JP5053341B2 - Method for producing laminated film edible oral administration agent - Google Patents

Description

The present invention is a novel film-type edible oral dosage form having a multilayer structure in which a very thin layer related to an edible oral dosage among pharmaceutical products, quasi drugs, cosmetics, foods and the like is laminated. The present invention relates to an improved manufacturing method.
Specifically, it consists only of substances that are recognized as foods and food additives and / or pharmaceuticals and pharmaceutical additives that are approved for oral administration. For example, the oral cavity such as the maxillary or gum mucosa or nasal mucosa. Mucosal patches, oral disease prevention patches that are applied to the affected area in the oral cavity for treatment and protection, oral therapeutic patches, oral malodor prevention patches, oral malodor prevention patches, and the oral digestive tract Oral pharmaceuticals for oral administration to be absorbed in the oral cavity, quasi-drugs having effects such as deodorizing action and health maintenance effect, and oral preparations such as foods, etc. The present invention relates to a novel and improved production method for producing an intraoral administration agent in the form of a laminated film having high productivity.

Various techniques have been proposed in the art for making oral preparations such as pharmaceuticals, quasi-drugs, cosmetics, and foods into sheets or films into oral preparations.
For example, Patent Document 1 discloses that a preparation solution for oral administration in which a film forming agent, a gel forming agent, an active substance, an inert filler, and a polar solvent are mixed is spread on a siliconized paper by a coating device, and is added at 80 ° C. It is described that a sheet-shaped oral preparation is produced by drying for ˜15 minutes, but it is not a structure in which the oral preparation layer is laminated in multiple layers.

In Patent Document 2, the preparation solution for buccal administration is coated on a suitable carrier material, dried, and then the obtained film-like buccal administration agent is peeled off from the carrier material to obtain a film buccal administration agent. The carrier material can be non-siliconized polyethylene terephthalate film, non-siliconized kraft paper, polyethylene impregnated kraft paper, or non-silicone polyethylene film, and the coating technique is knife over roll It is disclosed that it is preferable to use a coating head.
However, it is not taught to produce a film oral administration agent having a structure in which an oral administration agent layer is laminated in multiple layers.

  Patent Document 3 describes a sheet-like or tape-like oral administration agent for administering buprenorphine to the oral mucosa, and a plurality of sheet-like or oral administration layer preparation liquids containing buprenorphine are applied. Although a manufacturing method is described in which tape-like materials are combined to form a multilayer material to form a multilayer, no specific method for manufacturing a multilayer structure is taught.

Patent Document 4 describes a film oral administration agent having a multilayer structure comprising a drug-containing layer, a non-adhesive layer, and an adhesive layer.
In addition, as a manufacturing method, it is necessary to repeatedly apply or spray the oral preparation layer preparation liquid and dry the applied or sprayed oral preparation layer preparation liquid on a polytetrafluoroethylene petri dish. A method for obtaining a film-like intraoral administration agent having a multilayer structure is disclosed in Examples, but such a production method can be used on a laboratory scale but cannot be industrially adopted.
In addition, when applying or spraying another oral preparation layer preparation solution by hand on the formed oral preparation layer to form multiple layers, the oral preparation preparation solution is applied quantitatively and accurately. Or, it is difficult to spray, the exact amount of the drug component or the like cannot be controlled, and the obtained multilayer film-shaped oral administration agent cannot satisfy the quantitative accuracy required for the pharmaceutical preparation.

Patent Document 5 filed by the same applicant as the present application includes three types of layers, a, b, c, b, coating layer (a), drug layer I (b), and drug layer II (c). A film-like lozenge intraoral administration agent that is laminated in the order of a has been proposed.
As a manufacturing method of this film-like lozenge oral preparation, a method of forming a desired multilayer laminated structure by repeating spreading and drying of each edible oral preparation layer preparation liquid onto a polyester release film is described. Has been.

Japanese Patent No. 2559301 JP-T-2001-504106 JP-T-2001-506640 JP-A-9-235220 JP 2001-288074 A

In producing the multi-layer laminated film lozenge intraoral administration agent described in Patent Document 5 by the same applicant as that of the present application, the applicant must continuously move the resin film as shown in FIG. In addition, a coating apparatus 50 that continuously applies and dries the edible oral preparation layer preparation solution is employed.
This coating apparatus 50 guides the resin film 52 set on the resin film unwinding shaft 51 into the drying furnace 55 through the guide roll 53 and the doctor roll 54 and winds it with the resin film winding shaft 56. The resin film 52 is continuously moved.
During this time, the edible oral dosage layer preparation liquid 58 supplied to the edible oral dosage layer preparation liquid supply dam part 57 is applied onto the resin film. At this time, the resin film 52 on the guide roll 53 and A predetermined application amount can be obtained by adjusting the clearance with the doctor roll 54 to a predetermined dimension (see a partially enlarged view).
The coating layer 58a on the resin film 52 thus formed is dried by hot air uniformly blown from the hot air blowing device 59 by passing through the drying furnace 55, and a resin in which an edible oral dosage layer is formed. The film 60 is wound around the winding shaft 56 in a roll shape.

  Next, the oral dosage layer-forming resin film 60 wound around the winding shaft 56 in a roll shape is attached to the unwinding shaft 51 again, and an edible oral dosage layer preparation liquid 58 having the same composition or a different composition is prepared. A resin film in which two layers of edible oral administration agent layers are laminated can be produced by supplying the dam part 57, applying and drying again, and winding it on the winding shaft 56. By repeatedly performing such coating and drying, a film-like lozenge intraoral administration agent having a required multilayer structure can be produced with better productivity than the conventional methods described above.

However, even when the coating method as shown in FIG. 11 is adopted, in the same manner as in the conventional method, when a film-like edible oral administration agent having a multilayer structure is produced by repeated application and drying, Thus, it became difficult to accurately control the application amount of the edible oral dosage layer preparation liquid 58, and it was found that the quantitative accuracy required for the pharmaceutical preparation could not be satisfied.
That is, in the first application, the predetermined application amount can be accurately controlled by setting the clearance between the doctor roll 54 and the resin film 52 to a predetermined dimension.
However, the thickness of the dry edible oral dosage layer formed by the drying process after the first application varies depending on minute fluctuations in the conditions of the drying process and disturbances such as temperature and humidity of the day.
As a result, in the second application, no matter how accurate the clearance dimension between the doctor roll 54 and the resin film 52 is, the thickness to which the edible oral dosage layer preparation liquid 58 is actually applied is the first time. Since the gap between the upper surface of the formed dry edible oral dosage layer and the doctor roll 54 is formed, the coating thickness of the second edible oral dosage layer is the first edible oral dosage layer coating thickness. It will be further fluctuated due to fluctuations.
It is very difficult to measure the thickness variation after the drying process of the edible oral dosage layer 58a applied for the first time.

The inaccuracy of the coating amount of such an edible oral preparation layer preparation solution tends to increase as the number of coating / drying increases.
Moreover, as the number of times of application / drying increases, the time required for drying becomes longer, and the drying of the edible oral dosage layer for the second time takes 1.5 times the first time, and the third time. Takes twice as long.

  Therefore, the first object of the present invention is to satisfy the quantitative accuracy required for pharmaceutical preparations and the like even in the production of a film-shaped edible oral preparation having a multilayer structure, and also to the drying process and the like. An object of the present invention is to provide a new and improved method for producing an edible oral administration agent in the form of a laminated film having a multilayer structure in which extremely thin layers are laminated with excellent productivity, without causing time constraints. .

Furthermore, the second object of the present invention is to provide a further improved production method in a new and improved production method of a laminated film-like edible oral preparation having a multilayer structure in which extremely thin layers are laminated. There is to do.
That is, in order to obtain a film-shaped edible oral dosage form having a multilayer structure formed by laminating a plurality of thin layers, the edible oral dosage form preparation solution is spread on the surface of the resin film and dried. To produce a resin film in which an edible oral dosage layer of a predetermined thickness is formed, and in a state where these resin films are superposed with each other such that the edible oral dosage layer is opposed to each other, An edible oral dosage agent is applied when the edible oral dosage layer is pressure-bonded from the back surface and one of the two resin films sandwiching the edible oral dosage layer is adhered to each other. Has the strength to be able to form a film by itself, so that the edible oral dosage layer adheres to the peeled resin film, and the intended other resin film Edible oral preparation There was that situation that can not be held to arise.
The present invention solves this problem and presses a plurality of extremely thin layers having a thickness of several hundred μm to several tens of μm to form a thin multilayer structure having an overall thickness of about several thousand μm to several tens of μm. A laminated film that can peel only one of the two resin films sandwiching the edible edible oral dosage layer and securely hold the edible oral dosage layer on the other intended resin film Another object of the present invention is to provide a method for producing a edible edible oral preparation.

That is, the method for producing a laminated film-type edible oral dosage form according to claim 1 of the present invention, which is carried out in a batch system in which a roll film is formed in an intermediate step, has a predetermined thickness on the surface of a resin film and is acceptable. An oral dosage layer forming step of forming an edible oral dosage layer containing an edible thermoplastic material by coating and drying, and an oral dosage layer formation obtained in the oral dosage layer forming step Two roll films each formed with an edible oral dosage layer of the same component or different components obtained in the roll film forming step and the roll film forming step of winding a resin film in a roll shape to form the roll film, respectively while rewinding, scratch pressure applied from the back surface of the resin film overlaid such that each edible buccal adhesive layer surface are opposed to each other as 0.1~0.7MPa From a roll film orally administered agent layer pressure-bonding step for bringing the edible oral dosage layer into close contact with each other by pressurizing with the pressing roll, and the edible oral dosage layer adhering the two resin films superimposed above One of the resin films to be peeled and peeled is pre-peeled on both the surface on which the edible oral dosage layer is formed and the back surface on the opposite side. The other resin film holding the oral administration agent layer includes at least a resin film peeling step in which a release treatment is performed in advance on the back surface on which the edible oral administration agent layer is not formed. To do.
Similarly, the method for producing a laminated film-like edible oral dosage form according to claim 2 of the present invention, which is carried out in a batch system in which a roll film is formed in an intermediate step, has a predetermined thickness on the surface of the resin film, and An oral dosage layer forming step for forming an edible oral dosage layer containing an edible thermoplastic material by coating and drying, and an oral dosage layer obtained in the oral dosage layer forming step A roll film forming step of forming a roll film by winding a forming resin film, and two roll films formed with an edible oral dosage layer of the same component or different components obtained in the roll film forming step. While rewinding each, the edible oral administration agent layer surface is overlapped so as to face each other, and the pressure when pressing from the back surface of the resin film is 0.1 to 0.7 MPa. By pressing with a pressure roll, the roll film oral dosage layer pressure-bonding step for bringing the edible oral dosage layer into close contact with each other, and the two resin films sandwiching the edible oral dosage form layer in close contact with each other The above two sandwiching the edible oral dosage layer closely adhered to each other along the peripheral surface of the peeling roll provided in the conveying direction while being conveyed while being substantially aligned with the tangential direction in the pressing part of the pair of pressing rolls By pulling only one of the two resin films in a direction different from the transport direction and continuing to transport the other resin film holding the edible oral dosage layer in the transport direction, Only one of the two resin films is peeled off, and the peeled one resin film has a surface on which an edible oral dosage layer is formed. The other resin film that has been peeled in advance on both sides of the back side opposite to the above and that holds the edible oral dosage layer without being peeled, has at least an edible oral dosage layer. And a resin film peeling step in which a peeling process is performed in advance on the back surface that is not formed.
In addition, in the method for producing a laminated film-shaped edible oral dosage agent of the present invention by this batch method, a desired number of edible oral dosage layers can be formed as required.
This method relates to claim 3 of the present invention, wherein the oral cavity is formed by applying and drying an edible oral dosage layer containing an edible thermoplastic substance having a predetermined thickness on the surface of the resin film. A roll film forming step of forming the roll film by winding the oral dosage layer forming resin film obtained in the internal dosage layer forming step, the oral dosage layer forming step, and the roll film forming step; The two roll films formed with the edible oral dosage layer of the same component or different components obtained in step 1 above were rewound, and the respective edible oral dosage layer layers were laminated so that they face each other. A roll film for intraoral administration that brings the edible oral dosage layer into close contact with each other by pressurizing with a pair of pressing rolls at a pressure of 0.1 to 0.7 MPa when pressing from the back side Provided in the transport direction while transporting the two resin films sandwiching the edible intraoral dosage layer adhering to each other substantially in the tangential direction in the pressurizing part of the pair of pressing rolls, and the layer pressing step Along with the peripheral surface of the peeling roll, only one of the two resin films sandwiching the edible oral dosage layer closely attached to each other is drawn in a direction different from the transport direction, and the edible oral cavity By continuing to convey the other resin film holding the internal dosage layer in the conveying direction, only one of the two superimposed resin films is peeled off, and the other resin film to be peeled off The edible oral dosage layer is peeled in advance on both the surface on which the edible oral dosage layer is formed and the opposite side, and the edible oral dosage layer is held without peeling. In the other resin film, at least the edible oral dosage layer is not formed on the back side of the resin film peeling step that has been subjected to the peeling treatment in advance, and the adhesive multiple layers obtained in the resin film peeling step are allowed. In the multiple oral administration layer holding roll film forming process of forming a roll film by winding a resin film holding the edible oral dosage layer in a roll, and in the multiple oral administration layer holding roll film forming process A multi-oral dosage layer holding roll film for holding the obtained multi-layered edible oral administration agent, and a single layer of the same or different components as the above-mentioned multi-layered edible oral administration layer Alternatively, each edible oral dosage layer surface faces each other while rewinding another roll film formed with a plurality of edible oral dosage layers. In addition, a roll film multiple intraoral dosage layer crimping step for bringing the edible oral dosage layer into close contact with each other by applying pressure from a back surface of the resin film with a pair of pressing rolls, While the two resin films sandwiching the edible intraoral administration layer of the multi-layer are conveyed while being substantially aligned with the tangential direction in the pressurizing part of the pair of pressing rolls, on the peripheral surface of the peeling roll provided in the conveying direction Along one side of the two resin films sandwiching the multi-layered edible oral administration agent layer closely adhered to each other in the direction different from the transport direction, and the multi-layered edible oral cavity By continuing to transport the other resin film holding the dosage layer in the transport direction, only one of the two superimposed resin films is used. And the resin film peeled off step of peeling off, characterized in that it comprises a.
According to the invention of claim 3 as described above, it is possible to efficiently produce a laminated film-shaped edible oral administration agent in which a desired number of edible oral administration agent layers are laminated by using a pressure bonding method. It becomes possible.

As explained in detail above, according to the method for producing a laminated film edible oral dosage form of the present invention using a pressure bonding method in which the edible oral dosage form layers are brought into close contact with each other by a pair of pressing rolls, the edible oral cavity is used. Compared with the conventional multi-layer coating method by repeatedly applying and drying the internal preparation layer preparation solution, the quantitative accuracy required for pharmaceutical preparations is improved, and the drying process is time-constrained. The edible oral administration agent in the form of a laminated film having a multi-layer structure in which extremely thin layers are laminated can be obtained.
Furthermore, the layered structure obtained by the conventional layer coating method is obtained by the method of the present invention using the pressure bonding method, while the boundary of each layer of each edible oral administration agent layer is unclear and blurry. The resulting laminated structure can clearly identify the boundaries of each edible oral dosage layer, and such a laminated structure can be said to be a novel structure of a laminated film-like oral dosage agent obtained for the first time by the present invention. .
In addition, the fact that the boundaries of each layer of edible oral preparations that are laminated can be clearly identified means that the edible oral preparation layers are clearly separated without being mixed in the vicinity of the boundaries. As a result, the active ingredient concentration in each edible oral dosage layer can be accurately controlled.
Furthermore, according to the method for producing a laminated film edible oral dosage form of the present invention, the film-shaped oral dosage form has a strength capable of forming a film by itself, so that it is peeled off. The oral dosage layer adheres to the other resin film, and it is easy to cause trouble that the oral dosage layer cannot be held on the other intended resin film. While the two sandwiched resin films are transported while being substantially aligned with the tangential direction in the pressure part of the pair of pressing rolls, the edible oral administration closely adhered to each other along the peripheral surface of the peeling roll provided in the transporting direction. Only one of the two resin films sandwiching the agent layer is drawn in a direction different from the conveying direction, and the other resin film holding the edible oral dosage layer is retained. By continuing to convey the film in the conveying direction, it becomes possible to reliably hold the oral dosage layer on the other intended resin film, and the edible oral dosage form is excellent in productivity. The manufacturing method can be provided.

FIG. 1 is an explanatory view showing an embodiment of a crimping apparatus for carrying out the method of the present invention. (Example) FIG. 2 is an explanatory diagram of a conveyance direction of a pressure-bonded product delivered from a pressing roll in the pressure-bonding apparatus of FIG. (Example) FIG. 3 is an explanatory view of a positional relationship between a peeling roll of a film to be peeled and a winding shaft in the crimping apparatus of FIG. 1. (Example) 4 is an explanatory view showing an example of the operation of the crimping apparatus of FIG. (Example) FIG. 5 is an explanatory view showing an embodiment of a slitter device arranged in connection with the crimping device of FIG. 1. (Example) FIG. 6 is a perspective view showing an embodiment of an intraoral administration device for a final crimped product obtained by the method of the present invention. (Example) FIG. 7 is a perspective view showing another embodiment of the intraoral administration device for the final pressure-bonded product obtained by the method of the present invention. (Example) FIG. 8 is an explanatory view showing another embodiment of the crimping apparatus for carrying out the method of the present invention. (Example) FIG. 9 is an explanatory diagram of the laminated structure obtained in the example of the present invention. (Example) FIG. 10 is a photomicrograph (800 ×) showing a cross section of a final pressure-bonded product obtained by the method of the present invention and a similar laminated product obtained by a conventional lamination coating method. (Example) FIG. 11 is an explanatory view showing an example of a coating apparatus for carrying out a conventional lamination coating method.

In the method for producing a laminated film edible oral dosage form of the present invention, when an edible oral dosage form layer is applied and dried on the resin film surface, a coating apparatus 50 as shown in FIG. 11 is used. Can be preferably used.
In this coating apparatus 50, the resin film 52 unwound from the resin film unwinding shaft 52 passes through the drying furnace 55 and is wound around the resin film winding shaft 56, whereby the resin film 52 continuously moves. During this period, the edible oral dosage layer preparation liquid 58 stored in the edible oral dosage layer preparation liquid supply dam part 57 is applied onto the resin film 52 and dried. As a result, an edible oral dosage layer is formed on the surface of the resin film.
The application amount of the edible oral dosage layer can be controlled by adjusting the clearance between the doctor roll 54 and the resin film 52 in the dam portion 57.

Using such a coating apparatus 50, a plurality of edible oral dosage layers are formed on the resin film surface by repeating the application and drying of the edible oral dosage layer preparation solution a plurality of times. Can do.
Also, by repeating the application and drying of the edible oral preparation layer preparation solution of the same component or different components a plurality of times, the thickness of the edible oral preparation layer of the same component is increased, or it consists of various components It is also possible to form a plurality of edible oral dosage layers.

However, as described above, as the number of coating / drying increases, the coating amount of the edible oral dosage layer preparation solution becomes inaccurate and the time required for drying becomes longer. Is preferably about 2 to 3 times, preferably once.
Moreover, it is desirable that the thickness of the edible intraoral administration layer formed on the resin film surface by one application is about 1 to 300 μm.
When the coating thickness at one time is thicker than 300 μm, the drying time becomes too long and the productivity is deteriorated.

Using the coating apparatus 50 of FIG. 11, a single coating or a plurality of coatings with the same component or different components is performed, and a desired edible oral dosage layer is formed. Manufacturing.
The several types of intraoral dosage layer forming resin films 60 manufactured in this way are each wound into a roll shape by a take-up shaft 56 to be a roll film, and thereafter, using the crimping apparatus 10 illustrated in FIG. Two oral administration layer-forming resin films are pressure-bonded to produce a laminated film-shaped edible oral administration agent.

  That is, the pressure bonding apparatus 10 illustrated in FIG. 1 is formed by using, for example, two resin films each having a predetermined thickness of an edible intraoral administration layer manufactured using the coating apparatus 50 illustrated in FIG. , And a pair of pressing rolls 15 and 15 that pressurize from the back side of each resin film, and a plurality of press rolls that are in close contact with each other. A peeling roll 17 for peeling only one sheet 16a of two resin films (crimped product) 16 sandwiching an edible oral dosage layer, a take-up shaft 18 for winding the peeled film, and a plurality of doses remaining after peeling A take-up shaft 19 for winding the agent layer holding resin film (crimp product) 16b is provided.

  The take-up shaft 19 is used as a drive roll, one of the pressing rolls 15 and 15 is used as a drive roll, and a separate drive roll 34 is disposed between the peeling roll 17 and the take-up shaft 19. One drive roll serves as a transport mechanism for the multiple-dose layer-holding resin film, and can transport the multiple-dose layer-holding resin film 16b delivered from the pressing rolls 15 and 15 to the take-up shaft 19.

The direction in which the multiple-dose-layer-holding resin film 16b is conveyed by the conveyance mechanism is the same as the tangential direction in the pressure part of the pair of press rolls 15 and 15 as shown in FIG. 2, the deviation between the tangential direction T and the conveyance direction C is approximately within 30 °, preferably within 15 °, more preferably within 10 °, as shown in FIG. Just do it.
In other words, the conveyance direction may be within the range between the arrow Y1 and the arrow Y2 in FIG.

The edible oral dosage layer composed of a plurality of layers is strong enough to form a self-supporting film, so that the edible oral dosage layer adheres to one of the resin films 16a to be peeled off. This may cause a situation in which the other edible oral dosage layer cannot be held on the other resin film 16b.
Therefore, in the present invention, the peeling roll 17 is installed at a position along the conveyance direction of the multiple-dose layer-holding resin film delivered from the pressing rolls 15 and 15, and the multiple-dose layers that are in close contact with each other are provided. Only one sheet 16a of two sandwiched resin films 16 is wound by a winding shaft 18 that is pulled in a direction different from the transport direction of the multidose layer holding resin film 16b.
Thereby, it can peel well.
This peeling roll 17 is rotatably provided so that it may be accompanied with the movement of one resin film 16a to be peeled.

Further, in the present invention, as shown in FIG. 3, the diameter D of the peeling roll 17 is reduced to 6 cm or less, preferably 5 cm or less, and the peeling roll 17 is peeled off at the steepest angle along the peripheral surface of the small diameter peeling roll 17. By doing so, a plurality of edible oral dosage layers are reliably retained and retained on the intended other resin film 16b.
Further, the take-up shaft 18 for winding the resin film 16a to be peeled is preferably 45 ° or more from the transport direction C of the multiple-dose layer holding resin film 16b with respect to the resin film 16a to be peeled, starting from the peeling roll 17. Is preferably provided at a position to be pulled in at an angle of 60 ° or more.
In the example shown in FIG. 3, the take-up shaft 18 is provided at a position where the release resin film 16 a is drawn at an angle of about 80 ° with the conveyance direction C.

The operation of the crimping apparatus 10 of the present invention shown in FIG. 1 is as follows.
One of the roll films 11 on which the edible oral dosage layer is formed is set on the upper unwinding shaft 13 of the crimping device 10, and the roll film on which the edible oral dosage layer is formed. One 12 is set on the lower unwinding shaft 14.
These roll films 11 and 12 are respectively unwound at a predetermined speed, overlapped so that the edible oral dosage layer surfaces face each other, and passed between a pair of pressing rolls 15 and 15, thereby allowing resin Pressurized from the back side of the film, the edible oral dosage layer adheres closely.

When pressurizing with the press rolls 15, 15, the press rolls 15, 15 and the guide rollers in front of the press rolls 15, 15 are heated by an electric heater, a steam heater or the like built in the rollers, The temperature of the edible oral administration agent is 50 to 180 ° C, preferably 50 to 80 ° C.
This temperature needs to be appropriately selected depending on the type of resin film, the type of substance used for the edible oral dosage layer, etc., and the temperature at which the edible oral dosage layer is slightly softened and easily adhered. It is preferable to do.
Excessive high temperature should be avoided because there is a risk of the edible oral dosage layer melting and the solvent in the edible oral dosage layer volatilizing and bumping, and if the temperature is too low, sufficient adhesion will be achieved. It may disappear.
The pressure applied by the pressing roll is 0.05 to 1.5 MPa, preferably 0.1 to 0.7 MPa.
Excessive pressure is undesirable because the edible oral dosage layer is spread and affects the quantitative accuracy per unit area.
If the pressure is too low, sufficient adhesion cannot be obtained.

The press-bonded product 16 that has passed through the pressing rolls 15 and 15 has a structure in which both surfaces thereof are covered with a resin film, and a plurality of edible oral administration agent layers are adhered and laminated between them.
When the pressure-bonded product 16 passes through the film peeling roll 17, the resin film 16 a covering the upper surface is peeled off, and the peeled resin film front end portion is taken up by the peelable film take-up shaft 18. The resin film 16a can be peeled continuously.

In addition, after making the edible oral dosage layer adhere closely, until the resin film 16a is peeled from the adhered edible oral dosage layer, the temperature of the edible oral dosage layer adhering to each other, 10 ° C. from the temperature of the edible oral dosage layer when pressed by the pressing rolls 15 and 15 (when the edible oral dosage layer layers are stacked so as to face each other and pressed from the back surface of the resin film) It is preferable to cool above.
This cooling does not need to be performed excessively, and preferably the temperature of the cooled edible oral dosage layer is not below room temperature (or room temperature) so that it does not fall below 0 ° C.
Therefore, this cooling may be performed by increasing the distance between the pressing rolls 15 and 15 and the film peeling roll 17 so as to perform natural cooling by heat radiation. Also, normal temperature air such as sterile air or cooled air may be used. It may be cooled positively by spraying.
Thereby, the resin film 16a can be reliably peeled continuously from the press-bonded product 16.

  The pressure-bonded product 16b thus obtained, that is, the resin film holding a plurality of edible oral dosage layers, is wound up into a roll shape by a take-up shaft 19 and a multiple oral dosage layer holding roll film 20 is obtained. Is formed.

In the case of further laminating an edible oral dosage layer on the multiple oral dosage layer holding film 16b, the following is performed.
That is, the multiple oral preparation layer holding roll film 20 obtained above is removed from the take-up shaft 19 and set on the upper unwinding shaft 13 of FIG. The layer-holding roll film 20 or the roll film of the oral dosage form layer-forming resin film 60 obtained by the coating apparatus 50 of FIG. 11 is set on the lower unwinding shaft 14 and the operation exactly the same as the above-described pressure-bonding operation. May be repeated.

When two resin films holding the edible oral dosage layer are pressed between pressure rolls 15 and 15 and air is caught between the two resin films, poor bonding occurs. .
In this case, without stopping the operation of the crimping device 10, as shown in FIG. 4, the pair of rolls 21, 21 installed downstream of the pressing rolls 15, 15 are closed and closed, and the pressing rolls are closed. Open 15 and 15 gaps.
By this operation, the air entrained between the two resin films is easily pushed out by the closed rolls 21 and 21 and removed.
After the air is removed, the pressing rolls 15 and 15 are closed and the rolls 21 and 21 are opened, so that the normal crimping operation can be restored.

When the final crimped product is obtained by holding the desired multiple layers of the edible oral administration agent layer by the crimping device 10, the final crimped product is arranged downstream of the crimping device 10. The slitter device 30 is used to cut into narrow widths.
That is, as shown in FIG. 5, the press-bonded product 31 pressed by the pressing rolls 15 and 15 is peeled and removed from the resin film on the upper surface, and the final press-bonded product 31a (the press-bonded product 16b in FIGS. 1 and 4 is finally pressed). It may be a product).
This final crimped product 31a (for example, the edible oral dosage layer width 460 mm) is cut into 12 narrow crimped products 31b having a width of 36 mm, for example, by a slitter 32, and narrow crimped products on 12 reels 33a and 33b. 31b is wound up separately one by one.
The slitter 32 has 13 blades 32b projecting in the circumferential direction on the outer periphery of one roll 32a and provided in parallel with each other. As shown in FIGS. When winding on the winding shaft 19, the slitter 32 and the roll 34 below are opened and opened, and the slitter 32 does not function, and the final crimped product 31a is cut into a narrow width. At this time, the gap between the slitter 32 and the roll 34 below is closed, and the final crimped product 31a passing through the slitter 32 is cut into twelve narrow-width crimped products 31b.

In the example shown in FIG. 5, the final crimped product 31 a passes through the slitter 32 to be twelve narrow-width crimped products 31 b, of which the odd-numbered six narrow-width crimped products 31 b are arranged forward. Each of the six reels 33a coaxially set on the take-up shaft 35 is wound up one by one, and the even-numbered six narrow crimped products 31b are arranged coaxially with the product take-up shaft 19 disposed rearward. One reel is wound around each of the six reels 33b.
Note that the both ends cut residue 31c of the final press-bonded product 31a cut by the slitter 32 is taken up by the residue take-up shaft 36.

The narrow-width crimped product 31b (36 mm in width) cut in this way is obtained by using, for example, a circular laminated film-shaped oral administration agent using an oral administration device as shown in FIG. 6 or FIG. can do.
In the intraoral administration device 70 in FIG. 6, the narrow-width crimped product 31b wound around the reels 33a and 33b in FIG. 5, that is, one resin film is peeled off, and the surface of the remaining resin film 71 is left. The crimped product in which the multiple edible oral dosage layer 72 is held is intermittently unwound, and the remaining resin film 71 is peeled off by the film peeling roll 73 to obtain only the edible oral dosage layer 72. To do.
Next, the multiple edible intraoral dosage layer 72 is punched into a circle having a diameter of 15 mm, for example, by a punching device 74.
The punching device 74 includes a cutting blade 74a that reciprocates up and down and a fixing plate 74b that has a through-hole through which the cutting blade penetrates, and the edible oral dosage layer 72 that has been intermittently moved is positioned at the punching device 74. When the cutting blade 74a is moved upward and passes through the through hole of the fixing plate 74b, a circle having a diameter of 15 mm is punched from the edible oral dosage layer 72.
The punched circular edible oral dosage layer is sucked by the suction pad 75 disposed above the fixing plate 74b, dropped onto a conveyor (not shown), and sent to the packaging process.
The remaining edible oral administration agent layer residue 72 b after the round edible oral administration agent layer is peeled off is wound up as a residue winding roll 76.

In the intraoral administration device 80 of FIG. 7, the narrow-width crimped product 31b wound in a roll shape on the reels 33a and 33b of FIG. 5, that is, one of the resin films is peeled off, and the remaining resin film 71 is left. The crimped product having the plurality of edible oral dosage layers 72 held on the surface thereof is continuously unwound and sent to the punching device 81.
The punching device 81 includes a cutting blade roll 82 in which a circular cutting blade 82 a having a diameter of, for example, 15 mm protrudes from an outer peripheral surface of a rotating roll, and an anvil roll 83. Edible oral cavity so that it does not reach the back surface of the resin film 71 by the cutting blade 82a protruding from the cutting blade roll 82 when the crimped product is stationary while being sandwiched between the rolls 82 and 83. Only the internal dosage layer 72 is punched out.
The cutting depth by the cutting blade 82 a can be controlled by adjusting the clearance between the cutting blade roll 82 and the anvil roll 83.
In FIG. 7, the distance between the cutting blade roll 82 and the anvil roll 83 is illustrated for ease of understanding, but the actual cutting operation is performed by placing the cutting blade roll 82 at a position indicated by a one-dot chain line. Done.
In the state in which only the edible oral dosage layer is punched with the cutting blade 82a, the edible oral cavity is simply formed by forming the circular cut 72a corresponding to the shape of the cutting blade in the edible oral dosage layer 72. The internal dosage layer 72 remains held on the surface of the resin film 71.
In this state, when the resin film and the edible oral administration agent layer rotate as the anvil roll 83 rotates and move to the position where the suction pad 84 is disposed, the suction pad 84 moves toward the anvil roll 83. Then, the edible oral dosage layer 72 surrounded by the circular cut 72a is sucked off from the resin film 71, dropped onto a conveyor (not shown), and sent to the packaging process. The remaining edible oral administration agent layer residue 72b after the circular edible oral administration agent layer is peeled off is wound as a residue winding roll 85 together with the resin film 71.

The final product of the oral administration agent in the form of a laminated film produced by the intraoral administration device 70 or 80 is in a state in which the resin film is peeled from both surfaces.
Therefore, the two resin films overlapped in the crimping process are finally peeled off.
However, the final product shape of a laminated film-shaped oral administration agent is that a plurality of edible oral administration agent layers having predetermined dimensions are attached on the surface of the resin film, so that the oral administration user can use the resin film from the resin film. In some cases, the edible oral dosage layer may be peeled off before taking the product.
In the case of such a final product shape, it is only necessary to peel and remove one of the two resin films superimposed in the crimping process.

In the above description, the present invention is described by taking as an example a batch-type operation in which a resin film holding a single layer or multiple layers of an edible oral administration agent layer is once wound into a roll shape and pressure-bonded to each other. explained.
However, by using a plurality of coating devices, the oral dosage layer-forming resin film obtained by each coating device is directly pressed without forming a roll film, and further obtained in this way. A resin film holding a plurality of edible oral administration agent layers is used as a roll film, and is directly bonded to another resin film having a single or multiple edible oral administration agent layer formed thereon. It is possible to carry out the present invention also by continuous operation.

In the embodiment described above, the oral dosage layer-forming resin film 60 obtained by the coating apparatus 50 of FIG. 11 is once wound up into a roll shape by the winding shaft 56 to form a roll film, and then the crimping apparatus of FIG. 10 is pressure-bonded to another oral dosage form layer-forming resin film.
However, as shown in FIG. 8, before the oral dosage layer forming resin film 60 delivered from the drying furnace 55 of the coating apparatus 50 is wound into a roll shape, It is also possible to directly press-bond another oral administration agent layer forming resin film 61 in the vicinity of the outlet of the drying furnace 55.
That is, a set of two oral administration layer-forming resin films 60 and 61 are placed in the vicinity of the exit of the drying furnace 55 of the coating apparatus, with their edible oral administration layer layers facing each other. A pressure-bonded product can be directly obtained by applying pressure from the back surface of the resin film through the pressing rolls 62 and 62.
The pressure-bonded product is passed through a film peeling roll 63 to peel off the resin film on the upper surface. The peeled resin film is wound up by the peeling film take-up shaft 64 to continuously peel off the resin film, and then taken up by the take-up shaft 56. It can be set as the multiple intraoral administration agent layer holding | maintenance roll film 65 by winding up in roll shape.

In order to peel one resin film after pressure-bonding two resin films holding a single-layer or multiple-layer edible oral dosage form, at least the edible oral dosage form It is desirable that the surface (surface) on which the layer is formed is preliminarily treated by coating with a hydrophobic substance so that the resin film can be easily peeled from the edible oral dosage layer.
In addition, when a resin film holding a single layer or a plurality of layers of an edible oral administration agent layer is rolled into a roll film, the edible oral administration layer is in a state of being rolled up The resin film surface (back surface) where no is formed is also in contact with the edible oral dosage layer.
At this time, if the back surface of the resin film is not easily peeled off from the edible oral dosage layer, it is difficult to rewind the roll film.
Therefore, when the resin film holding the edible oral dosage layer is a roll film, the resin film to be peeled includes a surface on which the edible oral dosage layer is formed and a back surface on the opposite side. On the other hand, it is desirable to perform a peeling treatment on both sides of the film in advance. On the other hand, the resin film holding the edible oral dosage layer without being peeled is at least on the back side where the edible oral dosage layer is not formed. It is desirable to perform a peeling process in advance.
As the hydrophobic substance to be coated on the resin film during the peeling treatment, silicone resin or wax (honey wax) conforming to the standard of food additives can be used, and coating with metal foil such as aluminum foil or tin foil. You can also.

  As a resin film to be a base film for holding an edible oral dosage layer, polyethylene terephthalate, polyethylene naphthalate, copolymer polyester, polyimide, polypropylene, cellulose triacetate, vinyl acetate resin, ethylene-vinyl acetate copolymer , Polyethylene, polyvinyl chloride, polycarbonate, polypropylene, triacetate, a film made of a resin such as fluororesin (ETFE, PFA, FEP), and the like can be used as appropriate. In particular, polyethylene terephthalate (PET) can be preferably used.

The laminated structure of the oral administration agent in the form of a laminated film produced by the method of the present invention is not particularly limited, and various layers suitable for exhibiting a desired medicinal effect or function are laminated in an appropriate number. Can do.
In general, the laminated structure of a film-like oral administration agent consists of a coating layer constituting the outermost layer, a drug layer containing a base for the oral administration agent and an active ingredient, and a support layer if necessary. It is configured.
In this specification, “edible” shall consist only of foods and substances that are recognized as food additives and / or pharmaceuticals and pharmaceutical additives that are approved for oral administration. The term “edible edible oral dosage layer” is used as a generic term for the drug layer, the edible support layer, and the like.

The edible coating layer provides the function of protecting the surface of a film-like oral administration agent, or the function of adhering to the oral mucosa when used as a patch. For example, the following substances are used alone or in appropriate combination: Can be used.
Polyvinylpyrrolidone, gelatin, polyvinyl alcohol, sodium polyacrylate, starch, xanthan gum, karaya gum, hydroxypropyl cellulose, water-insoluble methacrylic acid copolymer, ethyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer, dimethylaminoethyl methacrylate・ Methyl methacrylate copolymer, carboxyvinyl polymer (trade name: Carbopol), tragacanth, gum arabic, locust bean gum, guar gum, dextrin, dextran, amylose, pullulan, chitosan, casein, alkyl alginate, etc.

As a base used together with an active ingredient in an edible drug layer, for example, the following substances can be used alone or in appropriate combination.
Polyvinylpyrrolidone, polyvinyl alcohol, sodium polyacrylate, carboxymethylcellulose, starch, xanthan gum, karaya gum, sodium alginate, methylcellulose, carboxyvinyl polymer, agar, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (also known as: Cellulose acetate phthalate, CAP), carboxymethyl ethyl cellulose (CMEM), ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymer (trade name: Carbopol), tragacanth, gum arabic, locust bean gum, guar gum, carrageenan (carrageenan), Dextrin, dextra , Amylose, carboxymethyl cellulose potassium, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, pullulan, chitosan, starch, polyvinyl alcohol, carboxymethyl cellulose, carboxymethyl starch, Plantago seed coat, galactomannan, Eudragit, casein, alginic acid alkyl ester.

The edible support layer is intended to prevent the active ingredient from eluting in the non-target part of the oral cavity. For example, the following substances are used alone or in appropriate combination, and are hardly soluble or insoluble in the oral cavity. The purpose can be achieved by using the following layers.
Gelatin, carboxymethylcellulose, methylcellulose, carboxyvinyl polymer, agar, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (also known as cellulose acetate phthalate, CAP), carboxymethylethylcellulose (CMEC), ethylcellulose, hydroxyethylcellulose , Hydroxypropyl methylcellulose, cellulose acetate phthalate, locust bean gum, guar gum, carrageenan (carrageenan), carboxymethylcellulose potassium, carboxymethylcellulose sodium, carboxymethylcellulose calcium, shellac resin (shellac, white transparent shellac), starch, cellulose acetate, poly Alkenyl alcohols, hydroxyethyl cellulose, carboxymethyl starch, Plantago seed coat, galactomannan, Eudragit like.

In the oral administration agent in the form of a laminated film produced by the method of the present invention, each layer of each edible oral administration agent layer (edible coating layer, drug layer, support layer, etc.) to be adhered to each other is described above. It is desirable to include at least one kind of substance exhibiting at least thermoplastic properties among edible substances such as
By containing this thermoplastic substance, the edible oral dosage layer is slightly softened by heating, and comes into close contact with each other.
Examples of particularly edible substances with remarkable thermoplasticity include the following substances, and each edible oral administration agent layer selected from these edible thermoplastic substances to be in contact with each other alone or in appropriate combination. It is desirable to be included in
Amylose, potassium carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, alkyl alginate, sodium alginate, ethyl cellulose, Eudra kit, carboxymethyl ethyl cellulose, carboxymethyl starch, carboxymethyl cellulose, agar, gelatin, shellac, dextran, dextrin, starch, tragacanth, Hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, polyvinylpyrrolidone, methacrylic acid copolymer, methylcellulose phthalate and the like.

Examples of pharmaceuticals that can be used as an active ingredient contained in the edible drug layer in the oral administration agent of the laminated sheet of the present invention include the following drugs.
Central nervous system drugs (hypnotic sedatives, anxiolytics, antiepileptics, antipyretic analgesics, antistimulants, stimulants, anti-parkinsonian drugs, neuropsychiatric drugs, general cold drugs, etc.), peripheral nervous system drugs ( Local anesthetics, skeletal muscle relaxants, autonomic nerve agents, antispasmodics, etc.), sensory organ drugs (ophthalmic drugs, antipruritics, etc.), cardiovascular drugs (cardiotonic drugs, arrhythmic drugs, diuretics, antihypertensive drugs) , Vasoconstrictors, vasodilators, hyperlipidemia agents, etc.), respiratory drugs (respiratory stimulants, antitussives, expectorants, bronchodilators, gargles, etc.), digestive tract drugs (anticidal agents) , Intestinal regulating agent, peptic ulcer agent, laxative, enema, etc.), hormone agent (salivary gland hormone agent, thyroid / parathyroid hormone agent, anabolic steroid agent, adrenal hormone agent, follicular hormone and luteinizing hormone agent, mixed hormone agent, etc. ), Genitourinary and anal drugs (uterine contractors, contraceptives) , Antiepileptics, etc., skin drugs (methoxalene, etc.), dental oral medicines (dental antibiotic preparations, etc.), vitamins, nourishing tonics (inorganic preparations, etc.), blood and body fluids (blood coagulation inhibitors) Etc.), liver disease agents, antidote agents, gout treatment agents, diabetes agents, cell stimulants, tumor agents (alkylating agents, antimetabolites, etc.), allergic agents (antihistamines, etc.), herbal medicines, Kampo medicines Antibiotic preparations, antiviral agents, anthelmintics, alkaloid narcotics (opium alkaloids, coca alkaloids, etc.), non-alkaloid narcotics (synthetic narcotics such as fentanyl citrate), etc.
In addition, examples of the active ingredient contained in the drug layer include oral administration such as quasi-drugs, cosmetics, health foods and the like having actions such as deodorizing action and health maintenance effect.

The edible coating layer, drug layer, and support layer, which are each edible oral dosage layer of the laminated film-shaped oral dosage form produced by the method of the present invention, dissolve the above-described components in, for example, the following solvents. Or it can obtain by apply | coating and drying in the intraoral administration agent layer formation process using what was disperse | distributed.
Water, ethanol, acetic acid, acetone, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, Isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrolane, acetonitrile , Chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N, N-dimethylacetamide, N, N-dimethylformamide, 1,4-dioxane, 2-eth Siethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, xylene, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, methylene chloride and the like.
Among these solvents, ethanol, water, ethyl acetate or a combination of these solvents (for example, ethanol-water mixture, ethanol-ethyl acetate mixture) is most preferably used.

In addition, each edible oral dosage layer of the laminated film-shaped oral preparation produced by the method of the present invention includes a plasticizer such as polyethylene glycol (macrogol), glycerin, propylene glycol, etc. Edible additives such as additives, flavoring agents, and coloring agents can be added.
Examples of the corrigent include sweeteners such as saccharin, glycyrrhizic acid, sucrose, fructose, and mannitol, refreshing agents such as menthol and mint oil, and organic acid compounds that impart acidity such as citric acid, tartaric acid, and fumar.
Natural or synthetic fragrances can be used as flavoring agents.
As the colorant, those used in usual preparations such as edible lakes can be used.

  As a method for producing a laminated film-like edible oral dosage form having a multilayer structure in which very thin edible oral dosage layers according to the present invention are laminated, a production example of a film-like troche is shown below. Is not limited to this.

<Preparation of coating layer preparation solution>
20.0 parts by weight of pullulan and 5.0 parts by weight of D-sorbitol were added to an appropriate amount of purified water and dissolved by stirring to prepare an edible coating layer preparation solution.

<Preparation of drug layer I preparation solution>
In an appropriate amount of ethanol, 1.5 parts by weight of cetylpyridinium chloride, 1.5 parts by weight of chlorpheniramine maleate, 4.5 parts by weight of Macrogol 400, 2.5 parts by weight of 1-menthol, 22.5 parts by weight of polyvinylpyrrolidone K90 And 59.0 parts by weight of hydroxypropylcellulose were added and dissolved by stirring. To this was added 3.8 parts by weight of dipotassium glycyrrhizinate and 0.5 parts by weight of sodium saccharin and dissolved by stirring. The mixture was further stirred and mixed to prepare an edible drug layer I preparation solution.

<Preparation of drug layer II preparation solution>
In an appropriate amount of ethanol, cetylpyridinium chloride 4.5 parts by weight, chlorpheniramine maleate 4.5 parts by weight, tannic acid 7.0 parts by weight, Macrogol 400 13.5 parts by weight, l-menthol 7.5 parts by weight Then, 67.5 parts by weight of polyvinylpyrrolidone K90 and 182.0 parts by weight of hydroxypropylcellulose were added and dissolved by stirring. To this, 11.2 parts by weight of dipotassium glycyrrhizinate and 1.5 parts by weight of sodium saccharin were added to an appropriate amount of purified water. In addition, what was stirred and dissolved was added, and further stirred and mixed to prepare an edible drug layer II preparation solution.

<Oral agent layer formation process>
(1) Application of coating layer + drug layer I (1) -1: Formation of coating layer A polyethylene terephthalate (PET) film whose back surface is subjected to silicone peeling treatment is set on the unwinding shaft 51 of the coating apparatus 50 in FIG. Then, the coating layer preparation solution was supplied to the dam portion 57, and the edible coating layer preparation solution was applied to the surface of the polyethylene terephthalate film (the surface not subjected to the silicone release treatment).
At this time, the clearance between the doctor roll 54 and the polyethylene terephthalate film was 30 μm, the coating amount was 30 g / m ² , the drying temperature in the drying furnace 55 was 60 ° C., and a polyethylene terephthalate having a coating layer thickness of 8 to 12 μm was formed. The film 200 m + α (corresponding to the loss length) was wound around the winding shaft 56 in a roll shape.

(1) -2: Application of the drug layer I on the coating layer The coating layer forming polyethylene terephthalate film wound in the roll shape obtained in the above (1) -1 is wound on the coating device 50 in FIG. It set to the delivery axis | shaft 51, the drug layer I preparation liquid was supplied to the dam part 57, and the edible drug layer I preparation liquid was apply | coated on the coating layer.
At this time, the clearance between the doctor roll 54 and the polyethylene terephthalate film is 500 μm, the coating amount is 280 g / m ^2, and a polyethylene terephthalate film having a thickness of 55 to 75 μm and a drug layer I of about 200 m is rolled onto the winding shaft 56. It was wound up into a shape.
The laminated structure of the intermediate product A thus obtained is shown in FIG.

(2) Application of drug layer II A polyethylene terephthalate film having a silicone release treatment on both sides is set on the unwinding shaft 51 of the coating apparatus 50 in FIG. An edible drug layer II preparation solution was applied to the surface of the terephthalate film.
At this time, the clearance between the doctor roll 54 and the polyethylene terephthalate film is 550 μm, the coating amount is 320 g / m ^2, and the polyethylene terephthalate film 400 m + β (corresponding to the loss length) on which the drug layer II having a thickness of 55 to 75 μm is formed is wound. The product was wound around the take-up shaft 56 in a roll shape.
The laminated structure of the intermediate product B thus obtained is shown in FIG.

<Oral agent layer adhesion processing process>
(1) 1st process The intermediate product B (about 400 m) wound by roll shape was set to the upper unwinding shaft 13 of the crimping | compression-bonding apparatus 10 of FIG. A (about 200 m) is set, and the edible oral dosage layer of the intermediate product A and the edible oral dosage layer of the intermediate product B face each other. The edible oral administration agent layers were laminated in close contact at a pressure bonding temperature of 65 ° C. and a pressure of 0.3 MPa of the edible oral administration agent layer.
Only the polyethylene terephthalate film of the intermediate product B positioned on the upper surface of the pressure-bonded product after passing through the pressing rolls 15 and 15 is drawn along the peripheral surface of the film peeling roll 17 and wound up by the peeling film winding shaft 18 to be laminated. After peeling from the product, the pressure-bonded product was wound up in a roll shape by the winding shaft 19.
The temperature of the pressure-bonded product when the polyethylene terephthalate film was peeled was 50 ° C. due to natural heat dissipation.
FIG. 9C shows a laminated structure of the intermediate product C (about 200 m) thus obtained.
At the end of the first step, 200 m out of about 400 m of the intermediate product B remains on the upper unwinding shaft 13 and the entire amount of about 200 m of the intermediate product A is unwound on the lower unwinding shaft 14. It is in a state.

(2) Second Step After the completion of the first step, the obtained intermediate product C (about 200 m) wound in a roll shape was set on the lower unwinding shaft 14 of the crimping apparatus 10 of FIG.
About 200 m of the remaining intermediate product B wound in a roll is set on the upper unwinding shaft 13.
In this state, the edible oral dosage layer of the intermediate product B and the edible oral dosage layer of the intermediate product C are opposed to each other under the same temperature and pressure conditions as in the first step. It passed between the press rolls 15 and 15, and the edible intraoral administration agent layer was stuck and laminated | stacked.
Only the polyethylene terephthalate film of the intermediate product B positioned on the upper surface of the pressure-bonded product after passing through the pressing rolls 15, 15 is drawn along the peripheral surface of the film peeling roll 17 and wound up by the peeling film take-up shaft 18 for pressure bonding. After peeling from the product, the pressure-bonded product was wound up in a roll shape by the winding shaft 19.
The temperature of the pressure-bonded product at the time of peeling was substantially the same as that in the first step. The crimped product thus obtained was separately rolled into a roll shape by 100 m to obtain an intermediate product D (100 m) and an intermediate product D ′ (100 m). These intermediate products D and D ′ have exactly the same laminated structure as shown in FIG.

(3) Third Step The intermediate product D (100 m) and intermediate product D ′ (100 m) of the same configuration wound in the roll shape obtained in the second step are transferred to the upper unwinding shaft of the crimping apparatus 10 as shown in FIG. 13 and the lower unwinding shaft 14, respectively, and a pair of presses under the same temperature and pressure conditions as in the first step so that the unwound intermediate product D and D 'edible oral dosage layer are opposite to each other. The edible intraoral administration agent layers were adhered to each other and laminated between rolls 15 and 15.
Only the polyethylene terephthalate film of the intermediate product D positioned on the upper surface of the pressure-bonded product after passing through the pressing rolls 15, 15 is drawn along the peripheral surface of the film peeling roll 17 and wound up by the peeling film take-up shaft 18 for pressure bonding. After peeling from the product, it is cut by passing through a slitter 32 that is in contact with the roll 34, and the cut narrow crimp product is alternately set on the product take-up shaft 35 and on the reel 33 a and the product take-up shaft 19. Each was wound around a reel 33b.
The temperature of the pressure-bonded product at the time of peeling was substantially the same as that in the first step. A laminated structure of the intermediate product E thus obtained is shown in FIG.

<Production process>
A method of punching only the laminated edible oral dosage layer so as not to reach the back surface of the polyethylene terephthalate film, using a circular blade having a diameter of 15 mm, the film-like laminate obtained as the intermediate product E, or After removing the polyethylene terephthalate film on the back side from the film-like laminate obtained as the intermediate product E to make only the laminated edible oral dosage layer, a circular film-like lozenge is obtained by punching with a circular blade. It was.

A micrograph of the cross-section of the film-like troche thus obtained was observed using “Digital Microscope BS-D8000II” (trade name, manufactured by Sonic Co., Ltd.) as “Method of the Invention” in FIG.
For comparison, FIG. 10 shows the result of observing the cross section of a conventional film-like laminate having the same laminated edible oral dosage layer obtained by using the coating apparatus 50 of FIG. It was shown as “Lamination coating method”.
In the cross section obtained by the method of the present invention, the boundaries X and X of each edible oral dosage layer can be clearly seen, and the laminated edible oral dosage layer can be clearly distinguished, whereas In the cross section obtained by the “lamination coating method”, the boundaries Y and Y of each edible oral dosage layer appear unclear and blurred, and the laminated edible oral dosage layer cannot be distinguished.
The reason is that when the edible oral preparation layer preparation liquid is further laminated on the coated and dried lower edible oral preparation layer, It is thought that the solvent penetrates and adheres to the lower edible oral dosage layer.

Phenomenon that the active ingredient in the preparation liquid moves to the lower edible oral dosage layer together with the solvent when the solvent of the edible oral dosage layer preparation liquid applied to the lower layer penetrates into the lower edible oral dosage layer Can also happen.
Such a phenomenon becomes an obstacle when, for example, the same active ingredient is to be contained at a different concentration for each edible oral dosage layer.
That is, even if the active ingredient content in each edible oral dosage layer preparation liquid is adjusted so that the low concentration is contained outside the laminated structure and the high concentration inside the active ingredient is contained, If the transfer of the active ingredient accompanying the penetration of the solvent occurs on the surface, the control of the active ingredient concentration in each edible oral dosage layer cannot be accurately performed.
On the other hand, the laminated structure in the crimping method according to the present invention is that each edible oral dosage layer is clearly separated at the boundary surface, so that the penetration of the solvent and the transfer of the active ingredient accompanying it are unlikely to occur. The active ingredient concentration in each edible oral dosage layer can be controlled with high accuracy.

10: Crimping device 11, 12, 20: Roll film 13, 14: Roll film unwinding shaft 15, 15: Press roll 17: Film peeling roll 19: Roll film winding shaft 30: Slitter device 32: Slitter 33a, 33b : Narrow-width crimping product take-up reel
50: Coating device 54: Doctor roll
55: Drying furnace 57: Edible edible oral dosage layer preparation liquid supply dam part 61, 61: Press roll 63: Film peeling roll 70, 80: Oral administration device 74, 81: Punching device X, Y: Boundary of laminated edible oral dosage layer

Claims (4)

An oral dosage layer forming step of forming an edible oral dosage layer containing a predetermined thickness on the surface of the resin film and containing an edible thermoplastic material ;
A roll film forming step of forming a roll film by winding the oral dose layer forming resin film obtained in the oral dose layer forming step into a roll;
While rewinding the two roll films that formed the edible oral dosage layer of the same component or different components obtained in the roll film forming step, the edible oral dosage layer layers were stacked so that the edible oral dosage layer surfaces face each other. In addition, the pressure at the time of pressurizing from the back surface of the resin film is set to 0.1 to 0.7 MPa, and the pressure is applied with a pair of pressing rolls so that the edible oral dosage layer is brought into close contact with each other. Process,
The two superimposed resin films are peeled off from the closely adhered edible oral dosage layer , and on one side of the peeled resin film, the surface on which the edible oral dosage layer is formed and the opposite back side And the other resin film that holds the edible oral dosage layer without being peeled at least on the back side where at least the edible oral dosage layer is not formed. A resin film peeling step that has been subjected to a peeling treatment ;
A method for producing a laminated film-shaped edible oral dosage agent comprising: An oral dosage layer forming step of forming an edible oral dosage layer containing a predetermined thickness on the surface of the resin film and containing an edible thermoplastic material ;
A roll film forming step of forming a roll film by winding the oral dose layer forming resin film obtained in the oral dose layer forming step into a roll;
While rewinding the two roll films that formed the edible oral dosage layer of the same component or different components obtained in the roll film forming step, the edible oral dosage layer layers were stacked so that the edible oral dosage layer surfaces face each other. In addition, the pressure at the time of pressurizing from the back surface of the resin film is set to 0.1 to 0.7 MPa, and the pressure is applied with a pair of pressing rolls so that the edible oral dosage layer is brought into close contact with each other. Process,
While the two resin films sandwiching the edible intraoral dosage layer in close contact with each other are transported while being substantially aligned with the tangential direction in the pressure part of the pair of press rolls, the circumference of the peeling roll provided in the transport direction Along the surface, only one of the two resin films sandwiching the edible oral dosage layer closely adhered to each other is drawn in a direction different from the transport direction, and the edible oral dosage layer is By continuing to convey the other held resin film in the conveying direction, only one resin film of the two superimposed resin films is peeled off, and one of the peeled resin films has an edible oral cavity. The other resin that has been subjected to a release treatment in advance on both the surface on which the internal dosage layer is formed and the back surface on the opposite side, and holds the edible oral dosage layer without being peeled The Irumu, and the resin film peeling step advance release treatment on the back of at least edible oral dosage layer is not formed is applied,
A method for producing a laminated film-shaped edible oral dosage agent comprising: An oral dosage layer forming step of forming an edible oral dosage layer containing a predetermined thickness on the surface of the resin film and containing an edible thermoplastic material ;
A roll film forming step of forming a roll film by winding the oral dose layer forming resin film obtained in the oral dose layer forming step into a roll;
While rewinding the two roll films that formed the edible oral dosage layer of the same component or different components obtained in the roll film forming step, the edible oral dosage layer layers were stacked so that the edible oral dosage layer surfaces face each other. In addition, the pressure at the time of pressurizing from the back surface of the resin film is set to 0.1 to 0.7 MPa, and the pressure is applied with a pair of pressing rolls so that the edible oral dosage layer is brought into close contact with each other. Process,
While the two resin films sandwiching the edible intraoral dosage layer in close contact with each other are transported while being substantially aligned with the tangential direction in the pressure part of the pair of press rolls, the circumference of the peeling roll provided in the transport direction Along the surface, only one of the two resin films sandwiching the edible oral dosage layer closely adhered to each other is drawn in a direction different from the transport direction, and the edible oral dosage layer is By continuing to convey the other held resin film in the conveying direction, only one resin film of the two superimposed resin films is peeled off, and one of the peeled resin films has an edible oral cavity. The other resin that has been subjected to a release treatment in advance on both the surface on which the internal dosage layer is formed and the back surface on the opposite side, and holds the edible oral dosage layer without being peeled The Irumu, and the resin film peeling step advance release treatment on the back of at least edible oral dosage layer is not formed is applied,
A multiple oral dosage layer holding roll film forming step of forming a roll film by winding a resin film holding a plurality of closely contacted edible oral dosage layers obtained in the resin film peeling step When,
Multi-oral dosage layer holding roll film for holding a multi-layered edible oral dosage agent obtained in the multi-oral dosage layer-holding roll film formation step, and the multi-edible edible oral cavity having the multi-oral dosage layer Each edible oral dosage layer surface is rewound with another roll film formed with an edible oral dosage layer consisting of a single layer or a plurality of layers of the same component or different components. Roll film multiple intraoral dosage layer pressure-bonding step for closely adhering the edible oral dosage layer by mutually overlapping and pressing with a pair of pressing rolls from the back of the resin film so as to face each other,
Peeling provided in the transport direction while transporting two resin films sandwiching the edible intraoral administration layer of the multilayered layers that are in close contact with each other substantially in line with the tangential direction in the pressure part of the pair of pressing rolls Along the circumferential surface of the roll, only one resin film of the two resin films sandwiching the edible oral dosage layer of the multiple layers in close contact with each other is drawn in a direction different from the transport direction, and the multiple layers Resin film peeling and removing step of peeling only one of the two superimposed resin films by continuing to transport the other resin film holding the edible oral dosage layer in the transport direction When,
A method for producing a laminated film-shaped edible oral dosage agent comprising: Claims, characterized in that the temperature of the edible oral dosage layer when pressurized from the back surface of the superposed with resin film as above edible buccal adhesive layer surface face each other with 50 ° C. to 180 ° C. Item 4. A method for producing a laminated film edible oral administration agent according to any one of Items 1 to 3 .