JP6972674B2 - Oral pharmaceutical product - Google Patents

Description

The present invention relates to an oral pharmaceutical preparation, and more particularly to an oral pharmaceutical preparation capable of suppressing the formation of a related substance by maintaining the stability of a drug component that changes in quality under acidic conditions.

Duloxetine hydrochloride (sometimes abbreviated as duloxetine), which is a serotonin-noradrenaline reuptake inhibitor (SNRI), has the property of being altered by hydrolysis under acidic conditions. For this reason, an enteric-coated preparation is conventionally known as a preparation using duloxetine (Patent Document 1), and is actually sold as an enteric-coated capsule (Non-Patent Document 1).

As described above, it is desired that a drug component that changes in quality under acidic conditions avoids unnecessary deterioration in the body after administration and sufficiently exerts a predetermined effect, and it is necessary to devise a dosage form.

On the other hand, it is desired that such a drug component can be provided in various dosage forms such as capsules and orally disintegrating tablets in consideration of enhancing its versatility.

Japanese Unexamined Patent Publication No. 8-040895

"Sainbalta (Registered Trademark) Capsules 20 mg, 30 mg" Pharmaceutical Interview Form, revised in April 2013 (revised 5th edition)

The present invention has a problem of solving the above-mentioned problems, and an object thereof is to suppress the formation of related substances derived from a drug component that changes in quality under acidic conditions, which is a constituent of the present invention, and to enable long-term storage of a pharmaceutical product. To provide an oral pharmaceutical product.

The present invention is an oral pharmaceutical preparation containing a drug component that changes in quality under acidic conditions and an inorganic alkalizing agent.

In one embodiment, the agent component that alters under acidic conditions is an antidepressant, an antiviral agent, a cardiac stimulant, an antibiotic, a digestive enzyme agent, or an agent for hyperlipidemia.

In one embodiment, the agent component that alters under acidic conditions is duloxetine, didanosine, digoxin, erythromycin, pancreatin, pravastatin, or pharmaceutically acceptable salts thereof.

In one embodiment, the inorganic alkalizing agent is a carbonate containing an alkali metal or an alkaline earth metal element, a bicarbonate, a hydroxide salt, or an oxide, or a combination thereof.

In one embodiment, the inorganic alkalizing agent is at least one compound selected from the group consisting of magnesium carbonate, potassium carbonate, sodium carbonate, magnesium oxide, magnesium hydroxide, calcium carbonate, and sodium hydrogen carbonate. be.

In one embodiment, the inorganic alkalizing agent is contained in a proportion of 0.0001 parts by weight to 10 parts by weight with respect to 1 part by weight of the drug component that is altered under the acidic conditions.

In one embodiment, the oral pharmaceutical formulation of the present invention comprises core particles and a plurality of laminated particles comprising an intermediate layer surrounding the core particles and a coating layer surrounding the intermediate layer.
The laminated particles contain the drug component that changes in quality under the acidic conditions and the inorganic alkalizing agent in the core particles.

According to the present invention, it can be provided in a dosage form such as an orally disintegrating tablet or a capsule, and it is possible to suppress the formation of related substances derived from the drug component even after long-term storage. Therefore, the efficacy and safety of the drug component can be maintained for a long period of time.

3 is a graph showing changes in the amount (%) of related substances with respect to the storage period when the formulations of Examples 1 and Comparative Examples 1 to 3 are stored under the conditions of 60 ° C. and 75% RH. 3 is a graph showing the change in the amount (%) of related substances with respect to the storage period when the formulations of Examples 2 and 3 and Comparative Example 3 are stored under the conditions of 60 ° C. and 75% RH.

Hereinafter, the present invention will be described in detail.

The oral pharmaceutical preparation of the present invention contains a drug component that changes in quality under acidic conditions.

In the present specification, the term "drug component that changes in quality under acidic conditions" (hereinafter, may be simply abbreviated as "drug component") means deterioration (for example, in the state of an aqueous solution or a solid containing an acidic substance). , Degradation, substitution, addition, desorption, polycondensation, oxidation, reduction or neutralization, or chemical reactions by combinations thereof) through which their physical and / or chemical properties change over time. Are collectively called. In one embodiment, the "acidic condition" in the "drug component that changes in quality under acidic conditions" constituting the present invention includes, for example, an aqueous solution having a pH of 1 to 6, preferably pH 1 to 4.

Examples of such drug components include, but are not limited to, antidepressants, antivirals, cardiac stimulants, antibiotics, digestive enzymes, and hyperlipidemia agents. Furthermore, more specific examples of the drug component include serotonin / noradrenaline reuptake inhibitors such as duroxetine; nucleic acid-based reverse transcriptase inhibitors such as didanosine; heart failure therapeutic agents such as digoxin; macrolide antibiotics such as erythromycin. Substances; digestive enzyme agents such as pancreatin; HMG-CoA reductase inhibitors such as pravastatin and / or therapeutic agents for hyperlipidemia; and pharmaceutically acceptable salts thereof (eg, sodium salt, potassium salt, lithium). Pharmaceutically acceptable alkali metal salts such as salts, calcium salts, magnesium salts, aluminum salts, ammonium salts, trimethylammonium salts, triethylammonium salts, monoethanolammonium salts, triethanolammonium salts, pyridinium salts, substituted pyridinium salts, etc. Alkaline earth metal salts, non-toxic metal salts, ammonium salts and substituted ammonium salts).

In the present invention, for example, when the above-mentioned drug component is duloxetine, it is possible to provide particularly excellent stability of the drug component with respect to the obtained oral pharmaceutical preparation. Duloxetine is also called (S)-(+)-N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine in the IUPAC name. For example, in Japan, depression / depression. It can be used to treat conditions, pain associated with diabetic neuropathy, pain associated with fibromyalgia, and pain associated with chronic back pain.

The oral pharmaceutical preparation of the present invention also contains an inorganic alkalizing agent.

In the present invention, the inorganic alkalizing agent is composed of an inorganic compound, and when coexisting with the above-mentioned drug component, it plays a role of adjusting the pH in an aqueous solution and the like, and the drug component under acidic conditions. Deterioration can be prevented. Furthermore, the inorganic alkalizing agent can suppress the formation of related substances due to the alteration of the above-mentioned drug components, which may occur during the storage of the oral pharmaceutical product.

Here, the term "related substance" used in the present specification refers to a general term for related substances derived from the drug component. It is known that some of the related substances of the above-mentioned drug components are safety problems because they have side effects such as antagonistic action against the drug components. As such related substances, for example, the above-mentioned drug component is duloxetine, and the retention time (Rettion Time (RT)) of the elution peak when duloxetine or the oral pharmaceutical product of the present invention is subjected to HPLC analysis is described herein. In the case of the analytical conditions shown in the examples of the book, the compound contained in the elution fraction represented in about 2.7 minutes can be mentioned.

The inorganic alkalizing agent is not necessarily limited, but is, for example, a carbonate containing an alkali metal or an alkaline earth metal element, a bicarbonate, a hydroxide salt, or an oxide, or a combination thereof. Examples of alkali metals that may constitute an inorganic alkalizing agent include sodium and potassium. Examples of alkaline earth metals that may constitute an inorganic alkalizing agent include magnesium and calcium. More specific examples of the inorganic alkalizing agent in the present invention include magnesium carbonate, potassium carbonate, sodium carbonate, magnesium oxide, magnesium hydroxide, calcium carbonate, and sodium hydrogen carbonate, and combinations thereof. In the present invention, for example, when duloxetine is used as the above-mentioned drug component, it is preferable to use magnesium carbonate because the stability of the duloxetine can be maintained most effectively.

In the oral pharmaceutical preparation of the present invention, the inorganic alkalizing agent is preferably 0.0001 parts by weight to 10 parts by weight, more preferably 0.001 parts by weight to 5 parts by weight, based on 1 part by weight of the coexisting drug component. It is contained in parts, more preferably 0.005 parts by weight to 3 parts by weight, and even more preferably 0.008 parts by weight to 1 part by weight. If the content of the inorganic alkalizing agent with respect to 1 part by weight of the drug component is less than 0.0001 part by weight, the formation of related substances due to the alteration of the drug component may not be sufficiently suppressed. When the content of the inorganic alkalizing agent with respect to 1 part by weight of the drug component exceeds 10 parts by weight, no further change is observed in the suppression of the formation of related substances, but rather the productivity as an oral pharmaceutical preparation is lowered. There is a risk.

In the present invention, another alkalizing agent may be contained as long as the action of the inorganic alkalizing agent on the above-mentioned drug component is not inhibited. Examples of such other alkalizing agents include amino sugars (eg, meglumine), amino acids (eg, arginine, histidine and lysine), and aminoalkylmethacrylate copolymers E (eg, Evonik®). )) Includes organic alkalizing agents. However, in one embodiment of the present invention, the oral pharmaceutical preparation of the present invention may not contain other alkalizing agents such as organic alkalizing agents other than the above-mentioned inorganic alkalizing agents. More preferred.

The oral pharmaceutical preparation of the present invention may contain other components used in ordinary tablets, powders, granules, pills and the like, if necessary, as long as the effects of the present invention are not impaired. Such other ingredients include, for example, excipients, disintegrants, binders, fluidizers, lubricants, flavors, and sweeteners, and combinations thereof.

The excipient is not particularly limited as long as it is generally pharmaceutically acceptable. Specific examples of excipients include sugar alcohols such as D-mannitol, xylitol, sorbitol, and erythritol; sugars such as glucose, lactose, sucrose (including purified sucrose), powdered sugar, trehalose, and dextran; glycerin fatty acid esters. Crystalline cellulose; and inorganic powders such as magnesium aluminometasilicate, synthetic hydrotalcite; and combinations thereof.

The disintegrant is not particularly limited as long as it is generally pharmaceutically acceptable. Specific examples of disintegrants include low-substituted hydroxypyropillulose (L-HPC), crospovidone, sodium carboxystarch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, Examples include light anhydrous silicic acid, synthetic aluminum silicate, crystalline cellulose, croscarmellose, croscarmellose sodium, carboxymethyl cellulose calcium, carmellose, and hydroxypropyl starch, and combinations thereof.

The binder is not particularly limited as long as it is pharmaceutically acceptable and general. Specific examples of binders include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, gelatin, agar, alginic acid, sodium alginate, dextrin, kitansan gum, gum arabic powder, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, pullulan, and moieties. Pregelatinized starch, as well as combinations thereof.

The fluidizing agent is not particularly limited as long as it is generally pharmaceutically acceptable. Specific examples of fluidizing agents include hydrous silicon dioxide, light anhydrous silicic acid, talc, synthetic aluminum silicate, titanium oxide, stearic acid, magnesium stearate, calcium stearate, and magnesium aluminometasilicate, as well as these. Combinations can be mentioned.

The lubricant is not particularly limited as long as it is a general drug that is pharmaceutically acceptable. Specific examples of the lubricant include stearyl sodium fumarate, stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester, and talc. .. Preferred are stearyl sodium fumarate, magnesium stearate, calcium stearate, and sucrose fatty acid esters, and combinations thereof.

The flavoring agent and the sweetening agent are not particularly limited as long as they are generally pharmaceutically acceptable.

In the oral pharmaceutical preparation of the present invention, the content of these other components is not particularly limited, and an appropriate amount can be arbitrarily selected by those skilled in the art as long as the effect of the present invention is not impaired.

In addition to the above-mentioned drug components, inorganic alkalizing agents and other components, the oral pharmaceutical preparation of the present invention contains, for example, a coating agent capable of surrounding them to form an enteric coating layer (enteric layer). May be.

Such a coating agent is not particularly limited as long as it is a general pharmaceutically acceptable one. Specific examples of the coating agent include hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), hypromellose phthalate ester, aminoalkylmethacrylate copolymer, methacrylic acid copolymer, hypromellose acetate succinate, and oxidation. Examples include titanium and polyethylene glycol (Macrogol 6000), and combinations thereof.

Further, the coating agent may contain other bases. Other bases include, but are not limited to, polyethylene glycol (PEG) such as sugar, sugar alcohol, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose, triethyl citrate, triacetin, macrogol, polysorbates, talc, and the like. And titanium oxide, and combinations thereof. Preferred are PEGs such as sugar, sugar alcohols, triacetin, macrogol, and talc, and combinations thereof. The sugar is not particularly limited, and examples thereof include glucose, fructose, lactose, sucrose, reduced maltose, and trehalose. The sugar alcohol is not particularly limited, and examples thereof include D-mannitol, erythritol, sorbitol, xylitol, maltitol, and lactitol. In the oral pharmaceutical preparation of the present invention, the other base may also be used as a material constituting the outermost layer that further surrounds the enteric coating layer.

In the oral pharmaceutical preparation of the present invention, the content of each of the coating agent and the other base is not particularly limited, and an appropriate amount thereof can be arbitrarily selected by those skilled in the art as long as the effect of the present invention is not impaired.

The oral pharmaceutical product of the present invention is used not only as a solid dosage form such as tablets, powders, granules, pills and capsules, but also as a liquid dosage form such as suspensions, emulsions and other liquids. be able to. In the present invention, it is preferably used as a tablet, and more preferably used as an orally disintegrating tablet, because it is easy for more patients to take, and it is easy to store and handle.

In the case of a dosage form such as a tablet or a capsule, the oral pharmaceutical preparation of the present invention is also composed of a plurality of laminated particles containing a drug component that changes in quality under the above acidic conditions and an inorganic alkalizing agent. It is preferable to have.

In one embodiment of the invention, the laminated particles comprises core particles, an intermediate layer surrounding the core particles, a coating layer further surrounding the intermediate layer, and further enclosing the coating layer as needed. It has an outermost layer.

In such laminated particles, the chemical component and the inorganic alkalizing agent that change in quality under the acidic conditions are preferably contained in the core particles. Even more preferably, the core particles are provided with a drug layer surrounding a core mainly composed of a material such as crystalline cellulose, and the drug layer is provided with a drug component and an inorganic system that are altered under the above acidic conditions. It contains an alkalizing agent and, if necessary, the above-mentioned binder and / or fluidizing agent.

The intermediate layer surrounding the core particles mainly contains the above-mentioned binder and / or fluidizing agent. The coating layer surrounding the intermediate layer mainly contains the above-mentioned coating agent, and may also contain the above-mentioned fluidizing agent and / or other base, if necessary. In addition, the outermost layer that surrounds the coating layer, if necessary, may contain the other bases described above.

In general, an organic alkalizing agent such as meglumine and a coating agent may cause an undesired reaction through water and reduce the acid resistance of the oral pharmaceutical preparation. On the other hand, in the present invention, in order to avoid such an undesired reaction, an inorganic alkalizing agent is used as the alkalizing agent, and as described above, the inorganic alkalizing agent contained in the core particles and the coating layer are used. By interposing an intermediate layer with the coating agent contained in the above, it is preferable to reduce the possibility that both of them come into contact with each other.

The average particle size of the core or core particles in the laminated particles, and the thickness of each layer of the drug layer, the intermediate layer, the coating layer, and the outermost layer vary depending on the type and content of the drug component that deteriorates under acidic conditions. Therefore, the appropriate size or amount may be arbitrarily selected by those skilled in the art.

Further, in the present invention, the laminated particles are mixed and tableted by means well known to those skilled in the art, for example, the excipients, disintegrants, fluidizers, flavors, sweeteners, lubricants and the like. Can be provided as a tablet. Alternatively, in the present invention, the product particles are contained in a hard capsule composed of a capsule material such as gelatin or hypromellose, or in a soft capsule composed of the capsule material and glycerin by means of retail to those skilled in the art. By doing so, it can be provided as a capsule such as a hard capsule and a soft capsule.

The oral pharmaceutical preparation of the present invention is administered to a patient in various dosages and administrations depending on the type of the above-mentioned drug component contained as the medicinal ingredient thereof. Further, the period until this administration is performed can be stored in a cool and dark place, for example. During this storage, the pharmaceutical components contained in the oral pharmaceutical preparation of the present invention are suppressed from forming related substances by the coexistence of an inorganic alkalizing agent. As a result, the storage period of the oral pharmaceutical product of the present invention is substantially extended, and the concern about deterioration of the drug component due to the storage period is eliminated, so that both the medical staff and the patient can feel more at ease. The oral pharmaceutical product can be used.

The oral pharmaceutical preparation of the present invention may be stored together with a desiccant such as silica gel. The desiccant reduces the chance that the oral pharmaceutical product of the present invention comes into contact with moisture in the air, which may further suppress the formation of related substances.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

(Example 1: Preparation of orally disintegrating lock (E1))
An orally disintegrating tablet containing 20 mg of duloxetine and having a total mass of 300 mg was prepared as follows.

First, in a fluidized layer granulator (manufactured by Paulek Co., Ltd .: MP-01 type), a predetermined amount is used to form a drug layer shown in Table 1 on a core composed of crystalline cellulose particles having an average particle diameter of 160 μm. Duroxetine hydrochloride, hypromerose, talc and magnesium carbonate are suspended in purified water. By spraying and drying the first suspension, the drug layer is arranged substantially uniformly on the surface of the primary particles (core). Particles) were obtained. The amount of the drug layer coated on the primary particles was about 181 parts by weight with respect to 100 parts by weight of the crystalline cellulose particles.

Next, in order to provide the intermediate layer shown in Table 1 on the primary particles, a second suspension in which predetermined amounts of hypromerose, talc and titanium oxide were added to purified water and ethanol was prepared, and this was used as the first suspension. By spraying and drying in a granulator containing the secondary particles, secondary particles in which the intermediate layer was arranged substantially uniformly on the surface were obtained. The amount of the coating of the intermediate layer in the secondary particles was about 62 parts by weight with respect to 100 parts by weight of the primary particles.

Then, in order to provide the coating layer shown in Table 1 on the secondary particles, a predetermined amount of HPMCP (hypromerose phthalic acid ester manufactured by Shinetsu Chemical Industry Co., Ltd., product number 55)), triethyl citrate, talc, and oxidation A third suspension of titanium added to purified water and ethanol was prepared, sprayed and dried in a granulator containing the secondary particles, whereby the coating layer was placed substantially uniformly on the surface. Third-order particles were obtained. The coating amount of the coating layer in the tertiary particles was about 68 parts by weight with respect to 100 parts by weight of the secondary particles.

Finally, in order to provide the outermost layer shown in Table 1 on the tertiary particles, a predetermined amount of D-mannitol is sprayed and dried in the granulator containing the tertiary particles to obtain the outermost layer. Obtained laminated particles in which the particles were arranged substantially uniformly on the surface. The amount of the outermost layer of the laminated particles was about 5 parts by weight with respect to 100 parts by weight of the tertiary particles.

Table 1 shows the content of each component contained in the obtained laminated particles.

Next, the excipients, disintegrants, fluidizers, fragrances, sweeteners and lubricants shown in Table 2 were added to the laminated particles, and the mixture was added to a mixer (manufactured by Tsutsui Rikagaku Kikai Co., Ltd .: S-3). It was added and mixed to obtain granules for tableting.

Then, the obtained granules are put into a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRGO) for tableting, and the weight is 300 mg, the tablet diameter is 9.0 mm, the tablet thickness is about 3.7 mm, and the hardness is about 50 N. Tablets (E1) with a disintegration time of about 20 seconds were obtained.

The content of magnesium carbonate in the tablet (E1) obtained above was 0.066% by weight, and was 0.0089 parts by weight with respect to 1 part by weight of duloxetine hydrochloride.

(Formation confirmation test for related substances)
The 10 tablets (E1) obtained above were grouped into one group, and each group was pillow-wrapped with aluminum foil to prepare a plurality of sealed packages. These packages were then stored in the dark at 60 ° C. and 75% relative humidity (RH) conditions for a storage period of 2 weeks.

Through such storage, the tablets in the package immediately after the package is prepared (immediately after storage) and the tablets taken out from each package after storage for 1 week and storage for 2 weeks (storage for 1 week and storage for 2 weeks). The amount (%) of a substance related to duroxetine hydrochloride was measured by high performance liquid chromatography (HPLC) under the following measurement conditions. For the amount (%) of this related substance, the percentage of the related substance to duroxetine hydrochloride was calculated based on the peak area of HPLC obtained from the measured tablet, and the maximum value of the percentage obtained for each package ( The maximum value in the group of related substances measured from the tablets contained in each package) was adopted.

<HPLC measurement conditions>
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 7.5 cm was filled with 3.5 μm octylsilylated silica gel for liquid chromatography.

Mobile phase: 3.4 g of potassium dihydrogen phosphate and 15 mL of triethylamine were dissolved in 1000 mL of water, and phosphoric acid was added to adjust the pH to 5.5. 300 mL of methanol and 100 mL of tetrahydrofuran were added to 600 mL of this prepared liquid and used.

Flow rate: The retention time of duloxetine was adjusted to about 4 minutes.
Temperature: 45 ° C
Detection wavelength: 230nm

The characteristics of the obtained tablet (E1) and the packaging state at the time of storage are shown in Table 3, and the change in the amount (%) of related substances with respect to the above-mentioned storage period for the tablet (E1) is shown in FIG.

(Comparative Example 1: Preparation of Orally Disintegrating Lock (CE1))
Laminated granules were prepared in the same manner as in Example 1 except that magnesium carbonate was not added to the prepared first suspension when the drug layer was provided on the core, and then the laminated granules were added to Example 1. The same amount of excipients, disintegrants, fluidizers, flavors, sweeteners and lubricants were added and mixed to prepare granules, and then the granules were tableted to obtain tablets (CE1). ..

The content of magnesium carbonate in the tablet (CE1) obtained above was 0% by weight, and was 0 part by weight with respect to 1 part by weight of duloxetine hydrochloride.

Except for the fact that this tablet (CE1) was used, a package by pillow packaging was prepared in the same manner as in Example 1, and the tablet was stored under the same storage conditions as in Example 1 to obtain the tablet contained in the package. The amount (%) of related substances was measured. The characteristics of this tablet (CE1) and the packaging condition at the time of storage are shown in Table 3, and the change in the amount (%) of related substances with respect to the above-mentioned storage period for the tablet (CE1) is shown in FIG.

(Comparative Example 2: PTP-packaged commercial capsule (CE2))
Capsules containing 20 mg of duloxetine hydrochloride per capsule pre-packaged with PTP (Eli Lilly Japan K.K.; Cinbalta® capsules 20 mg) will be referred to as commercially available capsules (CE2).

According to the package insert of the commercially available capsule (CE2), the content of magnesium carbonate in the capsule (CE2) is 0% by weight and 0 part by weight with respect to 1 part by weight of duloxetine hydrochloride. rice field.

This capsule (CE2) is packaged in a PTP package without performing the pillow packaging, and is stored under the same storage conditions as in Example 1 to obtain the capsule contained in the package. The amount (%) of related substances was measured. The characteristics of this capsule (CE2) and the packaging condition at the time of storage are shown in Table 3, and the change in the amount (%) of related substances with respect to the above-mentioned storage period for the capsule (CE2) is shown in FIG.

(Comparative Example 3: Pillow-wrapped commercial capsule (CE3))
A capsule containing 20 mg of duloxetine hydrochloride per capsule pre-packaged (Japan Eli Lilly Co., Ltd .; Sainbalta (registered trademark) capsule 20 mg) is taken out from the PTP packaging and packaged in pillow packaging in the same manner as in Example 1. The body was made. The capsule contained in such a pillow package is referred to as a commercially available capsule (CE3).

According to the package insert, the content of magnesium carbonate in the above-mentioned commercially available capsule (CE3) was 0% by weight, and was 0 part by weight with respect to 1 part by weight of duloxetine hydrochloride.

Except for the fact that the package containing this capsule (CE3) was used, the product was stored under the same storage conditions as in Example 1, and the amount (%) of the related substance of the tablet contained in the package was measured. The characteristics of this capsule (CE3) and the packaging condition at the time of storage are shown in Table 3, and the change in the amount (%) of related substances with respect to the above-mentioned storage period for the capsule (CE3) is shown in FIG.

As is clear from Table 3 and FIG. 1, the tablet (E1) of Example 1 containing magnesium carbonate is 2 as compared with the formulations (tablets and capsules) of Comparative Examples 1 to 3 not containing magnesium carbonate. The amount of related substances after weekly storage was significantly low. Further, as shown in FIG. 1, the tablet (E1) of Example 1 showed almost no change in the amount of related substances after storage for 1 week to storage for 2 weeks, and such behavior was exhibited in Comparative Example. It was clearly different from 1-3. As a result, the tablet (E1) obtained in Example 1 stably retains duloxetine hydrochloride, which is a drug component, as compared with the formulations of Comparative Examples 1 to 3, and enables longer-term storage. You can see that.

(Example 2: Preparation of capsule (E2))
A capsule having a total mass of 225 mg containing 30 mg of duloxetine was prepared as follows.

First, in a fluidized layer granulator (manufactured by Paulek Co., Ltd .: MP-01 type), a predetermined amount is used to form a drug layer shown in Table 4 on a core composed of crystalline cellulose particles having an average particle diameter of 620 μm. Duroxetine hydrochloride, hypromerose, talc and magnesium carbonate are suspended in purified water. By spraying and drying the first suspension, the drug layer is arranged substantially uniformly on the surface of the primary particles (core). Particles) were obtained. The amount of the drug layer coated on the primary particles was about 61 parts by weight with respect to 100 parts by weight of the crystalline cellulose particles.

Next, in order to provide the intermediate layer shown in Table 4 on the primary particles, a second suspension was prepared by adding a predetermined amount of hypromerose, talc and titanium oxide to purified water and ethanol, and this was used as the first suspension. By spraying and drying in a granulator containing the secondary particles, secondary particles in which the intermediate layer was arranged substantially uniformly on the surface were obtained. The amount of the coating of the intermediate layer in the secondary particles was about 40 parts by weight with respect to 100 parts by weight of the primary particles.

Then, in order to provide the coating layer shown in Table 1 on the secondary particles, a predetermined amount of HPMCP (hypromerose phthalic acid ester manufactured by Shinetsu Chemical Industry Co., Ltd., product number 55)), triethyl citrate, talc, and oxidation A third suspension of titanium added to purified water and ethanol was prepared, sprayed and dried in a granulator containing the secondary particles, whereby the coating layer was placed substantially uniformly on the surface. Third-order particles were obtained. The coating amount of the coating layer in the tertiary particles was about 17 parts by weight with respect to 100 parts by weight of the secondary particles.

Finally, the tertiary particles were subjected to static electricity removal finishing at the ratios shown in Table 4 using talc and light anhydrous silicic acid to obtain laminated particles.

Table 4 shows the content of each component contained in the obtained laminated particles.

Next, 180 mg of the laminated particles were encapsulated with HPMC capsules (No. 3 capsule manufactured by Qualicaps Co., Ltd.) to obtain a capsule (E2).

The content of magnesium carbonate in the capsule (E2) obtained above was 0.088% by weight, and was 0.0089 parts by weight with respect to 1 part by weight of duloxetine hydrochloride.

A capsule packaged in pillow packaging was prepared in the same manner as in Example 1 except that the capsule (E2) was used, and the capsule was stored under the same storage conditions as in Example 1 to contain the capsule. The amount (%) of the agent's related substances was measured. The characteristics of this capsule (E2) and the packaging state at the time of storage are shown in Table 5, and the change in the amount (%) of related substances with respect to the above-mentioned storage period for the capsule (E2) is shown in FIG.

(Example 3: Capsule coexisting with silica gel (E3))
Pillow in the same manner as in Example 2 except that when the capsule was prepared by pillow packaging using the capsule prepared in the same manner as in Example 2, 2 mg of silica gel was filled in the package together with the capsule. A package was prepared by packaging. The capsule contained in such a pillow package is referred to as a capsule (E3).

The content of magnesium carbonate in the capsule (E3) was 0.088% by weight, and was 0.0089 parts by weight with respect to 1 part by weight of duloxetine hydrochloride.

Except for the fact that the package containing the capsule (E3) was used, the mixture was stored under the same storage conditions as in Example 2, and the amount (%) of the related substance of the tablet contained in the package was measured. The characteristics of this capsule (E3) and the packaging condition at the time of storage are shown in Table 5, and the change in the amount (%) of related substances with respect to the above-mentioned storage period for the capsule (E3) is shown in FIG.

Table 5 and FIG. 2 also show the results of Comparative Example 2 in which the commercially available capsule (CE2) packaged in PTP was stored for comparison.

As is clear from Table 5 and FIG. 2, the capsules of Examples 2 and 3 containing magnesium carbonate (E2 and E3) were particularly compared with the capsules of Comparative Example 3 containing no magnesium carbonate for 2 weeks. The amount of related substances after storage was extremely low. As a result, the capsules of Examples 2 and 3 (E2 and E3) stably retain the drug component duloxetine hydrochloride as compared with the capsules of Comparative Example 2 already existing as commercial products, and are longer. It turns out that it enables storage for a period of time.

The oral pharmaceutical preparation of the present invention is, for example, an orally disintegrating tablet (OD tablet) in the production of various pharmaceutical preparations such as antidepressants, antiviral agents, cardiotonic agents, antibiotics, digestive enzyme agents, and hyperlipidemia agents. ), It is useful in that it can be applied to various dosage forms such as capsules.

Claims (3)

An oral pharmaceutical preparation containing a drug component that changes in quality under acidic conditions and an inorganic alkalizing agent.
The drug component that alters under the acidic conditions is duloxetine or a pharmaceutically acceptable salt thereof.
An oral pharmaceutical preparation containing magnesium carbonate as the inorganic alkalizing agent. The oral pharmaceutical preparation according to claim 1, wherein the inorganic alkalizing agent is contained in a ratio of 0.0001 parts by weight to 10 parts by weight with respect to 1 part by weight of the drug component that changes in quality under the acidic conditions. .. It contains a plurality of laminated particles comprising core particles, an intermediate layer surrounding the core particles, and a coating layer surrounding the intermediate layer.
The oral pharmaceutical preparation according to claim 1 or 2 , wherein the laminated particles contain a drug component that changes in quality under the acidic conditions and the inorganic alkalizing agent in the core particles.

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