Guanfacine preparations

Abstract

To provide a novel pharmaceutical composition that contains guanfacine or a pharmaceutically acceptable salt thereof and has improved stability.SOLUTION: A pharmaceutical composition contains guanfacine or a pharmaceutically acceptable salt thereof and an organic acid. The organic acid is at least one selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid and ascorbic acid.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof, and a tablet comprising the pharmaceutical composition. The present invention also relates to a method for preparing the pharmaceutical composition and a method for stabilizing the pharmaceutical composition. [Background technology]

[0002] Guanfacine or a pharmaceutically acceptable salt thereof generally has a selective alpha 2A It is known as an adrenergic receptor agonist and is useful in the treatment of attention-deficit hyperactivity disorder.

[0003] Several formulations containing guanfacine or a pharmaceutically acceptable salt thereof have been developed.

[0004] For example, Patent Document 1 discloses an oral preparation for once-daily administration containing 0.75 to 2% by weight of guanfacine hydrochloride, which contains 25 to 45% by weight of poly(methacrylic acid, ethyl acrylate), contains 1 to 4 mg of guanfacine, has a total weight of up to 340 mg, and is in the form of a tablet.

[0005] Patent Document 2 also discloses a pharmaceutical composition for treating myeloproliferative blood disorders, which comprises: (a) at least one specific pharmaceutically active agent having pH-dependent solubility; (b) at least one specific non-pH-dependent sustained-release agent; (c) at least one specific pH-dependent agent that increases the release rate of the at least one pharmaceutically active agent from a tablet at a pH above 5.5; and (d) a mixture of at least one specific organic acid. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 5726401 [Patent Document 2] Patent No. 4340840 Summary of the Invention [Problem to be solved by the invention]

[0007] However, the preparations containing guanfacine or a pharmaceutically acceptable salt thereof as described in Patent Documents 1 and 2 have room for improvement in terms of stability.

[0008] Therefore, one aspect of the present invention aims to provide a novel pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof and having improved stability, and a tablet containing the pharmaceutical composition. Another aspect of the present invention aims to provide a method for producing a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof, and a method for stabilizing the pharmaceutical composition. [Means for solving the problem]

[0009]

[0009] As a result of extensive research aimed at solving the above-mentioned problems, the present inventors have discovered for the first time that the stability of guanfacine or a pharmaceutically acceptable salt thereof can be improved by adding a specific organic acid to a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof, and have thus completed the present invention. That is, one aspect of the present invention includes the following configurations. <1> A pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof and an organic acid, The pharmaceutical composition, wherein the organic acid is at least one selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid. <2> The content of the organic acid is 2 to 10% by weight. <1> The pharmaceutical composition according to claim 1. <3> Further, the tablet contains at least one enteric base selected from the group consisting of carboxymethylethylcellulose and hypromellose acetate succinate. <1> or <2> The pharmaceutical composition according to claim 1. <4> The content of the enteric base is 5 to 35% by weight. <3> The pharmaceutical composition according to claim 1. <5> Contains a methacrylic acid copolymer, and the content of the methacrylic acid copolymer is less than 25% by weight. <1> ~ <4> 10. The pharmaceutical composition according to any one of the preceding claims. <6> <1> ~ <5> A tablet comprising the pharmaceutical composition according to any one of the preceding claims. <7> 1. A method for preparing a pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof, comprising: A production method comprising the step of adding at least one organic acid selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid. <8> 1. A method for stabilizing a pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof, comprising: A method characterized by including at least one organic acid selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid. [Effects of the Invention]

[0010] According to one aspect of the present invention, there are provided a novel pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof and having improved stability, and a tablet containing the pharmaceutical composition. Furthermore, according to another aspect of the present invention, there are provided a method for producing a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof, and a method for stabilizing the pharmaceutical composition. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows the results of a stability test using an enteric base (total affinity). [Figure 2] FIG. 1 shows the results of a stability test using organic acids (total related compounds). [Figure 3] FIG. 1 shows the results of a stability test using an enteric base (2,6-dichlorophenylacetic acid). [Figure 4] FIG. 1 shows the results of a stability test using an organic acid (2,6-dichlorophenylacetic acid). DETAILED DESCRIPTION OF THE INVENTION

[0012] An embodiment of the present invention will be described in detail below. In this specification, unless otherwise specified, "A to B" representing a numerical range means "A or more and B or less."

[0013] 1. Overview of the Invention A pharmaceutical composition according to one embodiment of the present invention (hereinafter referred to as "the pharmaceutical composition") comprises guanfacine or a pharmaceutically acceptable salt thereof, and an organic acid, wherein the organic acid is at least one selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid.

[0014] Furthermore, a tablet according to one embodiment of the present invention (hereinafter referred to as "the tablet") is characterized by containing the pharmaceutical composition.

[0015] Furthermore, a method for producing a pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention (hereinafter referred to as "this production method") is a method for producing a pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof, characterized in that it comprises a step of adding at least one organic acid selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid.

[0016] Additionally, a method for stabilizing a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention (hereinafter referred to as "the stabilization method") is a method for stabilizing a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof, characterized in that the composition contains at least one organic acid selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid.

[0017] The present inventors have conducted detailed studies on pharmaceutical compositions containing guanfacine or a pharmaceutically acceptable salt thereof from the viewpoint of stability, and as a result have succeeded in making the following findings.

[0018] In pharmaceutical compositions containing guanfacine or a pharmaceutically acceptable salt thereof, the stability of guanfacine or a pharmaceutically acceptable salt thereof is improved by including certain organic acids (e.g., succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid).

[0019] It has not been known that organic acids can contribute to the stabilization of pharmaceutical compositions containing guanfacine or a pharmaceutically acceptable salt thereof.Under these circumstances, the present inventors have focused on organic acids among the many components that can be contained in pharmaceutical compositions, and have surprisingly achieved an improvement in the stability of pharmaceutical compositions containing guanfacine or a pharmaceutically acceptable salt thereof by selecting and adding a specific organic acid.

[0020] Thus, the present invention provides an extremely useful novel pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof, and a tablet containing the pharmaceutical composition, since the present invention exhibits advantageous effects based on the above findings. In addition, in one aspect of the present invention, a method for producing a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof, and a method for stabilizing the pharmaceutical composition can be provided.

[0021] 2. Pharmaceutical Compositions (Guanfacine or a pharmaceutically acceptable salt thereof) The pharmaceutical composition contains crystalline or amorphous guanfacine or a pharmaceutically acceptable salt thereof as an active ingredient. One example of guanfacine or a pharmaceutically acceptable salt thereof is guanfacine hydrochloride. Guanfacine hydrochloride is a compound represented by the following formula (1), commonly known as N-amidino-2-(2,6-dichlorophenyl)acetamide monohydrochloride.

[0022] [ka]

[0023] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is medically suitable for use in contact with the tissues of humans or other mammals without causing excessive toxicity, irritation, allergic reactions, etc.

[0024] Pharmaceutically acceptable salts of guanfacine are well known in the art, and any can be used.The pharmaceutically acceptable salts of guanfacine include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc.; organic acid salts such as acetate, oxalate, maleate, fumarate, citrate, benzoate, methanesulfonate, etc.; addition salts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid, etc.The pharmaceutically acceptable salt of guanfacine is preferably guanfacine hydrochloride.

[0025] The content of guanfacine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is, for example, 2 to 10% by weight, preferably 3 to 9% by weight, based on the mass of the pharmaceutical composition.

[0026] (organic acid) The pharmaceutical composition contains at least one organic acid selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid (hereinafter, sometimes simply referred to as "organic acid"). The inclusion of the organic acid in the pharmaceutical composition improves the stability of guanfacine or a pharmaceutically acceptable salt thereof.

[0027] The content of the organic acid in the pharmaceutical composition is preferably 0.5 to 50% by weight, more preferably 1 to 30% by weight, and even more preferably 2 to 10% by weight, based on the mass of the pharmaceutical composition.

[0028] (enteric base) In one embodiment of the present invention, the pharmaceutical composition may contain an enteric base, which allows the pharmaceutical composition to be used as a material for an enteric formulation.

[0029] The enteric base is not particularly limited, but examples thereof include carboxymethylethylcellulose, hypromellose acetate succinate, methacrylic acid copolymer, etc. The enteric base may contain one of the above-mentioned bases or two or more of them.

[0030] The content of the enteric base in the present pharmaceutical composition is preferably 1 to 50% by weight, more preferably 3 to 40% by weight, and even more preferably 5 to 35% by weight, based on the mass of the pharmaceutical composition.

[0031] When the enteric base comprises carboxymethylethylcellulose and / or hypromellose acetate succinate, the content of these enteric bases in the pharmaceutical composition is preferably 1 to 30 wt %, more preferably 3 to 20 wt %, and even more preferably 5 to 15 wt %, based on the mass of the pharmaceutical composition.

[0032] Furthermore, when the enteric base contains a methacrylic acid copolymer, the content of the methacrylic acid copolymer in the pharmaceutical composition is preferably less than 25 wt. % based on the mass of the pharmaceutical composition, more preferably 22 wt. % or less, and even more preferably 20 wt. % or less. However, without being limited thereto, the content of the methacrylic acid copolymer in the pharmaceutical composition may be, for example, more than 45 wt. % based on the mass of the pharmaceutical composition.

[0033] (Other ingredients) The pharmaceutical composition may contain other ingredients besides those mentioned above, such as excipients, binders, lubricants, disintegrants, surfactants, plasticizers, and colorants.

[0034] The excipient is not particularly limited, but examples thereof include D-mannitol, lactose (e.g., lactose hydrate), sucrose, cornstarch, calcium phosphate, sorbitol, crystalline cellulose, light anhydrous silicic acid, etc. Preferably, crystalline cellulose and lactose (e.g., lactose hydrate) are used.

[0035] The binder is not particularly limited, but examples thereof include hydroxypropyl cellulose, hydroxypropylmethyl cellulose (also referred to as "hypromellose"), povidone, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate, or a combination of these polymers, pregelatinized starch, gelatin, agar, gum arabic, etc. Hypromellose is preferably used. Hypromellose with a viscosity range of 80 to 140,000 mPa·s is suitably used, and examples thereof include hypromellose 2208 (Methocel (trademark) K4M Premium CR, viscosity: 2,500 to 5,000 mPa·s).

[0036] The lubricant is not particularly limited, but examples thereof include inert substances such as talc, kaolin, and titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely ground silicon dioxide, sodium stearyl fumarate, and glycerin fatty acid esters. Glycerin fatty acid esters are preferably used.

[0037] The disintegrant is not particularly limited, but examples thereof include crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, carmellose, carmellose calcium, potato starch, etc. Crospovidone is preferably used.

[0038] The colorant is not particularly limited, but examples thereof include yellow colorants (e.g., yellow ferric oxide, yellow iron oxide, Food Yellow No. 4 Aluminum Lake, red iron oxide, etc.), red colorants (e.g., ferric oxide, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), black colorants (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), blue colorants (e.g., Blue No. 2 Aluminum Lake, etc.), caramel, etc. Preferably, yellow ferric oxide and Blue No. 2 Aluminum Lake are used.

[0039] The content of each of the additives is not particularly limited and can be appropriately set based on conventionally known techniques.

[0040] [3. Tablets] In one embodiment of the present invention, a tablet is provided comprising the pharmaceutical composition described in [2. Pharmaceutical Composition].

[0041] The present tablet contains the specific organic acid described above together with guanfacine or a pharmaceutically acceptable salt thereof, and therefore exhibits the effect of improving the stability of guanfacine or a pharmaceutically acceptable salt thereof.

[0042] The diameter of the present tablet is not particularly limited, but from the viewpoint of handleability, it is, for example, 5.0 to 16 mm, preferably 5.5 to 13 mm, and more preferably 5.8 to 11 mm.

[0043] The thickness of the present tablet is not particularly limited, but is, for example, 2.0 to 6.0 mm, preferably 2.5 to 5.5 mm, and more preferably 3.0 to 5.0 mm.

[0044] In one embodiment of the invention, the tablet contains, for example, 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine or a pharmaceutically acceptable salt thereof.

[0045] The contents of the various ingredients contained in the tablets are the same as those contained in the pharmaceutical compositions described in [2. Pharmaceutical Composition]. However, the phrase "based on the mass of the pharmaceutical composition" should be read as "based on the mass of the tablet."

[0046] The shape of the tablet is not particularly limited, and may be, for example, round, oval, spherical, rod-like, or doughnut-like.

[0047] Furthermore, the tablets may be further coated as needed. The tablets may be packaged as needed in PTP packaging, bottles, aluminum packaging, etc.

[0048] Examples of materials for PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, and metals such as aluminum. These materials may be used alone or in combination. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. The above resins can be molded using a known method into a resin sheet, and tablets can be placed in the molded pockets, which are then covered with aluminum foil to complete the packaging.

[0049] The PTP package containing the tablet may be further packaged in an aluminum pillow. This aluminum pillow may further contain a desiccant. Examples of desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite.

[0050] [4. Manufacturing method] In one embodiment of the present invention, there is provided a method for preparing a pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof, the method comprising the step of adding at least one organic acid selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid.

[0051] In this production method, the explanations of each component (e.g., "guanfacine or a pharmaceutically acceptable salt thereof" and "organic acid") are as described in [2. Pharmaceutical Composition].

[0052] In the present production method, the organic acid may be added by, for example, adding and mixing it simultaneously with the other components as described in the Examples, or by first preparing the components other than the organic acid and then adding the organic acid thereto. Preferably, the method described in the Examples is used.

[0053] The steps in this production method other than the addition of the organic acid can be carried out using any method used in the field of pharmaceutical compositions.

[0054] Furthermore, the pharmaceutical composition obtained by this production method can be directly compressed to obtain the present tablet.

[0055] The tableting pressure in this production method can be appropriately adjusted depending on the formulation and tablet shape, but is preferably in the range of 4 to 16 kN, for example. The tablet hardness can also be appropriately adjusted depending on the purpose, but is preferably in the range of 20 to 200 N, for example.

[0056] [5. Stabilization method] In one embodiment of the present invention, there is provided a method for stabilizing a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof, characterized in that the method comprises adding at least one organic acid selected from the group consisting of succinic acid, maleic acid, benzoic acid, glutamic acid, aspartic acid, and ascorbic acid.

[0057] As described above, the present stabilization method can stabilize a pharmaceutical composition containing guanfacine or a pharmaceutically acceptable salt thereof, and is therefore extremely useful in designing a formulation containing stable guanfacine or a pharmaceutically acceptable salt thereof.

[0058] In this stabilization method, the descriptions of each component (e.g., "guanfacine or a pharmaceutically acceptable salt thereof" and "organic acid") in [2. Pharmaceutical Composition] are incorporated by reference.

[0059] The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention. [Example]

[0060] An embodiment of the present invention will be described below.

[0061] [Measurement and evaluation methods] The evaluations in the examples and comparative examples were carried out by the following methods.

[0062] (Stability test) The stability of the pharmaceutical compositions or tablets prepared in the Examples and Comparative Examples was evaluated.

[0063] Specifically, a test tube containing the above pharmaceutical composition or a polyethylene bottle containing tablets was left standing under open conditions at 40°C and 75% RH for 4 weeks, after which the pharmaceutical composition or tablets were taken out and the amount of related substances (total related substances, 2,6-dichlorophenylacetic acid) was measured.

[0064] For each experimental example, the pharmaceutical composition or tablets were extracted with a certain amount of extraction solvent (70% methanol), filtered through a membrane filter, and used as a sample solution.

[0065] The above sample solution was subjected to HPLC under the following conditions, and with the peak areas of guanfacine and related substances in each sample solution taken as the reference value of 1, the formation ratio of related substances was calculated.

[0066] <HPLC measurement conditions> · Measurement wavelength: UV detector (measurement wavelength 230 nm) · Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is filled with 5-μm octadecylsilylated silica gel for liquid chromatography. · Column temperature: 40°C · Mobile phase A: A solution prepared by dissolving calcium dihydrogen phosphate in water, adding triethylamine, and adjusting the pH with phosphoric acid · Mobile phase B: A mixture of methanol / tetrahydrofuran · Flow rate: 1.2 mL / min · Liquid delivery: By changing the mixing ratio of mobile phase A and mobile phase B, the concentration gradient is controlled.

[0067] 〔Example 1〕 4 mg of the active ingredient (guanfacine hydrochloride) and the enteric base, dry methacrylic acid copolymer LD, were added and mixed at the ratios shown in Table 1 to obtain a pharmaceutical composition.

[0068] 〔Example 2〕 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the enteric base was hypromellose acetate succinate.

[0069] 〔Example 3〕 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the enteric base was carboxymethylethylcellulose.

[0070] Example 4 A pharmaceutical composition was obtained by adding succinic acid, an organic acid, to 4 mg of the drug substance (guanfacine hydrochloride) and mixing.

[0071] Example 5 A pharmaceutical composition was obtained in the same manner as in Example 4, except that the organic acid was changed to glutamic acid.

[0072] Example 6 A pharmaceutical composition was obtained in the same manner as in Example 4, except that the organic acid was ascorbic acid.

[0073] Comparative Example 1 A pharmaceutical composition was obtained in the same manner as in Example 1, except that no ingredients other than the drug substance were added.

[0074] Comparative Example 2 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the enteric base was hypromellose phthalate.

[0075] Comparative Example 3 A pharmaceutical composition was obtained in the same manner as in Example 4, except that the organic acid was fumaric acid.

[0076] Comparative Example 4 A pharmaceutical composition was obtained in the same manner as in Example 4, except that the organic acid was citric acid hydrate.

[0077] For the amounts of each component (enteric base and organic acid) in Examples 1 to 6 and Comparative Examples 1 to 4, see Table 1.

[0078] [Table 1]

[0079] [Result-1] The results of stability tests on pharmaceutical compositions containing guanfacine hydrochloride as a drug substance, which were prepared in the above Examples and Comparative Examples, are shown in Figures 1 to 4 and Table 1. In Figures 1 to 4 and Table 1, "Initial" indicates the test results using pharmaceutical compositions immediately after preparation, and "40°C, 75% RH open 4W" indicates the test results using pharmaceutical compositions that had been left under the open conditions.

[0080] Figures 1 and 3 and Table 1 show the evaluation of the stability of pharmaceutical compositions containing enteric bases. Related substances (total related substances, 2,6-dichlorophenylacetic acid) are degradation products of the active ingredient guanfacine hydrochloride, and their proportion increases with the degradation of guanfacine hydrochloride. Figures 1 and 3 and Table 1 demonstrate that the generation of related substances is suppressed when dry methacrylic acid copolymer LD, hypromellose acetate succinate, or carboxymethylethylcellulose is used as an enteric base. This indicates that these substances contribute to the stabilization of the active ingredient guanfacine hydrochloride.

[0081] Figures 2 and 4 and Table 1 show the evaluation of the stability of pharmaceutical compositions containing organic acids. Figures 2 and 4 and Table 1 show that the use of succinic acid, glutamic acid, and ascorbic acid as organic acids suppresses the generation of related substances. This indicates that these substances contribute to the stabilization of the active pharmaceutical ingredient, guanfacine hydrochloride.

[0082] Example 7 The components shown in Table 2 were mixed in the amounts shown in Table 2, and then subjected to direct compression at a tableting pressure of 8 kN to obtain tablets with a diameter of 7.0 mm. In Table 2, the unit of the amount of each component is "mg."

[0083] [Examples 8 to 10, Comparative Example 5] The components shown in Table 2 were mixed in the amounts shown in Table 2, and then subjected to direct compression at a tableting pressure of 12 kN to obtain tablets with a diameter of 7.8 mm. In Table 2, the unit of the amount of each component is "mg."

[0084] [Table 2]

[0085] [Result-2] The guanfacine hydrochloride (average particle size (D 50 The results of stability tests on tablets containing 2,6-dichlorophenylacetic acid (6 μm) as the active ingredient are shown in Table 3. In Table 3, "Initial" indicates the test results for tablets immediately after production, while "6D" and "9D" indicate the test results after 6 and 9 days, respectively. "ND" indicates that 2,6-dichlorophenylacetic acid was not detected.

[0086] [Table 3]

[0087] It was found from Table 3 that the use of the enteric base and organic acid used in the examples of the pharmaceutical composition suppressed the generation of the related substance, 2,6-dichlorophenylacetic acid. In other words, it was shown that the enteric base and organic acid used in the examples of the pharmaceutical composition also contribute to stabilization in tablets.

[0088] [Prescription Example 1] The components shown in Table 4 are mixed in the amounts shown in Table 4, and then subjected to direct compression at a tableting pressure of 12 kN to obtain tablets with a diameter of 7.8 mm. The proportions of each component in Table 4 are rounded to one decimal place.

[0089] [Table 4] [Industrial Applicability]

[0090] The present invention improves the stability of pharmaceutical compositions containing guanfacine or a pharmaceutically acceptable salt thereof, and therefore can be suitably used as novel pharmaceutical compositions containing guanfacine or a pharmaceutically acceptable salt thereof.

Claims

1. 1. A pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof, an organic acid, and a methacrylic acid copolymer; The pharmaceutical composition, wherein the organic acid is at least one selected from the group consisting of succinic acid, glutamic acid, and ascorbic acid.

2. 2. The pharmaceutical composition according to claim 1, wherein the content of the organic acid is 2 to 10% by weight.

3. 3. The pharmaceutical composition according to claim 1, further comprising at least one enteric base selected from the group consisting of carboxymethylethylcellulose and hypromellose acetate succinate.

4. 4. The pharmaceutical composition according to claim 3, wherein the content of the enteric base is 5 to 35% by weight.

5. A pharmaceutical composition described in any one of claims 1 to 4, wherein the content of the methacrylic acid copolymer is less than 25% by weight.

6. A tablet comprising the pharmaceutical composition of any one of claims 1 to 5.

7. 1. A method for preparing a pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer, comprising: A production method comprising the step of adding at least one organic acid selected from the group consisting of succinic acid, glutamic acid, and ascorbic acid.

8. 1. A method for reducing the occurrence of an analogue of guanfacine in a pharmaceutical composition comprising guanfacine or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer, comprising: A method comprising adding at least one organic acid selected from the group consisting of succinic acid, glutamic acid, and ascorbic acid.

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