Guanfacine-containing sustained-release formulation

Abstract

To provide a sustained release formulation that exhibits sufficient dissolution after 24 hours and comprises stable guanfacine or a pharmaceutically acceptable salt thereof.SOLUTION: A sustained release formulation comprises: guanfacine or a pharmaceutically acceptable salt thereof as an active ingredient; a binder; and a pH adjusting agent. Here, the pH adjusting agent is L-aspartic acid.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a sustained-release preparation containing guanfacine or a pharmaceutically acceptable salt thereof, particularly a sustained-release tablet containing guanfacine hydrochloride.

Background Art

[0002] Guanfacine (N-amidino-2-(2,6-dichlorophenyl)acetamide) is a type of selective α2A adrenergic receptor agonist and is used for treating attention deficit / hyperactivity disorder (AD / HD).

[0003] Regarding guanfacine, sustained-release preparations have been studied in order to maintain medication compliance by means of a simple titration and once-daily dosing frequency. Here, as general sustained-release technologies, dispersion in a sustained-release matrix, coating with a sustained-release base (hydrophobic polymer, pH-responsive polymer), adsorption to an ion-exchange resin, etc. are known (Patent Documents 1 and 2).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, Patent Documents 1 and 2 do not describe examples of specific sustained-release preparations for guanfacine, leaving room for study.

[0006] Therefore, an object of the present invention is to provide a sustained-release preparation containing guanfacine or a pharmaceutically acceptable salt thereof, which has sufficient elution property after 24 hours and good stability. [Means for solving the problem]

[0007] As a result of investigating the above problems, the present inventors found that by using L-aspartic acid as the pH adjuster in a sustained-release formulation containing guanfacine or a pharmaceutically acceptable salt thereof, a binder, and a pH adjuster, it is possible to provide a sustained-release formulation containing guanfacine or a pharmaceutically acceptable salt thereof that has sufficient dissolution after 24 hours and good stability, thus completing the present invention.

[0008] In other words, the present invention is [1] A sustained-release formulation comprising guanfacine or a pharmaceutically acceptable salt thereof as an active ingredient, a binder, and a pH adjuster, wherein the pH adjuster is L-aspartic acid. [2] The sustained-release formulation according to [1] above, wherein the content of the binder is 20 to 80% by mass, preferably 30 to 70% by mass, relative to the entire sustained-release formulation, and the binder is one or more selected from the group consisting of methylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, acrylic acid polymer, acrylic acid copolymer, methacrylic acid polymer, methacrylic acid copolymer, povidone, or polyethylene oxide. [3] The sustained-release formulation described in [1] or [2] above, wherein the dosage form is granules or tablets. Regarding. [Effects of the Invention]

[0009] According to the present invention, by providing a sustained-release formulation containing guanfacine or a pharmaceutically acceptable salt thereof together with a binder and L-aspartic acid as a pH adjuster, a sustained-release formulation with sufficient dissolution and good stability after 24 hours can be obtained. [Brief explanation of the drawing]

[0010] [Figure 1] This graph shows the elution rate (%) of guanfacine. [Modes for carrying out the invention]

[0011] The sustained-release formulation of the present invention comprises guanfacine or a pharmaceutically acceptable salt thereof as an active ingredient, a binder, and a pH adjuster, characterized in that the pH adjuster is L-aspartic acid. It is presumed that the sustained-release formulation of the present invention exhibits sufficient dissolution and good stability after 24 hours because L-aspartic acid shows appropriate pKa and solubility. Here, "sufficient dissolution after 24 hours" of the sustained-release formulation of the present invention means that when the dissolution test is conducted using water as the dissolution test solution according to the Japanese Pharmacopoeia dissolution test method, the dissolution rate reaches 50% after 24 hours from the start of the dissolution test. Furthermore, "good stability" of the sustained-release formulation of the present invention means that the increase of related substances over time is suppressed.

[0012] In this specification, the expression “pharmaceutically acceptable salt” means, when used herein in reference to guanfacine, a salt formed from the amidino group of guanfacine. Such salts include acid addition salts, such as inorganic or organic salts (e.g., hydrochloride, sulfate, phosphate, hydrobromide, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.). Hydrochloride salts are particularly preferred.

[0013] Guanfacine and pharmaceutically acceptable salts thereof can be commercially available without particular restriction, and pharmaceutically acceptable salts thereof may be derived from guanfacine by methods commonly used in the art.

[0014] The content of the active ingredient in the sustained-release formulation of the present invention is preferably 0.2% by mass or more, and more preferably 0.5% by mass or more, as guanfacine. A content of 0.2% by mass or more of the active ingredient in the sustained-release formulation tends to result in good formulation uniformity. Furthermore, the content of the active ingredient in the sustained-release formulation is preferably 5% by mass or less, and more preferably 3% by mass or less, as guanfacine. A content of 5% by mass or less of the active ingredient in the sustained-release formulation tends to make it easier to ensure the solubility of the active ingredient.

[0015] The binders to be included in the sustained-release formulation of the present invention are not particularly limited, and examples 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, acacia gum powder, 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 individually or in combination of two or more, but it is preferable to use at least one that has the ability to impart sustained-release properties to the formulation. Examples of binders capable of imparting 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, and polyethylene oxide. From the viewpoint of imparting appropriate sustained-release properties, hypromellose, povidone, and methacrylic acid copolymer are preferred as binders, and a combination of hypromellose, povidone, and methacrylic acid copolymer is more preferred.

[0016] The content of the binder in the sustained-release formulation is not particularly limited, but is preferably 20% by mass or more, and more preferably 30% by mass or more. A binder content of 20% by mass or more tends to make it easier to obtain the desired sustained-release characteristics. Furthermore, while the binder content in the sustained-release formulation is not particularly limited, it is preferably 80% by mass or less, and more preferably 70% by mass or less. A binder content of 80% by mass or less tends to make it easier to obtain the desired sustained-release characteristics.

[0017] The content of L-aspartic acid in a sustained-release formulation is not particularly limited as long as it can function as a pH adjuster to set the pH of the sustained-release formulation to the desired level, but it is preferably 1% by mass or more, and more preferably 3% by mass or more. A content of 1% by mass or more of L-aspartic acid in the sustained-release formulation tends to make it easier to obtain the desired dissolution characteristics. Furthermore, while the content of L-aspartic acid in a sustained-release formulation is not particularly limited, it is preferably 30% by mass or less, and more preferably 20% by mass or less. A content of 30% by mass or less of L-aspartic acid in the sustained-release formulation tends to make it easier to obtain the desired dissolution characteristics.

[0018] In addition to the above-mentioned active ingredient guanfacine or a pharmaceutically acceptable salt thereof, a binder, and L-aspartic acid, the sustained-release formulation of the present invention may contain additives commonly used in this field, such as excipients, disintegrants, fluidizers, lubricants, sweeteners, flavorings, and stabilizers, depending on the dosage form of the sustained-release formulation.

[0019] The excipient is not particularly limited, and examples thereof include crystalline cellulose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, starch (such as corn starch, potato starch, wheat starch, rice starch, pregelatinized starch, hydroxypropyl starch, etc.) and its derivatives, sugars (such as glucose, lactose, sucrose, refined sugar, powdered sugar, trehalose, dextran, dextrin, dextrate, etc.), sugar alcohols (such as D-mannitol, xylitol, sorbitol, erythritol, etc.), glycerin fatty acid esters, inorganic powders (such as magnesium aluminometasilicate, synthetic hydrotalcite), calcium phosphate anhydride, 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. Among them, crystalline cellulose, microcrystalline cellulose and sugars are preferred from the viewpoint of tablet formability, crystalline cellulose and lactose are more preferred, and it is particularly preferred to use them in combination of crystalline cellulose and lactose.

[0020] The content in the sustained-release preparation when using an excipient is not particularly limited, but is preferably 10 to 50% by mass and more preferably 20 to 40% by mass from the viewpoint of tablet formability.

[0021] The disintegrant is not particularly limited, and examples thereof include carmellose, sodium carmellose, microcrystalline cellulose, crystalline cellulose-sodium carmellose, cellulose acetate phthalate, wheat starch, rice starch, corn starch, potato starch, gelatinized starch, pregelatinized starch, hydroxypropyl starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, calcium carmellose, croscarmellose, sodium croscarmellose, and crospovidone. These may be used alone or in combination of two or more. Among them, crospovidone is preferably used from the viewpoint of tablet disintegration.

[0022] When using a disintegrant, the content in the sustained-release preparation is not particularly limited, but from the viewpoint of tablet disintegration property, it is preferably 0.1 to 3% by mass, more preferably 0.2 to 2% by mass.

[0023] The fluidizing agent is not particularly limited, and examples thereof include silicates such as calcium silicate, silicic anhydrides such as light silicic anhydride, hydrous silicon dioxide, talc, titanium oxide, stearic acid, magnesium stearate, calcium stearate, corn starch, sodium lauryl sulfate, and the like. These may be used alone or in combination of two or more. Among them, light silicic anhydride is preferable from the viewpoint of powder fluidity during continuous tableting.

[0024] When using a fluidizing agent, the content in the sustained-release preparation is not particularly limited, but from the viewpoint of powder fluidity during continuous tableting, it is preferably 0.1 to 2% by mass, more preferably 0.2 to 1% by mass.

[0025] The lubricant is not particularly limited, and examples thereof include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, sucrose fatty acid ester, polyethylene glycol, hardened oil, glycerin fatty acid ester (glyceryl stearate, glyceryl palmitate, glyceryl behenate), talc, beeswax, carnauba wax, cetyl alcohol, stearyl alcohol, and the like. These may be used alone or in combination of two or more. Among them, glycerin fatty acid ester is preferable from the viewpoints of lubricity and tablet disintegration property.

[0026] When using a lubricant, the content in the sustained-release preparation is not particularly limited, but from the viewpoints of lubricity and tablet disintegration property, it is preferably 3 to 25% by mass, more preferably 5 to 20% by mass.

[0027] The additives, such as sweeteners, flavorings, and stabilizers, are not particularly limited and are those commonly used in the relevant art. The amount of these additives in the sustained-release formulation can also be appropriately determined by those skilled in the art depending on the type of additive used.

[0028] The dosage form of the sustained-release formulation of the present invention is not particularly limited as long as it is an oral dosage form, and examples include granules, capsules, and tablets, with tablets being preferred from the viewpoint of ease of administration.

[0029] The sustained-release formulation of the present invention is useful for the treatment of attention deficit / hyperactivity disorder (ADHD) and other conditions.

[0030] The dosage of the sustained-release formulation of the present invention is not particularly limited within the bounds of common sense in the art. For example, for the treatment of attention deficit / hyperactivity disorder (ADHD), in patients under 18 years of age, administration should be started with 1 mg to 2 mg of guanfacine per day, and increased by 1 mg at intervals of at least one week up to a maintenance dose of 1 mg to 6 mg according to body weight. In patients 18 years of age or older, administration should be started with 2 mg of guanfacine per day, and increased by 1 mg at intervals of at least one week up to a maintenance dose of 4 to 6 mg per day.

[0031] (Method for manufacturing sustained-release formulations) As for the method of producing a sustained-release formulation, a method common in this art can be used depending on the dosage form, and is not particularly limited.

[0032] For example, if the sustained-release formulation of the present invention is a tablet, it can be manufactured by mixing, for example, guanfacine or a pharmaceutically acceptable salt thereof, a binder, and L-aspartic acid with other additives used in combination, and then compressing the resulting mixture into tablets. The method of tableting is not particularly limited, and methods such as using a tableting die, an upper punch and a lower punch, and using a hydraulic hand press, a single-stroke tablet press, a rotary tablet press, etc., can be used. Tableting should be performed with a tableting pressure such that the resulting tablets have an appropriate hardness, and the tableting pressure is adjusted as appropriate depending on the tableting method, the equipment used for tableting, the size of the tablets, etc.

[0033] The resulting tablets are not particularly limited in shape and can be disc-shaped, donut-shaped, polygonal plate-shaped, spherical, elliptical, or caplet-shaped, for example.

[0034] The present invention will be described in detail below based on examples, but the present invention is not intended to be limited to these examples. [Examples]

[0035] Details of the reagents used in the examples are described below. Guanfacine hydrochloride Hypromellose (Hydroxypropyl Methylcellulose): Japanese Pharmacopoeia XVIII Povidone: Japanese Pharmacopoeia XVIII Dried methacrylate copolymer LD: Pharmaceutical additive regulations Crystalline cellulose: Japanese Pharmacopoeia XVIII Light anhydrous silicic acid: Japanese Pharmacopoeia XVIII Lactose hydrate:Japanese Pharmacopoeia XVIII Crospovidone: Japanese Pharmacopoeia XVIII L-aspartic acid: Japanese Pharmacopoeia XVIII L-ascorbic acid: Japanese Pharmacopoeia XVIII Glycerin fatty acid ester: Food additive

[0036] In the above, "JP XVIII" refers to the 18th edition of the Japanese Pharmacopoeia, "Pharmaceutical Additives Standards 2018 and its supplements" refers to the Japanese Pharmaceutical Additives Standards 2018 and its supplements, and "Food Additives" refers to the 9th edition of the Japanese Compendium of Food Additives.

[0037] Example 1 and Comparative Example 1 Each component was weighed in the proportions shown in Table 1, and the total amount of 10 g was placed in a mortar and mixed. The resulting mixture was compressed into tablets using a single-shot tablet press (HANDTAB200, manufactured by Ichihashi Seiki Co., Ltd.) with a tablet diameter of 6.4 mm and a compression pressure of 8 kN to obtain a disc-shaped sustained-release formulation.

[0038] [Table 1]

[0039] Test Example 1: Dissolution Characteristics Test Dissolution tests were performed on the sustained-release formulations (n=3 each) produced in Example 1 and Comparative Example 1. The dissolution tests were conducted in accordance with the Japanese Pharmacopoeia dissolution test method, using a dissolution test machine (NTR-6000 series, manufactured by Toyama Sangyo Co., Ltd.) with water as the dissolution solution and the paddle method. The test conditions were a volume of 900 ml of dissolution solvent, a temperature of 37 ± 0.5 °C, and a paddle speed of 50 rpm. The results are shown as average values ​​in Table 2 and Figure 1.

[0040] [Table 2]

[0041] Table 2 and Figure 1 show that in Example 1, where L-aspartic acid was used as the pH adjuster, the dissolution rate after 24 hours from the start of the dissolution test exceeded 50%, demonstrating sufficient dissolution after 24 hours as a sustained-release formulation. On the other hand, in Comparative Example 1, where L-ascorbic acid was used as the pH adjuster, the dissolution rate after 24 hours from the start of the dissolution test did not reach 50%, and did not demonstrate sufficient dissolution after 24 hours as a sustained-release formulation.

[0042] Test Example 2: Contact Stability Test Guanfacine hydrochloride was mixed with L-aspartic acid, L-ascorbic acid, fumaric acid, or maleic acid in a 1:10 mass ratio using a mortar and pestle. 220 mg of the mixture was measured out and placed in a glass bottle. The resulting glass bottle was sealed (sealed) and stored at 40°C for 2 months. 10 mL of water / acetonitrile mixture (18:7) was added, and the mixture was extracted by sonication to measure the stability (amount of related substances) of guanfacine hydrochloride. The results are shown in Table 3. In Table 3, "Total Related Substances (%)" indicates the proportion of all related substances to guanfacine hydrochloride.

[0043] The concentrations of guanfacine hydrochloride analogs were measured by liquid chromatography under the following conditions. (HPLC analysis conditions) Detector: UV absorbance spectrophotometer (measurement wavelength: 268 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was packed with 3.5 μm octylsilylated silica gel for liquid chromatography. Column temperature: Constant temperature around 35°C Mobile phase A: 0.77 g of ammonium acetate was dissolved in 1000 mL of water, and acetic acid (100 mL) was added to adjust the pH to 3.5. 200 mL of acetonitrile was added to 800 mL of this solution. Mobile phase B: 0.77 g of ammonium acetate was dissolved in 1000 mL of water, and acetic acid (100 mL) was added to adjust the pH to 3.5. 680 mL of acetonitrile was added to 320 mL of this solution. Mobile phase delivery: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows. TIFF0007835098000003.tif50125 Flow rate: Approximately 1.0 mL per minute Area measurement range: 46 minutes after sample solution injection Injection volume: 20μL

[0044] [Table 3]

[0045] Table 3 shows that when L-aspartic acid, fumaric acid, and maleic acid were added to guanfacine hydrochloride as pH adjusters, the mixture was significantly more stable at 40°C for 2 months compared to when L-ascorbic acid was added.

Claims

1. A sustained-release formulation comprising guanfacine or a pharmaceutically acceptable salt thereof as an active ingredient, a binder, and a pH adjuster, wherein the pH adjuster is L-aspartic acid.

2. The sustained-release formulation according to claim 1, wherein the binder content is 20 to 80% by mass relative to the entire sustained-release formulation, and the binder is one or more selected from the group consisting of methylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, acrylic acid polymer, acrylic acid copolymer, methacrylic acid polymer, methacrylic acid copolymer, povidone, or polyethylene oxide.

3. The sustained-release formulation according to claim 1 or 2, wherein the dosage form is granules or tablets.

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