JPH0820537A - Solid preparation containing antiulcer agent - Google Patents

Abstract

PURPOSE:To obtain the solid preparation containing a cycloheptenopyridine derivative having a proton pump-inhibiting action and useful as an antiulcer agent as an active ingredient, excellent in productivity and good in storage stability on the aspects of both the content and the appearance. CONSTITUTION:The solid preparation is prepared by compounding a compound of the formula (R is H, lower alkyl; R<1> is H, lower alkyl capable of being substituted; R<2> is H, halogen) or its salt, e.g. 9-(benzimidazol-2-yl)sulfinyl-4- methoxy-2,3-cycloheptenopyridine with magnesium oxide as a stabilizer, spray- dried lactose, granulated lactose, anhydrous lactose, calcium hydrogen phosphate or anhydrous calcium hydrogen phosphate as an excipient, and a starch derivative, preferably partially alpha-starch-containing starch or hydroxypropyl starch as a disintegrating agent, and subsequently granulating the mixture without using a granulation solvent. The stabilizer is preferably used in an amount of 0.3-3 pts.wt., especially 0.5-1,5 pts.wt., per pt. wt. of the compound of the formula, and the disintegrating agent is preferably used in an amount of 5-30%, especially 10-20%, based on the whole weight of the preparation.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has stability and production of a cycloheptenopyridine derivative represented by the following general formula I or a salt thereof, which has a proton pump inhibitory action and is useful as an anti-ulcer agent, as an active ingredient. It relates to a solid preparation having excellent properties.

Embedded image [Wherein R is a hydrogen atom or a lower alkyl group, R ¹ is a hydrogen atom, a lower alkoxy group or a substituted lower alkoxy group, R 1
² represents a hydrogen atom or a halogen atom]

[0002]

2. Description of the Related Art Recently developed benzimidazole compounds having an H ⁺ -K ⁺ ATPase (proton pump) inhibitory action such as omeprazole strongly and persistently suppress gastric acid secretion and also have a gastric mucosal protective action. Therefore, it is attracting attention as a next-generation peptic ulcer treatment agent that replaces the histamine H ₂ receptor antagonists such as cimetidine and ranitidine that are currently widely used as therapeutic agents for peptic ulcer. Is already on the market. In particular, compound I or a salt thereof has a strong gastric acid secretion inhibitory action, and is expected to be clinically useful (JP-A-3-218372).
Issue). However, the stability of these benzimidazole derivative compounds including Compound I or a salt thereof is extremely poor, and they are rapidly decomposed particularly under humidified conditions and in an acidic to neutral aqueous solution, and are markedly colored yellow to reddish brown. . Therefore, it is necessary to appropriately stabilize these compounds when they are formulated into oral solid preparations. In particular,
When the compound I or a salt thereof is molded into an oral solid preparation such as a tablet, not only the compoundability with an additive usually used in a pharmaceutical formulation is poor, but also the compound I or a salt thereof becomes more unstable than the case of using the compound I or a salt alone. Significant decrease in content and color change during manufacture and over time. Particularly, additives having poor blending properties include cellulose and its derivatives. For example, when cellulose or a cellulose derivative is blended as an excipient, a disintegrating agent, a binder, a coating agent, etc., in addition to poor blending properties, it is stable. It also has a great influence on the sex and causes a particularly remarkable color change. In addition, when granulation is carried out with an organic solvent such as water or ethanol during preparation of the preparation, the content decrease and color change remarkably during the preparation and over time. Further, the compound I or its salt has a pH
In acidic aqueous solutions of 4 or less, the half-life at 37 ° C is 5
When administered orally,
It is easily decomposed by gastric acid, and there is concern that bioavailability may be reduced. On the other hand, in terms of production, compound I
Alternatively, the salt thereof has a remarkable adhesive property to metal and the like and an electrostatic property, and the powder is apt to stick to the punch during sticking (sticking), which makes it difficult to scale up for practical industrial production.

The inventors of the present invention have previously studied the stabilization of Compound I or a salt thereof, and as a result, have found that an amine (hereinafter abbreviated as amine) soluble in Compound I or a salt thereof at room temperature or soluble in an alcohol solvent is used. Compounding (Japanese Patent Laid-Open No. 5-1124
52), or compound I or a salt thereof with the amine, and a basic inorganic salt and a saccharide having no reducing property (JP-A-4-364127) to obtain a stable preparation. I disclosed that. As the amine in the conventional invention, monoethanolamine, diethanolamine, triethanolamine, ethylenediamine or diisopropanolamine, magnesium oxide, magnesium hydroxide or calcium carbonate as the basic inorganic salt, maltitol, mannitol as the sugar having no reducing property. Or lactitol was preferred.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention In the invention containing an amine as disclosed above, the amine is recognized as a pharmaceutical additive, and although its content is extremely small, it is not added if safety is possible. It is preferable. Further, in the present invention, the improvement of sticking was hardly achieved, and the saccharide having no reducing property had metal adhering property per se, which rather promoted sticking.

[0005]

In view of such circumstances, the present inventors have proposed a formulation containing Compound I or a salt thereof, which has stability and is excellent in manufacturability without adding an amine. As a result of intensive studies for designing, the present invention has been completed. That is, the present invention provides compound I or a salt thereof with magnesium oxide as a stabilizer, spray-dried lactose as an excipient, granulated lactose, anhydrous lactose, calcium hydrogen phosphate or anhydrous calcium hydrogen phosphate, and a starch derivative as a disintegrant. And a pharmaceutically acceptable lubricant additive as a lubricant or a binder, if desired, and then directly compression-molded to provide a novel antiulcer agent-containing solid preparation.

The substituent R of the compound of the general formula I is a hydrogen atom and a lower alkyl group such as a methyl group, an ethyl group, a propyl group and a butyl group, and R ¹ is a methoxy group, an ethoxy group, a propoxy group and a butoxy group. Examples of the lower alkoxy group such as allyloxy group and the substituted lower alkoxy group include trifluoroethoxy group, tetrafluoropropoxy group, cyclopropylmethoxy group, methoxyethoxy group, phenoxyethoxy group and benzyloxy group, and R ² is Halogen atoms such as hydrogen atom, chlorine atom, bromine atom, iodine atom and fluorine atom. Salts of compounds of general formula I include sodium,
Examples thereof include alkali metal salts with potassium and the like and alkaline earth metal salts with magnesium, calcium and the like.

Magnesium oxide is incorporated as a stabilizer. Conventionally, as a result of preparing a physical mixture of compound I or a salt thereof and various additives and comparing storage stability, it was found that the basic inorganic salt such as magnesium oxide has a sufficient stabilizing effect as compared with amine. There was not (JP-A-5-11245
No. 2). However, as a result of further intensive studies thereafter, when the additives specified in the present invention were blended as excipients, disintegrants, etc., and formulated into tablets etc., only magnesium oxide was blended as a stabilizer. It was found that the formulation also has stability equal to or higher than that of the formulation of the present invention containing both amine and magnesium oxide (JP-A-4-364127). Furthermore, the formulation of the present invention was superior to the formulations of the conventional invention in that it had very few adhesion and electrostatic properties which hindered the production in industrial mass production. On the other hand, basic inorganic salts other than magnesium oxide were not sufficiently stable when formulated in a system not using an amine together. Magnesium oxide blended in the present invention is listed in the Japanese Pharmacopoeia and is easily available (for example, manufactured by Kyowa Chemical Industry). There are heavy and light types on the market, but the heavy type is more preferable in view of tableting property. The compounding amount thereof is preferably 0.3 to 3 parts by weight, more preferably 0.5 to 1.5 parts by weight, relative to 1 part by weight of the compound I or a salt thereof.

The excipient compounded in the present invention is compounded for molding a direct compression preparation, is relatively inactive to the compound I or a salt thereof, is excellent in direct compression moldability, and is itself. It is preferable that there is almost no adhesion to the tableting punch,
For example, spray-dried lactose or granulated lactose obtained by spray-drying or granulating hydrous lactose to improve fluidity and compression moldability, anhydrous lactose having excellent fluidity and direct compression-moldability itself, and phosphoric acid. Calcium hydrogen or anhydrous calcium hydrogen phosphate. Such as spray drying product names as lactose Famatozu ^R DCL 11 (manufactured by DMV Corporation), trade name Dairakutozu ^R (manufactured by Freund Sangyo) as granulated lactose etc., Famatozu ^R DCL as anhydrous lactose
21 (manufactured by DMV) and the like, calcium hydrogen phosphate as trade name calcium hydrogen phosphate FF-100 (manufactured by Kyowa Chemical Industry Co., Ltd.), and anhydrous calcium hydrogen phosphate as trade name anhydrous calcium hydrogen phosphate GS (Kyowa Chemical Industry Co., Ltd. Manufactured). The blending amount of these excipients is not particularly limited as long as it is an amount sufficient for direct compression molding, but is usually blended in the range of 30 to 70 (W / W)% with respect to the weight of the entire formulation.

As the disintegrating agent blended in the present invention, a starch derivative which is relatively inactive to the compound I or its salt and has a strong disintegrating power is used. Examples thereof include partially pregelatinized starch or hydroxypropyl starch, and partially pregelatinized starch is particularly preferable because it has direct compression moldability. Partially pregelatinized starch is available under the trade name PCS ^R (manufactured by Asahi Kasei Kogyo) and hydroxypropyl starch under the trade name HPS ^R (manufactured by Freund Sangyo). From the viewpoint of promoting rapid disintegration in the human gastrointestinal tract and ensuring bioavailability, the preferable amount of these disintegrants is preferably 5 to 30 (W / W)% with respect to the weight of the entire preparation, and more preferably It is preferably 10 to 20 (W / W)%.

In the present invention, a pharmaceutically acceptable additive can be further compounded if desired, and examples thereof include a lubricant. The lubricant is preferably a metal stearate salt which is relatively inert to Compound I or a salt thereof, and examples thereof include magnesium stearate and calcium stearate. In addition, talc and the like can be used in combination.

The solid preparation of the present invention is preferably coated with an enteric coating agent to form an enteric-coated solid preparation in order to prevent decomposition of Compound I or a salt thereof by gastric acid and prevent deterioration of bioavailability.
The enteric coating agent incorporated in the present invention is compound I
Alternatively, a methacrylic acid copolymer which is relatively inert to the salt thereof is preferable. Examples of the methacrylic acid copolymer include a methacrylic acid / methyl methacrylate copolymer or a methacrylic acid / ethyl acrylate copolymer.
The methacrylic acid / methyl methacrylate copolymer has a trade name of Eudragit ^R L100 (manufactured by Rehm Pharma), and the methacrylic acid / ethyl acrylate copolymer has a trade name of Eudragit ^R L30D-55 (Reme.
(Pharma). Other additives that are used in combination with the enteric coating agent include triethyl citrate as a plasticizer, propylene glycol,
Examples include triacetin and the like, talc and the like as an adhesion preventing agent, and titanium oxide and the like as a white pigment.

The solid preparation of the present invention is produced by directly compression-molding a mixed powder without granulation with water or an organic solvent such as ethanol. The dosage form is preferably a tablet because it is the most convenient and can be easily coated as desired. Alternatively, a granule can be prepared by directly compression-molding into a plate shape and appropriately roughly crushing this.

Hereinafter, the present invention will be described in more detail with reference to Examples, Controls and Tests, but the present invention is not limited thereto.

【Example】

R = H In Examples 1-4 the general formula _{^{I, R 1 = OCH 3,}} R 2 = represented by H 9-(benzimidazol-2-yl) sulfinyl-4-methoxy-2,3-Shikuroheputeno Using sodium salt of pyridine (hereinafter referred to as compound Ia),
According to the components and amounts shown in, each component was uniformly mixed with a V-type mixer (manufactured by Paulec), and then the compound was directly compressed by using a rotary tableting machine with a powder forced-feeding device (manufactured by Hata Tekko Co., Ltd.). A plain tablet having a weight of 170 mg and a diameter of 7.5 mm and containing 20 mg or 30 mg as Ia was tabletted.

[0014]

[Table 1]

[0015] In Example 5 Example 2, except for using granulated lactose (Dairakutozu ^R) in place of spray-dried lactose, to obtain a plain tablet using the same method. Example 6 Example 2, except for using anhydrous lactose (Famatozu ^R DCL 21) in place of spray-dried lactose,
The same operation was performed to obtain a plain tablet. Example 7 In Example 2, calcium hydrogen phosphate (calcium hydrogen phosphate FF-10 was used instead of spray-dried lactose.
A plain tablet was obtained in the same manner except that 0) was used.

Example 8 In Example 2, instead of spray-dried lactose, anhydrous calcium hydrogen phosphate (anhydrous calcium hydrogen phosphate G
A plain tablet was obtained in the same manner except that S) was used. Example 9 Example 2, except for using hydroxypropyl starch (HPS ^R) in place of the partly pregelatinized starch, to give a plain tablet using the same method. Example 10 A plain tablet was obtained in the same manner as in Example 2 except that calcium stearate was used instead of magnesium stearate.

Control Example 1 [Deletion of Magnesium Oxide] A plain tablet was obtained in the same manner as in Example 2 except that magnesium oxide was removed and spray-dried lactose was added instead. Control Example 2 [Change of Excipient] The same operation as in Example 2 was carried out except that crystalline lactose (Pharmatose ^R 200M) was used instead of spray-dried lactose. However, the uncoated tablets obtained were extremely fragile and did not have the strength to withstand the subsequent tests. Comparative Example 3 [Composition of Cellulose Disintegrant] In the same manner as in Example 2, except that low-substituted hydroxypropyl cellulose (L-HPC) was used in place of the partially pregelatinized starch, the same operation was performed to obtain a plain tablet. .

Control Examples 4 to 7 [Addition of Granulation Solvent] According to the components and amounts shown in Table 2, compound Ia, magnesium oxide, spray-dried lactose and partially pregelatinized starch were put into a high speed mixer (Fukae Industry Co., Ltd.). After uniform mixing, Control Example 4 was an ethanol solution of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda), Control Example 5 was an aqueous solution of hydroxypropylmethylcellulose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.), and Control Example 6 was used. And in Control Example 7, only ethanol was added for granulation. After granulation, the granules were dried at 40 ° C. for 2 hours, sized with 20 mesh, mixed with magnesium stearate and talc, and mixed in the same manner as in Example 2 to obtain plain tablets.

[0019]

[Table 2]

Control Example 8 [Formulation of Conventional Invention: JP-A-4-364127] Of the components and amounts shown below, diethanolamine was added as a 2 (W / V)% ethanol solution to compound Ia and kneaded. After drying at 40 ° C for 2 hours, crush in a mortar,
The particles were sized with a mesh. Other ingredients were added to this, and the mixture was uniformly mixed with a V-type mixer and tabletted in the same manner as in Example 2 to obtain a plain tablet.

Control Example 9 [Formulation of Conventional Invention: JP-A-4-364127] A plain tablet was obtained in the same manner as in Control Example 8 except that mannitol was used instead of maltitol. Control Example 10 [Formulation of Conventional Invention: JP-A-4-364127] A plain tablet was obtained in the same manner as in Control Example 8 except that lactitol was used instead of maltitol.

[0022] In Example 11 Example 2, the compound R = H in the general formula I in place of _{^{Ia, R 1 = OCH 3,}} R 2 = 5-F represented by 9
A plain tablet was obtained in the same manner except that-(5-fluorobenzimidazol-2-yl) sulfinyl-4-methoxy-2,3-cycloheptenopyridine (hereinafter referred to as compound Ib) was used.

Comparative Example 11 A plain tablet was obtained in the same manner as in Comparative Example 1, except that the compound Ib was used in place of the compound Ia. Comparative Example 12 A plain tablet was obtained in the same manner as in Comparative Example 6 except that Compound Ib was used instead of Compound Ia. Control Example 13 A plain tablet was obtained in the same manner as in Control Example 8 except that the compound Ib was used in place of the compound Ia.

[0024] In Example 12 Example 2, R = H in the general formula I in place of compound Ia, represented by ^{_{R 1 = OCH 2 CH 2 OCH}} 3, R 2 = H 9- ( benzimidazol-2 Uncoated tablets were obtained in the same manner except that (yl) sulfinyl-4- (2-methoxyethoxy) -2,3-cycloheptenopyridine (hereinafter referred to as compound Ic) was used.

Control Example 14 A plain tablet was obtained in the same manner as in Control Example 1 except that Compound Ic was used instead of Compound Ia. Comparative Example 15 A plain tablet was obtained in the same manner as in Comparative Example 6 except that Compound Ic was used instead of Compound Ia. Control Example 16 A plain tablet was obtained in the same manner as in Control Example 8 except that the compound Ic was used in place of the compound Ia.

Example 13 In Example 2, instead of the compound Ia, 9- (benzimidazol-2-yl) represented by R = 3-CH ₃ , R ¹ ═OCH ₃ and R ² ═H in the general formula I was used. ) Sulfinyl-
Uncoated tablets were obtained in the same manner except that 4-methoxy-3-methyl-2,3-cycloheptenopyridine (hereinafter referred to as compound Id) was used.

Comparative Example 17 A plain tablet was obtained in the same manner as in Comparative Example 1, except that the compound Id was used in place of the compound Ia. Comparative Example 18 A plain tablet was obtained in the same manner as in Comparative Example 6 except that Compound Id was used instead of Compound Ia. Control Example 19 A plain tablet was obtained in the same manner as in Control Example 8 except that the compound Id was used in place of the compound Ia.

[0028] In Example 14 Example 2 is represented in the general formula I in place of Compound Ia at ^{R = H, R 1 = OCH} 2 Ph, R 2 = H 9
-(Benzimidazol-2-yl) sulfinyl-4
A plain tablet was obtained in the same manner except that -benzyloxy-2,3-cycloheptenopyridine (hereinafter referred to as compound Ie) was used.

Comparative Example 20 A plain tablet was obtained in the same manner as in Comparative Example 1, except that the compound Ie was used in place of the compound Ia. Control Example 21 A plain tablet was obtained in the same manner as in Control Example 6 except that Compound Ie was used instead of Compound Ia. Control Example 22 A plain tablet was obtained in the same manner as in Control Example 8 except that the compound Ie was used instead of the compound Ia.

Test Example 1 [Evaluation of Stability] The plain tablets obtained in Examples 1 to 10, Control Example 1 and Control Examples 3 to 10 were tested at 40 ° C. and 75% RH and 60%.
It was stored in various packaging forms under storage conditions of ° C, and the stability of content and appearance was evaluated. The plain tablet obtained in Control Example 2 was fragile and easily broken, so it was not subjected to the test. The material of the PTP used is hard polyvinyl chloride. The content is
After extracting from plain tablets with ethanol, add internal standard substance,
Quantify by liquid chromatography under the conditions shown below,
The residual rate (%) with respect to the content at the start was calculated. The appearance change was evaluated as ΔE by measuring the color difference with a spectroscopic color difference meter (TC-1300MK-II, manufactured by Tokyo Denshoku Co., Ltd.). It should be noted that the larger ΔE is, the more remarkable the change in color is as compared with the start time. The measurement results of the residual content rate and the color difference are shown in Tables 3 and 4.

[Conditions for Liquid Chromatography] Detector:
Ultraviolet absorptiometer (measurement wavelength: 280 nm) (manufactured by Waters) Column: YMC-A302 (manufactured by YMC) Column temperature: 40 ° C. Mobile phase: Phosphoric acid is added to diluted triethylamine (1 → 100) to adjust pH to 5.5. Adjust to. 500 ml of this liquid
Add 500 ml of methanol to. Internal standard: thymol Injection amount: Compound Ia and internal standard of 0.
8 and 4 μg

[0032]

[Table 3]

[0033]

[Table 4]

As shown in Tables 3 and 4, the plain tablets of the present invention are superior in content and appearance and have improved stability, as compared with the plain tablets of the conventional invention (Comparative Examples 8, 9 and 10). . The plain tablets (Control Example 1) which differed only in the removal of magnesium oxide were inferior in both content and appearance, and thus had reduced stability.
Especially, under the storage conditions of a glass bottle sealed at 60 ° C., the difference in stability from the plain tablet of the present invention was very remarkable. An uncoated tablet that differs only in that a cellulose-based disintegrating agent was added instead of the starch-based disintegrating agent (Control Example 3) was compared with the uncoated tablet of the present invention.
The change in content with time was almost the same, but the change in appearance was large and the stability decreased. Uncoated tablets that differ only in the addition of a binder as a solution and granulation (Comparative Examples 4 and 5) were significantly different in stability and content compared to the uncoated tablet of the present invention. The plain tablets (Comparative Example 6) which differed only in that they were granulated only with ethanol without adding a binder were more stable than the plain tablets with a binder, but compared with the plain tablet of the present invention, the content and appearance Both were inferior and the stability decreased. The plain tablet obtained by granulating only ethanol without adding a binder and further removing magnesium oxide (Control Example 7) had a large change in content and appearance compared with the plain tablet of the present invention, and the stability decreased.

Test Example 2 [Evaluation of tableting properties 1] About 1000 tablets per 1 punch for Examples 1 to 10 and Comparative Examples 8 to 10 (conventional invention) in which an excipient different from the present invention was blended. After locking, the surfaces of the upper and lower punches were observed. The evaluation of the observation results is shown in Table 5.

[0036]

[Table 5]

As shown in Table 5, when the plain tablet of the present invention was tableted, almost no sticking (sticking) of the powder to the punch was observed. However, in Example 4, 30 m
Due to the high content of the active ingredient in g tablet, a slight sticking of powder was observed as compared with the other 20 mg tablet examples. On the other hand, when the conventional 20 mg tablets (Comparative Examples 8 to 10) were tabletted, remarkable sticking was observed.

Test Example 3 [Evaluation of Manufacturability 2] In Test Example 2, about 1000 tablets per punch of each Example and Comparative Example were taken uncoated tablets at the end of tableting, and the rough surface of the uncoated tablets was examined. It was measured with a surface roughness profile measuring device (Surfcom 575A, manufactured by Tokyo Seimitsu Co., Ltd.) and expressed as a center line average roughness (Ra). The center line average roughness (Ra)
Is a value calculated from Formula 1 based on the result of measuring the unevenness of the surface as shown in Fig. 1 by contacting the minute measuring terminals along the center line of the surface of the uncoated tablet from end to end. Is. L is the measured length, and f (x) is an approximate expression of the waveform. The smaller Ra indicates the smoother surface of the plain tablet, and the larger Ra indicates that the surface is rougher. The Ra measurement results are shown in Table 6.

(Equation 1)

[0039]

[Table 6] If sticking occurs, the punch surface becomes rough and the surface of the uncoated tablet is also roughened. As shown in Table 6, the uncoated tablet of the present invention has a higher Ra than the uncoated tablet of the conventional invention.
Was remarkably small and the surface was smooth. From this point as well, the degree of sticking during tableting of the plain tablet of the present invention was obviously slight as compared with that during tableting of the conventional tablet.

Test Example 4 [Evaluation of Stability] Examples 11 to 14 and Control Examples 11 and 2
The plain tablet obtained in 2 was stored as a PTP packaged product at 40 ° C. and 75% RH for 1 month, and the stability of content and appearance was evaluated. The material of the PTP used is hard polyvinyl chloride. The content was quantified by the absolute calibration curve method (peak area) under the same liquid chromatographic method conditions as in Test Example 1 after extraction from the plain tablet with ethanol, and the residual rate (%) with respect to the content at the start was calculated. . The appearance change was evaluated as ΔE by measuring the color difference with a spectroscopic color difference meter (TC-1300MK-II, manufactured by Tokyo Denshoku Co., Ltd.). Table 7 shows the measurement results of the residual content ratio and the color difference.

[0041]

[Table 7]

As shown in Table 7, the plain tablets of the present invention have the same content stability and superior appearance stability as those of the plain tablets of the conventional invention (Controls 13, 16, 19 and 22). It was.
Uncoated tablets which differed only in the removal of magnesium oxide (Control Examples 11, 14, 17 and 20) and solvent-granulated uncoated tablets (Control Examples 12, 15, 18 and 21) were compared with the uncoated tablets of the present invention. , Content and appearance co-stability decreased.

Example 15 [Enteric coated tablet] The plain tablet obtained in Example 2 was enterically coated with Doria Coater (manufactured by Paulec) according to the following coating liquid formulation, and 1 tablet 182 m.
g of enteric coated tablets was obtained. [Coating liquid formulation] Eudragit ^R L 70 70 g Triethyl citrate 10 g (Citroflex ^R 2 (SC-60), Pfizer) Titanium oxide 10 g Talc 10 g Ethanol 950 ml Water 50 ml

Example 16 The uncoated tablet obtained in Example 4 was treated in the same manner as in Example 15 to obtain an enteric coated tablet. Example 17 The plain tablet obtained in Example 2 was subjected to enteric coating using a doria coater according to the following coating solution formulation to obtain 1 tablet 182 mg of enteric coated tablet. [Coating liquid formulation] Eudragit ^R L30D-55 1000 g (solid content 300 g) Triethyl citrate 43 g Titanium oxide 30 g Talc 30 g Water 1000 ml

Control Example 23 [Deletion of Magnesium Oxide] The plain tablets obtained in Control Example 1 were processed in the same manner as in Example 15 to obtain enteric coated tablets. Control Example 24 [Enteric coated tablet of conventional invention: JP-A-4-3644127] The uncoated tablet obtained in Control Example 8 was operated in the same manner as in Example 15 to obtain an enteric coated tablet.

Control Example 25 [Deletion of Magnesium Oxide and Blending of Cellulose Enteric Coating Agent] For the plain tablet obtained in Control Example 1,
According to the following coating liquid formulation, enteric coating was performed using a doria coater to obtain 1 tablet of 182 mg. [Coating liquid formulation] Hydroxypropyl methylcellulose phthalate 70 g Triethyl citrate 10 g Titanium oxide 10 g Talc 10 g Ethanol 950 ml Water 50 ml

Test Example 5 [Evaluation of Stability] Examples 15 to 17 and Control Examples 23 to 2
The enteric coated tablet obtained in Example 5 was stored in various packaging forms under storage conditions of 40 ° C. 75% RH and 60 ° C., and the stability of the content and appearance was evaluated in the same manner as in Test Example 1. The material of the PTP used is hard polyvinyl chloride. The results are shown in Table 8
And shown in Table 9.

[0048]

[Table 8]

[0049]

[Table 9] As shown in Tables 8 and 9, the enteric coated tablets of the present invention were more stable in content and appearance than the conventional enteric coated tablets (Control Example 24). The enteric coated tablets (Control Example 23), which differed only in the removal of magnesium oxide, had decreased content and stability in appearance. In the enteric coated tablet (Control Example 25) in which magnesium oxide was removed and which was coated with a cellulosic enteric coating agent, both the content and the stability of appearance were significantly reduced.

[0050]

INDUSTRIAL APPLICABILITY The solid preparation of the present invention has excellent manufacturability in practical production and is stable with little change in content and appearance even under severe conditions.

[Brief description of drawings]

FIG. 1 is a graph showing irregularities on the surface of an uncoated tablet measured by a surface roughness profiler.

[Explanation of symbols]

 Ra center line average roughness L measured length

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location A61K 47/02 J B 47/26 B 47/36 Z C07D 401/12 235 // (C07D 401 / 12 221: 04 235: 28)

Claims (5)

[Claims] 1. General formula I: [Wherein R is a hydrogen atom or a lower alkyl group, R ¹ is a hydrogen atom, a lower alkoxy group or a substituted lower alkoxy group, R 1
² represents a hydrogen atom or a halogen atom], and a cycloheptenopyridine derivative or salt thereof represented by the formula: magnesium oxide as a stabilizer, spray-dried lactose as an excipient, granulated lactose, anhydrous lactose, calcium hydrogen phosphate. Alternatively, a novel anti-ulcer agent containing anhydrous calcium hydrogen phosphate, a starch derivative as a disintegrating agent, and optionally other pharmaceutically acceptable additives, and then molded without using a granulating solvent Solid formulation. 2. The compounding amount of magnesium oxide is 0.1 part by weight with respect to 1 part by weight of the cycloheptenopyridine derivative or a salt thereof.
The solid preparation according to claim 1, which is 3 to 3 parts by weight. 3. The starch derivative according to claim 1 or 2, wherein the starch derivative is partially pregelatinized starch or hydroxypropyl starch, and the compounding amount thereof is 5 to 30 (W / W)% based on the total weight of the preparation. Solid formulation. 4. A novel anti-ulcer agent-containing enteric coated solid preparation, wherein the solid preparation according to any one of claims 1 to 4 is further coated with an enteric coating agent. 5. The enteric-coated solid preparation according to claim 4, wherein the enteric-coating agent is a methacrylic acid copolymer.