WO2002102353A1

WO2002102353A1 - Process for producing stable enteric sugar-coated tablet

Info

Publication number: WO2002102353A1
Application number: PCT/JP2002/005950
Authority: WO
Inventors: Hideyoshi Kobe; Yoichi Onuki; Tetsuo Kaneko; Katsumi Imamori
Original assignee: Ssp Co., Ltd.
Priority date: 2001-06-15
Filing date: 2002-06-14
Publication date: 2002-12-27
Also published as: KR20040007695A; HK1063727A1; TWI317290B; CN1243539C; KR100861444B1; CN1509167A; JP2002370971A; JP4856323B2

Abstract

A process for producing a stable enteric sugar-coated tablet, characterized by coating an uncoated tablet with an enteric polymer, subsequently forming a 20 to 300 μm-thick layer made of a water-soluble polymer and/or water-soluble saccharide, and then forming a sugar coating. Thus, an enteric sugar-coated tablet can be produced which is stable and in which the sugar coating neither discolors nor punctures nor cracks.

Description

Description Manufacturing method for stable enteric-coated sugar-coated tablets

The present invention relates to a method for producing a stable enteric-coated sugar-coated tablet, and more particularly to a method for producing an enteric-coated sugar-coated tablet which prevents discoloration and puncture of the sugar-coated tablet with time. Background art

The composition and formulation of the sugar-coating layer in sugar-coated tablets are diverse, and are often unknown and not yet clarified.

) And the “Pharmaceutical Development Course 18 Pharmaceutical Engineering” (Jinjinshokan), a film layer, a sub-coating layer, and a smoothing layer are generally formed sequentially on a central tablet to further prevent moisture penetration. It is manufactured by forming a layer of sucrose and finally glazing it with wax.

Sugar-coating operations are generally sub-coated to give the core tablets roundness (usually gelatin, gum arabic powder, aqueous solution of sucrose as sugar-coating solution, precipitated calcium carbonate as a spraying agent, a mixture of talc, sucrose and gum arabic powder). , Smoothing to make the surface smooth (usually a solution of gelatin, gum arabic, or aqueous sugar solution with precipitated calcium carbonate or talc as a sugar coating liquid), and coloring to create a smoother and more dense colored layer (Usually, a simple syrup containing a colorant and gelatin is used, starting with a light color and gradually increasing in density.) Finishing (usually a single syrup containing a colorant), and polishing (polishing) It usually consists of white wax or Carnauparo. Each of these operations is performed by alternately and repeatedly coating a sugar coating liquid (in sub-coating, mix an appropriate amount of a spraying agent). The breathability and permeability of the sugar coating layer are reduced by the dense coloring layer made of sugar crystals. Depends.

In general, enteric-coated sugar-coated tablets are coated with an enteric polymer that dissolves in the central tablet with an alcohol and then formed into a sugar-coated layer consisting of a sub-coating layer, a smoothing layer, a coloring layer, and a fixing layer. To manufacture. Enteric-coated products should be inactivated by gastric juice, such as enzymes, or stimulate the stomach, such as aspirin, or drugs that cause impaired digestion of the stomach. It is used for the preparation of drugs with certain properties.

As the enteric coating agent, an acidic and substantially insoluble but alkaline and soluble polymer material such as a cellulosic, biel or acrylic resin is used. These enteric coatings can be coated by dissolving in an organic solvent, or by using cellulosic polymers such as hydroxypropylmethylcellulose acetate succinate (HPMC AS) and propyloxymethylethylcellulose (CMEC). Is dispersed and coated in water. Latex-type water-based coating agents such as Eudragit L30D55 are often used. Recently, a method of dry-coating hydroxypropylmethylcellulose acetate succinate (HPMCAS) while spraying a liquid plasticizer has been developed.

However, conventional sugar-coated tablets have problems such as easy occurrence of cracks, punctures, and changes in color tone over time. These problems are mainly caused by the sugar coating of the sub-coating layer and the smoothing layer, which consist of gelatin, gum arabic powder, sucrose, precipitated calcium carbonate, kaolin, talc, etc. In this sugar-coating operation, it is unavoidable that some of the water in the sugar-coating liquid penetrates into the central tablet, and the last step of the sugar-coating layer. The coloring layer, which is a layer, has a very low water vapor permeability, so it completely blocks water vapor from the outside, but cannot release the moisture that has entered the central tablet, making the central tablet unstable to moisture. In the case of drugs, it will accelerate the degradation of the drug Due to that. This also causes punctures, cracks and discoloration of dragees. In particular, since water-based coatings and dry coatings use a large amount of plasticizers, the production of enteric-coated sugar-coated tablets with these coating agents is also affected by the plasticizer, and further causes the sugar-coated tablets to crack, puncture or discolor. Problems will arise.

As a countermeasure, there is a method of sufficiently drying the tablet when forming the sub-coating layer, a method of coating the center tablet with a waterproof film in advance, and then shifting to the sugar coating operation after the formation of the sub-coating layer. It is also possible to take. The process of forming this waterproof film is called protective coating.Since the film used must have a barrier property against moisture, it is often used with a coating agent that is insoluble in water. Is done. As a result, the thickness of finolem directly affects the disintegration and dissolution properties of tablets, so that attention must be paid to the control of the film thickness.This is a perfect measure to prevent cracking, puncturing and discoloration of dragees. It's hard to say.

Japanese Patent Application Laid-Open No. 11-43430 discloses a method of adding a pigment binder to a coloring layer or a finishing layer to prevent peeling or cracking of a sugar coating layer; Japanese Patent Application Laid-Open No. 7-55898 describes a method for enhancing the strength of a sugar-coated tablet by applying a film made of a high molecule soluble in both water and a lower alcohol to the sugar-coated tablet. A method is described in which high-purity maltitol and pullulan are used in place of sucrose as sugar coating materials to increase the impact resistance and prevent cracking, breakage, and changes over time. However, none of these methods is perfect.

Accordingly, there has been a strong demand for a method for producing a stable enteric-coated sugar-coated tablet without discoloration of the sugar-coated tablet over time and puncture of the sugar-coated tablet. Disclosure of the invention In the present invention, after coating an enteric polymer on an uncoated tablet, a 20-300 m-thick layer composed of a water-soluble polymer and Z or a water-soluble saccharide is formed, and then a sugar coating layer is formed. A method for producing an enteric-coated sugar-coated tablet, characterized by the following: BEST MODE FOR CARRYING OUT THE INVENTION

Enteric polymer coating agents include cellulosic polymers such as cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or carboxymethyl ester. Butyl cellulose (CMEC), etc .; vinyl polymers, for example, polyvinyl alcohol acetate phthalate (PV AP); acrylic polymers, for example, copolymers of methacrylic acid and ethyl acrylate (methacrylic acid copolymers L, S), etc. An acidic, substantially insoluble, but alkaline, soluble polymer material can be used. A preferred enteric coating is HPMCAS.

Enteric coating can be performed by dry-coating a fine powdered enteric polymer material while spraying a liquid plasticizer onto uncoated tablets. Further, the enteric coating agent may be coated by dissolving it in an organic solvent, may be dispersed in water and coated, or may be a latex-type liquid. Examples of the water-soluble polymer formed on the enteric polymer coating and the water-soluble polymer of the layer of Z or water-soluble saccharide include hydroxypropylcellulose (HPC), hydroxyfilm methylcellulose (HPMC), methylcell mouth, and force. Water-soluble cellulosic polymers such as sodium ropoxymethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; and pullulan and polyvinyl alcohol can be used. Of these, water-soluble cellulosic polymers, particularly hydroxypropylmethylcellulose (HPMC), are preferred.

Use sucrose, mannitol, glucose, lactose, etc. as water-soluble sugars be able to. Of these, sucrose is preferred.

The above-mentioned water-soluble polymer and water-soluble saccharide may be used alone or in a mixture thereof, or a water-soluble saccharide may be used on a water-soluble polymer or a water-soluble saccharide may be used on a raw saccharide. The hydrophilic polymer may be coated.

The layer thickness of the water-soluble polymer and / or water-soluble saccharide is 20 ^ m to 300 m, usually 22 to 300 wm, preferably 40 to 200 m, and particularly preferably. 4 8 to 15 ΠΙ ΠΙ. Specifically, when the water-soluble saccharide is used alone, the thickness of the layer is usually 40 to 300 m, preferably 48 to 200 m, and particularly preferably 60 to 150 m. In the case of a water-soluble polymer alone or a combination of a water-soluble polymer and a water-soluble saccharide, the thickness of the layer is usually 20 to 300 m, preferably 22 to 200 m, and particularly preferably 50 to 100 m. 1150 m. If it is less than 20 Am, sufficient puncture prevention and discoloration prevention effects cannot be obtained. When the water-soluble polymer layer and the water-soluble saccharide layer are separately coated, the total thickness of both layers may be in the above range.

The above-mentioned water-soluble polymer and water-soluble saccharide are each applied to an enteric-coated tablet in the form of an aqueous solution. For example, when a saccharide such as sucrose is used, it is in the form of an aqueous solution of 10 to 80% (by weight), and when a water-soluble polymer such as HPMC is used, an aqueous solution of 1 to 30% (by weight) is used. Can be used in the form of

The formation of the sugar coating layer after the formation of the water-soluble polymer and / or water-soluble saccharide layer is usually performed by a sugar coating operation including at least one of sub-coating, smoothing, coloring, and finishing, and then necessary. Polishing is performed accordingly. Particularly, when the diameter of the uncoated tablet is less than 7 bands, an enteric coating layer is formed, a water-soluble saccharide layer is formed, and a water-soluble polymer (especially, HPMC) layer is formed thereon. A sugar-coated tablet can also be formed by forming a coloring layer using sucrose syrup. Example Next, the present invention will be described specifically with reference to examples, but the present invention is not limited thereto.

Reference Example 1 (Preparation of central tablet)

A central tablet (uncoated tablet) having the composition shown in Table 1 below was prepared using a 5.5R, 4.5R punch with a size of 55 nig per tablet. The disintegrant hardness was 2.8 kg and the disintegration time (test solution: water) was 6 to 8 minutes.

4.7 kg of these tablets were charged into a ventilated pan coating machine (Hicoater HCT-48 Freund Sangyo Co., Ltd.), and the intake air temperature was 50 ° (product temperature: 45 ° C; Spraying a plasticizer solution of glycerin fatty acid ester (35Z20) at a spray rate of 20 g / min, hydroxypropylmethylcell mouth acetate succinate (trade name: AS—MF Shin-Etsu Chemical Co., Ltd.) / Talc ratio The powder obtained by uniformly mixing (10/6) was sprayed with 58 g of iiiin to perform dry coating to obtain 67 mg of an enteric film tablet per tablet.

table 1

(Center tablet composition)

Example 1

The enteric-coated film tablets prepared in Reference Example 1 were coated with a 65% sucrose syrup at 5 mg / tablet using a ventilated pan-coating device (manufactured by Heiko Ichiyuichi 48 Freund Corporation). A m layer of sucrose was formed. Further, a smoothing layer of 35 mg per tablet was formed with an aqueous suspension composed of 10% of kaolin, 10% of calcium carbonate, 5% of talc, 5% of titanium oxide, 4% of arabic gum powder and 40% of sucrose. Finally, a coloring layer of 5 mg per tablet was formed using 65% sucrose syrup to which an evening dye was added, and the mixture was glossed with wax to obtain enteric-coated sugar-coated tablets.

Example 2

The enteric-coated film tablets prepared in Reference Example 1 were sucrose 9 mg, film thickness 86 with 65% sucrose syrup using a ventilated pan-coating machine (Hikako Ichiyo 48, manufactured by Freund Corporation). Was formed. Further, a smoothing layer and a coloring layer were formed and glazed in the same manner as in Example 1 to obtain enteric-coated sugar-coated tablets. Example 3

The enteric-coated film tablet produced in Reference Example 1 was Using Coater 48, Freund Sangyo Co., Ltd.), a film having a thickness of 124 mg was formed with sucrose 13 mg with syrup of 65% sucrose. Further, an enteric-coated sugar-coated tablet was obtained by forming and smoothing a smoothing layer and a coloring layer in the same manner as in Example 1. Example 4

6% hydroxypropyl methylcellulose (HPMC) (TC-5R Shin-Etsu Chemical Co., Ltd.) was applied to the enteric-coated film tablet prepared in Reference Example 1 using a ventilated pan coating machine (Hi-Ko Yuichi 48 type, Freund Sangyo Co., Ltd.). A water-soluble film with a thickness of 22 mg and a hydroxypropylmethyl cell opening of 3 mg was formed with an aqueous solution. Further, a smoothing layer and a coloring layer were formed and glazed in the same manner as in Example 1 to obtain enteric-coated sugar-coated tablets.

Example 5

6% hydroxypropyl methylcellulose (TC-5R Shin-Etsu Chemical Co., Ltd.) was applied to the enteric-coated film tablet manufactured in Reference Example 1 using a ventilated pan-coating device (Hikko Itsuya- _48, manufactured by Freund Corporation). A water-soluble film having a thickness of 52 im and a thickness of 52 mg was prepared from an aqueous solution of hydroxypropyl propylmethylcellulose (7 mg). Further, a smoothing layer and a coloring layer were formed and glazed in the same manner as in Example 1 to obtain enteric-coated sugar-coated tablets.

Example 6

6% hydroxypropyl methylcellulose mouth (TC-15R Shin-Etsu Chemical Co., Ltd.) was applied to the enteric-coated film tablet manufactured in Reference Example 1 using a ventilated banco-coating device (Ikoter 48, manufactured by Freund Industrial Co., Ltd.). A water-soluble film having a thickness of 75 m and a hydroxypropylmethylcellulose concentration of 10 mg was formed with an aqueous solution. Further, a smoothing layer and a coloring layer were formed and glazed in the same manner as in Example 1 to obtain enteric-coated sugar-coated tablets.

Example 7

In addition to the enteric film tablet produced in Reference Example 1, Using a coater made of 65% sucrose, a layer of 3 mg of sucrose and a thickness of 28 m was formed using an icoter 48 type Freund Sangyo Co., Ltd.), followed by 6% hydroxypropyl methylcellulose (TC-15R (Shin-Etsu Chemical Co., Ltd.) A water-soluble film having a thickness of 75 m was formed with an aqueous solution of hydroxypropylmethylcellulose (1 Omg). Finally, a coloring layer of 5 mg per tablet was formed with a 65% sucrose syrup to which an evening dye had been added, and the mixture was glossed with wax to obtain enteric-coated sugar-coated tablets.

Example 8

The enteric-coated film tablet prepared in Reference Example 1 was applied to a sucrose syrup of 65% with a sucrose of 6% and a film thickness of 57 m using a ventilated pan-coating device (Hachiko Co., Ltd., type 48 Freund Corporation). Then, a 10% aqueous solution of hydroxypropylmethylcellulose (75 mg in thickness) was formed with a 6% aqueous solution of hydroxypropylmethylcellulose (TC-15R manufactured by Shin-Etsu Chemical Co., Ltd.). Lastly, a 5% per-pill coating layer was formed with 65% sucrose syrup to which an evening dye had been added, and the tablets were glossed to give enteric-coated sugar-coated tablets.

Comparative Example 1

The enteric-coated film tablets prepared in Reference Example 1 were applied to a 10% calcium carbonate, 5% talc, 5% titanium oxide, and 5% titanium oxide by using a ventilated pan coating machine (manufactured by Hikko Yuichi 48 Freund Corporation). An aqueous suspension composed of 4% of rubber powder and 40% of sucrose formed a smoothing layer of 35 mg per tablet. Next, a coloring layer of 5 mg per tablet was formed with 65% sucrose syrup to which a tar dye had been added, and the tablets were glossed to give enteric-coated sugar-coated tablets.

Comparative Example 2

The enteric film tablets prepared in Reference Example 1 were applied to a 65% sucrose syrup using a ventilated pan-coating machine (Hicoater 48, Freund Corporation) to produce 2 mg of sucrose and a film thickness of 19 m. Was formed. Further, a smoothing layer and a coloring layer were formed and glazed in the same manner as in Example 1 to obtain enteric-coated sugar-coated tablets. Comparative Example 3

6% hydroxypropyl methylcellulose (TC-15R Shin-Etsu Chemical Co., Ltd.) was applied to the enteric-coated film tablets prepared in Reference Example 1 using a ventilated pan coating machine (Hachikoa 48 type, Freund Sangyo Co., Ltd.). 2) Hydroxypropyl methylcellulose 2 mg, 15 m thick water-soluble film layer was formed with the aqueous solution. Further, a smoothing layer and a coloring layer were formed and glazed in the same manner as in Example 1 to obtain an enteric sugar-coated tablet.

Test example

The enteric-coated sugar tablets obtained in Examples 1 to 8 and Comparative Examples 1 to 3 were stored at 50 ° C, and punctures and appearance changes of the dragees after one month were observed. The results are shown in Table 2.

Table 2

Punk and appearance change

ΔΕ indicates a value obtained by measuring a sample at 50 ° C for one month using a color difference meter SQ2000 (manufactured by Nippon Denshoku Industries Co., Ltd.) at the time of manufacture of each sample.

E == 3 or less: No change compared to the time of manufacture

E = 3-5: slightly changed compared to the time of manufacture ΔΕ = 5 ～ 10 ： Compared to the time of manufacture, clearly changing Industrial applicability

According to the present invention, by coating a water-soluble polymer and / or a water-soluble saccharide on an enteric film, it becomes possible to produce a stable enteric-coated sugar-coated tablet without discoloration and puncture of the sugar-coated tablet.

Claims

The scope of the claims

1. After coating the uncoated tablet with the enteric polymer, a layer of water-soluble polymer and / or water-soluble saccharide having a thickness of 20 to 300 m is formed, and then a sugar coating layer is formed. A method for producing an enteric-coated sugar-coated tablet.

2. The method for producing an enteric-coated sugar-coated tablet according to claim 1, wherein the layer of the water-soluble polymer and / or the water-soluble saccharide contains hydroxypropylmethylcellulose.

3. The coating of the enteric polymer on the uncoated tablet is performed by a dry coating method in which the uncoated tablet is spray-coated with a finely powdered enteric polymer while spraying a plasticizer. 2. The method for producing an enteric-coated sugar-coated tablet according to 2.