Sustained-release solid preparation containing guanfacine hydrochloride

Abstract

To provide a sustained-release solid preparation containing guanfacine hydrochloride having excellent chemical stability.SOLUTION: The present invention provides a sustained-release solid preparation containing guanfacine hydrochloride as an active ingredient, wherein the cumulative 50% particle diameter D50 of the guanfacine hydrochloride is 30 to 60 μm, based on volume measurement by the laser diffraction and scattering method.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a sustained release solid preparation containing guanfacine hydrochloride, and more particularly to a sustained release solid preparation containing guanfacine hydrochloride which has excellent stability over time. [Background technology]

[0002] Guanfacine (N-amidino-2-(2,6-dichlorophenyl)acetamide) is a selective α2A-adrenergic receptor agonist that is used to treat attention-deficit / hyperactivity disorder (AD / HD).

[0003] Guanfacine is available in the form of hydrochloride, and in order to facilitate easy titration and maintain compliance by administering it once a day, a sustained-release formulation is available on the market under the name "Intuniv (registered trademark)" (Non-Patent Document 1).

[0004] On the other hand, Patent Document 1 discloses that the stability of a pregabalin formulation is improved by specifying the particle size of pregabalin, but makes no mention of other drugs or guanfacine hydrochloride. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2019 / 124358 [Non-patent literature]

[0006] [Non-Patent Document 1] Intuniv(R) 1mg / Intuniv(R) 3mg Package Insert (1st Edition) Summary of the Invention [Problem to be solved by the invention]

[0007] However, the solid preparation containing guanfacine hydrochloride of Non-Patent Document 1 leaves room for improvement in terms of chemical stability.

[0008] Therefore, an object of the present invention is to provide a sustained-release solid preparation containing guanfacine hydrochloride, which has good chemical stability. [Means for solving the problem]

[0009] As a result of investigating the above problems, the present inventors found that by adjusting the particle size of guanfacine hydrochloride to a predetermined range, the chemical stability of guanfacine hydrochloride in the obtained sustained-release solid preparation is improved, and thus completed the present invention.

[0010] That is, the present invention provides [1] A sustained-release solid preparation containing guanfacine hydrochloride as an active ingredient, which has a cumulative 50% particle diameter D of guanfacine hydrochloride measured by volume using a laser diffraction / scattering method. 50 A sustained release solid preparation having a particle size of 30 to 60 μm. [2] The cumulative 50% particle diameter D of guanfacine hydrochloride measured by volume standard using a laser diffraction / scattering method 50 is 30 to 60 μm, and the cumulative 90% particle diameter D 90 The sustained release solid preparation according to the above-mentioned [1], having a particle size distribution of 60 to 100 μm. [3] The cumulative 10% particle diameter D of guanfacine hydrochloride measured by volume standard using a laser diffraction / scattering method 10 is 10 to 20 μm, and the cumulative 50% particle diameter D 50 is 30 to 60 μm, and the cumulative 90% particle diameter D 90 The sustained release solid preparation according to the above-mentioned [1], having a particle size distribution of 60 to 100 μm; [4] The sustained release solid preparation according to the above-mentioned [1], comprising at least one additive selected from the group consisting of hypromellose, crystalline cellulose and light anhydrous silicic acid. Regarding. Effect of the Invention

[0011] According to the present invention, guanfacine hydrochloride has a cumulative 50% particle diameter D in a volume-based measurement measured by a laser diffraction / scattering method. 50 By using a particle size of 30 to 60 μm, a sustained-release solid preparation having good chemical stability can be provided. [Brief description of the drawings]

[0012] [Figure 1] 1 is a graph showing the stability of guanfacine hydrochloride. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The sustained-release solid preparation according to the present invention has a cumulative 50% particle diameter D 50 However, the present invention is characterized in that guanfacine hydrochloride having a particle size of 30-60 μm is used as an active ingredient, thereby improving the chemical stability of the sustained-release solid preparation containing guanfacine hydrochloride. This is presumably because, when a sustained-release solid preparation containing guanfacine hydrochloride having a particle size larger than a predetermined value is used, the surface area of ​​the guanfacine hydrochloride particles is reduced, and the contact area with the compounding components that may affect the stability of guanfacine hydrochloride is relatively reduced, improving the chemical stability of guanfacine hydrochloride in the preparation and suppressing the generation of related substances over time. In fact, the present inventors found that the compounding components hypromellose, crystalline cellulose, and light anhydrous silicic acid tend to affect the chemical stability of guanfacine hydrochloride in a contact stability test with guanfacine hydrochloride.

[0014] Guanfacine hydrochloride has a cumulative 50% particle diameter D 50 (Hereinafter, average particle diameter (D 50 As long as the average particle diameter (D) of the sintered body is 30 to 60 μm, commercially available sintered body can be used without any particular limitation. If necessary, the sintered body can be sieved to obtain a desired average particle diameter (D50 ) and particle size distribution can be prepared.

[0015] The mean particle size of guanfacine hydrochloride (D 50 ) is 30 μm or more from the viewpoint of the stability of guanfacine hydrochloride (2,6-dichlorophenylacetic acid production amount (%)), but in one embodiment, it is preferably 31 μm or more, 32 μm or more, 33 μm or more, 34 μm or more, 35 μm or more, 36 μm or more, 37 μm or more, 38 μm or more, 39 μm or more, 40 μm or more, 41 μm or more, 42 μm or more, 43 μm or more, 44 μm or more, 45 μm or more, 46 μm or more, 47 μm or more, 48 μm or more, 49 μm or more, 50 μm or more, 51 μm or more, 52 μm or more, 53 μm or more, 54 μm or more, 55 μm or more, 56 μm or more, 57 μm or more, 58 μm or more, or 59 μm or more. In addition, the average particle size (D 50 ) is 60 μm or less from the viewpoint of the stability of guanfacine hydrochloride (2,6-dichlorophenylacetic acid production amount (%)), but in one embodiment, it is preferably 59 μm or less, 58 μm or less, 57 μm or less, 56 μm or less, 55 μm or less, 54 μm or less, 53 μm or less, 52 μm or less, 51 μm or less, 50 μm or less, 49 μm or less, 48 ​​μm or less, 47 μm or less, 46 μm or less, 45 μm or less, 44 μm or less, 43 μm or less, 42 μm or less, 41 μm or less, 40 μm or less, 39 μm or less, 38 μm or less, 37 μm or less, 36 μm or less, 35 μm or less, 34 μm or less, 33 μm or less, 32 μm or less, or 31 μm or less.

[0016] The cumulative 90% particle diameter D of guanfacine hydrochloride measured by volume standard using the laser diffraction / scattering method 90 (Hereafter, particle diameter (D 90 From the viewpoint of the stability of guanfacine hydrochloride (the amount of 2,6-dichlorophenylacetic acid produced (%)), the particle size (D 90From the viewpoint of the stability of guanfacine hydrochloride (the amount of 2,6-dichlorophenylacetic acid produced (%)), the particle size (D 90 ) is preferably 61 μm or more, 62 μm or more, 63 μm or more, 64 μm or more, 65 μm or more, 66 μm or more, 67 μm or more, 68 μm or more, 69 μm or more, 70 μm or more, 71 μm or more, 72 μm or more, 73 μm or more, 74 μm or more, 75 μm or more, 76 μm or more, 77 μm or more, 78 μm or more, 79 μm or more, 80 μm or more, 81 μm or more, 82 μm or more, 83 μm or more, 84 μm or more, 85 μm or more, 86 μm or more, 87 μm or more, 88 μm or more, 89 μm or more, 90 μm or more, 91 μm or more, 92 μm or more, 93 μm or more, 94 μm or more, 95 μm or more, 96 μm or more, 97 μm or more, 98 μm or more, or 99 μm or more. In one embodiment, the particle size (D 90 ) is preferably 99 μm or less, 98 μm or less, 97 μm or less, 96 μm or less, 95 μm or less, 94 μm or less, 93 μm or less, 92 μm or less, 91 μm or less, 90 μm or less, 89 μm or less, 88 μm or less, 87 μm or less, 86 μm or less, 85 μm or less, 84 μm or less, 83 μm or less, 82 μm or less, 81 μm or less, 80 μm or less, 79 μm or less, 78 μm or less, 77 μm or less, 76 μm or less, 75 μm or less, 74 μm or less, 73 μm or less, 72 μm or less, 71 μm or less, 70 μm or less, 69 μm or less, 68 μm or less, 67 μm or less, 66 μm or less, 65 μm or less, 64 μm or less, 63 μm or less, 62 μm or less, or 61 μm or less.

[0017] The cumulative 10% particle diameter D of guanfacine hydrochloride measured by volume standard using the laser diffraction / scattering method 10 (Hereafter, particle diameter (D 10 From the viewpoint of the stability of guanfacine hydrochloride (the amount of 2,6-dichlorophenylacetic acid produced (%)), the particle size (D 10From the viewpoint of the stability of guanfacine hydrochloride (the amount of 2,6-dichlorophenylacetic acid produced (%)), the particle size (D 10 ) is preferably 11 μm or more, 12 μm or more, 13 μm or more, 14 μm or more, 15 μm or more, 16 μm or more, 17 μm or more, 18 μm or more, or 19 μm or more. In one embodiment, the particle size (D 90 ) is preferably 19 μm or less, 18 μm or less, 17 μm or less, 16 μm or less, 15 μm or less, 14 μm or less, 13 μm or less, 12 μm or less, or 11 μm or less.

[0018] The particle size distribution of guanfacine hydrochloride is as follows: mean particle diameter (D 50 ) is 30 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the average particle diameter (D 50 ) is 33 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the average particle diameter (D 50 ) is 35 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the average particle diameter (D 50 ) is 38 to 60 μm, and the particle diameter (D 90 ) is preferably 69 to 100 μm.

[0019] In addition, the particle size distribution of guanfacine hydrochloride is 10 ) is 10 to 20 μm, and the average particle size (D 50 ) is 30 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 10 to 20 μm, and the average particle size (D 50 ) is 30 to 60 μm, and the particle diameter (D 90In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 10 to 20 μm, and the average particle size (D 50 ) is 30 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 10 to 20 μm, and the average particle size (D 50 ) is 30 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 10 to 20 μm, and the average particle size (D 50 ) is 33 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 10 to 20 μm, and the average particle size (D 50 ) is 35 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 10 to 20 μm, and the average particle size (D 50 ) is 38 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 11 to 20 μm, and the average particle size (D 50 ) is 30 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 12 to 20 μm, and the average particle size (D 50 ) is 30 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10) is 11 to 20 μm, and the average particle size (D 50 ) is 33 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 12 to 20 μm, and the average particle size (D 50 ) is 35 to 60 μm, and the particle diameter (D 90 In one embodiment, the particle size distribution of guanfacine hydrochloride is preferably such that the particle diameter (D 10 ) is 12 to 20 μm, and the average particle size (D 50 ) is 38 to 60 μm, and the particle diameter (D 90 ) is preferably 69 to 100 μm.

[0020] The content of the active ingredient in the sustained release solid formulation of the present invention is not particularly limited, but is preferably 0.2% by mass or more, more preferably 0.5% by mass or more, in terms of guanfacine. By making the content of the active ingredient in the sustained release solid formulation 0.2% by mass or more, the formulation uniformity tends to be good. In addition, the content of the active ingredient in the sustained release solid formulation is preferably 5% by mass or less, more preferably 3% by mass or less, in terms of guanfacine. By making the content of the active ingredient in the sustained release solid formulation 5% by mass or less, the solubility of the active ingredient tends to be easily ensured.

[0021] In addition to the above-mentioned active ingredient guanfacine hydrochloride, the sustained-release solid preparation of the present invention may contain additives commonly used in this field, such as binders, excipients, flow agents, disintegrants, pH regulators, lubricants, sweeteners, flavors, stabilizers, etc., depending on, for example, the dosage form.

[0022] The binder is not particularly limited, and examples thereof include powdered cellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, carboxymethylcellulose, acrylic acid polymer, acrylic acid copolymer, methacrylic acid polymer, methacrylic acid copolymer, gelatin, agar, alginic acid, sodium alginate, xanthan gum, powdered acacia gum, karaya gum, locust bean gum, tragacanth gum, guar gum, acacia gum, carrageenan, povidone, polyethylene oxide, partially saponified polyvinyl alcohol, pullulan, starch, and partially pregelatinized starch. These may be used alone or in combination of two or more, but it is preferable to use at least one of them that can impart sustained release properties to the formulation. Examples of binders that can impart sustained release properties to such formulations include methylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, acrylic acid polymer, acrylic acid copolymer, methacrylic acid polymer, methacrylic acid copolymer, povidone, polyethylene oxide, etc. As the binder, from the viewpoint of imparting appropriate sustained release properties and stability, hypromellose and methacrylic acid copolymer are preferred, and it is more preferred to use a combination of hypromellose and methacrylic acid copolymer.

[0023] When a binder is used, the content in the sustained release solid formulation is not particularly limited, but is preferably 20% by mass or more, more preferably 30% by mass or more. By making the content of the binder in the sustained release solid formulation 20% by mass or more, it tends to be easy to obtain the desired sustained release characteristics. In addition, when a binder is used, the content in the sustained release solid formulation is not particularly limited, but is preferably 80% by mass or less, more preferably 70% by mass or less. By making the content of the binder in the sustained release solid formulation 80% by mass or less, it tends to be easy to obtain the desired sustained release characteristics.

[0024] The excipient is not particularly limited, and examples thereof include crystalline cellulose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, starch (corn starch, potato starch, wheat starch, rice starch, partially gelatinized starch, hydroxypropyl starch, etc.) and derivatives thereof, sugar (glucose, lactose, lactose hydrate, white sugar, refined white sugar, powdered sugar, trehalose, dextran, dextrin, dextrate, etc.), sugar alcohol (D-mannitol, xylitol, sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (magnesium aluminometasilicate, synthetic hydrotalcite), anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium sulfate, calcium hydrogen phosphate hydrate, and inorganic salts such as sodium hydrogen carbonate. The excipient may be used alone or in combination of two or more kinds. Among these, from the viewpoint of tablet formability, crystalline cellulose, microcrystalline cellulose, sugar, and sugar alcohols are preferred, crystalline cellulose, lactose, lactose hydrate, and D-mannitol are more preferred, and the use of a combination of crystalline cellulose and D-mannitol is even more preferred.

[0025] When an excipient is used, the content in the sustained release solid formulation is not particularly limited, but from the viewpoint of tablet moldability, it is preferably 10 to 50 mass%, more preferably 15 to 40 mass%, and even more preferably 15 to 30 mass%.

[0026] The fluidizing agent is not particularly limited, but examples thereof include silicates such as calcium silicate, anhydrous silicic acid such as light anhydrous silicic acid, hydrous silicon dioxide, talc, titanium oxide, stearic acid, magnesium stearate, calcium stearate, corn starch, sodium lauryl sulfate, etc. These may be used alone or in combination of two or more. Among them, light anhydrous silicic acid is preferred from the viewpoint of powder fluidity during continuous tableting.

[0027] When a flow agent is used, its content in the sustained release solid preparation is not particularly limited, but is preferably 0.1 to 3 mass %, more preferably 0.2 to 2 mass %, from the viewpoint of powder fluidity during continuous tableting.

[0028] The disintegrant is not particularly limited, and examples thereof include carmellose, carmellose sodium, microcrystalline cellulose, crystalline cellulose-carmellose sodium, cellulose acetate phthalate, wheat starch, rice starch, corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose calcium, croscarmellose, croscarmellose sodium, and crospovidone. These may be used alone or in combination of two or more. Among these, crospovidone is preferably used from the viewpoint of tablet disintegration.

[0029] When a disintegrant is used, its content in the sustained release solid preparation is not particularly limited, but is preferably 0.1 to 3 mass %, more preferably 0.2 to 2 mass %, from the viewpoint of tablet disintegration.

[0030] The pH regulator is not particularly limited, and acids such as aspartic acid, ascorbic acid, maleic acid, glutamic acid, citric acid, fumaric acid, tartaric acid, adipic acid, glucono delta-lactone, and malic acid can be used. These may be used alone or in combination of two or more. Among them, it is preferable to use aspartic acid, especially L-aspartic acid, as the pH regulator, since it is easy to obtain the desired dissolution characteristics and good stability.

[0031] The content of the pH regulator in the sustained release solid formulation when used is not particularly limited as long as it can play the role of the pH regulator to adjust the pH of the sustained release solid formulation to the desired value, but is preferably 1% by mass or more, more preferably 3% by mass or more, even more preferably 5% by mass or more, and particularly preferably 10% by mass or more. By making the content of the pH regulator in the sustained release solid formulation 1% by mass or more, it tends to be easy to obtain the desired dissolution characteristics. In addition, the content of the pH regulator in the sustained release solid formulation when used is not particularly limited, but is preferably 30% by mass or less, more preferably 20% by mass or less. By making the content of the pH regulator (particularly L-aspartic acid) in the sustained release solid formulation 30% by mass or less, it tends to be easy to obtain the desired dissolution characteristics.

[0032] The lubricant is not particularly limited, but examples thereof include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, sucrose fatty acid esters, polyethylene glycol, hardened oils, glycerin fatty acid esters (glyceryl stearate, glyceryl palmitate, glyceryl behenate), talc, beeswax, carnauba wax, cetyl alcohol, and stearyl alcohol. These may be used alone or in combination of two or more. Among them, glycerin fatty acid esters are preferred from the viewpoints of lubricity and tablet disintegration.

[0033] When a lubricant is used, its content in the sustained release solid preparation is not particularly limited, but is preferably 3 to 25% by mass, more preferably 5 to 20% by mass, from the viewpoints of lubricating properties and tablet disintegration properties.

[0034] The additives such as sweeteners, flavorings, stabilizers, etc. are not particularly limited, and those commonly used in the art can be used. The content of the additives in the sustained release solid preparation can be appropriately determined by a person skilled in the art depending on the type of additives used.

[0035] The sustained release solid preparation of the present invention may be in any dosage form, but is preferably in a dosage form suitable for oral solid preparations, and is particularly preferably in the form of a tablet.

[0036] The sustained release solid preparation of the present invention is useful for the treatment of attention-deficit / hyperactivity disorder (AD / HD) and the like.

[0037] The dosage of the sustained release solid preparation of the present invention is not particularly limited as long as it is within the scope of common knowledge in the technical field, and for example, in the treatment of attention deficit / hyperactivity disorder (AD / HD), administration is started at 1 mg to 2 mg of guanfacine per day for patients under 18 years of age, and increased by 1 mg at intervals of one week or more to a maintenance dose of 1 mg to 6 mg according to body weight. For patients aged 18 years or older, administration is started at 2 mg of guanfacine per day, and increased by 1 mg at intervals of one week or more to a maintenance dose of 4 to 6 mg per day.

[0038] (Manufacturing method of sustained release solid preparation) The method for producing the sustained-release solid preparation can be any method commonly used in this technical field depending on the dosage form, and is not particularly limited.

[0039] For example, when the sustained release solid preparation of the present invention is a tablet, the tablet may have a predetermined average particle diameter (D 50 ) or particle size distribution, and other additives to be used in combination, mixed, sieved as necessary, and tableted. The tableting method is not particularly limited, and for example, a method using a tableting mortar, upper and lower punches for tableting, a hydraulic hand press, a single punch tableting machine, a rotary tableting machine, or the like can be used. Tableting may be performed at a tableting pressure such that the resulting tablets have an appropriate hardness, and the tableting pressure is appropriately adjusted depending on the tableting method, the equipment used for tableting, the size of the tablets, and the like.

[0040] The shape of the resulting tablet is not particularly limited, and may be, for example, round, disk-like, doughnut-like, polygonal plate-like, spherical, elliptical, caplet-like, or the like.

[0041] The present invention will now be described in detail with reference to examples, but it is not intended that the present invention be limited to these examples. EXAMPLES

[0042] Details of the reagents used in the examples are given below. Guanfacine hydrochloride Hypromellose (hydroxypropyl methylcellulose): Japanese Pharmacopoeia XVIII Dry methacrylic acid copolymer LD: Pharmaceutical additives Microcrystalline cellulose: Japanese Pharmacopoeia XVIII Lactose monohydrate:Japanese Pharmacopoeia XVIII Light anhydrous silicic acid: Japanese Pharmacopoeia XVIII L-Aspartic Acid: Japanese Pharmacopoeia XVIII Glycerol fatty acid ester: food additive

[0043] In the above, JP XVIII refers to the 18th Edition of the Japanese Pharmacopoeia, Yakuhin Kiseki refers to the Pharmaceutical Excipients Standards 2018 and its supplement, and Shokuhin Kiseki refers to the 9th Edition of the Food Additives Standards.

[0044] Examples 1 to 3 and Comparative Examples 1 to 4 Guanfacine hydrochloride, hypromellose, dried methacrylic acid copolymer LD, crystalline cellulose, lactose monohydrate, light anhydrous silicic acid, L-aspartic acid, and glycerin fatty acid ester were weighed in the proportions shown in Table 1, and a total of 100 g was placed in a double-dispersion sieve (test sieve, Tokyo Screen Co., Ltd., sieve 355 μm), and mixed by stirring in a stirring mixer. The resulting mixture was compressed into tablets with a rotary tableting machine (VELA C, Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 6 kN and a tablet diameter of 7.0 mm to obtain round tablets. The particle size distribution of guanfacine hydrochloride used in each example and comparative example is shown in Table 2. The particle size distribution of guanfacine hydrochloride was measured by a laser diffraction / scattering method using a particle size distribution analyzer (Microtrac MT3300 EXII, manufactured by Microtrac Bell Co., Ltd.) (guanfacine hydrochloride was added to a hexane solution (0.1% (w / v)) of Span80 (sorbitan monooleate) to prepare a suspension, and after ultrasonic treatment for 3 minutes, the measurement was performed by a wet method). The cumulative 10th, 50th, and 90th percentile particle sizes on a volume basis (particle size (D 10 ), average particle diameter (D 50 ), particle size (D 90 )) are indicated.

[0045] [Table 1]

[0046] [Table 2]

[0047] Test Example 1: Stability test The tablets of guanfacine hydrochloride obtained in Examples 1 to 3 and Comparative Examples 1 to 4 were sealed and packaged in an aluminum pillow (PTP exterior pillow film with gusseted gusset, manufactured by Shohoku Laminate Kogyo Co., Ltd.), and the package was stored under an environment of 60°C temperature and humidity. The stability of the tablets (amount of 2,6-dichlorophenylacetic acid produced (%)) at the start of storage (n=1) and after one week of storage (n=1) was measured by HPLC under the following measurement conditions. Here, the amount of 2,6-dichlorophenylacetic acid produced (%) indicates the ratio of the mass of 2,6-dichlorophenylacetic acid to the mass of guanfacine in the tablet. The results are shown in Figure 1 and Table 3. (HPLC analysis conditions) Detector: Ultraviolet spectrophotometer (measurement wavelength: 220 nm) Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was packed with 5 μm octylsilylated silica gel for liquid chromatography. Column temperature: constant temperature around 27℃ Mobile phase A: 0.42 g of sodium bicarbonate was dissolved in 995 mL of water, 5 mL of 0.5 mol / L tetrabutylammonium phosphate solution was added, and then 5 mol / L sodium hydroxide solution was added to adjust the pH to 10.0. 100 mL of acetonitrile was added to 900 mL of this solution. Mobile phase B: 0.42 g of sodium bicarbonate was dissolved in 995 mL of water, 5 mL of 0.5 mol / L tetrabutylammonium phosphate solution was added, and then 5 mol / L sodium hydroxide solution was added to adjust the pH to 10.0. 700 mL of acetonitrile was added to 300 mL of this solution. Delivery of mobile phase: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows: TIFF2025058634000003.tif40121Flow rate: Approximately 1.0 mL per minute Area measurement range: 60 minutes after injection of sample solution Injection volume: 50μL

[0048] [Table 3]

[0049] From Table 3, the larger particle size, especially the average particle size (D 50 It can be seen that in Examples 1 to 3, which used guanfacine hydrochloride with a pH of 30 or more, the production of a related substance (2,6-dichlorophenylacetic acid) at 60° C. for one week was suppressed compared to Comparative Examples 1 to 4.

[0050] Reference test example 1: Contact stability test Guanfacine hydrochloride was mixed with hypromellose, dried methacrylic acid copolymer LD, crystalline cellulose, lactose monohydrate, light anhydrous silicic acid, L-aspartic acid, or glycerin fatty acid ester in a mortar at a mass ratio of 1:9. 220 mg of the mixture was weighed into a glass bottle. The resulting glass bottle was covered with a lid, sealed in an aluminum bag (closed system), and stored at 60°C for 1 week, 2 weeks, or 3 weeks. 20 mL of a 0.01 mol / L phosphate buffer solution / 2-propanol mixture (4:1) at pH 3.5 was added, sonicated, shaken well, and centrifuged to measure the stability of guanfacine hydrochloride (2,6-dichlorophenylacetic acid production amount (%)). The results are shown in Table 4. The 2,6-dichlorophenylacetic acid production amount was measured under the same conditions as in Test Example 1.

[0051] [Table 4]

[0052] From Table 4, it can be seen that among the ingredients, hypromellose, crystalline cellulose, and light anhydrous silicic acid may affect the stability of guanfacine hydrochloride when used in a formulation of guanfacine hydrochloride.

Claims

1. A sustained-release solid preparation containing guanfacine hydrochloride as an active ingredient, the cumulative 50% particle diameter D of guanfacine hydrochloride measured by a volume-based measurement using a laser diffraction / scattering method. 50 A sustained release solid preparation having a particle size of 30 to 60 μm.

2. The cumulative 50% particle diameter D of guanfacine hydrochloride measured by a volume-based measurement using a laser diffraction / scattering method is 50 is 30 to 60 μm, and the cumulative 90% particle diameter D 90 2. The sustained release solid preparation according to claim 1, having a particle size distribution of 60 to 100 μm.

3. The cumulative 10% particle diameter D of guanfacine hydrochloride measured by a volume-based measurement using a laser diffraction / scattering method is 10 is 10 to 20 μm, and the cumulative 50% particle diameter D 50 is 30 to 60 μm, and the cumulative 90% particle diameter D 90 2. The sustained release solid preparation according to claim 1, having a particle size distribution of 60 to 100 μm.

4. 2. The sustained release solid preparation according to claim 1, comprising as an additive at least one selected from hypromellose, crystalline cellulose and light anhydrous silicic acid.

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