JP6411265B2 - Entacapone-containing pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition comprising 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 Catechol-O-methyltransferase (COMT) inhibitors used in combination with dopa decarboxylase (DDC) inhibitors.

  As pharmaceutical compositions containing entacapone, film-coated tablets for oral administration have been proposed. For example, Patent Document 1 is a method for producing granules containing entacapone as the sole active ingredient used in tablets, comprising (1) entacapone, a binder and optionally one or more other excipients. Prepare a mixture and granulate the mixture using a granulation liquid or granulate entacapone with one or more optional other excipients and a granulation liquid containing a binder (2) A production method comprising drying and optionally sieving the granules of step (1), wherein the entacapone used in the production of the granules is in granular form and at least 90% of the entacapone particles are 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 Japanese Patent No. 4619537

  However, the technologies of Patent Document 1 and Patent Document 2 can improve the dissolution of entacapone from the preparation, and further improvement is necessary to suppress the color change over time of the preparation. It was. In particular, croscarmellose sodium, which is a disintegrant, sometimes markedly colored the entacapone-containing preparation. Therefore, an object of the present invention is to suppress coloring of an entacapone-containing preparation without reducing the dissolution of entacapone.

  In addition, it has been difficult to sufficiently increase the hardness of conventional entacapone-containing tablets, particularly tablets containing croscarmellose sodium. Then, the further subject of this invention is raising the hardness of an entacapone containing tablet. By increasing the tablet hardness, it is possible to suppress tablet abrasion during the coating process 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 a salt thereof, and the content of the carmellose calcium is 50% with respect to the entacapone or a salt thereof. % To 120% by weight is preferable.

  The pharmaceutical composition is preferably a tablet.

  ADVANTAGE OF THE INVENTION According to this invention, while being able to improve the dissolution property of the entacapone from a formulation, the pharmaceutical composition containing the entacapone or its salt which suppressed the color tone change of a formulation over time can be provided.

  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-methyltransferase (COMT) It is used as a treatment for Parkinson's disease. Entacapone has a yellow to greenish yellow color tone, is hardly soluble in ethanol, and hardly dissolves in water. Entacapone may be produced by a conventionally known method, or a commercially available product may be used.

(About the form of Entacapon)
Entacapone can be prepared, for example, by the methods 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) -isomer form. The (E) -isomer may take various polymorphic forms, for example polymorph A disclosed in US 5,135,950, or polymorph D disclosed in WO 2005/063696, or amorphous. Entacapone in the pharmaceutical composition of the present invention is usually crystalline.

(About Entacapone particle size)
The entacapone contained in the pharmaceutical composition of the present invention is in a granular form, and it is preferable that the volume particle diameter D90 of the entacapone particles is 56 μm or more. The volume particle size distribution of entacapone is measured by measuring the sample using a laser diffraction particle size measurement (LPD) and using a particle size analyzer (Mastersizer 2000, Malvern Instruments Ltd.). Measured.

(About Entacapone content)
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 is preferably 1% by weight or more and 99% by weight or less, and preferably 1% by weight or more and 50% by weight or less based on the total weight of the tablet (plain tablet). More preferably.

2. About a disintegrating agent This pharmaceutical composition contains the disintegrating agent, and contains disintegrant sodium starch glycolate and carmellose calcium. Moreover, it is preferable that this pharmaceutical composition does not contain croscarmellose sodium or does not contain substantially. By combining sodium starch glycolate and carmellose calcium, it is possible to improve the dissolution of entacapone from the preparation and to suppress the change in color tone of the preparation over time. Moreover, the hardness of an entacapone tablet can fully be increased by combining sodium starch glycolate and carmellose calcium.

  In addition, from the viewpoint of improving the dissolution of entacapone and suppressing color change, the content of sodium starch glycolate in the pharmaceutical composition is 1% by weight or more and 20% by weight or less, more preferably based on entacapone or a salt thereof. It is preferably 10% by weight or more and 20% by weight or less. 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 or less and 120% by weight or less with respect to entacapone or a salt thereof.

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

<Elution evaluation>
About the tablet produced in Test Examples 1-4, the dissolution property of entacapone was evaluated under the following conditions.
Test solution: Water Test method: Paddle method Test solution volume: 900 mL
Test solution temperature: 37 ± 0.5 ° C
Number of rotations: 50 rotations Test time: Maximum 60 minutes Detector: Ultraviolet absorptiometer (measurement wavelength 290 nm), (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 filled 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)

  The dissolved entacapone was quantified by filtering the solution and measuring the peak area of the filtrate by an automatic integration method. The measurement results are shown in Table 2.

  From the results of Table 2, it was found that the tablet of Test Example 1 containing croscarmellose sodium had the highest dissolution of entacapone. Next, the dissolution property of Entacapone from the tablet of Test Example 3 containing sodium starch glycolate was comparable to the dissolution property of Entacapone from the tablet of Test Example 4 containing carmellose calcium. On the other hand, it was found that the dissolution of entacapone of the tablet of Test Example 2 containing crospovidone was the lowest.

  Moreover, as shown in the below-mentioned Example, croscarmellose sodium changes a color of an entacapone tablet notably (refer the comparative example 4).

  Next, the hardness of the entacapone tablets prepared in Test Examples 1 to 4 was 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 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 examples of the present specification, the tablet was shaved 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 of entacapone, suppressing color change, and suppressing tablet scraping in the coating process in the manufacturing process, the present inventor disintegrated carmellose calcium and sodium starch glycolate. It was considered to select as an agent.

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

  About the entacapone 100 mg tablet produced in Test Examples 4-7, the dissolution property was evaluated under the test conditions described above. Table 5 shows the measurement results.

  From the results shown in Table 5, it was found that the dissolution of entacapone was improved with an increase in the content of carmellose calcium. In addition, the dissolution of entacapone of the tablets of Test Examples 4 to 7 was comparable to or better than the dissolution of Entacapone of the tablets of Test Example 1.

  Moreover, about the entacapone 100 mg tablet produced in Test Examples 4-7, tablet hardness was measured using the measuring apparatus mentioned above. 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 by the same method as in the examples of the present specification, the tablets did not collapse. The coating could be made while maintaining the tablet shape. On the other hand, when the tablet of Test Example 7 in which the content of carmellose calcium was 90% by weight with respect to Entacapone was coated, the tablet was shaved 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 having a content of 20% by weight based on entacapone were prepared. did.

  The reason why the content of sodium starch glycolate is the upper limit of 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 This is because it is 1600 mg, so that it can be blended only up to 20% by weight with respect to Entacapone.

  About the entacapone 100 mg tablet produced in Test Examples 8-10, the dissolution property was evaluated on the test conditions described above. Table 8 shows the measurement results.

  From the results of Table 8, it was found that the dissolution of entacapone of the tablets of Test Examples 8 to 10 was higher than that of the tablet of Test Example 1. Moreover, when the tablets of Test Example 5 and Test Example 8, Test Example 6 and Test Example 9, and Test Example 7 and Test Example 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 higher dissolution of entacapone.

  In addition, as can be seen from the examples described later, sodium starch glycolate may discolor the entacapone preparation when it is added alone (Comparative Example 2). However, both carmellose calcium and sodium starch glycolate are used together. It became clear that the discoloration of the entacapone preparation can be suppressed unexpectedly by adding it.

  Moreover, about the entacapone 100 mg tablet produced in Test Examples 8-10, tablet hardness was measured using the measuring apparatus mentioned above. 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. Table 9 shows the measurement results.

  From the results of Table 9, when the tablets of Test Examples 8 to 10 were coated by the same method as in the examples of the present specification, the tablets did not collapse and could be coated while maintaining the tablet shape. When the tablets of Test Example 7 and Test Example 10 are compared, the tablets of Test Example 7 containing carmellose calcium alone despite containing a high content of carmellose calcium (90 mg). Then, the coating could not be performed while maintaining the shape of the tablet, whereas the tablet of Test Example 10 in which carmellose calcium and sodium starch glycolate were co-blended could be coated while maintaining the shape of the tablet.

3. Other components The pharmaceutical composition of the present invention can be appropriately selected from other components that are acceptable in the pharmaceutical composition without particular limitation depending on the purpose. For example, excipients, disintegrants, binding agents Agents, lubricants and the like.

(About excipients)
In the pharmaceutical composition of the present invention, excipients usually used in the pharmaceutical field can be added as long as the effects of the present invention are not affected. 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 etc. can be used. These excipients can be used alone or in combination. As the excipient used in the pharmaceutical composition, D-mannitol and crystalline cellulose are preferably used from the viewpoint of moldability.

  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 with respect to the total weight of the pharmaceutical composition.

(About disintegrant)
In the pharmaceutical composition of the present invention, an acceptable disintegrant may be added as a pharmaceutical ingredient in addition to carmellose calcium and sodium starch glycolate, as long as the effects of the present invention are not affected. Examples of the disintegrant include low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, polyvinylpyrrolidone, corn starch, hydroxypropylmethylcellulose, and hydroxypropylcellulose.

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

(About lubricants)
The pharmaceutical composition of the present invention can be added with an acceptable lubricant as a pharmaceutical ingredient as long as it does not affect the effects of the present invention. The lubricant is not particularly limited and may be appropriately selected depending on the intended 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.

  Lubricants are formulated for the purpose of preventing powder adhering to the mortar and pestle when making tablets, but if the lubrication effect is too strong, the moldability becomes weak and a practical tablet hardness is obtained. More pressure than necessary. Tablets made at high pressure need to be made at as low a pressure as possible because the disintegration rate of the tablet tends to be delayed. From this point, it is preferable to use magnesium stearate, which can obtain a lubrication effect even with a small amount.

4). About the dosage form of a pharmaceutical composition This pharmaceutical composition may be a solid, semi-solid, or liquid preparation. More specifically, oral administration agents such as tablets, film-coated tablets, capsules, granules, fine granules, and dry syrups may be used, but tablets are preferred.

(About film-coated tablets)
When the pharmaceutical composition is a film-coated tablet, examples of the film coating base include a water-soluble film coating base. Examples of water-soluble film coating bases include cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose or sodium carboxymethylcellulose; polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer or polyvinylpyrrolidone. A synthetic polymer; or concentrated glycerin. The coating base may be used alone or in combination of two or more.

  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 anhydrous silicic acid. Examples of the brightening agent include carnauba wax and sodium lauryl sulfate.

  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 TABLEHARDNESS TESTER (manufactured by TOYAMA).

5. Usage and Dosage The present pharmaceutical composition is preferably not used alone but 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 such that entacapone is 100 mg to 200 mg.

6). Method for Producing Pharmaceutical Composition The method for producing the pharmaceutical composition is not particularly limited as long as the effects of the invention are not inhibited. Below, the manufacture example of the pharmaceutical composition which consists of a tablet is shown. The tablet is produced by a wet granulation method, and may include a first mixing step, a granulating step, a granulating step, a drying step, a second mixing step, and a tableting step.

<First mixing step>
The first mixing step is a step of obtaining powder granules by mixing entacapone, an excipient, and a disintegrant. The mixing method is not particularly limited as long as the entacapone, the excipient, and the disintegrant are mixed, and a known method can be appropriately selected according to the purpose. For example, kneading, kneading, sieving Excess, stirring and mixing, fluidized bed mixing (spraying) and the like.
Among these, kneading, stirring mixing, and fluidized bed mixing are preferable in that entacapone, an excipient, and a disintegrant can be mixed uniformly. Examples of the apparatus used for mixing include an agitation granulator, a high speed agitation granulator, and a fluidized bed granulator.
As mentioned above, the entacapone used for the production of powder granules is in granular form, preferably 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. More preferably, it has.

<Granulation process>
The granulation step is a step in which a binding liquid in which a binder is previously dissolved in purified water is added to the powder granules obtained in the first mixing step and stirred to obtain granulated granules. There is no restriction | limiting in particular as the method of granulating, A well-known method can be selected according to the objective.
For example, agitation granulation method using a high speed agitation granulator, cylindrical granulator, extrusion granulation method using a pelleter, etc., crushing granulation method for crushing a wet kneaded product using a speed mill, power mill, etc. Examples thereof include a rolling granulation method using a mizer, a power kneader, a speed mill, a malmerizer, etc., mainly for rolling operation, and a fluidized bed granulation method by a method such as spray drying.

<Drying process>
A drying process is a process of drying the granulation granule obtained at the granulation process and obtaining a dry granule. There is no restriction | limiting in particular as a method of drying, According to the objective, a well-known method can be selected. For example, there are blow drying and hot air drying, and examples of the drying device include a fluidized bed dryer, Freund, multiplex, box-type hot air circulation dryer, and shelf dryer.

<Sizing process>
The sizing step is a step of sizing the dried granules obtained in the drying step to obtain sized granules. There is no restriction | limiting in particular as a method of sizing, A well-known method can be selected according to the objective.

<Second mixing step>
The second mixing step is a step of obtaining a mixed granule by adding and mixing a lubricant to the sized granule obtained in the sizing step. 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 mixing, and fluidized bed mixing are preferable in that they can be mixed uniformly. Examples of the apparatus used for mixing include a container rotation type, a stirring granulator, a high-speed stirring granulator, a fluidized bed granulator, and the like.

<Tabletting process>
The tableting step is a step of filling the mixed granule obtained in the second mixing step and compression-molding it to obtain a tablet (plain tablet). There is no restriction | limiting in particular as a tableting method, According to the objective, a well-known method can be selected suitably, For example, a rotary tableting machine, a hydraulic press machine, a single tableting machine etc. are mentioned.

(About tableting pressure)
The tableting pressure at the time of 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.

(Temperature when tableting)
The temperature at the time of tableting is not particularly limited as long as the effect of the present invention is not impaired. In this invention, it is preferable to set it to the grade which does not melt | dissolve or melt | dissolve the saccharides to be used, and it is enough to carry out normally at room temperature (for example, about 20-30 degreeC).

(About coating process)
In order to coat the tablet (plain tablet) obtained by the tableting process, a coating process may be provided. A coating process is a process of providing at least 1 layer of film coating with respect to the tablet (plain tablet) obtained at the tableting process. There is no restriction | limiting in particular as a method of coating, A well-known method can be suitably selected according to the objective, For example, it is performed using a film coating apparatus.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this.

[Example 1]
As shown in Table 10, 100.00 mg of entacapone with 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 tumbled. It put into the mixer (made by Showa Chemical Machinery Co., Ltd.) and mixed for 10 minutes, and the powder granule was obtained.

  To the obtained powder granules, a binding solution in which 6.50 mg of hydroxypropylcellulose was previously dissolved in purified water was added and granulated to obtain granulated granules. The obtained granulated granules were dried at 60 ° C. for 10 hours using a shelf dryer to obtain dry granules. The obtained dried granules were sized with a screen diameter of φ0.8 mm to obtain sized granules. To the obtained granulated granules, 3.80 mg of magnesium stearate was placed in a tumbler type mixer (manufactured by Showa Chemical Machinery Co., Ltd.) and mixed for 2 minutes to obtain mixed granules.

The obtained mixed granules were tableted with a rotary tableting machine (VIRGO24 manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 1000 kgf, compression molded, and the major axis was about 13 mm, the minor axis was about 5.5 mm, and the thickness was about 4. Tablets (plain tablets) having a weight of 300.00 mg per tablet of 0 mm were prepared. The obtained tablets (plain tablets) were put in a fully automatic sugar-coated film coating apparatus (Freund Sangyo Co., Ltd.), sprayed with a coating solution, and dried until the exhaust temperature reached 60 ° C. to produce film-coated tablets.
In addition, the coating liquid here refers to 11.45 mg of hypromellose and 0.55 mg of concentrated glycerin in purified water and mixed with stirring. To this liquid, 1.00 mg of titanium oxide, a small amount of iron sesquioxide and yellow are mixed. A solution obtained by adding a solution of ferric sesquioxide in purified water and mixing with stirring.

[Example 2]
As shown in Table 10, film-coated tablets were prepared 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 except that the contents of D-mannitol, crystalline cellulose, carmellose calcium, and each of the coating component additives were changed and the total amount of uncoated tablets or film coated tablets was reduced. Film-coated tablets were prepared in the same manner as above.

[Example 4]
As shown in Table 10, Example 1 except that the contents of D-mannitol, crystalline cellulose, carmellose calcium, and each of the coating component additives were changed and the total amount of uncoated tablets or film coated tablets was reduced. Film-coated tablets were prepared in the same manner as above.

[Comparative Example 1]
As shown in Table 10, Comparative Example 1 contains only carmellose calcium, and the amount of each additive was changed, except that the total amount of uncoated tablets or total film-coated tablets was reduced. Film-coated tablets were prepared in the same manner.

[Comparative Example 2]
As shown in Table 10, Comparative Example 2 contains only sodium starch glycolate, and the amount of each additive was changed to reduce the amount of uncoated tablets or film-coated tablets. Film-coated tablets were prepared in the same manner as above.

[Comparative Example 3]
As shown in Table 10, Comparative Example 3 contains croscarmellose sodium instead of carmellose calcium, and the amount of each additive was changed to reduce the total amount of uncoated tablets or total 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) 100 mg” (manufactured by Novartis Pharma Co., Ltd.), which is a starting preparation mainly composed of entacapone.
“Comtan (registered trademark) tablet 100 mg” contains, in addition to the components of Example 1, polysorbate 80 and hydrogenated oil as an uncoated tablet component, and sucrose as a film coat component.

<Evaluation>
About the tablet produced by each Example and the comparative example, dissolution property, color tone change, and tablet hardness were evaluated.

1. Dissolution evaluation 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 solution: Water Test method: Paddle method Test solution volume: 900 mL
Test solution temperature: 37 ± 0.5 ° C
Number of rotations: 50 rotations Test time: Maximum 60 minutes Detector: Ultraviolet absorptiometer (measurement wavelength 290 nm), (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 filled 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)

  The dissolved entacapone was quantified by filtering the solution and measuring the peak area of the filtrate by an automatic integration method. Table 11 shows the measurement results.

From the results of Table 11, it can be seen that the tablets of Examples 1 to 4 containing sodium starch glycolate and carmellose calcium have a dissolution rate of entacapone of 60% or more after 60 minutes and a high dissolution rate of entacapone. It was.
In addition, the tablets of Examples 1 and 4 in which the content of sodium starch glycolate is 20% by weight with respect to entacapone and the content of carmellose calcium is 70% by weight or more with respect to entacapone, The dissolution rate of Entacapone was 68% or more, and it was found that the dissolution property of Entacapone was further increased.
On the other hand, the tablets of Comparative Examples 1 and 2 containing either one of sodium starch glycolate or calcium carmellose have a dissolution rate of entacapone of less than 60% after 60 minutes, and it is found that the dissolution property of entacapone is low. It was.
In addition, the tablet of Comparative Example 3 containing sodium starch glycolate and croscarmellose sodium and the tablet of Comparative Example 4 of the original preparation have an entacapone dissolution ratio of 60% or more after 60 minutes, I found it expensive.

2. Evaluation of color change Entacapone 100 mg tablets obtained in Examples 1 to 4 and Comparative Examples 1 to 4 were each placed in a sealed glass bottle and stored for 1 month under conditions of 55 ° C. and 75% RH, before and after storage. The color of the tablet was measured. The color tone is measured using a color tester (MODELSC-3 Suga Test Instruments Co., Ltd.), and the color difference is calculated from the color tone parameters, L (lightness), a (hue) and b (saturation) of each tablet by the following formula 1. The color change before and after storage was evaluated. ΔE means that the greater the numerical value, the greater the degree of color tone change.

  Table 12 shows the measurement results.

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

  The color difference of the tablet of Comparative Example 1 containing only carmellose calcium was less than 1, indicating that the color tone change 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 the original preparation is 1 or more, It was found that the color change was not suppressed.

3. Tablet hardness evaluation About the uncoated tablet (tablet before coating) of Entacapone 100 mg tablets obtained in Examples 1 to 4 and Comparative Examples 1 to 3, tablet hardness was 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. Table 13 shows the measurement results.

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

  Moreover, although the tablet of the comparative example 1 is not sufficiently soluble (Table 11), the color tone change is reduced (Table 12) and it has sufficient tablet hardness (Table 13). Therefore, it was considered that the dissolution property was improved by further increasing the amount (50 mg) of carmellose calcium which is a disintegrant. However, when the amount of carmellose calcium is excessive, the tablet hardness may be drastically reduced (see Test Example 7 above). On the other hand, the present inventor 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 of entacapone from the preparation and suppress the change in color tone of the preparation over time. I understood that I could do it. Furthermore, it was found that both improvement in tablet hardness and improvement in dissolution can be achieved.

  In addition, the specific content of each component used by the tablet of each Example and a comparative example is as showing in Table 14.

Claims (3)

A pharmaceutical composition comprising entacapone or a salt thereof, sodium starch glycolate, and carmellose calcium ,
The content of the sodium starch glycolate is 20% by weight or less based on the entacapone or a salt thereof,
A pharmaceutical composition containing no croscarmellose sodium .   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 a salt thereof, and the content of the carmellose calcium is 50% with respect to the entacapone or a salt thereof. 2. The pharmaceutical composition according to claim 1, wherein the composition is not less than 120% and not more than 120% by weight. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a tablet.