TW202210575A - Film for wrapping tablets - Google Patents

Abstract

Provided is a film including: a polymer of at least one of hypromellose and hydroxypropyl cellulose; and at least one additive selected from the group consisting of triethyl citrate, triacetin, propylene glycol, ethylene glycol, polyethylene glycol, and sugar alcohols. The film is for use in wrapping molded bodies containing a medicinal ingredient.

Description

Film to coat tablet

The present invention relates to a film for coating a tablet, a method for manufacturing a tablet, a tablet, and a method for improving the shape retention and/or chemical stability of the tablet.

As one of the methods used in the production of pharmaceutical preparations for oral administration, there is a method of adding additives such as excipients, binders, and disintegrating agents to the active ingredient to obtain a homogenized powder, and compressing the powder. After molding, film coating is performed to form a tablet in consideration of quality deterioration due to light or use of a patient. However, depending on the type of the active ingredient, it is sometimes difficult to tablet into a tablet having sufficient hardness to distribute it on the market, or to formulate and administer it. In some cases, a part of the formed body is damaged due to the physical impact during film coating, thereby destroying the quality of the tablet. Moreover, the stability of an active ingredient may be affected by the solvent used at the time of film coating.

Capsules are mentioned as forms other than lozenges. Capsules are produced, for example, by filling a preformed capsule with powder of the active ingredient and sealing it. However, in principle, capsules only have a fixed uniform shape and standardized size, so it is difficult to impart a characteristic appearance like a lozenge to the capsule. In addition, since voids exist in the capsules filled with powder, the amount of powder that can be filled into the capsules is reduced, and the capsules are increased in size. Furthermore, there are capsules that are easy to open, and the contents of the capsules can be replaced in this case. On the other hand, there is also a preparation in a form produced by compressing the powder filled in a cup formed from a thermoplastic film with a pestle and then sealing. However, since the mechanism of a capsule filling machine is used for powder filling of these preparations, it is difficult to precisely control the amount of powder to be filled.

As a method for solving such a problem, a molded body containing the medicinal ingredient of the orally administered preparation is sometimes covered with a thermoplastic sheet or film. In order to manufacture such a preparation, a method has been devised for forming a cup with an opening by pressing a mold against a thermoplastic sheet or film, inserting a molded body containing a medicinal ingredient into the cup, and then forming A lid that seals the opening of the cup (Patent Documents 1 to 3). prior art literature Patent Literature

Patent Document 1: International Publication No. 2018/074259 Patent Document 2: International Publication No. 2018/074260 Patent Document 3: International Publication No. 2018/074261

[Problems to be Solved by Invention]

By using the film containing hypromellose or hydroxypropyl cellulose, the dissolution property of the medicinal ingredient can be ensured and the molded body containing the medicinal ingredient can be covered. However, in order to form a cup for accommodating a molded body containing a medicinal ingredient, a film containing hypromellose or hydroxypropyl cellulose requires a relatively high molding temperature.

Accordingly, one aspect of the present invention relates to a film comprising at least one polymer of hypromellose or hydroxypropyl cellulose, and which can be formed at a lower forming temperature to accommodate a medicinally active ingredient The cup portion of the formed body. [Technical means to solve problems]

One aspect of the present invention provides a film comprising: at least one polymer of hypromellose or hydroxypropyl cellulose; and a polymer selected from the group consisting of triethyl citrate, triacetin, propylene glycol, ethylene glycol At least one additive in the group consisting of alcohol, polyethylene glycol and sugar alcohol; and the film is used to coat the shaped body containing the medicinal ingredient.

Another aspect of the present invention provides a method for manufacturing a lozenge, comprising: forming a cup by pressing the heated film of one aspect of the present invention against a mold, the cup forming an opening; A molded body containing a medicinal ingredient is inserted into the cup portion; and a lid portion covering the opening is formed with a lid portion film, whereby the molded body is covered by the lid portion and the cup portion.

Yet another aspect of the present invention provides a tablet comprising: a molded body containing a medicinal ingredient; a cup portion that accommodates the molded body and has an opening formed therein; and a lid portion that covers the opening. The said cup part is the said film of one aspect of this invention.

Yet another aspect of the present invention provides a method for improving the shape retention and/or chemical stability of a tablet, comprising: covering one or more films containing the above-mentioned film of one aspect of the present invention with a medicinal effect Forms of ingredients. [Effect of invention]

According to an aspect of the present invention, there is provided a film comprising at least one polymer of hypromellose or hydroxypropyl cellulose, which can be formed at a lower forming temperature to accommodate a film containing a medicinal ingredient. The cup portion of the formed body.

Hereinafter, some embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

1 and 2 are schematic views showing an example of a method for producing a tablet. The method shown in FIGS. 1 and 2 sequentially includes: as shown in (a), preparing the film 1 for the cup portion; as shown in (b) and (c), pressing the heated film 1 for the cup portion by pressing Abutting against the mold 30 to form a cup portion, the cup portion forming the opening 10; as shown in (d), the remaining portion 1C of the film 1 for the cup portion except the cup portion 10 is removed with a part of it remaining; as shown in (d) As shown in e), insert the granular molded body 5 containing the medicinal ingredient into the cup part 10; as shown in (f), remove the remaining part 1C of the cup part film 1 except the cup part 10; as shown in (f) As shown in g), the lid portion 20 covering the opening of the cup portion 10 is formed by the lid portion film 2, whereby the molded body 5 is covered by the lid portion 20 and the cup portion 10; as shown in (h), the lid portion is The remaining part 2C of the film 2 for the part except the cover part 20 is removed. Here, the term "overmolded body" means that the molded body is enclosed in one or more films.

The cup portion film 1 of one embodiment is a single-layer film comprising at least one polymer of hypromellose or hydroxypropyl cellulose, and additives.

The additive is at least one selected from the group consisting of triethyl citrate, triacetin, propylene glycol, ethylene glycol, polyethylene glycol and sugar alcohol. The molecular weight of polyethylene glycol may be 10,000 or less from the viewpoint of the formability of the cup portion film 1 and the like. The sugar alcohol may be, for example, sorbitol, erythritol, or xylitol.

The additive may be selected from the group consisting of triethyl citrate, triacetin, propylene glycol, ethylene glycol, and polyethylene glycol, or the group consisting of triethyl citrate and triacetin at least one of them.

The content of the additive is based on the total amount of the polymer and the additive, and may be, for example, 5 to 30% by mass, 5 to 20% by mass, or 5 to 15% by mass. When the content of the additive is 30 mass % or less, it is easy to obtain the film 1 for a cup portion which has good formability, is less likely to be wrinkled, and is excellent in handleability.

From the viewpoint of workability and the like, the tensile modulus of elasticity of the film 1 for a cup portion may be 800 MPa or more, or 900 MPa or more. The upper limit of the tensile modulus of elasticity of the film 1 for a cup portion is not particularly limited, but is, for example, about 2300 MPa. The measuring method of the tensile modulus of elasticity will be described in the examples described later.

The film 1 for cup parts may further contain a dye. The cup film 1 containing the pigment can provide a colored lozenge. Pigments can be, for example, inorganic pigments such as titanium oxide, ferric oxide, yellow ferric oxide, synthetic tar pigments, or combinations thereof. The content of pigments (especially inorganic pigments) may be, for example, 30% by mass or less based on the total amount of polymers and additives.

The film 1 for cup portions may further contain other components in addition to the polymers, additives, and dyes exemplified above. As an example of other components, a flavoring agent is mentioned. The content of other components may be 10 mass % or less, 5 mass % or less, 3 mass % or less, or 1 mass % or less based on the mass of the cup portion film 1 .

The thickness of the film 1 for cup portions may be, for example, 40 to 80 μm, or 20 to 100 μm.

The film for cup parts is not limited to the film which consists of only the film 1 for cup parts as the example shown in FIG. 1 . For example, the film for cups may have a base film containing the above-mentioned polymer and additives, and an adhesive layer provided on the base film. If the adhesive layer is provided, the cup portion 10 and the lid portion 20 can be joined more firmly. The subsequent layer may be, for example, a layer comprising copovidone, methacrylic acid copolymer LD, ethyl acrylate-methyl methacrylate copolymer, polyvinylpyrrolidone, or aminoalkyl methacrylate copolymer E.

The film 1 for a cup portion can be obtained, for example, by a method comprising the steps of applying a coating liquid containing a polymer, an additive and other components added as needed, and water to a substrate having a smooth flat portion such as a glass plate ; and allow the coating to dry.

When the heated film for cup portion 1 is pressed against the mold 30, the gap between the film for cup portion 1 and the mold 30 becomes a negative pressure, thereby forming a wall portion including the bottom portion 1A and the peripheral edge of the bottom portion 1A. 1B and a cup portion 10 having an opening formed by the end of the wall portion 1B. In order to press the mold 30 against the film 1 for cups, the mold 30 may be moved toward the film 1 for cups to be fixed, or the film 1 for cups may be moved toward the mold 30 to be fixed. When the mold 30 is separated from the cup portion film 1 , the remaining portion 1C of the cup portion film 1 other than the cup portion 10 usually remains around the cup portion 10 to some extent. The shape and size of the cup portion 10 are adjusted so that the molded body 5 can be accommodated. The bottom 1A may be curved as shown in the figure, or may be flat. The maximum value of the depth of the cup portion 10 (the depth from the remaining portion 1C) may be, for example, 8 mm or less. The maximum width of the cup portion 10 (the maximum value of the distance between the inner surfaces of the cup portion 10 when viewed from the depth direction of the cup portion 10 ) may be, for example, 16 mm or less.

The temperature (forming temperature) of the cup film 1 pressed against the mold 30 is adjusted so that the cup 10 of the desired shape can be appropriately formed. For example, the temperature of the cup film 1 to be formed is 100°C. ~180℃, or 120~160℃. The time for pressing the film 1 for the cup portion against the mold 30 may be within a range that does not affect the normal formation of the film.

After the cup portion 10 is formed, most of the remaining portion 1C around the cup portion 10 is removed. Therefore, the film 1 for cup portions can also be cut along the opening of the cup portion 10 by, for example, irradiating laser light.

Next, the molded body 5 containing the medicinal ingredient is inserted into the cup portion 10 . The molded body 5 can be formed by, for example, compression molding of a powder containing a medicinal component and other components added as needed. The shaped body may also have secant lines. Examples of ingredients other than medicinally effective ingredients include excipients, binders, disintegrants, lubricants, stabilizers, and preservatives. The maximum width of the molded body 5 is usually approximately the same as the maximum width of the cup portion 10 .

After the molded body 5 is inserted into the cup portion 10 , the remaining portion 1C is removed by a method such as irradiating laser light.

The heated lid portion film 2 is pressed against the exposed surface of the molded body 5 in which the cup portion 10 of the molded body 5 is inserted. By making the space|gap between the film 2 for lid parts and the cup part 10 which generate|occur|produce negative pressure, a lid part is formed, and the film 2 for lid parts and the cup part 10 are joined. The entire surface of the molded body 5 is covered by the lid portion 20 including the top wall portion 2A covering a part of the surface of the molded body 5 and the wall portion 2B extending from the periphery thereof, and the cup portion 10 in the lid portion film 2 . In other words, the molded body 5 is covered by the lid portion 20 and the cup portion 10 .

The temperature (molding temperature) of the film 2 for the lid portion pressed against the cup portion 10 in which the molded body 5 is inserted is adjusted so that the lid portion 20 of the desired shape can be appropriately formed. For example, the molding temperature may be 100 to 180°C, or 120 to 160°C.

The film 2 for lids is a thermoplastic film, and may be the same film as the film 1 for cups, for example. In order to make the inner surface of the wall portion 2B of the lid portion 20 adhere to the outer side surface of the wall portion 1B of the cup portion 10 , the lid portion 20 (film 2 for lid portion) may have the same base film as the film 1 for cup portion, and an adhesive layer disposed on the inner surface of the base film.

After the lid portion 20 is formed, the remaining portion 2C of the lid portion film 2 other than the lid portion 20 is removed by a method such as irradiating laser light.

After that, the tablet 50 is obtained by performing a process such as heating and shrinking as necessary, and the tablet 50 includes the molded body 5 , the cup portion 10 that accommodates the molded body 5 , and is joined to the cup portion 10 so as to enclose the molded body 5 . the cover part 20.

By covering the molded body containing the medicinal ingredient with two films including the film 1 for the cup portion and the film 2 for the lid portion, the molded body can be used for shape preservation properties such as When the chemical stability of the molded body is insufficient, a tablet that can be handled stably can also be obtained. Therefore, the film of this embodiment can also be used to improve the shape retention and/or chemical stability of an existing tablet having a shaped body containing a medicinal ingredient. Example

Hereinafter, the present invention will be further specifically described by way of examples. However, the present invention is not limited to these examples.

1. Raw materials Hypromellose (Hydroxypropyl methylcellulose) ・TC-5S (Viscosity of 2% aqueous solution (20℃): 15 mPa・s, Shin-Etsu Chemical Industry) ・TC-5R (Viscosity of 2% aqueous solution (20°C): 6 mPa·s, Shin-Etsu Chemical Industry) ・TC-5M (Viscosity of 2% aqueous solution (20℃): 4.5 mPa・s, Shin-Etsu Chemical Industry) ・TC-5E (Viscosity of 2% aqueous solution (20°C): 3 mPa·s, Shin-Etsu Chemical Industry) Hydroxypropyl cellulose ・HPC-M (Japan Soda) additive ・Triethyl citrate (Morimura Corporation) ・Triacetin (Kanto Chemical) ・Propylene glycol (Kanto Chemical) ・PEG400 (Sanyo Chemical, polyethylene glycol, average molecular weight 400) ・Copovidone (copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate (mass ratio = 3:2), Ashland) ・Polyvinylpyrrolidone (PVP K30, BASF) Pigment (pigment) ・Titanium oxide (Ishihara Sangyo)

2. Film making The coating liquid containing each raw material was adjusted according to the formula described in Table 1, Table 2, or Table 3 in the following order. The formulations described in each table are expressed as a ratio (mass %) based on the total amount of the polymer (hypromellose or hydroxypropyl cellulose) and the additive. First, the additive was dissolved in a mixed solvent of purified water/ethanol (volume ratio: 50/50). A coating liquid for film formation is obtained by dissolving hypromellose or hydroxypropyl cellulose in the obtained aqueous solution. After degassing the coating liquid under vacuum, it was coated on a glass plate with a fixed thickness using an electric film coater. The coating film was naturally dried for a day and night to form a film with a thickness of 60 μm. Films with a film thickness of 40 μm or 80 μm were also produced using the coating solutions of formulations 2 and 3.

3. Evaluation 3-1. Tensile test A short strip-shaped test piece with a width of 10 mm and a length of 50 mm was cut out from each film. After the test piece was left to stand in an environment of 25° C. and 60 RH for 1 hour, a tensile test was performed using EZ-test (manufactured by Shimadzu Corporation). The distance between the fixtures was set to 30 mm, and the test speed was set to 10 mm/min.

3-2. Formability (Formable temperature) A 5 cm square film for evaluation was cut out from the produced film. The film for evaluation was left to stand in an environment of 25°C and 60% RH for 1 hour. Next, using the coating preparation manufacturing apparatus provided with the heater for heating the film according to the manufacturing method of the coated ingot described in the embodiment of International Publication No. 2018/074261, the film was pressed against the film having an inner diameter of 7.5. The mold of the cylindrical portion of mm makes the gap between the film and the mold a negative pressure, thereby forming the cup portion. A forming test was performed while changing the set temperature of the heater for heating the film, and the formed cup portion was visually observed. The case of forming a cup with a shape that perfectly reflects the wall surface of the cylindrical portion of the mold was judged as "moldable", and the case of forming a cup with a shape larger than the inner diameter of the cylindrical portion of the mold was judged as "Unformable". FIG. 3 is a photograph showing an example of a cup portion formed by a molding test. In FIG. 3, "1" is an example of "formable", and "2" and "3" are examples of "impossible to form". The lowest temperature among the set temperatures of the device for forming the "formable" cup portion was recorded as the "formable set temperature". For example, when the set temperature of the heater used to heat the film is about 400°C, the temperature at the outlet of the heater is 305-310°C, the temperature near the upper surface of the film is 230°C, and the maximum temperature of the lower surface of the film is 120°C. °C.

4. Results The evaluation results are shown in Tables 1 to 4. It was confirmed that films of formulations containing triethyl citrate, triacetin, propylene glycol or polyethylene glycol as additives could be properly formed at lower forming temperatures compared to films of formulation 0 with no additives added. form the cup. In the case of Formulation 6, although it can be formed at the set temperature of the heater at 245° C., it is found that wrinkles are generated in the cup portion.

[Table 1] formula 0 1 2 3 4 5 6 Hypromellose TC-5S 100 92.5 87.5 70.0 82.5 77.5 65 additive Triethyl citrate 7.5 12.5 10.0 17.5 22.5 35 pigment Titanium oxide 20 Film thickness [μm] 60 60 60 60 60 60 60 Stretching test Maximum test force [N] 41.7 38.0 33.9 28.2 29.0 18.6 6.3 Breaking point [mm] 10.3 11.2 12.2 9.6 12.7 10.8 11.7 Modulus of elasticity [MPa] 1752 1514 1495 1807 1211 957 252 Formable setting temperature [℃] 410 360 330 375 305 265 245*

[Table 2] formula 0 2 7 8 9 10 11 Hypromellose TC-5S 100 87.5 87.5 87.5 87.5 87.5 87.5 additive Triethyl citrate 12.5 Triacetin 12.5 Propylene Glycol 12.5 PEG400 12.5 Copovidone 12.5 PVP K30 12.5 Film thickness [μm] 60 60 60 60 60 60 60 Stretching test Maximum test force [N] 41.7 33.9 32.3 36.0 31.6 39.9 33.9 Breaking point [mm] 10.3 12.2 12.8 10.3 17.7 10.1 9.7 Modulus of elasticity [MPa] 1752 1495 1343 1607 1232 1761 1656 Formable setting temperature [℃] 410 330 330 390 355 415 420

[table 3] formula 0 2 12 13 14 15 Hypromellose TC-5S 100 87.5 TC-5R 87.5 TC-5M 87.5 TC-5E 87.5 Hydroxypropyl cellulose HPC-M 87.5 additive Triethyl citrate 12.5 12.5 12.5 12.5 12.5 Film thickness [μm] 60 60 60 60 60 60 Stretching test Maximum test force [N] 41.7 33.9 22.9 20.7 21.2 32.7 Breaking point [mm] 10.3 12.2 9.4 6.4 2.4 14.0 Modulus of elasticity [MPa] 1752 1495 1334 1446 1437 1442 Formable setting temperature [℃] 410 330 310 265 260 330

[Table 4] formula 0 2 3 Hypromellose TC-5S 100 87.5 70.0 additive Triethyl citrate 12.5 10.0 pigment Titanium oxide 20 Film thickness [μm] 60 40 60 80 40 60 80 Formable setting temperature [℃] 410 315 330 360 340 375 395

1: film for cup 1A: Bottom 1B: Wall 1C: The rest 2: Film for cover 2A: Top wall 2B: Wall 2C: The rest 5: Formed body 10: Cup Department 20: Cover 30: Mold 50: Lozenges

FIG. 1 is a schematic view showing an example of a method for producing a tablet. Fig. 2 is a schematic view showing an example of a method for producing a tablet. FIG. 3 is a photograph showing an example of a cup portion formed by a molding test.

1: film for cup

1A: Bottom

1B: Wall

1C: The rest

10: Cup Department

30: Mold

Claims (12)

A film comprising: at least one polymer of hypromellose or hydroxypropyl cellulose; and at least one additive selected from the group consisting of triethyl citrate, triacetin, propylene glycol, ethylene glycol, polyethylene glycol, and sugar alcohols; and The film is used to coat the shaped body containing the medicinal ingredient. The film according to claim 1, wherein the content of the additive is 5 to 30% by mass based on the total amount of the polymer and the additive. The film of claim 1 or 2, wherein the tensile modulus of elasticity of the film is 800 MPa or more. The film of any one of claims 1 to 3, wherein the film further comprises a pigment. The film of any one of claims 1 to 4, wherein the above-mentioned additive is triethyl citrate, triacetin, or a combination thereof. The film according to any one of claims 1 to 5, comprising a base film comprising the above-mentioned polymer and the above-mentioned additive, and an adhesive layer provided on the above-mentioned base film. The film of any one of claims 1 to 6, which is used for the manufacture of lozenges by a method comprising the steps of: by pressing the heated film against a mold, forming a tablet for containing a medicinally active ingredient The shaped body is inserted into the cup. The film of claim 7, which is used to manufacture a lozenge by a method further comprising the step of removing the rest of the film except for the cup portion. A kind of manufacture method of lozenge, it comprises: Forming a cup by pressing a heated film as claimed in any one of claims 1 to 6 against a mould, the cup forming an opening; Insert a shaped body containing a medicinal ingredient into the cup; and The said molded object is covered by the said cover part and the said cup part by forming the cover part which covers the said opening with the film for a cover part. The method of claim 9, further comprising: after inserting the molded body into the cup portion, removing the remaining portion of the film excluding the cup portion. A lozenge comprising: A shaped body containing a medicinally active ingredient; a cup portion that accommodates the above-mentioned molded body and forms an opening; and a cover portion, which covers the above-mentioned opening; The above-mentioned molded body is covered by the above-mentioned lid portion and the above-mentioned cup portion, and The above-mentioned cup portion is the film according to any one of claims 1 to 6. A method for improving the shape retention and/or chemical stability of a tablet, comprising: coating a shaped body containing a medicinal ingredient with one or more films comprising the film according to any one of claims 1 to 6.

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