Tablets containing tadalafil and method for producing the same

Abstract

To provide tadalafil-containing tablets that can be easily prepared even if the need arises to administer by grinding or suspending, or to adjust the dosage and are resistant to color change under light irradiation.SOLUTION: There is provided a method for producing a tablet containing granules containing tadalafil, in which iron oxide is contained by adding powders in one or both of the inside and outside of the granules.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to tablets containing tadalafil and a method for producing the same.

Background Art

[0002] Tablets are known as a dosage form excellent in portability and quantitativeness and are widely used in pharmaceuticals. Tablets are produced by molding a granulated or mixed product of an active ingredient and other additives such as excipients by a method such as compression. In addition to tablets coated with saccharides, polymer compounds, etc. for the purpose of improving the taste and stability and controlling the solubility and absorbability, such as sugar-coated tablets and film-coated tablets, there are also types of tablets that have not been coated by methods such as compression, and such tablets are called plain tablets.

[0003] On the other hand, tadalafil (chemical name: (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1’,2’:1,6]pyrido[3,4-b]indole-1,4-dione) is a phosphodiesterase 5 inhibitor represented by the following formula (1), and as a pharmaceutical having an effect on the treatment of erectile dysfunction, pulmonary arterial hypertension, and urinary disorders associated with benign prostatic hyperplasia, products with different tadalafil contents have been manufactured and sold in order to have appropriate dosages for each disease (Non-Patent Documents 1, 2, 3).

[0004]

Chemical Formula

[0005] However, when tadalafil is made into a plain tablet, color change and content reduction may occur due to light irradiation (Non-Patent Document 4).

[0006] In addition, film-coated tablets coated with a film coating agent containing a coloring agent such as titanium oxide or iron oxide on plain tablets containing tadalafil are commercially available. However, when administering tadalafil preparations to patients with dysphagia such as children and the elderly, the tablets may be crushed or suspended at the discretion of the clinical site for dose adjustment and improved palatability. When crushed, film-coated tablets require a force to break the film layer, so they are more difficult to crush than plain tablets. Furthermore, the broken film layer is difficult to crush and tends to remain as fragments. Therefore, when adjusting the dose for children, especially during the treatment of pulmonary arterial hypertension, care must be taken to ensure that the tadalafil content is uniform. Also, when suspending for use, the film layer must be broken beforehand. Moreover, since the film coating agent affects the permeability of the tube used for suspension administration, there is a possibility that suspension administration may become impossible due to tube blockage even when the film layer is broken. Therefore, there is a need for tadalafil-containing tablets that are easy to dispense even when there is a clinical need for administration or dose adjustment by crushing or suspension.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0008] An object of the present invention is to provide a tadalafil-containing tablet that is easy to formulate even when administration by pulverization or suspension or the need for dose adjustment occurs, and that is less likely to undergo a change in color tone under light irradiation. [Means for Solving the Problems]

[0009] Generally, when a colorant is contained inside or outside the granules (for example, an additive layer) in a tablet, in order to enhance the dispersibility of the colorant, a method (liquid addition) is used in which the colorant is dissolved or dispersed in a solvent or dispersion medium and then added to other powdery or granular components such as excipients to manufacture the tablet. However, as a result of intensive research on tadalafil-containing tablets that are less likely to undergo a change in color tone under light irradiation, the present inventors have, quite unexpectedly, found that by a method (powder addition) in which iron oxide is added in a powdery state to other powdery or granular components without dissolving or dispersing it in a solvent or dispersion medium, when iron oxide is contained in either or both of the inside and outside of the granules of the tadalafil-containing tablet, a tadalafil-containing tablet that is less likely to undergo a change in color tone under light irradiation can be obtained, and thus completed the present invention.

[0010] That is, the present invention relates to the following <1> to <15>. <1> A method for manufacturing a tablet containing granules containing tadalafil, wherein iron oxide is contained in either or both of the inside and outside of the granules by powder addition (hereinafter, also referred to as "the method for manufacturing a tablet of the present invention"). <2> A method for manufacturing a tablet containing granules containing tadalafil, wherein iron oxide is contained in both the inside and outside of the granules by powder addition.

[0011] <3> A method for manufacturing a tablet containing granules containing tadalafil, including the following steps S1-1 to S1-4. (Step S1-1) A step of obtaining a powdery or granular composition containing tadalafil and iron oxide by dry-containing powdery iron oxide in a powdery or granular component containing tadalafil (Step S1-2) A step of granulating the powdery or granular composition obtained in Step S1-1 (Step S1-3) A step of mixing the granules obtained in step S1-2 with an additive (Step S1-4) A step of tableting the mixture obtained in step S1-3

[0012] <4> The production method according to <3>, wherein the powdery or granular component used in step S1-1 further contains a first excipient. <5> The production method according to <3> or <4>, wherein step S1-2 is a step of adding a kneading liquid to the powdery or granular composition obtained in step S1-1, kneading the composition, and granulating the kneaded product obtained by the kneading. <6> The production method according to any one of <3> to <5>, wherein step S1-3 is a step of dry-adding and mixing powdery iron oxide to the granules obtained in step S1-2 to obtain a powdery or granular mixture containing the granules obtained in step S1-2 and powdery iron oxide. <7> The production method according to any one of <3> to <5>, wherein step S1-3 is a step of dry-adding and mixing powdery iron oxide and a second excipient to the granules obtained in step S1-2 to obtain a powdery or granular mixture containing the granules obtained in step S1-2, powdery iron oxide, and the second excipient.

[0013] <8> A production method of a tablet containing granules containing tadalafil, including the following steps S2-1 to S2-2. (Step S2-1) A step of dry-adding and mixing powdery iron oxide to the granules containing tadalafil to obtain a powdery or granular mixture containing the granules containing tadalafil and powdery iron oxide (Step S2-2) A step of tableting the mixture obtained in step S2-1

[0014] <9> The production method according to any one of <1> to <8>, wherein the iron oxide is one or more selected from yellow ferric oxide and ferric oxide. <10> The production method according to any one of <1> to <9>, wherein the tablet is a plain tablet.

[0015] A tablet (hereinafter also referred to as "the tablet of the present invention") containing granules containing tadalafil and containing iron oxide compounded by adding powder to either or both of the inside and outside of the granules. A tablet containing granules containing tadalafil and containing iron oxide compounded by adding powder to both the inside and outside of the granules. The tablet according to <11> or <12>, wherein the iron oxide is at least one selected from yellow ferric oxide and ferric oxide. The tablet according to any one of <11> to <13>, wherein the outside of the granules is an additive layer and the granules are dispersed in the additive layer. The tablet according to any one of <11> to <14>, which is a core tablet.

Advantages of the Invention

[0016] According to the present invention, it is possible to provide a tadalafil-containing tablet that is easy to prepare even when administration by pulverization or suspension or the need for dose adjustment occurs, and is less likely to change in color tone under light irradiation.

Embodiments for Carrying Out the Invention

[0017] 〔Tablet〕 The tablet of the present invention is characterized by containing granules containing tadalafil and containing iron oxide compounded by adding powder to either or both of the inside and outside of the granules.

[0018] Here, in this specification, "adding powder" refers to an adding method in which it is added to other powdery or granular components in a powdery state without dissolving or dispersing in a solvent or dispersion medium. Note that "adding liquid" refers to an adding method in which it is dissolved or dispersed in a solvent or dispersion medium and then added to other powdery or granular components in a state of being dissolved or dispersed in the solvent or dispersion medium. In order to disperse uniformly, a coloring agent is generally added by the above-mentioned adding liquid. However, according to the present invention, quite unexpectedly, even though it contains iron oxide by adding powder, a tablet that is less likely to change in color tone under light irradiation is provided.

[0019] Tadalafil is a compound represented by the following formula (1).

[0020] [Chemical formula]

[0021] In the present invention, tadalafil includes, in addition to the free form of tadalafil, its pharmaceutically acceptable salts and their solvates, but the free form of tadalafil is preferred. Also, as tadalafil, a powdery form is preferred. The cumulative 90% particle size of powdery tadalafil is not particularly limited, but from the viewpoints of solubility, bioavailability, etc., 1 to 100 μm is preferred, 1 to 50 μm is more preferred, and 1 to 25 μm is particularly preferred.

[0022] The content of tadalafil is preferably 5 to 20% by mass, more preferably 10 to 18% by mass, still more preferably 12 to 14% by mass, and particularly preferably 12.5 to 13.5% by mass based on the total mass of the tablets of the present invention. The content of tadalafil is preferably 7.5 to 25% by mass, more preferably 10 to 22% by mass, still more preferably 12 to 20% by mass, and particularly preferably 14 to 17% by mass based on the total mass of the granules.

[0023] The content of tadalafil per tablet is not particularly limited, and the dosage used clinically can be appropriately selected. Specifically, it is usually 2.5 to 20 mg, preferably 5 to 20 mg, more preferably 10 to 20 mg in terms of the free form. When used as a therapeutic agent for pulmonary arterial hypertension, it is particularly preferred to contain 20 mg in terms of the free form.

[0024] As the iron oxide used in the tablets of the present invention, one or more selected from yellow ferric oxide and ferric oxide are preferred from the viewpoints of no change in color tone and no color unevenness, and a combination of yellow ferric oxide and ferric oxide is particularly preferred. As the iron oxide, a powdery one is preferred. The average particle diameter of the powdery iron oxide is preferably from 0.1 to 3.0 μm, more preferably from 0.1 to 1.5 μm, and particularly preferably from 0.1 to 0.5 μm. The average particle diameter of the iron oxide can be measured by the laser diffraction / scattering method.

[0025] The tablets of the present invention contain iron oxide compounded by adding powder to either one or both of the inside and outside (for example, the additive layer) of the granules, but may contain iron oxide both inside and outside the granules. Specifically, the tablets of the present invention include embodiments containing iron oxide compounded by adding powder both inside and outside the granules, embodiments containing iron oxide compounded by adding powder inside the granules but not containing iron oxide outside the granules, embodiments containing iron oxide compounded by adding powder inside the granules and containing iron oxide compounded by adding liquid outside the granules, embodiments containing iron oxide compounded by adding liquid inside the granules and containing iron oxide compounded by adding powder outside the granules, and embodiments not containing iron oxide inside the granules but containing iron oxide compounded by adding powder outside the granules. In addition, for not only the powder addition but also the above liquid addition, as the iron oxide, a powdery one is preferred. Among these, from the viewpoints of no color tone change, no color unevenness, etc., embodiments containing iron oxide compounded by adding powder both inside and outside the granules, embodiments containing iron oxide compounded by adding powder inside the granules but not containing iron oxide outside the granules, embodiments containing iron oxide compounded by adding liquid inside the granules and containing iron oxide compounded by adding powder outside the granules, and embodiments not containing iron oxide inside the granules but containing iron oxide compounded by adding powder outside the granules are preferred, and the embodiment containing iron oxide compounded by adding powder both inside and outside the granules is particularly preferred. When tadalafil-containing granules are made to contain iron oxide by adding powder both inside and outside, tablets with less color unevenness can be obtained.

[0026] As the total iron oxide content, from the viewpoints of no color tone change, no color unevenness, etc., it is preferably 0.05 to 5% by mass, more preferably 0.1 to 4% by mass, still more preferably 0.4 to 3% by mass, still more preferably 0.6 to 2% by mass, and particularly preferably 0.8 to 1% by mass based on the total mass of the tablets of the present invention. When using yellow iron sesquioxide as the iron oxide, as the total content of yellow iron sesquioxide, from the viewpoints of no color tone change, no color unevenness, etc., it is preferably 0.05 to 5% by mass, more preferably 0.1 to 4% by mass, still more preferably 0.3 to 3% by mass, still more preferably 0.4 to 2% by mass, and particularly preferably 0.6 to 1% by mass based on the total mass of the tablets of the present invention. When using iron sesquioxide as the iron oxide, as the total content of iron sesquioxide, from the viewpoints of no color tone change, no color unevenness, etc., it is preferably 0.01 to 3% by mass, more preferably 0.1 to 2% by mass, still more preferably 0.15 to 1.5% by mass, still more preferably 0.2 to 1% by mass, and particularly preferably 0.25 to 0.5% by mass based on the total mass of the tablets of the present invention.

[0027] As the content of the powdered iron oxide, from the viewpoints of no color tone change, no color unevenness, etc., it is preferably 0.05 to 5% by mass, more preferably 0.1 to 4% by mass, still more preferably 0.4 to 3% by mass, still more preferably 0.6 to 2% by mass, and particularly preferably 0.8 to 1% by mass based on the total mass of the tablets of the present invention. When adding powder to yellow iron sesquioxide, as the content of the powdered yellow iron sesquioxide, from the viewpoints of no color tone change, no color unevenness, etc., it is preferably 0.05 to 5% by mass, more preferably 0.1 to 4% by mass, still more preferably 0.3 to 3% by mass, still more preferably 0.4 to 2% by mass, and particularly preferably 0.6 to 1% by mass based on the total mass of the tablets of the present invention. When adding powder to iron sesquioxide, as the content of the powdered iron sesquioxide, from the viewpoints of no color tone change, no color unevenness, etc., it is preferably 0.01 to 3% by mass, more preferably 0.1 to 2% by mass, still more preferably 0.15 to 1.5% by mass, still more preferably 0.2 to 1% by mass, and particularly preferably 0.25 to 0.5% by mass based on the total mass of the tablets of the present invention.

[0028] When adding iron oxide powder inside the granules, from the viewpoints of no color tone change, no color unevenness, etc., the content of the iron oxide powder added inside the granules is preferably 0.05 to 5% by mass, more preferably 0.1 to 3% by mass, still more preferably 0.15 to 1% by mass, still more preferably 0.2 to 0.6% by mass, and particularly preferably 0.3 to 0.5% by mass based on the total mass of the granules. When adding yellow ferric oxide powder inside the granules, from the viewpoints of no color tone change, no color unevenness, etc., the content of the yellow ferric oxide powder added inside the granules is preferably 0.01 to 3% by mass, more preferably 0.05 to 2% by mass, still more preferably 0.075 to 1% by mass, still more preferably 0.1 to 0.5% by mass, and particularly preferably 0.2 to 0.4% by mass based on the total mass of the granules. When adding ferric oxide powder inside the granules, from the viewpoints of no color tone change, no color unevenness, etc., the content of the ferric oxide powder added inside the granules is preferably 0.005 to 3% by mass, more preferably 0.01 to 1.5% by mass, still more preferably 0.025 to 1% by mass, still more preferably 0.05 to 0.5% by mass, and particularly preferably 0.1 to 0.3% by mass based on the total mass of the granules.

[0029] When adding iron oxide powder outside the granules, from the viewpoints of no color tone change, no color unevenness, etc., the content of the iron oxide powder added outside the granules is preferably 0.05 to 10% by mass, more preferably 0.1 to 7.5% by mass, still more preferably 0.5 to 5% by mass, still more preferably 1 to 5% by mass, and particularly preferably 2 to 4% by mass based on the total mass outside the granules. When adding yellow ferric oxide powder outside the granules, from the viewpoints of no color tone change, no color unevenness, etc., the content of the yellow ferric oxide powder added outside the granules is preferably 0.05 to 10% by mass, more preferably 0.1 to 7.5% by mass, still more preferably 0.25 to 5% by mass, still more preferably 0.5 to 5% by mass, and particularly preferably 1 to 3% by mass based on the total mass outside the granules. When adding iron sesquioxide powder to the outside of the granules, from the viewpoints of no change in color tone and no color unevenness, etc., the content of the iron sesquioxide powder added to the outside of the granules is preferably 0.01 to 2% by mass, more preferably 0.05 to 1.5% by mass, still more preferably 0.1 to 1% by mass, still more preferably 0.2 to 1% by mass, and particularly preferably 0.4 to 0.8% by mass with respect to the total mass of the outside of the granules.

[0030] The mass ratio of iron oxide in the granules to iron oxide outside the granules (preferably the mass ratio of iron oxide added as powder inside the granules to iron oxide added as powder outside the granules) is not particularly limited, but the range of 1:0.4 to 1:3 is preferable, and the range of 1:0.6 to 1:1.6 is more preferable.

[0031] The mass ratio of iron oxide (preferably iron oxide added as powder inside the granules) in the granules to tadalafil in the granules is not particularly limited, but the range of 1:10 to 1:100 is preferable, and the range of 1:25 to 1:80 is more preferable.

[0032] As the tablets of the present invention, from the viewpoints of no change in color tone and no color unevenness, etc., those containing an excipient in addition to tadalafil and iron oxide are preferable. Further, the tablets of the present invention may contain, in addition to these components, drugs other than tadalafil and additives other than iron oxide and excipients. The additives other than iron oxide and excipient may be pharmaceutically acceptable ones, and examples thereof include binders, disintegrants, surfactants, lubricants, colorants (excluding iron oxide), fluidizing agents, preservatives, sweeteners, flavoring agents, flavoring agents / spices, stabilizers, etc. One of these may be used alone or two or more thereof may be used in combination. The additives other than iron oxide and excipient are preferably in powder form. As the granules in the tablets of the present invention, those containing tadalafil, iron oxide blended with powder addition, and further containing an excipient (in this specification, the excipient contained inside the granules is also referred to as the "first excipient") are preferred. In addition to tadalafil, iron oxide blended with powder addition, and the first excipient, those further containing one or more selected from a binder, a disintegrant, and a surfactant are more preferred, and those containing tadalafil, iron oxide blended with powder addition, the first excipient, and a binder are even more preferred. The average particle size of the granules in the tablets of the present invention is usually 60 to 140 μm, preferably 90 to 110 μm. The average particle size can be measured by the sieving method.

[0033] As the tablets of the present invention, those containing an excipient (in this specification, the excipient contained outside the granules is also referred to as the "second excipient") outside the granules in addition to iron oxide blended with powder addition are preferred. In addition to iron oxide blended with powder addition and the second excipient, those further containing one or more selected from a disintegrant, a lubricant, and a colorant (excluding iron oxide) are more preferred, and those containing iron oxide blended with powder addition, the second excipient, and a disintegrant are even more preferred.

[0034] In addition, as the outside of the granules, an additive layer can be mentioned. As tablets containing such an additive layer as the outside of the granules, from the viewpoints of no change in color tone, no color unevenness, etc., tablets containing the additive layer and the granules dispersed in the additive layer, wherein the granules contain tadalafil and contain iron oxide blended with powder addition in either one or both of the inside of the granules and the additive layer (hereinafter, this tablet is also referred to as "tablet (α)") are preferred. Note that at least a part of the granules contained in the tablet (α) may be dispersed in the additive layer, and as long as at least a part of the granules are dispersed in the additive layer, a plurality of granules in the additive layer may be in contact with each other. The additive layer is preferably a solid additive layer. The mass ratio of the granules to the additive layer in the tablets of the present invention is preferably in the range of 1:0.01 to 1:1.25, more preferably in the range of 1:0.05 to 1:1, and particularly preferably in the range of 1:0.1 to 1:0.5. As the total content of the granules and the additive layer, 90 to 100% by mass, more preferably 95 to 100% by mass, still more preferably 99 to 100% by mass, and particularly preferably 100% by mass, are preferred based on the total mass of the tablets of the present invention.

[0035] Examples of the above excipient include anhydrous lactose, lactose hydrate, D-mannitol, anhydrous calcium hydrogen phosphate, crystalline cellulose, and the like. One of these may be used alone or two or more thereof may be used in combination. Among these, from the viewpoints of no change in color tone and no color unevenness, lactose hydrate and crystalline cellulose are preferred, and a combination of lactose hydrate and crystalline cellulose is more preferred. As the first excipient, lactose hydrate is particularly preferred, while as the second excipient, crystalline cellulose is particularly preferred. Also, as the excipient, a powdery one is preferred.

[0036] From the viewpoints of no change in color tone and no color unevenness, the total content of the excipient is preferably 50 to 90% by mass, more preferably 60 to 85% by mass, and particularly preferably 70 to 80% by mass based on the total mass of the tablets of the present invention. When lactose hydrate is used as the excipient, the content of lactose hydrate is preferably 30 to 75% by mass, more preferably 40 to 70% by mass, still more preferably 50 to 70% by mass, and particularly preferably 55 to 65% by mass based on the total mass of the tablets of the present invention from the viewpoints of no change in color tone and no color unevenness. When crystalline cellulose is used as the excipient, the content of crystalline cellulose is preferably 7 to 35% by mass, more preferably 10 to 30% by mass, and particularly preferably 14 to 23% by mass based on the total mass of the tablets of the present invention from the viewpoints of no change in color tone and no color unevenness.

[0037] From the viewpoints of no change in color tone and no color unevenness, the content of the first excipient is preferably 60 to 85% by mass, more preferably 65 to 80% by mass, and particularly preferably 70 to 77.5% by mass based on the total mass of the granules. As the content of the second excipient, from the viewpoints of no change in color tone, no color unevenness, etc., 75 to 97.5% by mass, more preferably 80 to 95% by mass, and particularly preferably 85 to 92.5% by mass are preferable with respect to the total mass of the outside of the granules.

[0038] Examples of the above binder include hydroxypropyl cellulose, methyl cellulose, povidone, and the like. One of these may be used alone or two or more thereof may be used in combination. Among these, hydroxypropyl cellulose is preferable. Note that the binder may be added as a powder or as a liquid. As the content of the binder, 0.1 to 7.5% by mass, more preferably 0.3 to 5% by mass, and particularly preferably 1 to 2% by mass are preferable with respect to the total mass of the tablets of the present invention. When the binder is contained inside the granules, as the content of the binder inside the granules, 0.1 to 7.5% by mass, more preferably 1 to 5% by mass, and particularly preferably 1.5 to 2% by mass are preferable with respect to the total mass of the granules.

[0039] Examples of the above disintegrant include starch, carboxymethyl cellulose, croscarmellose sodium, and the like. One of these may be used alone or two or more thereof may be used in combination. Among these, croscarmellose sodium is preferable. As the content of the disintegrant, 5 to 10% by mass, more preferably 6 to 9% by mass, and particularly preferably 7 to 8.5% by mass are preferable with respect to the total mass of the tablets of the present invention. When the disintegrant is contained inside the granules, as the content of the disintegrant inside the granules, 1 to 15% by mass, more preferably 3 to 12% by mass, and particularly preferably 7 to 9% by mass are preferable with respect to the total mass of the granules. When the disintegrant is contained outside the granules, as the content of the disintegrant outside the granules, 1 to 15% by mass, more preferably 3 to 12% by mass, and particularly preferably 5 to 9% by mass are preferable with respect to the total mass of the outside of the granules.

[0040] Examples of the surfactant include sodium lauryl sulfate, sucrose fatty acid ester, polyoxyethylene polyoxypropylene glycol, etc. One of these may be used alone or two or more thereof may be used in combination. Among these, sodium lauryl sulfate is preferred. As the content of the surfactant, 0.01 to 3% by mass is preferred, 0.05 to 1% by mass is more preferred, and 0.1 to 0.6% by mass is particularly preferred, based on the total mass of the tablets of the present invention. When the surfactant is contained inside the granules, as the content of the surfactant and the disintegrant inside the granules, 0.05 to 1.5% by mass is preferred, 0.1 to 1% by mass is more preferred, and 0.3 to 0.6% by mass is particularly preferred, based on the total mass of the granules.

[0041] Examples of the lubricant include magnesium stearate, talc, etc. One of these may be used alone or two or more thereof may be used in combination. Among these, magnesium stearate is preferred. As the content of the lubricant, 0.1 to 5% by mass is preferred, 0.3 to 3% by mass is more preferred, and 0.5 to 1% by mass is particularly preferred, based on the total mass of the tablets of the present invention.

[0042] Examples of the colorant other than the iron oxide include titanium oxide, Food Blue No. 1, Food Blue No. 2, Food Red No. 3, Food Yellow No. 4, Aluminum Lake of Food Blue No. 1, Aluminum Lake of Food Blue No. 2, Aluminum Lake of Food Red No. 3, Aluminum Lake of Food Yellow No. 4, etc. One of these may be used alone or two or more thereof may be used in combination.

[0043] Also, the tablets of the present invention are preferably for oral administration. Specific dosage forms of the tablets of the present invention include, for example, ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, enteric-coated tablets, sustained-release tablets, etc. In addition, the tablets of the present invention may or may not be film-coated. For example, they include plain tablets, film-coated tablets, sugar-coated tablets, multilayer tablets, nucleated tablets, and the like. Among these, plain tablets are preferred. When using plain tablets, even when there is a clinical need for administration by crushing or suspension or for dose adjustment, dispensing becomes easy. Note that plain tablets can be coated to the extent that the effects of the present invention are not impaired for improving the taste of taking the tablets, etc., but it is preferred to use them as plain tablets as they are. As used herein, a plain tablet refers to a tablet that has not been subjected to a coating treatment with saccharides, film-forming materials, or the like.

[0044] 〔Method for manufacturing tablets〕 Next, the method for manufacturing the tablets of the present invention will be described. The method for manufacturing tablets containing granules containing tadalafil of the present invention is characterized in that iron oxide is contained in either one or both of the inside and outside of the granules by powder addition. For example, the following manufacturing methods P1 and P2 can be mentioned. Note that the meaning of each term in the method for manufacturing tablets is the same as the meaning of each term in the tablets of the present invention, and each component used in the method for manufacturing tablets is preferably used in an amount such that the content and ratio of each component in the tablets are within the ranges described above. <Manufacturing method P1> A method for manufacturing tablets containing granules containing tadalafil, including the following steps S1-1 to S1-4. Note that "dry method" refers to a method that is carried out without dissolving or dispersing in a solvent or dispersion medium. (Step S1-1) A step of obtaining a powdery or granular composition containing tadalafil and iron oxide by containing powdery iron oxide in a powdery or granular component containing tadalafil by the dry method (powder addition). (Step S1-2) A step of granulating the powdery or granular composition obtained in Step S1-1. (Step S1-3) A step of mixing the granules obtained in Step S1-2 with an additive. (Step S1-4) A step of tableting the mixture obtained in Step S1-3.

[0045] <Manufacturing Method P2> A method for manufacturing a tablet containing granules containing tadalafil, including the following steps S2-1 to S2-2. (Step S2-1) A step of dry-adding (powder addition) powdered iron oxide to the granules containing tadalafil and mixing them to obtain a powdery or granular mixture containing the granules containing tadalafil and powdered iron oxide. (Step S2-2) A step of tableting the mixture obtained in Step S2-1.

[0046] Here, the manufacturing method P1 will be described in detail. (Step S1-1) The powdery or granular components used in Step S1-1 may contain additives other than iron oxide. By using additives other than iron oxide, additives other than iron oxide can be incorporated into the granules. As the powdery or granular components used in Step S1-1, those containing tadalafil and a first excipient (preferably lactose hydrate) are preferred, and those containing tadalafil, a first excipient, a binder, and a disintegrant are more preferred. At this time, as long as they are contained by dry method (powder addition), the order of blending into the powdery or granular composition of tadalafil, powdered iron oxide, a first excipient, a binder, and a disintegrant does not matter. As tadalafil, powdered iron oxide, a first excipient, a binder, and a disintegrant, those listed as those contained in the tablet can be used. Moreover, it is preferable to mix the first excipient and iron oxide sufficiently. Preferred examples of Step S1-1 include a method of mixing and diluting powdered iron oxide with an additive containing a first excipient or the like, adding tadalafil to the obtained mixture and further mixing, a method of mixing and pulverizing iron oxide and an additive containing a first excipient or the like, adding tadalafil to the obtained pulverized product and further mixing, a method of mixing and pulverizing iron oxide, an additive containing a first excipient or the like, and tadalafil, etc. In addition, iron oxide, an additive containing a first excipient or the like, and tadalafil may be pulverized in advance and then mixed.

[0047] As a method for mixing a dilution powder, known methods can be used. For example, there are methods of mixing using a container rotation type mixer such as a V-type mixer or a conical type mixer, or a container fixed type mixer such as a Nauta mixer, a ribbon mixer, or a stirring granulator. As a method for mixing and pulverizing or pulverizing, known methods can be used. For example, there are methods of mixing and pulverizing or pulverizing using a mechanical pulverizer such as a cutter mill, a roll mill, or a pin mill, or a pneumatic flow type pulverizer such as a jet mill.

[0048] Further, as the production method P1, it is preferable to include a step of adding and kneading a kneading liquid to the powdery or granular composition obtained in step S1-1 prior to step S1-2 after step S1-1. When this step is performed, the kneaded product obtained in this step is used for granulation in step S1-2. Examples of the kneading liquid include water, hydrous alcohol, and a binding liquid. One of these may be used alone or two or more thereof may be used in combination. Examples of the binding liquid include a mixed liquid of a binder, a surfactant, and water or hydrous alcohol. As the binder and the surfactant, those exemplified as those contained in tablets can be used.

[0049] (Step S1-2) The granulation in step S1-2 may be performed, for example, with reference to known granulation methods described in the General Rules for Preparations of the Japanese Pharmacopoeia, Seventeenth Revision, etc. The granulation may be performed by a wet granulation method or a dry granulation method, but a wet granulation method is preferable. Specifically, examples include extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, and crushing granulation, but stirring granulation is preferable. It should be noted that the granules obtained in step S1-2 are preferably dried and sized prior to use in step S1-3.

[0050] (Step S1-3) The additive used in Step S1-3 forms an additive layer. Examples of the additive include iron oxide, a second excipient (preferably crystalline cellulose), and additives other than iron oxide and the excipient. As the iron oxide, the second excipient, and the additives other than iron oxide and the excipient, those listed as contained in the tablets can be used. As Step S1-3, a step of dry-adding (powder-adding) powdery iron oxide to the granules obtained in Step S1-2 and mixing them to obtain a powdery or granular mixture containing the granules obtained in Step S1-2 and the powdery iron oxide is preferable. When adding iron oxide powder both inside and outside the granules, the iron oxide added inside and the iron oxide added outside may be of the same type or different types. In Step S1-3, it is preferable to add a second excipient to the above-mentioned granules together with the powdery iron oxide. More preferably, one or more selected from a second excipient, a disintegrant, a lubricant, and a colorant (excluding iron oxide) are added to the above-mentioned granules together with the powdery iron oxide. Particularly preferably, a second excipient, a disintegrant, and a lubricant are added to the above-mentioned granules together with the powdery iron oxide. At this time, a colorant (excluding iron oxide) may be further added. Note that the order of blending the above-mentioned granules, powdery iron oxide, second excipient, disintegrant, lubricant, and colorant (excluding iron oxide) does not matter. For example, a method of performing dispersion mixing of powdery iron oxide with an additive containing a second excipient or the like, and adding the granules obtained in Step S1-2 to the obtained mixture and further mixing them can be mentioned. The dispersion mixing may be performed in the same manner as the dispersion mixing in Step S1-1.

[0051] (Step S1-4) Tableting in Step S1-4 may be performed according to a conventional method using a rotary tableting machine, a single-shot tableting machine, or the like. Note that it is preferable to adjust the particle diameter of the granules and / or the additive by a method such as pulverization before or after mixing the granules and the additive. By this operation, the content uniformity of the tablets can be improved.

[0052] Step S2-1 of Production Method P2 may be performed in the same manner as Step S1-3 of Production Method P1. Note that the granules containing tadalafil used in Step S2-1 may be prepared by a known method. In addition, the step S2-2 of the production method P2 may be performed in the same manner as the step S1-4 of the production method P1.

[0053] Note that the tablets of the present invention can be compression-molded without using an external lubrication method, but can also be molded using an external lubrication method. In this case, after mixing the components excluding the lubricant, tableting may be performed while spraying the lubricant into a mortar and pestle, or after previously mixing a part of the lubricant with the components excluding the lubricant, tableting may be performed while spraying the remaining lubricant into the mortar and pestle.

Examples

[0054] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. Note that Examples 7, 8, 10, and 11 are reference examples.

[0055] The measurement conditions for each measurement in this example are as shown below. <Light stability test Color difference (ΔE)> The color difference was evaluated as follows in accordance with JIS Z8722 using a color difference meter (Color Analyzer TC-1800MK-II manufactured by Tokyo Denshoku Co., Ltd.). The three stimulus values (X, Y, Z) of the tablets before the start of storage (before light irradiation) and after storage under light irradiation (after 1,200,000 lx·hr light irradiation) were measured by reflection light measurement (2-degree field of view) with a measurement wavelength of 380 to 780 nm, a diffraction grating of 1200 mm, a measurement diameter of 5 mm, and standard light C, and the Lab color space coordinates L (lightness or luminance), a (red - green), and b (yellow - blue) of the International Commission on Illumination (CIE) were calculated. Next, after obtaining ΔL, Δa, and Δb, which are the differences in color space coordinates before and after light irradiation, the color difference (ΔE) was measured by the following formula. When the value of the color difference (ΔE) was greater than 6.5, it was evaluated as "×", and when the value of the color difference (ΔE) was 6.5 or less, it was evaluated as "○".

[0056]

Number

[0057] <Absence of color unevenness> The color unevenness was evaluated by measuring the ratio of the non-colored area as follows, in addition to visual evaluation immediately after production. An optical microscope image (grayscale image) in an area of about 2000×1500 μm on the tablet surface was acquired using a laser Raman microscope (RAMANforceVIS-NIR-TEN manufactured by Nanophoton), and then binarization image conversion was performed using an optical microscope (Digital Microscope VHX-700F manufactured by Keyence). For the binarization image conversion, the luminance range of 140 - 255 was set as the threshold value, and pixels with luminance values lower than the threshold value were converted into the colored area, while pixels with luminance values within the threshold range were converted into the non-colored area. The area of the non-colored area in the converted image was calculated, and the ratio of the non-colored area occupying the entire image was obtained. Note that color unevenness means that color non-uniformity is recognized in the appearance of the tablet. When the ratio of the non-colored area is 18% or more, it is regarded as having color unevenness.

[0058] Also, in this example, the following were used for lactose hydrate, hydroxypropyl cellulose, croscarmellose sodium, sodium lauryl sulfate, yellow ferric oxide, ferric oxide, crystalline cellulose, talc, titanium oxide, and magnesium stearate. Lactose hydrate: Pharmatose200M (hereinafter also referred to as "P200M"), SuperTab11SD (hereinafter also referred to as "SD") (above, DFE Pharma), Hydroxypropyl cellulose: HPC-L fine powder (Nippon Soda), Croscarmellose sodium: Ac-Di-Sol (FMC), Sodium lauryl sulfate: NIKKOL SLS (Nikko Chemicals), Yellow ferric oxide: Yellow ferric oxide (Kisuika Kasei), Ferric oxide: Ferric oxide (Kisuika Kasei), Crystalline cellulose: Ceolus KG-802 (Asahi Kasei), Talc: Micro Ace P-3 (Nippon Talc), Titanium oxide: Titanium oxide A-HR (Froint Industries), Magnesium stearate: Magnesium stearate vegetable (Taihei Chemical Industry)

[0059] (Example 1) Tablets (plain tablets, weight 150 mg, hardness 50 N, thickness 3.3 mm) containing 20 mg of tadalafil per tablet were obtained by the following steps. (1) 137.7 g of lactose hydrate (P200M), 0.6 g of yellow ferric oxide, and 0.3 g of ferric oxide were mixed by trituration, and then 135 g of lactose hydrate (SD), 6 g of hydroxypropyl cellulose, and 30 g of croscarmellose sodium were added and mixed. Thereafter, 60 g of tadalafil was added and mixed. (2) To the mixed powder obtained in the above step, 70 mL of a binding solution prepared by dissolving 1.2 g of hydroxypropyl cellulose and 1.95 g of sodium lauryl sulfate in purified water and 80 mL of purified water were added, and granulation was carried out using a high-speed stirring granulator (mixed granulation step). (3) Next, the granules obtained in the above mixed granulation step were dried (drying step), and then sized using a JIS test sieve (sizing step). (4) Subsequently, to the sized product obtained in the above sizing step, a powder obtained by previously mixing 67.5 g of crystalline cellulose, 0.9 g of yellow ferric oxide, and 0.3 g of ferric oxide by trituration and 6.3 g of croscarmellose sodium were added and mixed, and further 2.25 g of magnesium stearate was added and mixed (granule mixing step). Thereafter, tableting (tableting step) was carried out to obtain the core tablets of Example 1.

[0060] (Examples 2 to 6, 8 to 11) Core tablets containing 20 mg of tadalafil per tablet were produced in the same manner as in Example 1, except that the components, amounts (mass %), and final formulation weights shown in Tables 1 to 2 were used. In Example 6, talc was used by mixing it by trituration with crystalline cellulose together with yellow ferric oxide and ferric oxide in the granule mixing step. In Example 9, titanium oxide was used by mixing it by trituration with crystalline cellulose together with yellow ferric oxide and ferric oxide in the granule mixing step.

[0061] (Example 7) Tablets (core tablets, weight 160 mg, hardness 50 N, thickness 3.5 mm) containing 20 mg of tadalafil per tablet were obtained by the following steps. (1) 280.05 g of lactose hydrate (145.05 g of P200M + 135.00 g of SD), 6 g of hydroxypropyl cellulose, and 30 g of croscarmellose sodium were mixed, and then 60 g of tadalafil was added and mixed. (2) To the mixed powder obtained in the above step, 1.2 g of hydroxypropyl cellulose, 1.95 g of sodium lauryl sulfate, 0.6 g of yellow ferric oxide, and 0.3 g of ferric oxide were dissolved or dispersed in 70 mL of a binding solution and 80 mL of purified water, and granulation was carried out using a high-speed stirring granulator (mixed granulation step). (3) Next, the granulated product obtained in the above mixed granulation step was dried (drying step), and then sized using a JIS test sieve (sizing step). (4) Subsequently, to the sized product obtained in the above sizing step, a powder obtained by previously triturating and mixing 90.0 g of crystalline cellulose, 0.9 g of yellow ferric oxide, and 0.3 g of ferric oxide, 6.3 g of croscarmellose sodium, and 2.4 g of magnesium stearate were added and mixed (granule mixing step), and then tableting (tableting step) was carried out to obtain the core tablets of Example 7.

[0062] (Comparative Example 1) Tablets containing 20 mg of tadalafil per tablet (core tablets, weight 160 mg, hardness 50 N, thickness 3.5 mm) were obtained by the following steps. (1) 280.05 g of lactose hydrate (145.05 g of P200M + 135.00 g of SD), 6 g of hydroxypropyl cellulose, and 30 g of croscarmellose sodium were mixed, and then 60 g of tadalafil was added and mixed. (2) To the mixed powder obtained in the above step, 1.2 g of hydroxypropyl cellulose, 1.95 g of sodium lauryl sulfate, 1.5 g of yellow ferric oxide, and 0.6 g of ferric oxide were dissolved or dispersed in 70 mL of a binding solution and 80 mL of purified water, and granulation was carried out using a high-speed stirring granulator (mixed granulation step). (3) Next, the granulated product obtained in the above mixed granulation step was dried (drying step), and then sized using a JIS test sieve (sizing step). (4) Subsequently, to the sized product obtained in the above sizing step, 90.0 g of crystalline cellulose and 6.3 g of croscarmellose sodium were added and mixed, and then 2.4 g of magnesium stearate was added and mixed (granule mixing step), and then tableting (tableting step) was carried out to obtain the core tablets of Comparative Example 1.

[0063] (Comparative Examples 2 - 3) Tablets containing 20 mg of tadalafil per tablet were produced in the same manner as in Comparative Example 1, except that the components and amounts (mass %) were as described in Table 2.

[0064]

Table 1

[0065]

Table 2

[0066] Table 3 shows the color difference (ΔE) when the tablets of the Examples and Comparative Examples were irradiated with light of 1.2 million lx·hr, the presence or absence of color unevenness immediately after production, and the non - colored area (%).

[0067]

Table 3

[0068] Tablets obtained by adding iron oxide in liquid form without adding powder (Comparative Examples 1 and 2) had insufficient light stability (color difference ΔE: about 8.14 - 10.45). In contrast, tablets obtained by adding iron oxide powder to at least one of the inside and outside of the granules (Examples 1 - 11) were less likely to undergo a change in color tone under light irradiation (color difference ΔE: 6.5 or less). In particular, tablets obtained by adding iron oxide powder to both the inside and outside of the granules (Examples 1 - 6 and 9) were extremely unlikely to undergo a change in color tone under light irradiation (color difference ΔE: 5.0 or less), and there was also less color unevenness immediately after production. Note that a color tone change also occurred when no iron oxide was added (Comparative Example 3) (color difference ΔE: 21.74), and the color tone changes observed in Comparative Examples 1 and 2 are considered to be due to tadalafil rather than iron oxide.

Claims

1. A method for manufacturing a tablet containing granules containing tadalafil, including the following steps S1-1 to S1-4, wherein step S1-3 is a step of dry-adding and mixing powdery iron oxide to the granules obtained in step S1-2 to obtain a powdery or granular mixture containing the granules obtained in step S1-2 and powdery iron oxide (however, excluding the case where the tablet is an orally disintegrating tablet). (Step S1-1) A step of dry-containing powdery iron oxide in a powdery or granular component containing tadalafil to obtain a powdery or granular composition containing tadalafil and iron oxide (Step S1-2) A step of granulating the powdery or granular composition obtained in step S1-1 by a wet granulation method (Step S1-3) A step of mixing the granules obtained in step S1-2 and an additive (Step S1-4) A step of tableting the mixture obtained in step S1-3

2. The manufacturing method according to claim 1, wherein the powdery or granular component used in step S1-1 further contains a first excipient.

3. The manufacturing method according to claim 1 or 2, wherein step S1-2 is a step of adding and kneading a kneading liquid to the powdery or granular composition obtained in step S1-1, and granulating the kneaded product obtained by the kneading.

4. The manufacturing method according to any one of claims 1 to 3, wherein step S1-3 is a step of dry-adding and mixing powdery iron oxide and a second excipient to the granules obtained in step S1-2 to obtain a powdery or granular mixture containing the granules obtained in step S1-2, powdery iron oxide, and the second excipient.

5. The manufacturing method according to any one of claims 1 to 4, wherein steps S1-1 and S1-3 are performed so that the total content of iron oxide is 0.6 to 2% by mass.

6. The manufacturing method according to any one of claims 1 to 5, wherein the iron oxide is one or more selected from yellow ferric oxide and ferric oxide.

7. The manufacturing method according to any one of claims 1 to 6, wherein the tablet is a plain tablet.

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