CA1219214A - Sealed capsule - Google Patents
Sealed capsuleInfo
- Publication number
- CA1219214A CA1219214A CA000501422A CA501422A CA1219214A CA 1219214 A CA1219214 A CA 1219214A CA 000501422 A CA000501422 A CA 000501422A CA 501422 A CA501422 A CA 501422A CA 1219214 A CA1219214 A CA 1219214A
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- Prior art keywords
- capsule
- capsules
- sealing
- gelatin
- overlap
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Abstract
TITLE: APPARATUS AND METHOD FOR SEALING CAPSULES
ABSTRACT OF THE DISCLOSURE
Methods are disclosed for the sealing of gelatin capsules having hard shell coaxial cap and body parts which overlap when telescopically joined. Also de-scribed are apparatus and sealing fluids to seal the capsules.
ABSTRACT OF THE DISCLOSURE
Methods are disclosed for the sealing of gelatin capsules having hard shell coaxial cap and body parts which overlap when telescopically joined. Also de-scribed are apparatus and sealing fluids to seal the capsules.
Description
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.
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.
:" ,;
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
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.
:" ,;
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.
~ 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
.: , .
:
~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.
~ 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.
, . . . .
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 .. :,. . . .
.
.:, . , .;
. "., ~.
- .
. ~:. .", , :,, : , ,, r .~ ' '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 . ~
, .
~ .
. .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~
. ...
.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;
.
,. ' ,,': .'~,. :' .
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.
, ~ 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 - - .
~ _ .
.
..
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..........
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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.
' 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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:
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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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( 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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.
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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, ~' ' .
...
::
2~
......... ....... .
'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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.
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j. - j.... j 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.
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' ''' '
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.
, . . . .
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 .. :,. . . .
.
.:, . , .;
. "., ~.
- .
. ~:. .", , :,, : , ,, r .~ ' '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 . ~
, .
~ .
. .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;
. , .
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....... ......
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~
. ...
.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~
.
, ~ 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.
.
, ~ , ., :" ' . .. . , ~, - .
:~ .
1~92~
, . ........
...... -- ..................... --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.
, , , ~ .
.""~" ", ,11 92~
.
' 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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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.
. . .
- :.
:
~ , .
' . ~ !
( 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 .
' ' ' ' ' :
!
.
',''~", ~ ' .
2~Z~
. 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, ~' ' .
...
::
2~
......... ....... .
'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~.
- .
' . ' ', " ' " ' , . ' .' '' '. " j ~ .
.
' '''' ~ ~ ' 92~4 .. .. .........
j. - j.... j 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 .
:- ,:
.. , . . ..
- . . -: . , ., ..., . - - ,. ~ . : .
.
. . .. ~
~92~
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.
mab/
' ''' '
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A hard gelatin capsule comprising cap and body parts which have been telescopically joined with the wall of one part overlapping a wall of the other part, characterized in that the region of overlap has been 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.
2. A capsule as defined in claim 1, wherein said capsule is filled with powder.
3. A capsule as defined in claim 1, wherein said capsule is filled with paste contents.
4. A capsule as defined in claim 1, wherein said capsule is filled with tablet, pellets, granular or micro-capsule contents.
5. A capsule as defined in claim 1, wherein said capsule is filled with liquid contents.
6. A capsule as defined in claim 1, wherein said capsule is filled with liquid and solids contents.
7. A capsule as defined in claim 1, wherein said sealing fluid is a mixture including an aliphatic monohydric alcohol having from 1 to 4 carbon atoms.
8. A capsule as defined in claim 7, wherein said aliphatic monohydric alcohol is in the range of about 60% to about 90% of the mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000501422A CA1219214A (en) | 1983-02-18 | 1986-02-07 | Sealed capsule |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US468,022 | 1983-02-18 | ||
| US06/468,022 US4539060A (en) | 1983-02-18 | 1983-02-18 | Apparatus and method of sealing capsules |
| CA000438716A CA1255271A (en) | 1983-02-18 | 1983-10-11 | Apparatus and method for sealing capsules |
| CA000501422A CA1219214A (en) | 1983-02-18 | 1986-02-07 | Sealed capsule |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000438716A Division CA1255271A (en) | 1983-02-18 | 1983-10-11 | Apparatus and method for sealing capsules |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1219214A true CA1219214A (en) | 1987-03-17 |
Family
ID=25670176
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000501422A Expired CA1219214A (en) | 1983-02-18 | 1986-02-07 | Sealed capsule |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1219214A (en) |
-
1986
- 1986-02-07 CA CA000501422A patent/CA1219214A/en not_active Expired
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