JP6735007B2 - Pharmaceutical composition containing entacapone - Google Patents

Description

The present invention relates to a pharmaceutical composition containing entacapone, which is a peripheral COMT (catechol-O-methyltransferase) inhibitor.

Entacapone, ((2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide, is used to treat Parkinson's disease (PD) and levodopa and A catechol-O-methyltransferase (COMT) inhibitor used in combination with a dopa decarboxylase (DDC) inhibitor.

As a pharmaceutical composition containing entacapone, a film-coated tablet for oral administration has been proposed. For example, in Patent Document 1, there is provided a method for producing granules containing entacapone as a single active ingredient used for tablets, comprising (1) entacapone, a binder and optionally one or more other excipients. Preparing a mixture and granulating the mixture with a granulating liquid, or granulating entacapone with a granulating liquid containing a binder, together with one or more optional other excipients. (2) A manufacturing method comprising drying and optionally sieving the granules of step (1), wherein the entacapone used to manufacture the granules is in granular form, at least 90% of the entacapone particles being 55 μm It is disclosed to have a diameter of less than.

Patent Document 2 discloses an oral molding composition containing a pharmaceutically effective amount of entacapone or a pharmaceutically acceptable salt thereof and croscarmellose sodium.

Patent No. 5336181 Patent No. 4619537

However, the techniques of Patent Document 1 and Patent Document 2 can improve the dissolution of entacapone from the preparation, and further improvement is necessary in order to suppress the color tone change of the preparation over time. It was In particular, croscarmellose sodium, which is a disintegrant, sometimes markedly colored the preparation containing entacapone. Then, the subject of this invention is suppressing the coloring of the entacapone containing formulation, without reducing the elutability of entacapone.

In addition, it has been difficult to sufficiently increase the hardness of conventional tablets containing entacapone, particularly tablets containing croscarmellose sodium. Therefore, a further object of the present invention is to increase the hardness of tablets containing entacapone. By increasing the tablet hardness, it is possible to suppress scraping of the tablet in the coating step in the tablet manufacturing process.

The pharmaceutical composition of the present invention is characterized by containing entacapone or a salt thereof, sodium starch glycolate, and carmellose calcium.

The content of the sodium starch glycolate is 1% by weight or more and 20% by weight or less with respect to the entacapone or the salt thereof, and the content of the carmellose calcium is 50% by weight with respect to the entacapone or the salt thereof. % And 120% by weight or less is preferable.

The pharmaceutical composition is preferably a tablet.

According to the present invention, it is possible to provide a pharmaceutical composition containing entacapone or a salt thereof, which is capable of improving the dissolution of entacapone from a preparation and suppressing the color tone change of the preparation over time.

The pharmaceutical composition contains entacapone or a salt thereof, sodium starch glycolate, and carmellose calcium, and may contain other additives acceptable as a pharmaceutical composition.

1. About Entacapone Entacapone ((E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide) inhibits catechol-O-methyl transferase (COMT). It is used as a therapeutic agent for Parkinson's disease. Entacapone has a yellow to greenish yellow color tone, is hardly soluble in ethanol, and has a property of being almost insoluble in water. Entacapone may be produced by a conventionally known method, or a commercially available product may be used.

(About the form of entacapone)
Entacapone can be prepared, for example, by the method described in US 5,446,194 and US 5,135,950. Entacapone can exist as any mixture of (E)- and (Z) isomers, or in the form of substantially pure (E)- or (Z) isomers. Preferably, entacapone is in a substantially pure (E)-isomeric form. The (E)-isomer may take various polymorphic forms, such as polymorph A disclosed in US 5,135,950, or polymorph D disclosed in WO 2005/063696, or amorphous. The entacapone in the pharmaceutical composition of the present invention is usually crystalline.

(About particle size of entacapone)
The entacapone contained in the pharmaceutical composition of the present invention is in a granular form, and the entacapone particles preferably have a volume particle size D90 of 56 μm or more. The volume particle size distribution of entacapone is measured by using a laser diffraction particle size measurement (LPD) and measuring a sample using a particle size analyzer (Mastersizer 2000, Melvern Instruments Ltd.). To be measured.

(About the content of Entacapone)
The content of entacapone in the pharmaceutical composition is preferably 1% by weight or more and 99% by weight or less, and more preferably 1% by weight or more and 50% by weight or less. When the pharmaceutical composition is a tablet, the content of entacapone with respect to the total weight of the tablet (plain tablet) is preferably 1% by weight or more and 99% by weight or less, and 1% by weight or more and 50% by weight or less Is more preferable.

2. Disintegrant The disintegrant is contained in the present pharmaceutical composition, which contains disintegrants sodium starch glycolate and carmellose calcium. In addition, it is preferable that the present pharmaceutical composition does not contain croscarmellose sodium or does not contain croscarmellose sodium. By combining sodium starch glycolate and carmellose calcium, the elutability of entacapone from the preparation can be improved and the change in color tone of the preparation over time can be suppressed. Further, the hardness of the entacapone tablet can be sufficiently increased by combining sodium starch glycolate and carmellose calcium.

Further, from the viewpoint of improving the dissolution property of entacapone and suppressing the change in color tone, the content of sodium starch glycolate in the pharmaceutical composition is 1% by weight or more and 20% by weight or less, and more preferably, with respect to entacapone or a salt thereof. It is preferably 10% by weight or more and 20% by weight or less. Further, the content of carmellose calcium in the pharmaceutical composition is more preferably 50% by weight or more and 120% by weight or less, preferably more than 70% by weight and 120% by weight or less with respect to entacapone or a salt thereof.

First, the present inventors tried to select an appropriate disintegrant from the viewpoint of improving the dissolution property of entacapone. Therefore, as shown in Table 1, entacapone 100 mg tablets (Test Examples 1 to 4) containing the main drug entacapone and various disintegrants were prepared, and the dissolution properties of entacapone were confirmed.

<Elution evaluation>
With respect to the tablets produced in Test Examples 1 to 4, the dissolution properties of entacapone were evaluated under the following conditions.
Test liquid: Water Test method: Paddle method Test liquid amount: 900 mL
Test solution temperature: 37±0.5℃
Rotation speed: 50 rotations Test time: Maximum 60 minutes Detector: Ultraviolet absorptiometer (measurement wavelength 290nm), (SPD-20A type manufactured by Shimadzu Corporation)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm is packed with 5 μm of phenylated silica gel for liquid chromatography. Column temperature: 25° C.
Mobile phase: diluted phosphoric acid (1→100)/acetonitrile mixture (1:1)

To determine the amount of dissolved entacapone, the solution was filtered, and the peak area of the filtrate was measured by the automatic integration method. The measurement results are shown in Table 2.

From the results of Table 2, it was found that the tablets of Test Example 1 containing croscarmellose sodium had the highest dissolution rate of entacapone. Next, the dissolution rate of entacapone in the tablets of Test Example 3 containing sodium starch glycolate and the dissolution rate of entacapone in the tablets of Test Example 4 containing carmellose calcium were similar. On the other hand, it was found that the tablet of Test Example 2 containing crospovidone had the lowest dissolution rate of entacapone.

In addition, as shown in Examples described later, croscarmellose sodium significantly changes the color of entacapone tablets (see Comparative Example 4).

Next, the hardness of the entacapone tablets produced in Test Examples 1 to 4 was measured using a TABLET HARDNESS TESTER (manufactured by TOYAMA). A tablet hardness of 6.0 kg or more was evaluated as ◯, and a tablet hardness of less than 6.0 kg was evaluated as x. The evaluation results are shown in Table 3.

When the tablet of Test Example 1 containing croscarmellose sodium was coated in the same manner as in the example of the present specification, the tablet was scraped and the tablet shape could not be maintained. On the other hand, when the tablets of Test Example 2 containing crospovidone, Test Example 3 containing sodium starch glycolate and Test Example 4 containing carmellose calcium were coated, the tablets did not collapse and could be coated while maintaining the tablet shape. ..

From the above, from the viewpoint of improving the dissolution property of entacapone, suppressing the color change and suppressing the scraping of the tablet in the coating step in the manufacturing process, the present inventor disintegrates carmellose calcium and sodium starch glycolate, The selection as an agent was considered.

As shown in Table 4, in addition to Test Example 4, entacapone 100 mg tablets (Test Example 5 to Test Example 7) containing only carmellose calcium as a disintegrant and having different contents were prepared.

The dissolution properties of the entacapone 100 mg tablets produced in Test Examples 4 to 7 were evaluated under the test conditions described above. The measurement results are shown in Table 5.

From the results shown in Table 5, it was found that the elutability of entacapone is improved as the content of carmellose calcium is increased. The dissolution of entacapone in the tablets of Test Examples 4 to 7 was comparable to or better than the dissolution of entacapone in the tablets of Test Example 1.

Moreover, the tablet hardness of the entacapone 100 mg tablets produced in Test Examples 4 to 7 was measured using the above-described measuring device. A tablet hardness of 6.0 kg or more was evaluated as ◯, and a tablet hardness of less than 6.0 kg was evaluated as x. The evaluation results are shown in Table 6.

When the tablets of Test Examples 4 to 6 in which the content of carmellose calcium was 20% by weight or more and 70% by weight or less with respect to entacapone were coated in the same manner as in the examples of the present specification, the tablets were not broken. , It was possible to coat while maintaining the tablet shape. On the other hand, when the tablets of Test Example 7 having a carmellose calcium content of 90 wt% with respect to entacapone were coated, the tablets were scraped and the tablet shape could not be maintained.

Next, as shown in Table 7, entacapone 100 mg tablets (test examples 8 to 10) containing sodium starch glycolate together with carmellose calcium as a disintegrant and the content thereof was 20% by weight with respect to entacapone were prepared. did.

The reason why the content of sodium starch glycolate is 20% by weight with respect to entacapone is that the maximum daily dose of sodium starch glycolate is 320 mg, and the maximum daily dose of entacapone is Because it is 1600 mg, it can be blended only up to 20% by weight with respect to entacapone.

The dissolution properties of the entacapone 100 mg tablets produced in Test Examples 8 to 10 were evaluated under the test conditions described above. The measurement results are shown in Table 8.

From the results of Table 8, it was found that the tablets of Test Examples 8 to 10 had higher entacapone dissolution than the tablets of Test Example 1. Further, the tablets of Test Example 5 and Test Example 8, the test example 6 and Test Example 9, and the test examples 7 and 10 are compared, that is, tablets containing the same amount of carmellose calcium are compared. It was found that the tablets of Test Example 8, Test Example 9 and Test Example 10 containing sodium starch glycolate had a higher dissolution rate of entacapone.

Further, as can be seen from the examples described below, sodium starch glycolate may cause discoloration of the entacapone preparation when blended alone (Comparative Example 2), but carmellose calcium and sodium starch glycolate are mixed together. It has been clarified that the discoloration of the entacapone preparation can be unexpectedly suppressed by incorporating it.

Moreover, the tablet hardness of the entacapone 100 mg tablets produced in Test Examples 8 to 10 was measured using the above-described measuring device. A tablet hardness of 6.0 kg or more was evaluated as ◯, and a tablet hardness of less than 6.0 kg was evaluated as x. The measurement results are shown in Table 9.

From the results of Table 9, when the tablets of Test Examples 8 to 10 were coated in the same manner as in the examples of the specification of the present application, the tablets were not disintegrated and could be coated while maintaining the tablet shape. Comparing the tablets of Test Example 7 with those of Test Example 10, the tablets of Test Example 7 in which carmellose calcium alone was blended, although both contained a high content of carmellose calcium (90 mg). However, the tablet could not be coated while maintaining the tablet shape, whereas the tablet of Test Example 10 in which carmellose calcium and sodium starch glycolate were co-blended could be coated while maintaining the tablet shape.

3. Regarding other components: In the pharmaceutical composition of the present invention, generally, other components acceptable for the pharmaceutical composition can be appropriately selected depending on the purpose without any limitation, and examples thereof include an excipient, a disintegrant, and a binder. Agents and lubricants.

(About excipient)
To the pharmaceutical composition of the present invention, an excipient that is usually used in the field of formulation can be added as long as it does not affect the effects of the present invention. The excipient is not particularly limited and may be appropriately selected depending on the intended purpose. D-mannitol, crystalline cellulose, sucrose, maltose (maltose), fructose, glucose, maltitol, sorbitol, xylitol, erythritol, maltose. Sugars and the like can be used. These excipients can be used alone or in combination. From the viewpoint of moldability, it is preferable to use D-mannitol and crystalline cellulose as the excipient used in the present pharmaceutical composition.

The content of the excipient is preferably 1% by weight or more and 99% by weight or less, more preferably 1% by weight or more and 45% by weight or less, based on the total weight of the pharmaceutical composition.

(About disintegrants)
In the pharmaceutical composition of the present invention, in addition to carmellose calcium and sodium starch glycolate, a disintegrating agent which is acceptable as a pharmaceutical ingredient can be added as long as the effect of the present invention is not affected. Examples of the disintegrator include low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, polyvinylpyrrolidone, corn starch, hydroxypropylmethylcellulose, and hydroxypropylcellulose.

(About binder)
To the pharmaceutical composition of the present invention, a binder acceptable as a pharmaceutical ingredient can be added as long as the effect of the present invention is not affected. Examples of the binder include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, croscarmellose sodium and the like. Among these, it is preferable to use hydroxypropyl cellulose.

(About lubricants)
The pharmaceutical composition of the present invention may contain a lubricant that is acceptable as a pharmaceutical ingredient, as long as the effect of the present invention is not affected. The lubricant is not particularly limited and may be appropriately selected depending on the purpose, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, Examples include sodium stearyl fumarate and the like.

Lubricants are blended for the purpose of preventing powder adhering to a die or pestle when producing tablets, but if the lubricating effect is too strong, moldability becomes weak and practical tablet hardness is obtained. You must put more pressure on it. Tablets made at high pressures need to be made at as low a pressure as possible because tablet disintegration rates tend to be delayed. From that point, it is preferable to use magnesium stearate, which can obtain a lubricating effect even in a small amount.

4. Dosage Form of Pharmaceutical Composition The pharmaceutical composition may be a solid, semi-solid or liquid formulation. More specifically, oral administration agents such as tablets, film-coated tablets, capsules, granules, fine granules and dry syrups may be used, but tablets are preferable.

(About film coated tablets)
When the present pharmaceutical composition is a film-coated tablet, examples of the film-coating base include a water-soluble film-coating base and the like. Water-soluble film coating bases include, for example, cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose or sodium carboxymethyl cellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers or polyvinylpyrrolidone. Synthetic polymers; or concentrated glycerin and the like can be mentioned. The coating base may be a single type or a combination of two or more types.

The film coating base may further contain a coloring agent, a brightening agent and the like. Examples of the colorant include yellow ferric oxide, ferric oxide, titanium oxide, and light silicic acid anhydride. Examples of the brightening agent include carnauba wax, sodium lauryl sulfate and the like.

The tablet hardness of the tablet of the present invention is usually 5 kgf or more, preferably 6 kgf or more, and more preferably 7 kgf or more. The hardness of the tablet can be measured using a TABLET HARDNESS TESTER (manufactured by TOYAMA).

5. Regarding Usage and Dose The present pharmaceutical composition is preferably not used alone, but is preferably used in combination with levodopa/carbidopa or levodopa/benserazide hydrochloride. The dose depends on the severity and age of the patient, but the daily dose for an adult is 100 mg to 200 mg of entacapone.

6. Manufacturing Method of Pharmaceutical Composition The manufacturing method of the present pharmaceutical composition is not particularly limited as long as the effects of the invention are not impaired. Below, the example of manufacture of the pharmaceutical composition which consists of tablets is shown. The tablet is manufactured by a wet granulation method and may include a first mixing step, a granulating step, a sizing step, a drying step, a second mixing step and a tableting step.

<First mixing step>
The first mixing step is a step of mixing entacapone, an excipient and a disintegrant to obtain powder granules. The mixing method is not particularly limited as long as entacapone, the excipient, and the disintegrant are mixed, and a known method can be appropriately selected depending on the purpose, for example, kneading, kneading, and sieving. Mixing, stirring and mixing, fluidized bed mixing (spraying) and the like.
Among these, kneading, stirring and mixing, and fluidized bed mixing are preferable in that entacapone, an excipient and a disintegrant can be uniformly mixed. Examples of the apparatus used for mixing include a stirring granulator, a high-speed stirring granulator, and a fluidized bed granulator.
As mentioned above, the entacapone used for producing the powder granules is preferably in a granular form, at least 90% of the entacapone particles have a diameter of 56 μm or more, and at least 90% of the entacapone particles have a diameter of 80 μm or more. It is more preferable to have.

<Granulation process>
The granulation step is a step in which a binding solution prepared by dissolving a binder in purified water is added to the powder granules obtained in the first mixing step, and the mixture is stirred and mixed to obtain granulated granules. The granulation method is not particularly limited, and a known method can be selected according to the purpose.
For example, agitation granulation method using a high speed agitation granulator, an extrusion granulation method using a cylindrical granulator, a pelleter, etc., a crushing granulation method for crushing a wet kneaded product using a speed mill, a power mill, etc., a mini Examples of the method include a rolling granulation method in which a granizer is mainly used for rolling operation using a mizer, a power kneader, a speed mill, a marumerizer, and the like, and a fluidized bed granulation method by a method such as spray drying.

<Drying process>
The drying step is a step of drying the granulated granules obtained in the granulating step to obtain dried granules. The method for drying is not particularly limited, and a known method can be selected according to the purpose. For example, there are blast drying, hot air drying and the like, and examples of the drying device include a fluidized bed dryer, Freund, multiplex, box type hot air circulation type dryer, shelf type dryer and the like.

<Sizing process>
The sizing step is a step of sizing the dried granules obtained in the drying step to obtain sized granules. The method of sizing is not particularly limited, and a known method can be selected according to the purpose.

<Second mixing step>
The second mixing step is a step of adding a lubricant to the sized granules obtained in the sizing step and mixing them to obtain mixed granules. The mixing method is not particularly limited, and a known method can be appropriately selected according to the purpose. Examples thereof include kneading, kneading, sieving, stirring and mixing, and fluidized bed mixing (spraying). .. Among these, kneading, stirring and mixing, and fluidized bed mixing are preferable because uniform mixing is possible. Examples of the apparatus used for mixing include a container rotating type, a stirring granulator, a high-speed stirring granulator, a fluidized bed granulator, and the like.

<Tabletting process>
The tableting step is a step in which the mixed granules obtained in the second mixing step are filled and compression-molded to obtain tablets (plain tablets). The method for tableting is not particularly limited, and a known method can be appropriately selected according to the purpose, and examples thereof include a rotary tableting machine, a hydraulic press machine, and a single-shot tableting machine.

(About tableting pressure)
The tableting pressure during tableting is not particularly limited, and can be appropriately adjusted depending on the device used, the principle, the size, the type of the main drug, and the like. When using the apparatus as described above, for example, the tableting pressure is preferably 300 kgf or more and 2000 kgf or less.

(About temperature during tableting)
The temperature at the time of tableting is not particularly limited as long as the effects of the present invention are not impaired. In the present invention, it is preferable to set it so that the saccharide used is not dissolved or melted, and it is usually sufficient to perform it at room temperature (for example, about 20 to 30°C).

(About coating process)
A coating step may be provided to coat the tablets (plain tablets) obtained by the tableting step. The coating step is a step of providing at least one layer of film coating on the tablet (plain tablet) obtained in the tableting step. The coating method is not particularly limited, and a known method can be appropriately selected according to the purpose. For example, a film coating apparatus is used.

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

[Example 1]
As shown in Table 10, 100.00 mg of entacapone having a volume particle size D90 of 59 μm, 59.20 mg of D-mannitol, 36.00 mg of crystalline cellulose, 20.00 mg of sodium starch glycolate and 74.50 mg of carmellose calcium were tumbler type. The mixture was placed in a mixer (Showa Kagaku Kikai Kosakusho) and mixed for 10 minutes to obtain powder granules.

A binding solution prepared by previously dissolving 6.50 mg of hydroxypropyl cellulose in purified water was added to the obtained powder granules and granulated to obtain granulated granules. The obtained granulated granules were dried at 60° C. for 10 hours using a shelf dryer to obtain dried granules. The obtained dried granules were sized with a screen diameter of φ0.8 mm to obtain sized granules. 3.80 mg of magnesium stearate was placed in the obtained sized granules in a tumbler type mixer (manufactured by Showa Kagaku Kikai Kosakusho) and mixed for 2 minutes to obtain mixed granules.

The resulting mixed granules were tabletted with a rotary tableting machine (VIRGO24, Kikusui Seisakusho) at a tableting pressure of 1000 kgf and compression-molded to obtain a major axis of about 13 mm, a minor axis of about 5.5 mm and a thickness of about 4. A tablet (plain tablet) having a weight of 00.00 mm and a weight of 300.00 mg per tablet was prepared. The obtained tablets (plain tablets) were placed in a fully-automatic sugar-coated film coating apparatus (manufactured by Freund Sangyo Co., Ltd.), sprayed with a coating solution, and dried until the exhaust temperature reached 60°C to prepare film-coated tablets.
In addition, the coating liquid mentioned here means that hypromellose (11.45 mg) and concentrated glycerin (0.55 mg) are put into purified water in advance and stirred and mixed, and 1.00 mg of titanium oxide, a trace amount of iron sesquioxide and yellow are added to this liquid. A solution prepared by adding iron sesquioxide to purified water and stirring and mixing the solution.

[Example 2]
As shown in Table 10, a film-coated tablet was produced in the same manner as in Example 1 except that the contents of D-mannitol, sodium starch glycolate and carmellose calcium were changed.

[Example 3]
As shown in Table 10, Example 1 was repeated except that the contents of D-mannitol, crystalline cellulose, carmellose calcium, and each additive of coating components were changed to reduce the total amount of uncoated tablets or the total amount of film-coated tablets. A film-coated tablet was prepared in the same manner as in.

[Example 4]
As shown in Table 10, Example 1 was repeated except that the contents of D-mannitol, crystalline cellulose, carmellose calcium, and each additive of coating components were changed to reduce the total amount of uncoated tablets or the total amount of film-coated tablets. A film-coated tablet was prepared in the same manner as in.

[Comparative Example 1]
As shown in Table 10, Comparative Example 1 was the same as Example 1 except that it contained only carmellose calcium and the amount of each additive was changed to reduce the total amount of uncoated tablets or the total amount of film-coated tablets. A film-coated tablet was prepared by the same method.

[Comparative example 2]
As shown in Table 10, Comparative Example 2 was the same as Example 1 except that sodium starch glycolate alone was contained and the amount of each additive was changed to reduce the total amount of uncoated tablets or the total amount of film-coated tablets. A film-coated tablet was prepared in the same manner as in.

[Comparative Example 3]
As shown in Table 10, in Comparative Example 3, croscarmellose sodium was contained in place of carmellose calcium, and the amount of each additive was changed to reduce the total amount of uncoated tablets or the total amount of film-coated tablets. Produced a film-coated tablet in the same manner as in Example 1.

[Comparative Example 4]
As shown in Table 10, Comparative Example 4 is a commercially available "Comtan (registered trademark) tablet 100 mg" (manufactured by Novartis Pharma Co., Ltd.), which is a starting formulation containing entacapone as a main ingredient.
"Comtan (registered trademark) tablet 100 mg" contains, in addition to the components of Example 1, polysorbate 80 and hydrogenated oil as uncoated tablet components, and sucrose as a film coat component.

<Evaluation>
The tablets prepared in each of the examples and comparative examples were evaluated for dissolution, color change and tablet hardness.

1. Evaluation of Dissolution The dissolution properties of the entacapone 100 mg tablets obtained in Examples 1 to 4 and Comparative Examples 1 to 4 were evaluated under the following test conditions.
Test liquid: Water Test method: Paddle method Test liquid amount: 900 mL
Test solution temperature: 37±0.5℃
Rotation speed: 50 rotations Test time: Maximum 60 minutes Detector: Ultraviolet absorptiometer (measurement wavelength 290nm), (SPD-20A type manufactured by Shimadzu Corporation)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm is packed with 5 μm of phenylated silica gel for liquid chromatography. Column temperature: 25° C.
Mobile phase: Mobile phase: diluted phosphoric acid (1→100)/acetonitrile mixture (1:1)

To determine the amount of dissolved entacapone, the solution was filtered, and the peak area of the filtrate was measured by the automatic integration method. The measurement results are shown in Table 11.

From the results in Table 11, it was found that the tablets of Examples 1 to 4 containing sodium starch glycolate and carmellose calcium had a dissolution rate of entacapone of 60% or more after 60 minutes, indicating that the dissolution rate of entacapone was high. It was
In addition, the tablets of Examples 1 and 4 in which the content of sodium starch glycolate was 20% by weight with respect to entacapone and the content of carmellose calcium was 70% by weight or more with respect to entacapone, after 60 minutes It was found that the dissolution rate of entacapone was 68% or more, and the dissolution of entacapone was further enhanced.
On the other hand, the tablets of Comparative Examples 1 and 2 containing any one of sodium starch glycolate or carmellose calcium had an entacapone dissolution rate of less than 60% after 60 minutes, indicating that the entacapone dissolution rate was low. It was
In addition, the tablets of Comparative Example 3 containing sodium starch glycolate and croscarmellose sodium and the tablets of Comparative Example 4 of the starting formulation had an entacapone dissolution rate of 60% or more after 60 minutes, and the entacapone dissolution rate was 60% or more. I found it expensive.

2. Color Tone Change Evaluation Each of the entacapone 100 mg tablets obtained in Examples 1 to 4 and Comparative Examples 1 to 4 was placed in a closed glass bottle and stored for 1 month under the condition of 55° C. and 75% RH. The color of the tablets was measured. The color tone is measured using a color tester (MODELS C-3 Suga Test Instruments Co., Ltd.), and the color difference is calculated from the color tone parameter of each tablet, L (lightness), a (hue) and b (saturation) by the following mathematical formula 1. Then, the change in color tone before and after storage was evaluated. Note that ΔE means that the larger the numerical value, the greater the degree of color tone change.

The measurement results are shown in Table 12.

From the results of Table 12, it was found that the color difference of the tablets of Examples 1 to 4 containing sodium starch glycolate and carmellose calcium was less than 1, and the change in color tone was suppressed. The color difference of the tablet of Example 4 in which the content of sodium starch glycolate is 20% by weight relative to entacapone and the content of carmellose calcium is 90% by weight or more relative to entacapone, the color difference is less than 0.5. It was found that the change in color tone was further suppressed.

The color difference of the tablet of Comparative Example 1 containing only carmellose calcium was less than 1, and it was found that the change in color tone was suppressed to the same extent as the tablet of Example 2. On the other hand, the color difference between the tablet of Comparative Example 2 containing only sodium starch glycolate, the tablet of Comparative Example 3 containing sodium starch glycolate and croscarmellose sodium, and the tablet of Comparative Example 4, which is a starting formulation, is 1 or more, It was found that the change in color tone was not suppressed.

3. Tablet hardness evaluation The tablet hardness of the plain tablets (tablets before coating) of the entacapone 100 mg tablets obtained in Examples 1 to 4 and Comparative Examples 1 to 3 were measured using TABLET HARDNESS TESTER (manufactured by TOYAMA). A tablet hardness of 6.0 kg or more was evaluated as ◯, and a tablet hardness of less than 6.0 kg was evaluated as x. The measurement results are shown in Table 13.

As can be seen from the results in Table 13, all the entacapone 100 mg uncoated tablets obtained in Examples 1 to 4 and Comparative Examples 1 to 3 have sufficient tablet hardness. Therefore, coating could be performed while maintaining the shape of the plain tablet.

In addition, the tablet of Comparative Example 1 has a sufficient tablet hardness (Table 13) although the dissolution property is not sufficient (Table 11), the change in color tone is reduced (Table 12). Therefore, it was also considered that the elution property was improved by further increasing the amount of carmellose calcium (50 mg) which is a disintegrant. However, if the amount of calcium carmellose is excessive, the tablet hardness may decrease sharply (see Test Example 7 described above). On the other hand, the present inventor has realized improvement in dissolution while maintaining tablet strength by combining sodium starch glycolate.

From the above, the tablets of Examples 1 to 4 containing sodium starch glycolate and carmellose calcium can improve the dissolution property of entacapone from the preparation and suppress the color tone change over time of the preparation. I knew I could do it. Further, it has been found that both improvement in tablet hardness and improvement in dissolution can be achieved.

The specific contents of each component used in the tablets of Examples and Comparative Examples are as shown in Table 14.

Claims (1)

A tablet containing entacapone or a salt thereof, sodium starch glycolate, and carmellose calcium,
Total content of the carmellose calcium and the sodium starch glycolate is state, and are 22.7% by weight or more with respect to said tablet,
Tablets without croscarmellose sodium .