CA1241874A - Multiple soft capsules and production thereof - Google Patents
Multiple soft capsules and production thereofInfo
- Publication number
- CA1241874A CA1241874A CA000445354A CA445354A CA1241874A CA 1241874 A CA1241874 A CA 1241874A CA 000445354 A CA000445354 A CA 000445354A CA 445354 A CA445354 A CA 445354A CA 1241874 A CA1241874 A CA 1241874A
- Authority
- CA
- Canada
- Prior art keywords
- soft capsule
- capsule
- water
- film
- liquor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/30—Encapsulation of particles, e.g. foodstuff additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
Abstract
ABSTRACT
The present invention relates to a multiple soft capsule in which a soft capsule is contained in another soft capsule and the production thereof. The multiple soft capsule is useful for various industrial fields such as medicine, foods, table luxuries and the like. Especially, the multiple capsule is useful in medical field, for instance, in combining two or more components which cannot be enclosed together in a single capsule or in the dissolution control in vivo of the medicines by properly selecting the kind of the film-forming substance for the outer and inner soft capsules.
The present invention relates to a multiple soft capsule in which a soft capsule is contained in another soft capsule and the production thereof. The multiple soft capsule is useful for various industrial fields such as medicine, foods, table luxuries and the like. Especially, the multiple capsule is useful in medical field, for instance, in combining two or more components which cannot be enclosed together in a single capsule or in the dissolution control in vivo of the medicines by properly selecting the kind of the film-forming substance for the outer and inner soft capsules.
Description
MUI.TIPLE SOFT CAPSULES ~D PRODUCTION T~EREOF
BRIEF DESCRIPTION OF DRAWING
Fig50 1 and 2 are schematic vertical sectional views illustrating the embodiments of nozzle paxt for producing a multiple soft capsule.
Figs. 3 and 4 are schematic flow sheets illustrating the production of a multiple soft capsule.
BACK GROUND OF THE INVENTION
Various softencapsulated medicines, foods, table luxuries and the like are widely on the market, and as those con~aining solid fillers therein, there are known oily soft capsules in which solid and oil agents are encapsulated with a capsule film-forming substance consisting mainly of gelatin (refer to Japanes~ Patent Publication No.
42044/1982)o E~owever, a multiple soft capsule in which one ~0 or more inner soft capsules are contained together with a liquid material in an outer soft capsule has not previously been proposed.
SUMMARY OF THE INVENTIQ~
The present invention provides multiple soft cap~ules containing one or more inner soft capsules in an outer soft capsule, which are especially useful in combining two or more component~ which cannot b~ enclosed together in a single capsule or in the regulation of the ra-te of dissolution in vivo of the medicines by properly selecting the kind of -the film-forming subs-tance for -the outer and inner soft capsules.
According to a broad aspec-t of the present inventlon, there is provided a multiple soft capsule wherein one or more inner soft capsules containing oil and having a water-sol.uble film on the inner capsule oil is contained with outer capsule oil in an outer soft capsule having a water-soluble film on the outer capsule oil.
According to further broad aspect of the present invention, there is provided a method for producing a multiple soft capsule characterized in that an inner soft capsule and an outer capsule liquor to be encapsulated in an outer soft capsule are pushed together out of the ring-form tip of an inner nozzle, and at the same time, an outer film-forming liquor for the ou-ter soft capsule is pushed~ut of the ring-form tip of an~outer nozzle as arranged.in the form of concentric circle outside the ring-form tip, thereby to form a multiple jet which is then discharged into a cooling liquor.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel multiple soft capsules in which a soft capsule is contained in another sof-t capsule.
Hitherto, various softencapsulated medicines, foods, table luxuries, e-tc. are widely on the market, and as those containing solid fillers therein, there are known oily soft capsules in which solid and oil agen-ts are enclosed with a capsule film-forming substance consisting mainly of gelatin (refer to 3aparlese Patent Application No. 42044/
1982).
The presen-t inventors found tha-t the use of soft-encapsulated products is markedly ex-tended by causing a soft capsule to contain another soft capsule therein.
The gist of the present lnvention is -to provide mul-tiple soft capsules in which one or more inner soft 7~
- 2a -capsules are con-tained in an outer soft capsule.
The film-forming substance of the soft capsules, ei-ther inner soft capsule or outer one, used in the present invention is not particularly limited, but as preferred substances, there are given, for example.
those containing . .. ... _ , ~
3 R ~L~
gelatin alone as an essential component; those containing (a~ gelatin, (b) a water-soluble polyhydric alcohol or .its water-soluble derivative as an essential component; or those which are obtained by treating a composition containing ~a~
gelatin, ~b) a water-soluble polyhydric alcohol or its water-soluble derivative and (c) a lower methoxylpectin or sodium alginate with a compound capable of geletinizing an aqueous solution of lower methoxylpectin or sodium alginate, and the like.
Of the film-forming substances for the soft capsules, as to gelatin and the water-soluble polyhydric alcohol or its water-soluble derivative, those of a grade so far used for producing soft capsules may be used as such.
As the water-soluble polyhydric alcohol or its water-soluble derivative, there are given~ for example, glycerin, polyglycerin, sorbite, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, ethylene oxide/propylene oxide copolymer, oligosaccharide, sugar ester, glyceride, sorbitan ester and the like, which are not however to be regarded as limitative.
When gelatin and the watar-soluble polyhydric alcohol or its water-soluble derivative are used as a film-forming substance for soft capsule, it is preferred that the amount of gelatin used and that of the water-soluble polyhydric alcohol ox its water-soluble derivative used are 60 to 90 weight % and 10 to 40 weight %, respectively, based on the total weight of the capsule film.
~ '7~
When gelatin, a lower methoxylpectin and the water-soluble polyhydric alcohol or its water-solubl~
derivative are used as a film-forming substance for soft capsule, it is preferred that the amounts of the first, second and the latter used are 65 to 75 weight %, 5 to 20 weight %, preferably 10 to 15 weight %, and 10 to 30 weight %, respectively, based on the total weight of the capsule ~ilm .
When gelatin, sodium alginate and the water-soluble polyhydric alcohol or its water-soluble derivative are used as a film-forming substance for soft capsule, it is preferred that the amounts of the first, second and the latter used are 65 to 85 weight %, 1 to 10 weight %, preferably 30 to 5 weight ~ and 10 to 30 weight %, respectively, based on the total weight OI the capsule film.
A preferred lower methyoxylpectin is ene in which the molecular weight is not less than 200,000 and the degree of methoxy~ at.ion is 1 to 6 ~, particularly 3 . 5 to 5 %.
As the compound capable of gelatinizing aqueous solutions of a lower methoxylpectin or sodium alginate, there may properly be used the salt of polyvalent metals having two or more valences, particularly the water-soluble salts of calcium, magnesium, etc. for a lower methoxylpectin, and water-soluble calcium salts such as calcium chloride, calcium phosphate, etc. for sodium alginate .
- 5 ~
The multiple soft capsule according to the present invention may be used, in addition to tho~e which are taken or~lly such as medicines, foods, table luxuries, etcO, for those which are applied to industrial uses ~uch as various industrial products le.g two-component type adhesives, ~tc.), feeds, agricultural and horticultural chemicals, cosmet.ics, medical supplie~ and the like. Co~sequently, the film-forming substance for the inner and outer soft capsules, kind of liquors to be encapsulated in the inner soft capsule (the liquor i~ referred to as an inner capsu~le liquor hereinafter~, size of the capsules, number of the inner soft capsules contained and the like may properly be selected according to the object of use and usages.
The multiple soft capsule according to the present invention i5 suitable in the fields of medicines, foods and table luxuries, par~icularly in the field of medicines.
When the multiple soft capsule is medicines, the rate of dissolution in vivo of the medicines can b2 regulated by properly selecting the kind of the film-forming substanc~ for the outer and inner soft capsules.
For example, by making the film of the outer soft capsule soluble at stomach by preparing the film from the foregoing film-forming components (a) and (b), and by making the film of the innex sof~ capsule soluble at intestine by preparing the film ~rom the foregoing film-forminy components (a~, (b) and (c), various excellent effects can be obtained~ for example, the efficacy o~ medicines can be maintained in vivo, or mPdicines can be protected from decomposition by gastric juice.
Next, production of the multiple soft capsule according to the present invention will be illustrated with reference to the accompanying drawings.
Fig. l is a schematic vertical sectional view illustrating one embodiment of the nozzle part of a suitable equipment for producing the multiple soft capsule according to the present invention.
The multiple soft capsule (7) according to the present invention is obtained as follows.
An inner soft capsule (3) (containing a proper inner capsule liquor~ sent to the nozzle part, and an outer capsule liquor (41 to b~ filled in an outer soft capsule, as sent from A and passed through a slit (6), are pushed together out of the ring-form tip of an inner nozzle (l), and at the same time therewith, an outer film-forming liquor (5) for the outer soft capsule, as sent from B, is pushed out of the ring-form tip of an outer nozzle (2) arranged outside said ring-form tip and in the form of concentric circle, thereby to form a double jet which is then discha.rged into a cooling liquor (8).
In this case, when the inner soft capsule (3) is a double soft capsule, a triple soft capsule is obtained, and when it is a triple sot capsule, a quadruple soft capsule is obtained. In the same manner as above, any of desired multiple soft capsusles may be produced.
- 7 ~
In the prior art method wherein the filler is a liquid only~ the encapsulation is made easy and the particle diameter is made uniform by giving moderate perturbation to the multiple jet flow using a perturbation means to cause the flow to be cut well. In the method of the present invention described above, however, the inner soft capsule (3~, on being pushed out of the tip of the nozzle, acts to pull the outer capsule liquor (4) and outer film-forming liquor (5) into the flow, so that the same effect as with the perturbation means can be given to the multiple jet flow.
of course, in the method of the pre.sent invention, a proper perturbation means may be employed if desired according to -the kind and property of the inner soft capsule and the number thereof containedO
With the multiple sot capsule produced as above using the foregoing gelatin or (a) and (b) as essential components for the film of the outer soft capsule, it suffices to use a vegetable oil, mineral oil, animal oil or the like as a cooling liquor and after solidiying the capqule by cooling, to dry and wash the capsule as such.
While, with the multiple soft capsule produced as above using the oregoing (a), Ib~ and (c) as essential components for the film of the outer soft capsule, the capsule, after solidified by cooling, i5 brought into contact with a solu~ion, preferably an aqueous solution of ~he compound capable of gelatinizing aqueous solutions of a ~ J~ ~'7~
lower methoxylpectin or sodium alginate. In this case, it is a common practice to dip the capsule to be treated in an aqueous solution containing 1 to 10 weight %, preferably 3 to 5 weight % of said compound at 5C to 30C, preferably 10C to 15C for 1 to 5 minutes, preferably 1 to 3 minutes.
The contact between the multiple soft capsule and the treating liquor may be carried out, in addition to the dipping method, by other methods such a-~ the spraying method. But the dipping method is most simple as well as applicable uniformly. The multiple soft capsule treated as above is then dried and washed.
Another me~hod sui~able to produce the multiple soft capsule ~ccording to the present inv~n~ion is a method characterized in that an inner capsule liquor, a film~forming liquor for the inner soft capsule (shorten as an inner film-forming liquor hereinafter), an outer capsule liquor and an outer film-forming liquor therefor are at the same time pushed out of the first nozzle, second one, third one and forth one respectively, as arranged in the form of concentric circle, having increasing xadii in this order, thereby to form a multiple jet which i3 then discharged into a cooliny liquor. Fig. 2 is a schematic vertical sectional view illustrating one embodiment of the nozzle part of an equipment for practicing ~his method.
In the equipment shown in Fig. 2, the multiple soft capsule (7) according to the present invention is obtained as follows:
- 9 ~
An inner capsule liquor (11'~ sent from C, an inner film-forming liquor (12') sent from D, an outer capsule liquor (13') sent from A and outer film-forming liquor (14') ent from B are at the same time pushed out of the ring-form tips of the first nozzle (11), second one (12), third one (13) and fourth one (14), respectively, as ar~anged in th0 Eorm of concentric circle, having increasing radii in this order, thereby to form a multiple jet flow which is then discharged into a cooling liquor (8).
Also in this case, with the multiple soft capsule produced using the foregoing (a) and (b) as essential components for the film of the vuter soft capsule, it suffices to dry and wash the capsule as such~ But, with the multiple soft capsule produced using the foregoing (a), (b) and (cl as said components, the capsule, after treated as above, is dried and washed.
The present invention extends the use of softencapsulated products in all the industrial fields, and particularly it is effective in combining two or more components which cannot be enclosed together in a single capsule because oE incompatibility and the like. Further, a synergistic effect~ sustained effect, etc. can also be obtained depending upon the components contained.
Ths aesthetic appearance of the multiple soft capsule according to the present invention is ~xpected to contribute ~o extending demands or said encapsulated product.
Next, the present invention will be illustrated with reference to the following examples.
Example 1 According to the conventional method, a garlic oil-containing inner soft capsule (particle diameterl 2mm) was prepared using an inner film-forming liquor of the following recipe.
Recipe for the inner film-forming liquor:
Paxts by weight Gelatin 16 D-sorbite 4 Purified water 80 According to the flow sheet shown in Fig. 3, the inner soft capsule obtained above and a vitamin E-containing oil were ~ncapsulated together using an outer film forming liquor for outer soft capsule of the following recipe to obtain a double capsule having an outside diameter of 6mm.
Recipe of the outer film-forming liquor:
Parts by wei~ht Gelatin 16 d-soxbite Purified water 80 The flow sheet in Fig. 3 will be illustrated later. A vitamin E-containing oil (4) (an outer capsule liquor) is sent from an outer capsule liquor storage tank (19) to an inner capsule storage tank (18) through a pump (20) to mix with inner soft capsules. The temperature of said outer capsule liquor ~4) is kept constant (in this example, 20 + 1C), and the viscosity of the liquor i5 preferably 400cps. The inner sof~ capsule t3) and the liquor (4) are sent together, at a flow rate of 0.3 mlJmin., from the tank (18) through a pipe (29) (inside diameter,
BRIEF DESCRIPTION OF DRAWING
Fig50 1 and 2 are schematic vertical sectional views illustrating the embodiments of nozzle paxt for producing a multiple soft capsule.
Figs. 3 and 4 are schematic flow sheets illustrating the production of a multiple soft capsule.
BACK GROUND OF THE INVENTION
Various softencapsulated medicines, foods, table luxuries and the like are widely on the market, and as those con~aining solid fillers therein, there are known oily soft capsules in which solid and oil agents are encapsulated with a capsule film-forming substance consisting mainly of gelatin (refer to Japanes~ Patent Publication No.
42044/1982)o E~owever, a multiple soft capsule in which one ~0 or more inner soft capsules are contained together with a liquid material in an outer soft capsule has not previously been proposed.
SUMMARY OF THE INVENTIQ~
The present invention provides multiple soft cap~ules containing one or more inner soft capsules in an outer soft capsule, which are especially useful in combining two or more component~ which cannot b~ enclosed together in a single capsule or in the regulation of the ra-te of dissolution in vivo of the medicines by properly selecting the kind of -the film-forming subs-tance for -the outer and inner soft capsules.
According to a broad aspec-t of the present inventlon, there is provided a multiple soft capsule wherein one or more inner soft capsules containing oil and having a water-sol.uble film on the inner capsule oil is contained with outer capsule oil in an outer soft capsule having a water-soluble film on the outer capsule oil.
According to further broad aspect of the present invention, there is provided a method for producing a multiple soft capsule characterized in that an inner soft capsule and an outer capsule liquor to be encapsulated in an outer soft capsule are pushed together out of the ring-form tip of an inner nozzle, and at the same time, an outer film-forming liquor for the ou-ter soft capsule is pushed~ut of the ring-form tip of an~outer nozzle as arranged.in the form of concentric circle outside the ring-form tip, thereby to form a multiple jet which is then discharged into a cooling liquor.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel multiple soft capsules in which a soft capsule is contained in another sof-t capsule.
Hitherto, various softencapsulated medicines, foods, table luxuries, e-tc. are widely on the market, and as those containing solid fillers therein, there are known oily soft capsules in which solid and oil agen-ts are enclosed with a capsule film-forming substance consisting mainly of gelatin (refer to 3aparlese Patent Application No. 42044/
1982).
The presen-t inventors found tha-t the use of soft-encapsulated products is markedly ex-tended by causing a soft capsule to contain another soft capsule therein.
The gist of the present lnvention is -to provide mul-tiple soft capsules in which one or more inner soft 7~
- 2a -capsules are con-tained in an outer soft capsule.
The film-forming substance of the soft capsules, ei-ther inner soft capsule or outer one, used in the present invention is not particularly limited, but as preferred substances, there are given, for example.
those containing . .. ... _ , ~
3 R ~L~
gelatin alone as an essential component; those containing (a~ gelatin, (b) a water-soluble polyhydric alcohol or .its water-soluble derivative as an essential component; or those which are obtained by treating a composition containing ~a~
gelatin, ~b) a water-soluble polyhydric alcohol or its water-soluble derivative and (c) a lower methoxylpectin or sodium alginate with a compound capable of geletinizing an aqueous solution of lower methoxylpectin or sodium alginate, and the like.
Of the film-forming substances for the soft capsules, as to gelatin and the water-soluble polyhydric alcohol or its water-soluble derivative, those of a grade so far used for producing soft capsules may be used as such.
As the water-soluble polyhydric alcohol or its water-soluble derivative, there are given~ for example, glycerin, polyglycerin, sorbite, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, ethylene oxide/propylene oxide copolymer, oligosaccharide, sugar ester, glyceride, sorbitan ester and the like, which are not however to be regarded as limitative.
When gelatin and the watar-soluble polyhydric alcohol or its water-soluble derivative are used as a film-forming substance for soft capsule, it is preferred that the amount of gelatin used and that of the water-soluble polyhydric alcohol ox its water-soluble derivative used are 60 to 90 weight % and 10 to 40 weight %, respectively, based on the total weight of the capsule film.
~ '7~
When gelatin, a lower methoxylpectin and the water-soluble polyhydric alcohol or its water-solubl~
derivative are used as a film-forming substance for soft capsule, it is preferred that the amounts of the first, second and the latter used are 65 to 75 weight %, 5 to 20 weight %, preferably 10 to 15 weight %, and 10 to 30 weight %, respectively, based on the total weight of the capsule ~ilm .
When gelatin, sodium alginate and the water-soluble polyhydric alcohol or its water-soluble derivative are used as a film-forming substance for soft capsule, it is preferred that the amounts of the first, second and the latter used are 65 to 85 weight %, 1 to 10 weight %, preferably 30 to 5 weight ~ and 10 to 30 weight %, respectively, based on the total weight OI the capsule film.
A preferred lower methyoxylpectin is ene in which the molecular weight is not less than 200,000 and the degree of methoxy~ at.ion is 1 to 6 ~, particularly 3 . 5 to 5 %.
As the compound capable of gelatinizing aqueous solutions of a lower methoxylpectin or sodium alginate, there may properly be used the salt of polyvalent metals having two or more valences, particularly the water-soluble salts of calcium, magnesium, etc. for a lower methoxylpectin, and water-soluble calcium salts such as calcium chloride, calcium phosphate, etc. for sodium alginate .
- 5 ~
The multiple soft capsule according to the present invention may be used, in addition to tho~e which are taken or~lly such as medicines, foods, table luxuries, etcO, for those which are applied to industrial uses ~uch as various industrial products le.g two-component type adhesives, ~tc.), feeds, agricultural and horticultural chemicals, cosmet.ics, medical supplie~ and the like. Co~sequently, the film-forming substance for the inner and outer soft capsules, kind of liquors to be encapsulated in the inner soft capsule (the liquor i~ referred to as an inner capsu~le liquor hereinafter~, size of the capsules, number of the inner soft capsules contained and the like may properly be selected according to the object of use and usages.
The multiple soft capsule according to the present invention i5 suitable in the fields of medicines, foods and table luxuries, par~icularly in the field of medicines.
When the multiple soft capsule is medicines, the rate of dissolution in vivo of the medicines can b2 regulated by properly selecting the kind of the film-forming substanc~ for the outer and inner soft capsules.
For example, by making the film of the outer soft capsule soluble at stomach by preparing the film from the foregoing film-forming components (a) and (b), and by making the film of the innex sof~ capsule soluble at intestine by preparing the film ~rom the foregoing film-forminy components (a~, (b) and (c), various excellent effects can be obtained~ for example, the efficacy o~ medicines can be maintained in vivo, or mPdicines can be protected from decomposition by gastric juice.
Next, production of the multiple soft capsule according to the present invention will be illustrated with reference to the accompanying drawings.
Fig. l is a schematic vertical sectional view illustrating one embodiment of the nozzle part of a suitable equipment for producing the multiple soft capsule according to the present invention.
The multiple soft capsule (7) according to the present invention is obtained as follows.
An inner soft capsule (3) (containing a proper inner capsule liquor~ sent to the nozzle part, and an outer capsule liquor (41 to b~ filled in an outer soft capsule, as sent from A and passed through a slit (6), are pushed together out of the ring-form tip of an inner nozzle (l), and at the same time therewith, an outer film-forming liquor (5) for the outer soft capsule, as sent from B, is pushed out of the ring-form tip of an outer nozzle (2) arranged outside said ring-form tip and in the form of concentric circle, thereby to form a double jet which is then discha.rged into a cooling liquor (8).
In this case, when the inner soft capsule (3) is a double soft capsule, a triple soft capsule is obtained, and when it is a triple sot capsule, a quadruple soft capsule is obtained. In the same manner as above, any of desired multiple soft capsusles may be produced.
- 7 ~
In the prior art method wherein the filler is a liquid only~ the encapsulation is made easy and the particle diameter is made uniform by giving moderate perturbation to the multiple jet flow using a perturbation means to cause the flow to be cut well. In the method of the present invention described above, however, the inner soft capsule (3~, on being pushed out of the tip of the nozzle, acts to pull the outer capsule liquor (4) and outer film-forming liquor (5) into the flow, so that the same effect as with the perturbation means can be given to the multiple jet flow.
of course, in the method of the pre.sent invention, a proper perturbation means may be employed if desired according to -the kind and property of the inner soft capsule and the number thereof containedO
With the multiple sot capsule produced as above using the foregoing gelatin or (a) and (b) as essential components for the film of the outer soft capsule, it suffices to use a vegetable oil, mineral oil, animal oil or the like as a cooling liquor and after solidiying the capqule by cooling, to dry and wash the capsule as such.
While, with the multiple soft capsule produced as above using the oregoing (a), Ib~ and (c) as essential components for the film of the outer soft capsule, the capsule, after solidified by cooling, i5 brought into contact with a solu~ion, preferably an aqueous solution of ~he compound capable of gelatinizing aqueous solutions of a ~ J~ ~'7~
lower methoxylpectin or sodium alginate. In this case, it is a common practice to dip the capsule to be treated in an aqueous solution containing 1 to 10 weight %, preferably 3 to 5 weight % of said compound at 5C to 30C, preferably 10C to 15C for 1 to 5 minutes, preferably 1 to 3 minutes.
The contact between the multiple soft capsule and the treating liquor may be carried out, in addition to the dipping method, by other methods such a-~ the spraying method. But the dipping method is most simple as well as applicable uniformly. The multiple soft capsule treated as above is then dried and washed.
Another me~hod sui~able to produce the multiple soft capsule ~ccording to the present inv~n~ion is a method characterized in that an inner capsule liquor, a film~forming liquor for the inner soft capsule (shorten as an inner film-forming liquor hereinafter), an outer capsule liquor and an outer film-forming liquor therefor are at the same time pushed out of the first nozzle, second one, third one and forth one respectively, as arranged in the form of concentric circle, having increasing xadii in this order, thereby to form a multiple jet which i3 then discharged into a cooliny liquor. Fig. 2 is a schematic vertical sectional view illustrating one embodiment of the nozzle part of an equipment for practicing ~his method.
In the equipment shown in Fig. 2, the multiple soft capsule (7) according to the present invention is obtained as follows:
- 9 ~
An inner capsule liquor (11'~ sent from C, an inner film-forming liquor (12') sent from D, an outer capsule liquor (13') sent from A and outer film-forming liquor (14') ent from B are at the same time pushed out of the ring-form tips of the first nozzle (11), second one (12), third one (13) and fourth one (14), respectively, as ar~anged in th0 Eorm of concentric circle, having increasing radii in this order, thereby to form a multiple jet flow which is then discharged into a cooling liquor (8).
Also in this case, with the multiple soft capsule produced using the foregoing (a) and (b) as essential components for the film of the vuter soft capsule, it suffices to dry and wash the capsule as such~ But, with the multiple soft capsule produced using the foregoing (a), (b) and (cl as said components, the capsule, after treated as above, is dried and washed.
The present invention extends the use of softencapsulated products in all the industrial fields, and particularly it is effective in combining two or more components which cannot be enclosed together in a single capsule because oE incompatibility and the like. Further, a synergistic effect~ sustained effect, etc. can also be obtained depending upon the components contained.
Ths aesthetic appearance of the multiple soft capsule according to the present invention is ~xpected to contribute ~o extending demands or said encapsulated product.
Next, the present invention will be illustrated with reference to the following examples.
Example 1 According to the conventional method, a garlic oil-containing inner soft capsule (particle diameterl 2mm) was prepared using an inner film-forming liquor of the following recipe.
Recipe for the inner film-forming liquor:
Paxts by weight Gelatin 16 D-sorbite 4 Purified water 80 According to the flow sheet shown in Fig. 3, the inner soft capsule obtained above and a vitamin E-containing oil were ~ncapsulated together using an outer film forming liquor for outer soft capsule of the following recipe to obtain a double capsule having an outside diameter of 6mm.
Recipe of the outer film-forming liquor:
Parts by wei~ht Gelatin 16 d-soxbite Purified water 80 The flow sheet in Fig. 3 will be illustrated later. A vitamin E-containing oil (4) (an outer capsule liquor) is sent from an outer capsule liquor storage tank (19) to an inner capsule storage tank (18) through a pump (20) to mix with inner soft capsules. The temperature of said outer capsule liquor ~4) is kept constant (in this example, 20 + 1C), and the viscosity of the liquor i5 preferably 400cps. The inner sof~ capsule t3) and the liquor (4) are sent together, at a flow rate of 0.3 mlJmin., from the tank (18) through a pipe (29) (inside diameter,
2.5mm), an extruder ll6) and the pipe (29) to a double nozzle 517) (inner nozzle diameter, 3.0mm; outer nozzle diameter, 6.0mm). An aligning machine (15) is set between the extruder (16) and double nozzle (17) to make a distance between the inner soft capsules constant (in this example, pitch number, 2.5mm). The number of the inner soft capsules extruded is fixed to 8/sec. ~hile an outer film-forming liquor (5), while being maintained at a constant temperatuxe (in this example, 60 + 2C), is sent, at a flow rate of 0.2 ml/sec, from a film-forming liquor storage tank (21) through a pump (22) to -the double nozzle (17) to form a double jet which is then discharged into a cooling liquor (vegetable oil in this example). The cooling liquor (8) is kept at a low and constant tempexature (9 + 0.5C in this example) by a cooler (24) and circulated by means of a pump (27), at a flow rate of 240 ml/sec, through a cooling pipe (28) (inside diameter, 120mm; length, lOOOmm), forming pipe (23) (inside diameter, 30mm; length, 600mm) set in the cooling pipe 128), tank (26), pump (27) and ~ooler t24) in this order. The capsules for~ed ~n the forming pipe (23) are sent, together with the circulating flow of tha cooling liquor (8~, to a separatox l25~ (sieve~ wherein the capsules are separa~ed '7~
from the cooling liquor (8)l and then dried and washed. The outside diameter of the outer soft capsule of the double capsule ~hus obtained is 6 + O.2mm.
Example 2 In the same manner as in Example 1, a double capsule of the following recipe wa~ prepared.
Diameter of the inner soft capsule: 4 mm Inner capsule liquor:
parts by weight ethylcysteine hydrogene 30 chloride safflower oil 70 Recipe for an inne.r film-forming liquor:
parts by weight Gelatin 75 D-sorbite 20 Sodium alginate5 Water 300 Diameter of the outer soft capsule: 8mm Outer capsule liquox:
parts by welght cytric acid carbeta- 10 pentane safflower oil 90 Recipe for an outer film-forminy liquor:
parts by~wei~ht Gelatin 80 ~J~ ~'7 D-sorbite 20 Water 350 Manufacturing condition:
Pitch of aligning machine (15): 4.5mm Forming pip2 (23): inside diameter, 30mm;
length, 60Omm;
Cooling pipe (28~: inside diameter, 120mm length, lOOOmm Pipe (29): inside diameter, 4.5~m Temperature of the outer film-forming liquor: 60C
Temperature of the outer capsule liquor: 20C
Temperature of the cooling liquor: 9C
Flow rate of the outer film-forming liquor:
0.4 ml/sec Flow rate o the outer capsule liquor:
0.3 ml/sec Flow rate of the cooling liquor: 240 ml/sec Number of inner capsules extruded: 8/sec The ou~er soft capsule of the double capsule thus obtained is soluble at stomach and the inner soft capsule thereof is soluble at intestine, so that the efficacy oE the respective medicines is displayed effectively.
Example 3 According to the flow sheet shown in Fig. 4 double capsule having an outside dia~eter of 8mm i5 obtained.
The recipes of the capsule are as follows:
Inner capsule liquor:
14 ~
parts b~_we~ht Vitamin B220 Safflower oil 80 Inner film-forming liquor:
~arts bY wei~ht Gelatin 30 Purified water 70 Outer capsule liquor:
~r~ ~v ~ t Vitamin E 50 Wheat germ oil 50 Outer film-forming liquor:
Gelatin 25 D~sorbite 5 Purified water 70 The above inner capsule liquor, inner film-forming liquor, outer capsule liquor and outer film-forming liquor are charged in an inner capsule liquor storage tank (30), an inner film-forming liquor storage tank (31~, an outer capsule liquor storage tank ~32) and an outer film-forming liquor storage tank (333, respectively, which are kept at following temperatures:
Inner Gapgule liquor 10 ~ 1 oc Inner film-for~ing liquor60 + 2VC
Outer cap~ule liquor 2n ~ 1 oc Outer film-forming liquor60 ~ 1C
- 15 ~ 3 7~.
Every storage tank is connected with the first nozzle t~ 1.5 mm) ~ , the second nozzle ~0 2.5 m~) tl2), the third nozzle (~ 3 mm~ (131, and the fourth nozzle (~ 5 mm) (14), respectively, to which the inner capsule liquor, inner film-forming liquor, outer capsule liquor and ou~er film-forming liquor are sent by pumps at flow rates of 0.5 ml/sec, 0.1 ml/sec, 1.0 ml/sec and 0.3 ml/sec, respec~ively, to be pushed into a cooling liquor Ivegetable oil in this example) ~8) stocked in a forming pipe tinside diameter:
30 mm, length: 600 mm) t23). The cooling liquor is circulated through cooling pipe (28) at a constant flow rate (240 ml/sec in this example~, as maintained at a given uniform temperature (9 + 0.5C) by cooler (24). An ohtained double capsule is sent to a separator (60 meshes) by the cooling liquor, dried and washedO The obtained soft capsule has an averagQ outside diameter of 8 mm and inner capsule diameter of 5 mm. The content of the every soft capsule is as follows:
Inner capsule liquor 60 mg (average) Inner film-forming liquor 10 mg taverage) Outer capsule liquor 120 mg (average) Outer fi.lm-forming liquor 46 mg (average)
from the cooling liquor (8)l and then dried and washed. The outside diameter of the outer soft capsule of the double capsule ~hus obtained is 6 + O.2mm.
Example 2 In the same manner as in Example 1, a double capsule of the following recipe wa~ prepared.
Diameter of the inner soft capsule: 4 mm Inner capsule liquor:
parts by weight ethylcysteine hydrogene 30 chloride safflower oil 70 Recipe for an inne.r film-forming liquor:
parts by weight Gelatin 75 D-sorbite 20 Sodium alginate5 Water 300 Diameter of the outer soft capsule: 8mm Outer capsule liquox:
parts by welght cytric acid carbeta- 10 pentane safflower oil 90 Recipe for an outer film-forminy liquor:
parts by~wei~ht Gelatin 80 ~J~ ~'7 D-sorbite 20 Water 350 Manufacturing condition:
Pitch of aligning machine (15): 4.5mm Forming pip2 (23): inside diameter, 30mm;
length, 60Omm;
Cooling pipe (28~: inside diameter, 120mm length, lOOOmm Pipe (29): inside diameter, 4.5~m Temperature of the outer film-forming liquor: 60C
Temperature of the outer capsule liquor: 20C
Temperature of the cooling liquor: 9C
Flow rate of the outer film-forming liquor:
0.4 ml/sec Flow rate o the outer capsule liquor:
0.3 ml/sec Flow rate of the cooling liquor: 240 ml/sec Number of inner capsules extruded: 8/sec The ou~er soft capsule of the double capsule thus obtained is soluble at stomach and the inner soft capsule thereof is soluble at intestine, so that the efficacy oE the respective medicines is displayed effectively.
Example 3 According to the flow sheet shown in Fig. 4 double capsule having an outside dia~eter of 8mm i5 obtained.
The recipes of the capsule are as follows:
Inner capsule liquor:
14 ~
parts b~_we~ht Vitamin B220 Safflower oil 80 Inner film-forming liquor:
~arts bY wei~ht Gelatin 30 Purified water 70 Outer capsule liquor:
~r~ ~v ~ t Vitamin E 50 Wheat germ oil 50 Outer film-forming liquor:
Gelatin 25 D~sorbite 5 Purified water 70 The above inner capsule liquor, inner film-forming liquor, outer capsule liquor and outer film-forming liquor are charged in an inner capsule liquor storage tank (30), an inner film-forming liquor storage tank (31~, an outer capsule liquor storage tank ~32) and an outer film-forming liquor storage tank (333, respectively, which are kept at following temperatures:
Inner Gapgule liquor 10 ~ 1 oc Inner film-for~ing liquor60 + 2VC
Outer cap~ule liquor 2n ~ 1 oc Outer film-forming liquor60 ~ 1C
- 15 ~ 3 7~.
Every storage tank is connected with the first nozzle t~ 1.5 mm) ~ , the second nozzle ~0 2.5 m~) tl2), the third nozzle (~ 3 mm~ (131, and the fourth nozzle (~ 5 mm) (14), respectively, to which the inner capsule liquor, inner film-forming liquor, outer capsule liquor and ou~er film-forming liquor are sent by pumps at flow rates of 0.5 ml/sec, 0.1 ml/sec, 1.0 ml/sec and 0.3 ml/sec, respec~ively, to be pushed into a cooling liquor Ivegetable oil in this example) ~8) stocked in a forming pipe tinside diameter:
30 mm, length: 600 mm) t23). The cooling liquor is circulated through cooling pipe (28) at a constant flow rate (240 ml/sec in this example~, as maintained at a given uniform temperature (9 + 0.5C) by cooler (24). An ohtained double capsule is sent to a separator (60 meshes) by the cooling liquor, dried and washedO The obtained soft capsule has an averagQ outside diameter of 8 mm and inner capsule diameter of 5 mm. The content of the every soft capsule is as follows:
Inner capsule liquor 60 mg (average) Inner film-forming liquor 10 mg taverage) Outer capsule liquor 120 mg (average) Outer fi.lm-forming liquor 46 mg (average)
Claims (26)
1. A multiple soft capsule wherein one or more inner soft capsules containing oil and having a water-soluble film on said inner capsule oil is contained with outer capsule oil in an outer soft capsule having a water soluble film on said outer capsule oil.
2. A multiple soft capsule according to claim 1, which contains medicine, food or table luxuries.
3. A multiple soft capsule according to claim 1 or 2, wherein film-forming substance for the one or more inner soft capsules and the outer soft capsule essentially comprises gelatin.
4. A multiple soft capsule according to claim 1, wherein a film-forming substance for the one or more inner soft capsules and the outer soft capsule essentially comprises (a) gelatin and (b) a water-soluble polyhydric alcohol or its water-soluble derivative.
5. A multiple soft capsule according to claim 1, wherein a film-forming substance for the one or more inner soft capsules and the outer soft capsule is obtained by treating a composition containing essentially: (a) gelatin, (b) a water-soluble poly-hydric alcohol or its water-soluble derivative and (c) a lower methoxylpectin or sodium alginate, with a compound capable of gelatinizing an aqueous solution of said (c).
6. A multiple soft capsule according to claim 4 or 5, wherein the water-soluble polyhydric alcohol is selected from the group consisting of glycerin, sorbite, sugar ester and sorbitan ester.
7. A multiple soft capsule according to claim 5, wherein the lower methoxylpectin has a molecular weight of not less than 200,000 and a degree of methoxylation of 1 to 6%.
8. A multiple soft capsule according to claim 4, wherein the contents of gelatin and the water-soluble polyhydric alcohol or its water-soluble derivative are 60 to 90 weight % and 40 to 10 weight %, respectively, based on the total weight of the film.
9. A multiple soft capsule according to claim 5, wherein the contents of gelatin, the lower methoxylpectin and the water-soluble polyhydric alcohol or its water-soluble derivative are 65 to 75 weigth %, 5 to 20 weight %
and 10 to 30 weight %, respectively, based on the total weight of the film.
and 10 to 30 weight %, respectively, based on the total weight of the film.
10. A multiple soft capsule according to claim 5, wherein the contents of gelatin, sodium alginate and the water-soluble polyhydric alcohol or its water-soluble derivative are 65 to 85 weight %, 1 to 10 weight % and 10 to 30 weight %, respectively, based on the total weight of the film.
11. A multiple soft capsule according to claim 1, having a double capsule structure that the outer soft capsule is soluble at stomach and the inner soft capsule is soluble at intestine.
12. A method for procuding a multiple soft capsule characterized in that an inner soft capsule and an outer capsule liquor to be encapsulated in an outer soft capsule are pushed together out of the ring-form tip of an inner nozzle, and at the same time, an outer film-forming liquor for the outer soft capsule is pushed out of the ring-form tip of an outer nozzle as arranged in the form of concentric circle outside said ring-form tip, thereby to form a multiple jet which is then discharged into a cooling liquor.
13. A method for producing a multiple soft capsule according to claim 12, wherein the outer film-forming liquor essentially comprises gelatin.
14. A method for producing a multiple soft capsule according to claim 12, wherein the outer film-forming liquor essentially comprises (a) gelatin and (b) a water-soluble polyhydric alcohol or its water-soluble derivative.
15. A method for producing a multiple soft capsule according to claim 12, wherein the outer film-forming liquor essentially comprises (a) gelatin, (b) a water-soluble polyhydric alcohol or its water-soluble derivative and (c) a lower methoxylpectin or sodium alginate, and the obtained multiple soft capsule is further treated with a compound capable of gelatinizing an aqueous solution of said lower methoxylpectin or sodium alginate.
16. A method for producing a multliple soft capsule characterized in that an inner capsule liquor for an inner soft capsule, an inner film-forming liquor therefor an outer capsule liquor for an outer soft capsule and an outer film-forming liquor therefor are at the same time pushed out of the first nozzle for said inner capsule liquor, second one for said outer capsule liquor, third one for said outer capsule liquor and fourth one for said outer film-forming liquor respectively, as arranged in the form of concentric circle, having increasing radii in this order, thereby to form a multiple jet which is then discharged into a cooling liquor.
17. A method for producing a multiple soft capsule according to claim 16, wherein the inner film-forming liquor and/or the outer film-forming liquor essentially comprises gelatin.
18. A method for producing a multiple soft capsule according to claim 16, wherein the inner and/or outer film-forming liquor essentially comprises (a) gelatin and (b) water-soluble polyhydric alcohol or its water-soluble derivative.
19. A method for producing a multiple soft capsule according to claim 16, wherein the outer film-forming liquor essentially comprises (a) gelatin, (b) a water-soluble polyhydric alcohol or its water-soluble derivative and (c) a lower methoxylpectin or sodium alginate, and the obtained multiple soft capsule is further treated with a compound capable of gelatinizing an aqueous solution of said lower methoxylpectin or sodium alginate.
20. A multiple soft capsule according to claim 4, wherein the film-forming substance for the inner soft capsule and the outer soft capsule comprises (a) gelatin and (b) sorbite as the water-soluble poly-hydric alcohol, the inner soft capsule oil contains Vitamin B2, and the outer soft capsule oil contains Vitamin E.
21. A multiple soft capsule comprising:
at least one inner soft capsule and an outer capsule oil contained within an outer soft capsule, said inner and outer capsules having capsule walls of a water-soluble film, said inner soft capsule containing an inner capsule oil.
at least one inner soft capsule and an outer capsule oil contained within an outer soft capsule, said inner and outer capsules having capsule walls of a water-soluble film, said inner soft capsule containing an inner capsule oil.
22. A multiple soft capsule according to claim 21, wherein said at least one inner soft capsule comprises a plurality of inner soft capsules.
23. A multiple soft capsule according to claim 21, which comprises a single inner soft capsule.
24. A multiple soft capsule according to claim 21, the water soluble film of at least one of the inner and outer soft capsules essentially comprises a) gelatin, and b) a water-soluble polyhydric alcohol or its water-soluble derivative.
25. A multiple soft capsule according to claim 21, wherein said capsule walls comprise a) gelatin and b) a water-soluble polyhydric alcohol or its water-soluble derivative.
26. A multiple soft capsule according to claim 24 or 25, wherein the capsule wall of the at lest one inner soft capsule comprises a) gelatin and b) sorbite;
the inner capsule oil contains Vitamin B2; and the outer capsule oil contains Vitamin E.
the inner capsule oil contains Vitamin B2; and the outer capsule oil contains Vitamin E.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58006287A JPS59131355A (en) | 1983-01-17 | 1983-01-17 | Multiple soft capsule |
| JP6287/1983 | 1983-01-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1241874A true CA1241874A (en) | 1988-09-13 |
Family
ID=11634170
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000445354A Expired CA1241874A (en) | 1983-01-17 | 1984-01-16 | Multiple soft capsules and production thereof |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4695466A (en) |
| EP (1) | EP0116311B1 (en) |
| JP (1) | JPS59131355A (en) |
| KR (1) | KR840007353A (en) |
| AT (1) | ATE43963T1 (en) |
| CA (1) | CA1241874A (en) |
| DE (1) | DE3478662D1 (en) |
| ES (1) | ES528899A0 (en) |
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|---|---|---|---|---|
| WO2011150506A1 (en) * | 2010-06-03 | 2011-12-08 | Accucaps Industries Limited | Multi phase soft gel capsules, apparatus and method thereof |
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| GB715879A (en) * | 1952-06-23 | 1954-09-22 | Scherer Corp R P | Improvements in or relating to gelatin capsule and method of making the same |
| US3275519A (en) * | 1965-10-01 | 1966-09-27 | Jacob A Glassman | Peroral pellet and the method of making same |
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| DE2729068A1 (en) * | 1977-06-28 | 1979-01-11 | Rainer Dr Med Liedtke | Releasing incompatible pharmaceuticals from capsules - by including a second capsule inside the first |
| JPS5599177A (en) * | 1979-01-23 | 1980-07-28 | Nippon Carbide Ind Co Ltd | Production of artificial fish roe for food |
| JPS5655310A (en) * | 1979-10-15 | 1981-05-15 | Mitsubishi Paper Mills Ltd | Production of double-layered capsule |
| US4394287A (en) * | 1981-04-10 | 1983-07-19 | Eurand America, Inc. | Incorporation of finely divided additives at the surface of microcapsule walls |
| US4532123A (en) * | 1982-03-04 | 1985-07-30 | Battelle Development Corporation | Dual Microcapsules and process for their preparation |
-
1983
- 1983-01-17 JP JP58006287A patent/JPS59131355A/en active Granted
-
1984
- 1984-01-16 AT AT84100398T patent/ATE43963T1/en not_active IP Right Cessation
- 1984-01-16 KR KR1019840000154A patent/KR840007353A/en not_active Application Discontinuation
- 1984-01-16 EP EP84100398A patent/EP0116311B1/en not_active Expired
- 1984-01-16 DE DE8484100398T patent/DE3478662D1/en not_active Expired
- 1984-01-16 ES ES528899A patent/ES528899A0/en active Granted
- 1984-01-16 CA CA000445354A patent/CA1241874A/en not_active Expired
-
1986
- 1986-11-18 US US06/931,940 patent/US4695466A/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011150506A1 (en) * | 2010-06-03 | 2011-12-08 | Accucaps Industries Limited | Multi phase soft gel capsules, apparatus and method thereof |
| AU2011261118B2 (en) * | 2010-06-03 | 2016-09-29 | Catalent Ontario Limited | Multi phase soft gel capsules, apparatus and method thereof |
| US9844512B2 (en) | 2010-06-03 | 2017-12-19 | Catalent Ontario Limited | Multi phase soft gel capsules, apparatus and method thereof |
| US11173125B2 (en) | 2010-06-03 | 2021-11-16 | Catalent Ontario Limited | Multiphase soft gel capsules, apparatus and method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| US4695466A (en) | 1987-09-22 |
| ES8502395A1 (en) | 1985-01-01 |
| JPH0333338B2 (en) | 1991-05-16 |
| ATE43963T1 (en) | 1989-06-15 |
| EP0116311B1 (en) | 1989-06-14 |
| KR840007353A (en) | 1984-12-07 |
| ES528899A0 (en) | 1985-01-01 |
| DE3478662D1 (en) | 1989-07-20 |
| EP0116311A1 (en) | 1984-08-22 |
| JPS59131355A (en) | 1984-07-28 |
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