EP0228067A2 - Seamless soft capsule - Google Patents
Seamless soft capsule Download PDFInfo
- Publication number
- EP0228067A2 EP0228067A2 EP86117918A EP86117918A EP0228067A2 EP 0228067 A2 EP0228067 A2 EP 0228067A2 EP 86117918 A EP86117918 A EP 86117918A EP 86117918 A EP86117918 A EP 86117918A EP 0228067 A2 EP0228067 A2 EP 0228067A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- stream
- film
- composite jet
- forming
- cells
- 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.)
- Granted
Links
- 239000007901 soft capsule Substances 0.000 title claims abstract description 43
- 239000000126 substance Substances 0.000 claims abstract description 87
- 239000002131 composite material Substances 0.000 claims abstract description 81
- 239000007788 liquid Substances 0.000 claims abstract description 59
- 210000004027 cell Anatomy 0.000 claims abstract description 43
- 239000002775 capsule Substances 0.000 claims abstract description 27
- 210000002421 cell wall Anatomy 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 13
- 238000005520 cutting process Methods 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 22
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 5
- 238000009740 moulding (composite fabrication) Methods 0.000 description 48
- 239000003814 drug Substances 0.000 description 13
- 239000010408 film Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 238000000638 solvent extraction Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- 108010010803 Gelatin Proteins 0.000 description 5
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 210000000936 intestine Anatomy 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 239000005662 Paraffin oil Substances 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- -1 alkali metal salts Chemical class 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002826 coolant Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000009969 flowable effect Effects 0.000 description 2
- 210000003739 neck Anatomy 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229940099898 chlorophyllin Drugs 0.000 description 1
- 235000019805 chlorophyllin Nutrition 0.000 description 1
- 239000010630 cinnamon oil Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
Images
Classifications
-
- 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
Definitions
- This invention relates to a seamless soft capsule, and more specifically, to a seamless soft capsule having a multicellular structure, and a method of its production.
- a multicellular soft capsule having its inside partitioned by a film was recently proposed (see Japanese Laid-Open Patent Publication No. l09520/l985).
- This patent document states that the multicellular soft capsule is obtained by partitioning a soft capsule shell composed of an upper film and a lower film into two cells by means of a partitioning film, and filling different drugs into the two cells.
- two drugs which are not desired to be mixed can be stably included in a single soft capsule.
- materials having different solubilities and dissolving speeds it is possible to cause one part of a single capsule to be released and absorbed in the stomach and the other part, in the intestines. It is also possible to make one part of the capsule fast-releasing and the other part slow-releasing.
- the capsule shell Since the proposed multicellular soft capsule is produced by a rotary method or a flat plate method, the capsule shell has seams. Hence, in spite of the aforesaid advantages, it has the defect that the filled drugs leak from the seams, or air comes through the seams to deteriorate the contents oxidatively. Furthermore, by the rotary method or the flat plate method, it is difficult to produce multicellular soft capsules having a small size, and moreover, the cost of production becomes high. Furthermore, since both surfaces of the partitioning film in the aforesaid muticellular soft capsule are formed of the same material, if a drug to be filled in one of the cells reacts with the components of the partitioning film, it cannot be included in such a capsule.
- Another object of this invention is to provide a simple and inexpensive method of producing the aforesaid seamless soft capsule, which can easily give capsules of a small size as well.
- a soft capsule composed of a plurality of cells coalesced to each other and filling substances encapsulated in the individual cells, the wall of at least one of the cells being formed of a material different from a material forming the wall of at least one of the other cells, and said capsule being seamless.
- the seamless soft capsule of this invention is produced by a method which comprises
- the reference numeral l represents a tank holding a film-forming liquid substance A for forming a cell wall; 2, a tank holding a film-forming substance B which is different from the substance A; 3, a tank holding a filling substance C; and 4, a tank holding another filling substance D.
- the tanks l, 2, 3 and 4 are individually provided with heating means (not shown) for maintaining the substances A, B, C and D at suitable temperatures for maintaining them flowable.
- the substances A, B, C and D are supplied to the tanks l, 2, 3 and 4 respectively.
- Metering pumps ll, 2l, 3l and 4l are provided for feeding the substances A, B, C and D of the tanks l, 2, 3 and 4 to a composite nozzle 5.
- the composite nozzle 5 is a duplex nozzle consisting of outside nozzles 5l and 52 having a semielliptical cross sectional shape resulting from partitioning an elliptical tube by a partitioning wall 50 at its center and inside nozzles 5a and 5b of a smaller diameter disposed nearly centrally in the outside nozzles 5l and 52 respectively.
- the outside nozzles 5l and 52 communicate with the tanks l and 2, and the inside nozzles 5a and 5b, with the tanks 3 and 4.
- the composite nozzle 5 faces downwardly along a downwardly flowing stream of a liquid medium e within a capsule-forming tank 6.
- the specification of the composite nozzle 5 may be freely changed according, for example, to the use of the capsule to be produced.
- a typical specification is that in Figure 2, the elliptical tube has an outside long diameter d l of 5 to 20 mm and an outside short diameter d s of 3 to l2 mm, and the inside nozzles have an outside diameter of d i of 2 to 9 mm, and the individual tubes have a thickness of 0.l to 2 mm.
- the liquid medium e formed, for example, of liquid paraffin is sent to a heat exchanger 72 from a recovery hopper 7 concurrently acting as a storage tank by means of a pump 7l.
- a heat exchanger 72 it is cooled to a moderate temperature of, for example, about 5°C and supplied to the upper portion of the capsule-forming tank 6. It becomes a downwardly flowing stream within the capsule-forming tank 6, and is circulated to the recovery hopper 7 via a capsule recovery tube 6l.
- a part of the liquid medium e is supplied to a pulse stream-forming device 74 by means of a pump 73 from the hopper 7. It is converted to a regular pulse stream in the pulse stream-forming device 74 and supplied to a pulse stream nozzle 8 provided within the capsule-forming tank 6.
- the pulse stream nozzle 8 is a circular nozzle provided immediately below, and coaxially with, the composite nozzle 5 and having a slightly larger diameter than the diameter of the elliptical tube of the composite nozzle 5.
- a pulsating stream of the liquid medium e from the nozzle 8 is extruded toward the center of the nozzle 8 from an annular slit formed within the nozzle 8 in such a manner as to surround a single composite jet stream formed by the composite nozzle 5
- Film-forming liquid substances A and B for cell wall formation and filling substances C and D to be filled in a capsule are sent under pressure to nozzles 5l, 52, 5a and 5b constituting the composite nozzle 5 by means of the metering pumps ll, 2l, 3l and 4l.
- a composite jet stream composed of a stream of the film-forming substance A and a single stream of the filling substance C is extruded into, and along, the downwardly flowing liquid medium flow within the capsule-forming tank 6, and from the nozzle 52, a composite jet stream composed of a stream of the film-forming substance B and a stream of the filling substance D is likewise extruded into, and along, the downwardly flowing liquid medium stream within the capsule-forming tank 6.
- the two composite jet streams extruded as above, nearly simultaneously with their formation, are coalesced to each other into a single composite jet stream within the downwardly flowing stream of the liquid medium e owing to the surface tensions of the film-forming liquid substances A and B.
- the speeds of extruding the composite jet streams, and the flow rate of the downwardly flowing stream of the liquid medium e can be varied depending upon, for example, the types of the film-forming liquid substances forming the composite jet streams, the type of the liquid medium e and the size of the composite nozzle, and any skilled person in the art would be able to determine optimum conditions easily by routine experiments.
- the jet stream is drawn downwardly by the downwardly flowing stream of the liquid medium e , and successively cut off at the neck portions by the downwardly drawing force.
- Each cut droplet f contains the filling substances C and D encapsulated in the film-forming liquid substances A and B by the surface tension of the substances A and B, and is formed into a seamless capsule, which is roundish as a whole, while moving down through the downwardly flowing stream of the liquid medium e .
- the capsules formed advance to the hopper 7 via the recovery tube 6l while being cooled and solidified.
- the capsules are separated from the liquid medium e by a separator 70, supplied to a conveyor 9 provided on one side of the separator 70, and sent to a drying step where they are dried to produce a final product.
- the film-forming substance for cell formation may be any material which can be formed into a thin film from its melt or solution, and after film formation can be solidified by cooling and/or drying.
- Substances usually employed in forming the shell of a soft capsule may be used in this invention. Examples include film-forming substances composed of gelatin or gelatin derivatives such as succinic gelatin and incorporated therein, plasticizers [such as glycerol, sorbitol, propylene glycol and Carbowax (polyethylene glycol)], essences and flavors (such as peppermint oil, cinnamon oil and strawberry), dyes (such as yellow No. 4, yellow No. 5, red No. l, blue No.
- opacifying agents such as titanium dioxide and red iron oxide
- solubility controlling agents such as cellulose acetate phthalate, alkali metal salts of hydroxypropylmethyl cellulose, alkali metal salts of hydroxymethyl cellulose acetate succinate, alkali metal salts of alginic acid, alkali metal salts of polyacrylic acid, methyl cellulose, carboxymethyl cellulose, casein, collagen, agar powder, polyvinyl alcohol and pectin)), etc. selected as desired. It is generally used as a liquid by dissolving it in water under heat.
- the filling substance to be encapsulated in each cell of the soft capsule of this invention can be any drug which does not dissolve the cell wall nor react with the components of the cell wall. It is preferably liquid when it is to be filled in the cell in accordance with the method of this invention. Accordingly, when the drug is a solid, it is desirably filled in a flowable state as a solution, emulsion or suspension.
- At least one of a plurality of cells constituting the resulting soft capsule can have a different dissolving time in the digestive tract from at least one of the other cells (for example, whether fast-releasing or slow-releasing), or at least one cell may have different dissolving characteristic from at least one of the other cells (for example, whether released and adsorbed in the stomach or the intestines).
- the filling substances to be encapsulated in the cells may be varied from cell to cell.
- a single capsule may be obtained in which a drug expected to be fast-acting is filled in a fast-dissolving cell and a drug desired to be slow-acting is filled in a slow-dissolving cell.
- a single capsule cell may be obtained in which a drug expected to develop its effect in the stomach is filled in a cell soluble at the stomach, and another drug expected to develop its effect in the intestines is filled in a cell soluble at the intestines.
- the shape of the soft capsule l0 can be selected by changing the shape of the end surface of the composite nozzle 5 on the extrusion side. Some modified examples of the composite nozzle 5 will be described below.
- the composite nozzle 5 shown in Figure 4 is composed of duplex outside nozzles 5l and 52 having a cocoon-shaped cross section and smaller-diameter inside nozzles 5a and 5b disposed coaxially within the outside nozzles 5l and 52 respectively.
- the capsule l0 obtained by using this composite nozzle 5 has a cocoon-shaped cross-section as shown in Figure 5. It is a seamless soft capsule in which filling substances c and d are independently encapsulated in cells a and b .
- Figures 6 and 8 show other examples of the composite nozzle 5. These nozzles 5 are each divided into three outside nozzles 5l, 52 and 53 by two or three partitioning walls 50 and smaller-diameter inside nozzles 5a, 5b and 5c are disposed centrally in the outside nozzles 5l, 52 and 53 respectively.
- Figure l0 shows still another example of the composite nozzle 5 in which a large-diameter tube of an elliptical cross-sectional shape is divided into a large-diameter outside nozzle 5l and a small-diameter outside nozzle 52 by a partitioning wall 50 at a site about l/3 as viewed from one end surface of the tube, inside nozzles 5a and 5b having a smaller diameter are disposed in the large-diameter outside nozzle 5l in spaced-apart relationship, and an inside nozzle 5c having a smaller diameter is disposed centrally in the small-diameter outside nozzle 52.
- the soft capsule l0 produced in this way is a seamless soft capsule composed of a unitary structure of a cell a and two filling substances c and h independently encapsulated in it and a cell b and one filling substance d encapsulated in it, as shown in Figure ll.
- the soft capsule l0 shown in Figure ll and the method of production using the composite nozzle shown in Figure l0 give a caspsule in which two filling substances c and h are independently encapsulated in a cell having a cell wall of the same material. Hence, they are beneficial when different drugs which are to be released simultaneously from one cell a but should not be mixed beforehand are used as the filling substances c and h .
- the single composite jet stream formed along the flow of the liquid medium e may be cut to a predetermined length from its leading end in the flowing direction by intermittently increasing the speed of the downwardly flowing stream of the liquid medium e , and intermittently pulling off the composite jet stream downwardly by the quickened downwardly flowing liquid stream, instead of applying a pulsating flow of the liquid medium e sideways to the composite jet stream in the embodiments described above.
- the single composite jet stream can be cut successively to a predetermined length.
- one capsule contains a plurality of cells whose cell walls are made of different materials.
- the present invention is suitable for filling both a substance to be released and absorbed in the stomach and a substance to be released and absorbed in the intestines, or at least two substances having different dissolving times, in a separated state in a single capsule. Since the soft capsule of the invention is seamless, the filled substances can be retained stably while preventing their deterioration by oxidation or otherwise.
- capsules of any desired sizes can be produced, and capsules having a smaller size than in the prior art can be easily produced at low cost.
- a film-forming substance A was filled in tank l, and a film-forming substance B, in tank 2.
- These film-forming substances A and B were extruded from composite nozzle 5 having a outside long diameter (d l ) of l3 mm, an outside short diameter (d s ) of 9 mm and a thickness of l mm ( Figure 2) by metering pumps ll and 2l.
- the amount of each of the film-forming substances A and B was 65.7 g/min.
- a filling substance C was filled in tank 3, and another filling substance D, in tank 4.
- the filling substances C and D were extruded from nozzles 5a and 5b having an outside diameter (di) of 3 mm, an inside diameter of 2 mm and a thickness of 0.5 mm ( Figure 2) by metering pumps 3l and 4l.
- the amount of each of the filling substances extruded was 36 g/min.
- Composite jet streams composed of the film-forming subtances A and B and the filling substances C and D flowed at a rate of l0 meters/min.
- a paraffin oil as a cooling medium e within vessel 7 and heat-exchanger 72 was maintained at 3°C, and flowed downwardly in capsule-forming tank 6 at a flow rate of l5 m/min.
- a pulsating flow of the paraffin oil generated from pulse flow generator 74 was extruded at equal time intervals from pulse flow nozzle 8 accurately l5 times per second.
- capsules were formed at a rate of l5 per second at intervals of about ll mm. After drying, each of the caspsules had a long diameter of 8 mm and a short diameter of 6 mm, and the amount of each of the filling substances was 40 mg per capsule.
- the film-forming substance A is a solution consisting of 20 parts of gelatin, 5 parts by weight of glycerol, 8 parts by weight of sorbitol and 67 parts by weight of purified water which was maintained at about 60°C.
- the film-forming substance B was a solution consisting of l8 parts by weight of gelatin, 5 parts by weight of glycerol, 2.5 parts by weight of sodium alginate and 74.5 parts by weight of purified water which was maintained at about 60°C.
- the filling substances C and D were solutions composed of different drugs which were maintained at about 25°C.
- the film a dissolved in several minutes to release the core c , whereas the film b did not dissolve for more than 2 hours.
- both the films a and b dissolved within 2 to 3 minutes.
- film-forming substances A and B were extruded from a composite nozzle having an outside long diameter (D l ) of 7.5 mm, an outside short diameter (D s ) of 3.5 mm and a thickness of 0.5 mm.
- the amount of each of the film-forming substances A and B extruded was 2l.9 g/min.
- filling substances C and D were extruded extruded from nozzles 5a and 5b having an outside diameter (d i ) of l mm and a thickness of 0.l mm.
- the amount of each of the substances C and D extruded was l8.6 g/min.
- the speed of the composite jet stream at this time was 6 m/min.
- a paraffin oil was used as a cooling medium e and caused to flow in capsule-forming tank 6 at a rate of 22.5 m/min.
- a pulsating flow of the paraffin oil generated from the pulse stream generator 74 was extruded from pulse stream nozzle 8 at equal time intervals accurately 50 times per second.
- capsule-forming tank 6 fifty capsules were formed per second at intervals of about 7.5 mm. After drying, each of the capsule had a long diameter of 3.5 mm and a short diameter of 2.5 mm. The amount of each of the filling substances C and D was about 6.2 mg.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Rigid Containers With Two Or More Constituent Elements (AREA)
- Wrappers (AREA)
Abstract
- (a) preparing a plurality of composite jet streams each consisting of a stream of a film-forming liquid substance for forming a cell wall and within said stream of a film-forming liquid substance a single stream, or a plurality of independent streams, of a filling substance having flowability, the film-forming liquid subtance in at least one of the composite jet streams being different from the film-forming liquid substance in at least one of the other composite jet streams,
- (b) advancing the plurality of composite jet streams in closely spaced relationship into and through a stream of a liquid medium substantially incapable of dissolving the film-forming liquid substance in the flowing direction of the liquid medium stream,
- (c) coalescing the adjacent composite jet streams to each other to form a single composite jet stream in the liquid medium stream,
- (d) cutting the single composite jet stream to a predetermined length successively from its leading end in the liquid medium stream, and
- (e) solidifying the cell walls of the resulting soft capsule.
Description
- This invention relates to a seamless soft capsule, and more specifically, to a seamless soft capsule having a multicellular structure, and a method of its production.
- A multicellular soft capsule having its inside partitioned by a film was recently proposed (see Japanese Laid-Open Patent Publication No. l09520/l985). This patent document states that the multicellular soft capsule is obtained by partitioning a soft capsule shell composed of an upper film and a lower film into two cells by means of a partitioning film, and filling different drugs into the two cells. As a result, two drugs which are not desired to be mixed can be stably included in a single soft capsule. By using materials having different solubilities and dissolving speeds, it is possible to cause one part of a single capsule to be released and absorbed in the stomach and the other part, in the intestines. It is also possible to make one part of the capsule fast-releasing and the other part slow-releasing.
- Since the proposed multicellular soft capsule is produced by a rotary method or a flat plate method, the capsule shell has seams. Hence, in spite of the aforesaid advantages, it has the defect that the filled drugs leak from the seams, or air comes through the seams to deteriorate the contents oxidatively. Furthermore, by the rotary method or the flat plate method, it is difficult to produce multicellular soft capsules having a small size, and moreover, the cost of production becomes high. Furthermore, since both surfaces of the partitioning film in the aforesaid muticellular soft capsule are formed of the same material, if a drug to be filled in one of the cells reacts with the components of the partitioning film, it cannot be included in such a capsule.
- It is an object of this invention to provide a multicellular seamless soft capsule free from the aforesaid defects.
- Another object of this invention is to provide a simple and inexpensive method of producing the aforesaid seamless soft capsule, which can easily give capsules of a small size as well.
- Further objects and advantages of this invention will become apparent from the following detailed description.
- According to one aspect of this invention, there is provided a soft capsule composed of a plurality of cells coalesced to each other and filling substances encapsulated in the individual cells, the wall of at least one of the cells being formed of a material different from a material forming the wall of at least one of the other cells, and said capsule being seamless.
- According to another aspect of this invention, the seamless soft capsule of this invention is produced by a method which comprises
- (a) preparing a plurality of composite jet streams each consisting of a stream of a film-forming liquid substance for forming a cell wall and within said stream of a film-forming liquid substance a single stream, or a plurality of independent streams, of a filling substance having flowability, the film-forming liquid substance in at least one of the composite jet streams being different from the film-forming liquid substance in at least one of the other composite jet streams,
- (b) advancing the plurality of composite jet streams in closely spaced relationship into and through a stream of a liquid medium substantially incapable of dissolving the film-forming liquid substance in the flowing direction of the liquid medium stream,
- (c) coalescing the adjacent composite jet streams to each other to form a single composite jet stream in the liquid medium stream,
- (d) cutting the single composite jet stream to a predetermined length successively from its leading end in the liquid medium stream, and
- (e) solidifying the cell walls of the resulting soft capsule.
- The capsule and the method of producing it in accordance with this invention will be specifically described with reference to the accompanying drawings in which:
- Figure l is a systematic view, partly in section, of one example of an apparatus used to practice the method of this invention in its entirety;
- Figure 2 is an enlarged end view of a composite nozzle in the apparatus shown in Figure l;
- Figure 3 is an enlarged sectional view of a seamless soft capsule produced in accordance with this invention by the apparatus of Figure l;
- Figure 4 is an end view showing another example of the composite nozzle;
- Figure 5 is a sectional view of a seamless soft capsule produced by using the composite nozzle of Figure 4;
- Figure 6 is an end view of still another example of the composite nozzle;
- Figure 7 is a sectional view of a seamless soft capsule produced by using the composite nozzle of Figure 6;
- Figure 8 is an end view of yet another example of the composite nozzle;
- Figure 9 is a sectional view of a seamless soft capsule produced by using the composite nozzle of Figure 8;
- Figure l0 is an end view of a further example of the composite nozzle;
- Figure ll is a sectional view of a soft capsule produced by using the composite nozzle of Figure l0; and
- Figure l2 is an enlarged sectional view of the principal parts of a still further example of the composite nozzle.
- In Figure l, the reference numeral l represents a tank holding a film-forming liquid substance A for forming a cell wall; 2, a tank holding a film-forming substance B which is different from the substance A; 3, a tank holding a filling substance C; and 4, a tank holding another filling substance D. The tanks l, 2, 3 and 4 are individually provided with heating means (not shown) for maintaining the substances A, B, C and D at suitable temperatures for maintaining them flowable. The substances A, B, C and D are supplied to the tanks l, 2, 3 and 4 respectively. Metering pumps ll, 2l, 3l and 4l are provided for feeding the substances A, B, C and D of the tanks l, 2, 3 and 4 to a
composite nozzle 5. Thecomposite nozzle 5, as shown in Figures l and 2, is a duplex nozzle consisting ofoutside nozzles 5l and 52 having a semielliptical cross sectional shape resulting from partitioning an elliptical tube by a partitioningwall 50 at its center and insidenozzles outside nozzles 5l and 52 respectively. Theoutside nozzles 5l and 52 communicate with the tanks l and 2, and theinside nozzles tanks 3 and 4. Thecomposite nozzle 5 faces downwardly along a downwardly flowing stream of a liquid medium e within a capsule-forming tank 6. - The specification of the
composite nozzle 5 may be freely changed according, for example, to the use of the capsule to be produced. For example, for use in making a capsule used as a medicine, a typical specification is that in Figure 2, the elliptical tube has an outside long diameter dℓ of 5 to 20 mm and an outside short diameter ds of 3 to l2 mm, and the inside nozzles have an outside diameter of di of 2 to 9 mm, and the individual tubes have a thickness of 0.l to 2 mm. - The liquid medium e formed, for example, of liquid paraffin is sent to a
heat exchanger 72 from a recovery hopper 7 concurrently acting as a storage tank by means of a pump 7l. In theheat exchanger 72, it is cooled to a moderate temperature of, for example, about 5°C and supplied to the upper portion of the capsule-forming tank 6. It becomes a downwardly flowing stream within the capsule-forming tank 6, and is circulated to the recovery hopper 7 via a capsule recovery tube 6l. A part of the liquid medium e is supplied to a pulse stream-formingdevice 74 by means of apump 73 from thehopper 7. It is converted to a regular pulse stream in the pulse stream-formingdevice 74 and supplied to apulse stream nozzle 8 provided within the capsule-forming tank 6. - The
pulse stream nozzle 8 is a circular nozzle provided immediately below, and coaxially with, thecomposite nozzle 5 and having a slightly larger diameter than the diameter of the elliptical tube of thecomposite nozzle 5. A pulsating stream of the liquid medium e from thenozzle 8 is extruded toward the center of thenozzle 8 from an annular slit formed within thenozzle 8 in such a manner as to surround a single composite jet stream formed by thecomposite nozzle 5 - Film-forming liquid substances A and B for cell wall formation and filling substances C and D to be filled in a capsule are sent under pressure to
nozzles composite nozzle 5 by means of the metering pumps ll, 2l, 3l and 4l. From the nozzle 5l, a composite jet stream composed of a stream of the film-forming substance A and a single stream of the filling substance C is extruded into, and along, the downwardly flowing liquid medium flow within the capsule-forming tank 6, and from thenozzle 52, a composite jet stream composed of a stream of the film-forming substance B and a stream of the filling substance D is likewise extruded into, and along, the downwardly flowing liquid medium stream within the capsule-forming tank 6. Since thenozzles 5l and 52 form an integral unit via a partitioningwall 50, the two composite jet streams extruded as above, nearly simultaneously with their formation, are coalesced to each other into a single composite jet stream within the downwardly flowing stream of the liquid medium e owing to the surface tensions of the film-forming liquid substances A and B. - The speeds of extruding the composite jet streams, and the flow rate of the downwardly flowing stream of the liquid medium e can be varied depending upon, for example, the types of the film-forming liquid substances forming the composite jet streams, the type of the liquid medium e and the size of the composite nozzle, and any skilled person in the art would be able to determine optimum conditions easily by routine experiments. As tentative standards, it is convenient to adjust the extruding speed of each composite jet stream to about 4 to 40 m/min., and the flow rate of the downwardly flowing liquid medium stream to about 5 to 50 m/min.
- The single composite jet stream so formed undergoes impact of the regular pulse stream of the liquid medium e from the
pulse stream nozzle 8, whereby as shown in Figure l, necks or narrowed parts are formed at certain intervals beginning with its leading end. The jet stream is drawn downwardly by the downwardly flowing stream of the liquid medium e, and successively cut off at the neck portions by the downwardly drawing force. Each cut droplet f contains the filling substances C and D encapsulated in the film-forming liquid substances A and B by the surface tension of the substances A and B, and is formed into a seamless capsule, which is roundish as a whole, while moving down through the downwardly flowing stream of the liquid medium e. The capsules formed advance to thehopper 7 via the recovery tube 6l while being cooled and solidified. In thehopper 7, the capsules are separated from the liquid medium e by aseparator 70, supplied to a conveyor 9 provided on one side of theseparator 70, and sent to a drying step where they are dried to produce a final product. - By the method described above, there are obtained unitary seamless soft capsules l0 in which a cell a formed of the film-forming substance A and the filling substance C encapsulated in it is coalesced to a cell b formed of the film-forming substance B which is different from the substance A and the filling substance D encapsulated in it, and the cell wall is of a double structure at the coalesced part, as shown in Figure 3.
- The film-forming substance for cell formation may be any material which can be formed into a thin film from its melt or solution, and after film formation can be solidified by cooling and/or drying. Substances usually employed in forming the shell of a soft capsule may be used in this invention. Examples include film-forming substances composed of gelatin or gelatin derivatives such as succinic gelatin and incorporated therein, plasticizers [such as glycerol, sorbitol, propylene glycol and Carbowax (polyethylene glycol)], essences and flavors (such as peppermint oil, cinnamon oil and strawberry), dyes (such as yellow No. 4, yellow No. 5, red No. l, blue No. l and copper chlorophyllin), opacifying agents (such as titanium dioxide and red iron oxide), solubility controlling agents (such as cellulose acetate phthalate, alkali metal salts of hydroxypropylmethyl cellulose, alkali metal salts of hydroxymethyl cellulose acetate succinate, alkali metal salts of alginic acid, alkali metal salts of polyacrylic acid, methyl cellulose, carboxymethyl cellulose, casein, collagen, agar powder, polyvinyl alcohol and pectin)), etc. selected as desired. It is generally used as a liquid by dissolving it in water under heat.
- The filling substance to be encapsulated in each cell of the soft capsule of this invention can be any drug which does not dissolve the cell wall nor react with the components of the cell wall. It is preferably liquid when it is to be filled in the cell in accordance with the method of this invention. Accordingly, when the drug is a solid, it is desirably filled in a flowable state as a solution, emulsion or suspension.
- According to the method of this invention, by using a combination of two or more suitable film-forming substances selected from those exemplified above, at least one of a plurality of cells constituting the resulting soft capsule can have a different dissolving time in the digestive tract from at least one of the other cells (for example, whether fast-releasing or slow-releasing), or at least one cell may have different dissolving characteristic from at least one of the other cells (for example, whether released and adsorbed in the stomach or the intestines).
- Furthermore, in the present invention, the filling substances to be encapsulated in the cells may be varied from cell to cell. As a result, a single capsule may be obtained in which a drug expected to be fast-acting is filled in a fast-dissolving cell and a drug desired to be slow-acting is filled in a slow-dissolving cell. Alternatively, a single capsule cell may be obtained in which a drug expected to develop its effect in the stomach is filled in a cell soluble at the stomach, and another drug expected to develop its effect in the intestines is filled in a cell soluble at the intestines.
- The shape of the soft capsule l0 can be selected by changing the shape of the end surface of the
composite nozzle 5 on the extrusion side. Some modified examples of thecomposite nozzle 5 will be described below. - The
composite nozzle 5 shown in Figure 4 is composed of duplex outsidenozzles 5l and 52 having a cocoon-shaped cross section and smaller-diameter insidenozzles outside nozzles 5l and 52 respectively. The capsule l0 obtained by using thiscomposite nozzle 5 has a cocoon-shaped cross-section as shown in Figure 5. It is a seamless soft capsule in which filling substances c and d are independently encapsulated in cells a and b. - Figures 6 and 8 show other examples of the
composite nozzle 5. Thesenozzles 5 are each divided into threeoutside nozzles partitioning walls 50 and smaller-diameter insidenozzles outside nozzles outside nozzles inside nozzles composite nozzles 5, there can be produced seamless soft capsules l0 in which the filling substances c, d and h are encapsulated in the cells a, b and g formed from cell walls of different materials, as shown in Figures 7 and 9. - Figure l0 shows still another example of the
composite nozzle 5 in which a large-diameter tube of an elliptical cross-sectional shape is divided into a large-diameter outside nozzle 5l and a small-diameter outsidenozzle 52 by apartitioning wall 50 at a site about l/3 as viewed from one end surface of the tube, insidenozzles inside nozzle 5c having a smaller diameter is disposed centrally in the small-diameter outsidenozzle 52. - When the
composite nozzle 5 shown in Figure l0 is used, different film-forming substances and different filling substances are simultaneously extruded along the stream of the liquid medium in the apparatus shown in Figure l from theoutside nozzles 5l and 52, and theinside nozzles - The soft capsule l0 produced in this way is a seamless soft capsule composed of a unitary structure of a cell a and two filling substances c and h independently encapsulated in it and a cell b and one filling substance d encapsulated in it, as shown in Figure ll.
- The soft capsule l0 shown in Figure ll and the method of production using the composite nozzle shown in Figure l0 give a caspsule in which two filling substances c and h are independently encapsulated in a cell having a cell wall of the same material. Hence, they are beneficial when different drugs which are to be released simultaneously from one cell a but should not be mixed beforehand are used as the filling substances c and h.
- Even when the
outside nozzles 5l and 52 of thecomposite nozzle 5 are not unitary but are slightly spaced from each other as shown in the embodiment given in Figure l2, composite jet streams extruded separately from thenozzles 5l and 52 are coalesced into a single composite jet stream by the pulsating flow of the liquid medium, and cut to a predetermined length from its leading end in the flowing direction. Hence, the method of this invention can be practiced in the same way by using thecomposite nozzle 5 shown in Figure l2. - The single composite jet stream formed along the flow of the liquid medium e may be cut to a predetermined length from its leading end in the flowing direction by intermittently increasing the speed of the downwardly flowing stream of the liquid medium e, and intermittently pulling off the composite jet stream downwardly by the quickened downwardly flowing liquid stream, instead of applying a pulsating flow of the liquid medium e sideways to the composite jet stream in the embodiments described above. By this alternative procedure, too, the single composite jet stream can be cut successively to a predetermined length.
- According to this invention, one capsule contains a plurality of cells whose cell walls are made of different materials. Hence, the present invention is suitable for filling both a substance to be released and absorbed in the stomach and a substance to be released and absorbed in the intestines, or at least two substances having different dissolving times, in a separated state in a single capsule. Since the soft capsule of the invention is seamless, the filled substances can be retained stably while preventing their deterioration by oxidation or otherwise. According to the method of this invention, capsules of any desired sizes can be produced, and capsules having a smaller size than in the prior art can be easily produced at low cost.
- The following Example illustrates the present invention more specifically.
- Referring to Figure l, a film-forming substance A was filled in tank l, and a film-forming substance B, in tank 2. These film-forming substances A and B were extruded from
composite nozzle 5 having a outside long diameter (dℓ) of l3 mm, an outside short diameter (ds) of 9 mm and a thickness of l mm (Figure 2) by metering pumps ll and 2l. The amount of each of the film-forming substances A and B was 65.7 g/min. - In the meantime, a filling substance C was filled in tank 3, and another filling substance D, in
tank 4. The filling substances C and D were extruded fromnozzles - A paraffin oil as a cooling medium e within
vessel 7 and heat-exchanger 72 was maintained at 3°C, and flowed downwardly in capsule-forming tank 6 at a flow rate of l5 m/min. A pulsating flow of the paraffin oil generated frompulse flow generator 74 was extruded at equal time intervals frompulse flow nozzle 8 accurately l5 times per second. - Within the capsule-forming tank, capsules were formed at a rate of l5 per second at intervals of about ll mm. After drying, each of the caspsules had a long diameter of 8 mm and a short diameter of 6 mm, and the amount of each of the filling substances was 40 mg per capsule.
- The film-forming substance A is a solution consisting of 20 parts of gelatin, 5 parts by weight of glycerol, 8 parts by weight of sorbitol and 67 parts by weight of purified water which was maintained at about 60°C.
- The film-forming substance B was a solution consisting of l8 parts by weight of gelatin, 5 parts by weight of glycerol, 2.5 parts by weight of sodium alginate and 74.5 parts by weight of purified water which was maintained at about 60°C.
- The filling substances C and D were solutions composed of different drugs which were maintained at about 25°C.
- By the above procedure, there was produced a seamless soft capsule l0 which contained a core c composed of the filling substance C encapsulated in a gastric-soluble film a composed of the film-forming substance A and a core d composed of the filling substance D encapsulated in an enteric-soluble film b independently from each other, with the film portion separating the core c from the core d being of a double structure.
- When the resulting soft capsule l0 was immersed in the first solution (gastric juice) stipulated in the Revised Method of Testing Disintegration in accordance with Japanese Pharmacopoeia, the film a dissolved in several minutes to release the core c, whereas the film b did not dissolve for more than 2 hours.
- When the soft capsule l0 was immersed in the second solution (intestinal fluid) in the Revised Method of Testing Disintegration in accordance with Japanese Pharmacopoeia, both the films a and b dissolved within 2 to 3 minutes.
- In the same way as in Example l, film-forming substances A and B were extruded from a composite nozzle having an outside long diameter (Dℓ) of 7.5 mm, an outside short diameter (Ds) of 3.5 mm and a thickness of 0.5 mm. The amount of each of the film-forming substances A and B extruded was 2l.9 g/min.
- In the meantime, filling substances C and D were extruded extruded from
nozzles - A pulsating flow of the paraffin oil generated from the
pulse stream generator 74 was extruded frompulse stream nozzle 8 at equal time intervals accurately 50 times per second. - In capsule-forming tank 6, fifty capsules were formed per second at intervals of about 7.5 mm. After drying, each of the capsule had a long diameter of 3.5 mm and a short diameter of 2.5 mm. The amount of each of the filling substances C and D was about 6.2 mg.
Claims (9)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT86117918T ATE67401T1 (en) | 1985-12-26 | 1986-12-23 | SOFT SEAMLESS CAPSULES. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP297182/85 | 1985-12-26 | ||
JP29718285 | 1985-12-26 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0228067A2 true EP0228067A2 (en) | 1987-07-08 |
EP0228067A3 EP0228067A3 (en) | 1988-06-01 |
EP0228067B1 EP0228067B1 (en) | 1991-09-18 |
Family
ID=17843233
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP86117918A Expired EP0228067B1 (en) | 1985-12-26 | 1986-12-23 | Seamless soft capsule |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0228067B1 (en) |
JP (1) | JPH06104193B2 (en) |
AT (1) | ATE67401T1 (en) |
DE (1) | DE3681572D1 (en) |
ES (1) | ES2024418B3 (en) |
GR (1) | GR3002754T3 (en) |
Cited By (10)
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EP0585368A1 (en) * | 1991-04-25 | 1994-03-09 | Univ Brown Res Found | Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products. |
US5800829A (en) * | 1991-04-25 | 1998-09-01 | Brown University Research Foundation | Methods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core |
GB2338896A (en) * | 1998-07-02 | 2000-01-12 | Reckitt & Colmann Prod Ltd | Chewable oral dosage unit with multilpe reservoirs |
WO2001054645A1 (en) * | 2000-01-26 | 2001-08-02 | Jongkang Yi | A soft capsule packaging machine |
WO2003094897A1 (en) * | 2002-05-09 | 2003-11-20 | Chugai Seiyaku Kabushiki Kaisha | Photostabilized soft capsule |
WO2004024057A1 (en) * | 2002-09-13 | 2004-03-25 | Freund Corporation | Process for producing seamless capsule quickly dissolving in the oral cavity |
US7025911B2 (en) | 2002-09-13 | 2006-04-11 | Freund Corporation | Manufacturing method for oral quick-dissolving seamless capsule |
WO2007066178A2 (en) * | 2005-12-08 | 2007-06-14 | Mcneil-Ppc, Inc. | Capsules or microcapsules with stable outer hydrophilic layer for rapid buccal disintegration |
US7670612B2 (en) | 2002-04-10 | 2010-03-02 | Innercap Technologies, Inc. | Multi-phase, multi-compartment capsular delivery apparatus and methods for using same |
US7691407B2 (en) | 1999-07-30 | 2010-04-06 | Smithkline Beecham Plc | Multi-component pharmaceutical dosage form |
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US7883721B2 (en) | 2001-01-30 | 2011-02-08 | Smithkline Beecham Limited | Pharmaceutical formulation |
GB0102342D0 (en) | 2001-01-30 | 2001-03-14 | Smithkline Beecham Plc | Pharmaceutical formulation |
JP2006521366A (en) * | 2003-03-28 | 2006-09-21 | シグモイド・バイオテクノロジーズ・リミテッド | Solid oral dosage forms containing seamless microcapsules |
TW200526274A (en) | 2003-07-21 | 2005-08-16 | Smithkline Beecham Plc | Pharmaceutical formulations |
WO2005044174A1 (en) * | 2003-11-07 | 2005-05-19 | Freund Corporation | Seamless capsule manufacturing method, seamless capsule manufacturing device, and seamless capsule |
TW201240679A (en) | 2004-03-12 | 2012-10-16 | Capsugel Belgium Nv | Pharmaceutical formulations |
JP5183104B2 (en) * | 2006-06-19 | 2013-04-17 | 森下仁丹株式会社 | Multiple soft capsules for bad breath removal |
US20090297455A1 (en) * | 2006-08-09 | 2009-12-03 | Koninklijke Philips Electronics N.V. | Device for and a method of activating a physiologically effective substance by ultrasonic waves, and a capsule |
JP2009119148A (en) * | 2007-11-16 | 2009-06-04 | Freunt Ind Co Ltd | Apparatus and method for producing multi-color seamless capsule |
KR101974680B1 (en) * | 2011-11-16 | 2019-05-02 | 모리시타 진탄 가부시키가이샤 | Insect pest repellant |
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- 1986-12-23 ES ES86117918T patent/ES2024418B3/en not_active Expired - Lifetime
- 1986-12-23 DE DE8686117918T patent/DE3681572D1/en not_active Expired - Fee Related
- 1986-12-23 AT AT86117918T patent/ATE67401T1/en not_active IP Right Cessation
- 1986-12-23 EP EP86117918A patent/EP0228067B1/en not_active Expired
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WO2004024057A1 (en) * | 2002-09-13 | 2004-03-25 | Freund Corporation | Process for producing seamless capsule quickly dissolving in the oral cavity |
WO2007066178A2 (en) * | 2005-12-08 | 2007-06-14 | Mcneil-Ppc, Inc. | Capsules or microcapsules with stable outer hydrophilic layer for rapid buccal disintegration |
WO2007066178A3 (en) * | 2005-12-08 | 2007-09-07 | Warner Lambert Co | Capsules or microcapsules with stable outer hydrophilic layer for rapid buccal disintegration |
Also Published As
Publication number | Publication date |
---|---|
ATE67401T1 (en) | 1991-10-15 |
DE3681572D1 (en) | 1991-10-24 |
JPS62234542A (en) | 1987-10-14 |
JPH06104193B2 (en) | 1994-12-21 |
ES2024418B3 (en) | 1992-03-01 |
EP0228067B1 (en) | 1991-09-18 |
GR3002754T3 (en) | 1993-01-25 |
EP0228067A3 (en) | 1988-06-01 |
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