at room temperature and 20%
relative humidity for 90 seconds.
- For the formation of a complete and strong bond at
body and cap overlap, the capsules were treated by hot
_ air at a temperzture of 70C for 60 seconds.
The capsules were both tamper-proof and liquid-
tight.
; Example 8
- 100 capsules, size 2, were filled with lactose,
joined and placed in a sieve with a diame~er of 20 cm,
the latter being covered with another sieve.~ ~he
capsules were completely immersed for 4 seconds in a
sealing fluid consisti~g of water containing 0. M
sodium sulfate (~a2SO4) and 0.1% sodium lauryl
sulfate at SC.
The excess fluid was removed from the capsule
surface by a strong air jet at room temperature and 20
relative humidity for 90 seconds. In order to form a
strong physical bond at the body and cap overlap, the
capsules were irradiated or 2 seconds with
electromagnetic energy (microwaves) at 2.4 GHz at a
field strength of 171 V/cm.
All capsules could not be separated without
destroying.
Example 9
; 100 capsules, size 2, were filled with lactose,
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'joined and placed in a sieve with a diameter of 20 c~,
the latter being covered by another sieve. The capsules
were completely immersed for 3 seconds into a sealing
fluid consisting of an aqueous solution of 1.0%
~ 5 hydrolyzed gelatin having an average molecular weight
of about 5,000 Dalton (using hydrolyzed gelatin having
a molecular weight of 5,000 sold under the trademark:
POLYPRO 5000~; trademark owned and material supplied by
Hormel Inc., Chicago, Illinois) at 5C.
The excess fluid uas removed from the capsule
surface by a strong air jet at room temperature and 20
relative humidity for 90 seconds.
For the formation of a strong and lasting physical
bond at the body and cap overlap, the capsules were
1~ then treated with hot air at a temperature of 70C for
60 seconds.
The capsules could not be separated without
r' destroying them.
Example 10
100 capsules, sixe 2, were filled wlth rape seed
oil, joined and placed in a sieve with a diameter of 20
- cm, the latter being covered with another sieve. The
- capsules were completely immersed-for 3 seconds in a
- sealing fluid consisting of an aqueous solution of 1.5%
hydrol~zed gel2tin having an average molecular weight
of about 2000 Dalton (using ~ydrolyzed gelatin having a
molecular weight of 2,000 sold under the trademark:
PEPTEIN 2000~; trademark owned and material supplied by
Hormel IncL, Chicago, Illinois), and containing 0.1%
sodium lauryl sulfate at 5C.
The excess fluid was removed from the capsule
surface by a strong air jet, at room temperature and
20%,relative humidity for 90 seconds.
For the formation of a strong bond at body and cap
overlap, the capsules were irradiated ~or 4 seconds
with electromagnetic energy (microwaves) at 2.4 GHz at
a field strength of 171 V/c~.
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26
All capsules proved to be liquid tight and tamper-
. proof.
ExamDle 11
100 capsules, size 2, were filled with rape seed
- 5 oil, joined and placed in a sieve with a diameter of 20
cm, the latter being covered with another sieve. The
- capsules were completely immersed for 3 seconds (at
5~C) into a sealing fluid consisting of an aqueous
solution of 1% polyvinyl-pyror~done (average molecular
weight of 25,000 Dalton) containing 0.1% sodium lauryl
sulfate.
The excess ~luid was removed from the capsule
surface by a strong air jet at room temperature and 20
relative hur~.idity for g0 seconds.
For the formation of a strong bond at body and
cap overlap, the capsules were irradiated for 4
seconds with electromagnetic energy (microwaves) at
: 2.4 ÇHz at a field strength of 171 V/cm.
All capsules proved to be liquid tight and tamper-
proof.Exam~le 12
; 20 capsules, size 2, were filled with lactose and
joined.
An acce~table bond of the overlap could be obtained
without the application of a sealing fluid thereto by
providing the thermal energy locally to the overlap by
a metal stamp, coated with TEFLON~, at a temperature of
180C for 1 second.
The~stamp treatment was either performed on one or
more spots at the circumference of the capsule overlap.
All capsules could not be separated without
destroying them. ~he visible mark left by the stamp
made the capsules tamper-evident.
Example 13
10 capsules, size 2, were filled with rape seed
oil and joined.
A complete bond at a 360 angle of the oveFlap
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circumference could be obtained without the application of
a sealing fluid thereto by providing the thermal energy-
locally to the overlap by 3 metal stamps (bars) coated with
TEFLON R each one sealing a segment of 120 at the overlap
of the capsule.
With these 3 segmental stamps, a complete ring
of a bond at overlap was obtained thus avoidingthe leakage of
the liquid content and resultingin atamper-evident capsule.
The above described apparatus and method for
producing the capsule of the present invention are also described
and are claimed in above-identified copending parent application
Serial No. 438,716.
This invention has been described in terms of
specific embodiments set forth in detail, but it should be
understood that these are by way of illustration only and
that the invention is not necessarily limited thereto. Modi-
fications and variations will be apparent from this disclosure
and may be resorted to without departing from the spirit of
this invention, as those skilled in the art will readily under-
stand. Accordingly, such variations and modifications of
the disclosed invention are considered to be within the purview
and scope of this invention and the following claims.
- 27 -
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