WO2021153716A1

WO2021153716A1 - Controlled release composition

Info

Publication number: WO2021153716A1
Application number: PCT/JP2021/003157
Authority: WO
Inventors: Shoji Furuta; Hiroki WAKAMORI; Naoto Hattori; Chihiro ISHIDA
Original assignee: Nippon Shinyaku Co., Ltd.
Priority date: 2020-01-31
Filing date: 2021-01-29
Publication date: 2021-08-05
Also published as: AR121207A1; UY39054A; TW202140010A

Abstract

It is an object of the present invention to provide a controlled release composition which can prevent a sudden rise in the blood concentration of an active ingredient and can maintain the blood concentration for a long time.

Description

CONTROLLED RELEASE COMPOSITION

The present invention relates to a controlled release composition comprising (1) a water-soluble polymer, wherein the water-soluble polymer forms a hydrogel in water and the strength of the hydrogel is less than10N. The present invention also relates to controlled release composition comprising (1) a water-soluble polymer, (2) a water-soluble additive, and (3) at least one active ingredient, wherein the water-soluble polymer forms a hydrogel in water and the strength of the hydrogel is less than 10N. Further, the present invention relates to a use of the controlled release composition of the present invention, a method of preventing and/or treating a disease by administrating the controlled release composition of the present invention and a method of preparing the controlled release composition of the present invention.

A sustained release composition can gradually release an active ingredient, and therefore can maintain a blood concentration of the active ingredient over a long period of time. A sustained release composition has advantages such as duration of active ingredient efficacy due to sustained release of the active ingredient, a reduction in adverse effects due to prevention of sudden rise of the blood concentration of the active ingredient, a reduction in troublesome medication and prevention of medication failure due to a decrease in administration frequency, and improvement of medication compliance, and therefore, recently, the development of sustained release compositions has been advanced for many active ingredients. A hydrogel matrix preparation is an example of a sustained release formulation. The hydrogel matrix preparation can control the release of the active ingredient by adjusting the gelation rate or speed of the gel base material.

Selexipag, 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “Compound A”) is known to have an excellent prostaglandin I₂ (hereinafter referred to as “PGI₂”) receptor agonistic effect and show various medicinal effects such as a platelet aggregation inhibitory effect, a vasodilating effect, a bronchial smooth muscle dilating effect, a lipid deposition inhibitory effect, and a leukocyte activation inhibitory effect (see, for example, PTL 1 to PTL 6). At present, a preparation containing Compound A as an active ingredient is used as a therapeutic agent for pulmonary arterial hypertension in the form of a normal tablet (PTL 7).

[PTL 1] WO 2002/088084
[PTL 2] WO 2009/157396
[PTL 3] WO 2009/107736
[PTL 4] WO 2009/154246
[PTL 5] WO 2009/157397
[PTL 6] WO 2009/157398
[PTL 7] WO 2017/098998
[PTL 8] WO 2010/150865
[PTL 9] US 2014/0221397
[PTL 10] US 2011/0178103
[PTL 11] US 2011/0015211
[PTL 12] US 2011/0118254
[PTL 13] US 2011/0105518

[NPL 1] Uptravi Tablets 0.2 mg, Uptravi Tablets 0.4 mg, Pharmaceutical Interview Form revised on November 2016 (2^nd edition)
[NPL 2] Hepatology, 2007, Vol. 45, No. 1, pp. 159-169
[NPL 3] PubMed: Nihon Yakurigaku Zasshi, 2001, Feb, 117(2), pp. 123-130, Abstract
[NPL 4] International Angiology, 29, Suppl. 1 to No. 2, pp. 49-54, 2010
[NPL 5] Japanese Journal of Clinical Immunology, Vol. 16, No. 5, pp. 409-414, 1993
[NPL 6] Japanese Journal of Thrombosis and Hemostasis, Vol. 1, No. 2, pp. 94-105, 1990, Abstract
[NPL 7] The Journal of Rheumatology, Vol. 36, No. 10, pp. 2244-2249, 2009
[NPL 8] The Japanese Journal of Pharmacology, Vol. 43, No. 1, pp. 81-90, 1987
[NPL 9] British Heart Journal, Vol. 53, No. 2, pp. 173-179, 1985
[NPL 10] The Lancet, 1, 4880, pt 1, pp. 569-572, 1981
[NPL 11] European Journal of Pharmacology, 449, pp. 167-176, 2002
[NPL 12] The Journal of Clinical Investigation, 117, pp. 464-72, 2007
[NPL 13] American Journal of Physiology Lung Cellular and Molecular Physiology, 296: L648-L656, 2009

As a result of intensive studies for achieving the above object, the present inventors found that there is a problem in a pharmaceutical composition containing Compound A as an active ingredient that the controlled release of Compound A is variable in a mammalian.
The inventors have also found that controlled release composition, containing a water-soluble polymer which can form a hydrogel with a certain gel strength, can maintain the blood concentration of Compound A for a long time, and thus have completed the present invention.

That is, the present invention relates to a controlled release composition according to any one of the following [1] to [29] (hereinafter also referred to as “controlled release composition of the present invention”). Also, the present invention relates to a use of the controlled release composition, a method of preventing and/or treating a disease by administrating the controlled release composition and a method of preparing the controlled release composition according to the following [30] to [32].

[1] A controlled release composition comprising (1) a water-soluble polymer, wherein the water-soluble polymer forms a hydrogel in water and the strength of the hydrogel is less than 10N.
[2] The controlled release composition according to [1], wherein an aqueous solution of (1) the water-soluble polymer has a viscosity of 1000 mPa・s or more at a concentration of 10 weight % or less.
[3] The controlled release composition according to [1], wherein (1) the water-soluble polymer is at least one selected from the group of polyethylene oxide (PEO), a cellulose derivative, preferably hypromellose (HPMC), methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose (HPC), hydroxyethylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, polyvinyl alcohol (PVA), alginic acid, an alkali metal salt of alginic acid, ammonium alginate, carrageenan, xanthan gum, and Arabic gum.
[4] The controlled release composition according to [1], wherein (1) the water-soluble polymer is 25 to 70 weight % based on the total weight of the composition.
[5] The controlled release composition according to any one of [1] to [4], further comprising (2) a water soluble additive.
[6] The controlled release composition according to [5], wherein 1 g of (2) the water-soluble additive can be dissolved in 6 ml or less of water.
[7] The controlled release composition according to any one of [5] or [6], wherein (2) the water-soluble additive is at least one selected from the group of polyvinylpyrrolidone (PVP) and sugars preferably sugar alcohol.
[8] The controlled release composition according to any one of [5] to [7], wherein (2) the water-soluble additive is 20 to 65 weight % based on the total weight of the composition.
[9] The controlled release composition according to any one of [1] to [8], further comprising (3) an active ingredient.
[10] The controlled release composition according to [9], wherein (3) the active ingredient is selexipag.
[11] The controlled release composition according to [9] or [10], wherein (3) the active ingredient is 0.05 to 1 weight % based on the total weight of the composition.
[12] The controlled release composition according to any one of [1] to [11], wherein (1) the water-soluble polymer and (2) the water-soluble additive in the ratio is 1:0.3 to 1:2.5.
[13] The controlled release composition according to any one of [1] to [12], wherein (1) the water-soluble polymer is at least one selected from the group polyethylene oxide (PEO) and hypromellose (HPMC).
[14] The controlled release composition according to [13], wherein the range of molecular weight of the PEO is 900,000 to 7,000,000, preferably 2,000,000 to 7,000,000.
[15] The controlled release composition according to [13] or [14], wherein the PEO is 20 to 70 weight % based on the total weight of the composition.
[16] The controlled release composition according to any one of [13] to [15], wherein the range of the viscosity of an aqueous solution of the HPMC is 3000 to 140000mP・s at a concentration of 2 weight %.
[17] The controlled release composition according to any one of [13] to [16], wherein the HPMC is 5 to 20 weight % based on the total weight of the composition.
[18] The controlled release composition according to any one of [5] to [17], wherein (2) the water-soluble additive is at least one selected from the group of polyvinylpyrrolidone (PVP) and D-mannitol.
[19] The controlled release composition according to [18], wherein K value of the PVP is 10 to 120, preferably 20 to 40.
[20] The controlled release composition according to [18] or [19], wherein the PVP is 10 to 65 weight % based on the total weight of the composition.
[21] The controlled release composition according to any one of [18] to [20], wherein D-mannitol is 10 to 25 weight % based on the total weight of the composition.
[22] The controlled release composition according to any one of [1] to [21], wherein the strength of the hydrogel is less than 5N.
[23] The controlled release composition according to any one of [1] to [22], wherein the strength of the hydrogel is measured by rheometer with moving speed of 10 mm/min and sensor size of 13.3 mm in diameter, 6 hours after putting the composition in water of 37℃.
[24] The controlled release composition according to any one of [1] to [23], wherein the controlled release composition is in a form of tablet or film coated tablet.
[25] A controlled release composition comprising (1) a water-soluble polymer, (2) a water-soluble additive, and (3) at least one active ingredient, wherein the water-soluble polymer forms a hydrogel in water and the strength of the hydrogel is less than 10N.
[26] The controlled release composition according to any one of [1] to [25], wherein the release rate of the active ingredient is 0 to 50% after 6 hours in the dissolution test and/or 70 to 100% after 24 hours in the dissolution test.
[27] The controlled release composition according to any one of [1] to [26], wherein the controlled release composition has a water holding capacity of 400 to 800%.
[28] The controlled release composition according to any one of [1] to [27] for use in the treatment of a disease.
[29] The controlled release composition according to [28], wherein the disease is at least one selected from the group of symptoms associated with diabetic neuropathy, diabetic gangrene, a peripheral circulatory disturbance, chronic arterial occlusion, intermittent claudication, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina pectoris, glomerulonephritis, diabetic nephropathy, chronic renal failure, bronchial asthma, interstitial pneumonia, pulmonary fibrosis, a chronic obstructive pulmonary disease, tubulointerstitial nephritis, an inflammatory bowel disease, or spinal canal stenosis.
[30] Use of the controlled release composition according to any one of [1] to [29] for the manufacture of a medicament for the treatment of a disease.
[31] A method of preventing and/or treating a disease comprising administration of a suitable amount of the controlled release composition according to any one of [1] to [29] to a subject in need thereof.
[32] A method of preparing the controlled release composition according to any one of [1] to [29].

The present invention relates to a controlled release composition comprising (1) a water-soluble polymer, wherein the water-soluble polymer forms a hydrogel in water and the strength of the hydrogel is less than10N. The present invention also relates to controlled release composition comprising (1) a water-soluble polymer, (2) a water-soluble additive, and (3) at least one active ingredient, wherein the water-soluble polymer forms a hydrogel in water and the strength of the hydrogel is less than10N. Further, the present invention relates to a method of preventing and/or treating a disease by administrating the controlled release composition of the present invention and a method of preparing the controlled release composition of the present invention. Hereinafter, the present invention is described in detail.

(1) Water-Soluble Polymer
A “water-soluble polymer” as used herein refers to a polymer which becomes highly viscous when it is dissolved in water.

In one embodiment of the present invention, an aqueous solution of (1) the water-soluble polymer has a viscosity of 1000 mPa・s or more at a concentration of 10 weight % or less.
Particularly, an aqueous solution of the water-soluble polymer has a viscosity of 1000 mPa・s or more at 25°C, preferably at a concentration of 0.01 to 10 weight % at 25°C, more preferably at a concentration of 0.1 to 10 weight % at 25°C, still more preferably at a concentration of 1.0 to 10 weight % at 25°C.
In one embodiment of the present invention, an aqueous solution of (1) the water-soluble polymer at a concentration of 10 weight % or less has a viscosity in the range of 1000 to 2000 mPa・s at 25°C.
For the water-soluble polymer to be used in the controlled release composition of the present invention, if the viscosity of an aqueous solution of the polymer at a concentration of 10 weight % or less exceeds 2000 mPa・s at 25°C, the concentration of the solution can be adjusted to reduce the viscosity to 2000 mPa・s or less.

In one embodiment of the present invention, the viscosity of the aqueous solution of the water-soluble polymer can be measured using a rotary viscometer (Rheometer R/S Plus, manufactured by Brookfield, Inc.) after the water-soluble polymer is dissolved in water and the resulting solution is left to stand at 25°C for about 24 hours to prepare a sample. The measurement is performed at a measurement temperature of 25°C and at a rotation speed of 10 rpm, and the viscosity is measured after 300 seconds from the start of the measurement.

In one embodiment of the present invention, the content of the water-soluble polymer in the controlled release composition of the present invention is not particularly limited if the water-soluble polymer forms hydrogel with suitable gel strength, an upper limit is, for example, 70 wt%, 55 wt%, or 45 wt% with respect to the total weight of the controlled release composition, a lower limit is, for example, 25 wt%, 30 wt% or 40 wt% with respect to the total weight of the controlled release composition. The upper limit and the lower limit can be used in combination, for example, within the range from 25 wt% to 70 wt% with respect to the total weight of the controlled release composition.

In one embodiment of the present invention, example of a water-soluble polymer includes polyethylene oxide (PEO), hypromellose (HPMC), methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose (HPC), hydroxyethylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, polyvinyl alcohol (PVA), alginic acid, an alkali metal salt of alginic acid, ammonium alginate, carrageenan, xanthan gum, and Arabic gum. Particularly, PEO and HPMC are preferred.

In one embodiment of the present invention, a water-soluble polymer can be used solely or in combination and can be selected at least one from the group of polyethylene oxide (PEO), hypromellose (HPMC), methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose (HPC), hydroxyethylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, polyvinyl alcohol (PVA), alginic acid, an alkali metal salt of alginic acid, ammonium alginate, carrageenan, xanthan gum, and Arabic gum, preferably at least one selected from the group of PEO and HPMC.

In one embodiment of the present invention, the range of molecular weight of PEO is 900,000 to 7,000,000, preferably 2,000,000 to 7,000,000.

In one embodiment of the present invention, the PEO is 20 to 70 weight % based on the total weight of the composition.

HPMC is a cellulose derivative having a hydroxypropoxyl group and a methoxy group in the molecule.

In one embodiment of the present invention, the range of the viscosity of an aqueous solution of the HPMC is 3000 to 140000mP・s at a concentration of 2 weight %.

In one embodiment of the present invention, the HPMC is 5 to 20 weight % based on the total weight of the composition.

In one embodiment of the present invention, example of HPMC includes Metolose (Registered Trademark) 60SH-4000SR (manufactured by Shin-Etsu Chemical Co., Ltd.), Metolose (Registered Trademark) 60SH-8000SR (Shin-Etsu Chemical Co., Ltd.), Metolose (Registered Trademark) 65SH-4000SR (manufactured by Shin-Etsu Chemical Co., Ltd.), Metolose (Registered Trademark) 65SH-15000SR (Shin-Etsu Chemical Co., Ltd.), Metolose (Registered Trademark) 90SH-100SR (manufactured by Shin-Etsu Chemical Co., Ltd.), Metolose (Registered Trademark) 90SH-4000SR (manufactured by Shin-Etsu Chemical Co., Ltd.), Metolose (Registered Trademark) 90SH-15000SR (manufactured by Shin-Etsu Chemical Co., Ltd.), and Metolose 90SH-100000SR (manufactured by Shin-Etsu Chemical Co., Ltd.), and any of these equivalents can be obtained as a commercially available product.

HPC is a cellulose derivative having a hydroxypropoxyl group in the molecule. In one embodiment of the present invention, example of HPC includes Klucel (Registered Trademark) HXF (manufactured by Ashland, Inc.), Klucel (Registered Trademark) MXF (manufactured by Ashland, Inc.), Klucel (Registered Trademark) GXF (manufactured by Ashland, Inc.), NISSO HPC H (manufactured by Nippon Soda Co., Ltd.), and NISSO HPC VH (manufactured by Nippon Soda Co., Ltd.), and any of these equivalents can be obtained as a commercially available product.

PVA is a polymeric compound represented by the following general formula and obtained by saponification of polyvinyl acetate, which is obtained by polymerizing a vinyl acetate monomer.

In one embodiment of the present invention, example of PVA includes Gohsenol (Registered Trademark) EG-48P (manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) and Parteck (Registered Trademark) SRP80 (manufactured by Merck, Inc.), and either of these can be obtained as a commercially available product.

In one embodiment of the present invention, example of alkali metal salt of alginic acid includes sodium alginate and potassium alginate.

(2) Water-Soluble Additive
A “water soluble additive” as used herein refers to a additive which can be dissolved in water.

In one embodiment of the present invention, preferably 1g of a “water soluble additive” can be dissolved in 6 ml or less of water.

In one embodiment of the present invention, the content of a “water soluble additive” in the controlled release composition of the present invention is not particularly limited if the water-soluble polymer forms hydrogel with suitable gel strength, an upper limit is, for example, 65 wt%, 50 wt%, or 40 wt% with respect to the total weight of the controlled release composition, a lower limit is, for example, 25 wt%, 30 wt% or 40 wt% with respect to the total weight of the controlled release composition. The upper limit and the lower limit can be used in combination, for example, within the range from 20 wt% to 65 wt% with respect to the total weight of the controlled release composition.

In one embodiment of the present invention, a “water soluble additive” is at least one selected from the group of a polyvinylpyrrolidone (PVP) and a sugar alcohol.

In one embodiment of the present invention, a “water soluble additive” is a polyvinylpyrrolidone (PVP).

In one embodiment of the present invention, K value of a PVP is 10 to 120, preferably 20 to 40.

In one embodiment of the present invention, a “water soluble additive” is sugar alcohol, preferably D-mannitol.

In one embodiment of the present invention, D-mannitol is 10 to 25 weight % based on the total weight of the composition.

In one embodiment of the present invention, (1) a water-soluble polymer and (2) a water-soluble additive in the ratio is not particularly limited, but is 1:0.3 to 1:2.5.

(3) Active ingredient
In one embodiment of the present invention, the controlled release composition of the present invention may contain an active ingredient.

In one embodiment of the present invention, an active ingredient is such as 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “Compound A”).

Compound A is a known compound described in, for example, PTL 1 and PTL 8, and can be easily obtained by a person skilled in the art according to the method described in these patent literatures.
In one embodiment of the present invention, Compound A may be an optical isomer, a pharmaceutically acceptable salt, an amorphous form (see WO2017/029594, WO2017/042731, WO2018/015975, etc.) or a crystal form thereof, or a mixture thereof, especially a crystal form of Compound A. Compound A is selexipag and the solubility of selexipag is classified as “Practically insoluble, or insoluble” according to the Japanese Pharmacopeia 17th edition.

Examples of such crystal form of Compound A in the controlled release composition of the present invention include Form-I crystal, Form-II crystal and Form-III crystal of Compound A, as well as Form-IV to -IX crystals of Compound A (see WO2017/040872, WO2018/022704, WO2018/015974, etc.).
Particularly, Form-I, Form-II and Form-III crystals of Compound A, as listed below, are preferred, and Form-I crystal of Compound A is more preferable.
Compound A is known to have, for example, the following three crystal forms (see, for example, PTL 8).
(1) A Form-I crystal of Compound A, for which a powder X-ray diffraction diagram is obtained using a Cu-Kα radiation (λ=1.54Å), and which shows diffraction peaks at the following diffraction angles (2θ): 9.4°, 9.8°, 17.2°, and 19.4° in the powder X-ray diffraction spectrum of Compound A.
(2) A Form-II crystal of Compound A, for which a powder X-ray diffraction diagram is obtained using a Cu-Kα radiation (λ=1.54Å), and which shows diffraction peaks at the following diffraction angles (2θ): 9.0°, 12.9°, 20.7°, and 22.6° in the powder X-ray diffraction spectrum of Compound A.
(3) A Form-III crystal of Compound A, for which a powder X-ray diffraction diagram is obtained using a Cu-Kα radiation (λ=1.54Å), and which shows diffraction peaks at the following diffraction angles (2θ): 9.3°, 9.7°, 16.8°, 20.6°, and 23.5° in the powder X-ray diffraction spectrum of Compound A.

The powder X-ray diffraction spectrum charts of the above three crystal forms are shown in FIGS. 1 to 3. The powder X-ray diffraction spectra of these crystal forms were measured using RINT-Ultima III (manufactured by Rigaku Corporation) (target: Cu, voltage: 40 kV, current: 40 mA, scan speed: 4°/min).

In one embodiment of the present invention, an active ingredient of the controlled release composition of the present invention may be an active form of Compound A, which is the compound of the formula:

hereinafter referred to as "Compound B".
　In one embodiment of the present invention, Compound B may be optical isomer, pharmaceutically acceptable salt, amorphous form or crystal form thereof, or a mixture thereof, as an active ingredient.

In one embodiment of the present invention, the content of Compound A which is the active ingredient of the controlled release composition of the present invention is not particularly limited, but is preferably within the range from 0.05 wt% to 1.0 wt% with respect to the total weight of the controlled release composition.

(4) Strength of hydrogel
A controlled release composition comprising (1) a water-soluble polymer, and the water-soluble polymer forms a hydrogel in water with a certain strength of the hydrogel.

In one embodiment of the present invention, an upper limit of the strength of the hydrogel is 10N, preferably is, 5N and a lower limit is not particularly limited, if the strength can be measured, for example, 0.2N. The upper limit and the lower limit can be used in combination. Particularly, the strength of the hydrogel, for example, is less than 10N, less than 5N, 0.2N to 10N, and 0.2N to 5N.

In one embodiment of the present invention, the strength of the hydrogel is measured by rheometer with moving speed of 10 mm/min and sensor size of 13.3 mm in diameter, 6 hours after putting the composition of the present invention in water of 37°C.
In one embodiment of the present invention, the strength of the hydrogel can be measured particularly as follows;
(I) A tablet was put on the stainless sieve (JIS Z 8801,2006, APERTURE:1mm, WIRE DIA:0.56mm), and then the set of tablet and sieve were immersed in 37℃ water. After 6 hours, the set of tablet and sieve was taken from water.
(II) The tablet on the sieve was pressed down from the top and time-dependent change of load (unit: N) was recorded in order to calculate the gel strength of the tablet.
Apparatus: Digital force gauge (IMADA, ZTA-50N) and standard type vertical motorized test stand (IMADA, MX2-500N)
Condition: Moving speed 10mm/min, sensor shape 13.3 mm diameter flat tip (IMADA, A-2, and data sampling rate every 0.1 second
(III) Gel strength was defined as the inflection point of the load (unit: N) with respect to time. The inflection point was calculated as the minimum value of F (n) satisfying the condition (i) to (iv) below.
(i) ΔF(n)＝F(n＋1)-F(n)
(ii) ΔF(n)＞0.1 N
(iii) ΔF(n)＞2ΔF(n-1)
(iv) ΔF(n+1)＞2ΔF(n-1)
F(n) is the load measured in the n-th time.

(5) Release rate of the active ingredient
In one embodiment of the present invention, the controlled release composition of the present invention has the release rate of an active ingredient of 0 to 50% after 6hours in the dissolution test and/or 70 to 100% after 24hours in the dissolution test according to the Japanese Pharmacopeia 17th edition, for example, JP dissolution test method 2 (paddle method), Test liquid: 900mL JP 2nd fluid for the dissolution test, Paddle speed: 200 rpm, and Liquid temperature: 37°C.
In one embodiment of the present invention, a controlled release composition forms a hydrogel which do not disintegrate for 6 hours in the dissolution test.

(6) Water holding capacity
In one embodiment of the present invention, a controlled release composition of the present invention has a water holding capacity is 400 to 800%.

(7) Other Additives
In one embodiment of the present invention, the controlled release composition of the present invention may contain pharmaceutically acceptable additives other than the above-mentioned components as long as the effect of the present invention is not inhibited. For example, an additive such as an excipient, a binder, a disintegrating agent, a fluidizing agent, a lubricant, a plasticizer, a coloring agent, a taste masking agent, or a flavoring agent can be blended therein in an appropriate amount as needed. These additives may be used alone, or two or more of these additives may be used in combination.

In one embodiment of the present invention, the amount of “other additives” is not particularly limited, but is for example, within the range from 0 wt% to 55 wt% with respect to the total weight of the controlled release composition.

In one embodiment of the present invention, example of other additives includes cornstarch, microcrystalline cellulose, low Substituted hydroxypropylcellulose, and magnesium stearate.

In one embodiment of the present invention, examples of the additive includes hypromellose 2910 ( 6 mPa・s), propylene glycol, titanium dioxide, yellow ferric oxide, iron oxide red and carnauba wax for coating.

(8) Other Active Ingredients
In one embodiment of the present invention, so long as it does not inhibit the effect of the invention, the controlled release composition of the present invention may comprise, in addition to the components as described above, a pharmaceutically active ingredient such as an agent for the treatment or prevention of the diseases as described above, an investigational new active ingredient for the diseases as described above, and the like.

(9) Shape of controlled release composition
In one embodiment of the present invention, the shape of the controlled release composition of the present invention may be, but not limited to, a round, an ellipse, oblong, an odd shape such as a doughnut shape, or the like.
The tablet thickness of the controlled release composition of the present invention is not particularly limited, but is suitably, for example, within the range from 1 mm to 10 mm, and is preferably within the range from 2 mm to 9 mm.
The size of the controlled release composition of the present invention is not particularly limited, however, for example, the minor axis (in the case of a circular tablet, the diameter) is suitably within the range from 1 mm to 20 mm, and is preferably, for example, within the range from 2 mm to 14 mm.
The weight of the controlled release composition of the present invention is not particularly limited, but is suitably within the range from 5 mg to 1000 mg.

(10) Method for producing controlled release composition of the present invention
The controlled release composition of the present invention can be produced by a conventional method in the pharmaceutical technical field using the above-mentioned various types of additives.
The controlled release composition of the present invention can be produced by, for example, mixing Compound A which is the active ingredient with various types of additives, followed by direct compression molding, or by granulating Compound A which is the active ingredient and various types of additives, followed by compression molding of the resulting granules as such or a mixture of the resulting granules with another additive.
The compression molding method is not particularly limited, and a known device can be appropriately selected, and for example, a method using a device such as a compression testing device, an oil hydraulic press, or a tableting machine, or the like can be exemplified. Examples of the compression testing device include a universal material testing device (AUTOGRAPH, manufactured by Shimadzu Corporation). Examples of the tableting machine include a rotary tableting machine (Clean Press Correct 12, manufactured by Kikusui Seisakusho, Ltd.).
As for the pressure at the time of compression molding, the conditions suitable for a desired device and a desired compression molded material may be appropriately selected.
Further, a capsule formulation can be produced by filling a capsule with the above-mentioned compression-molded material. As the capsule, a known capsule can be used, and for example, a gelatin capsule and an HPMC capsule can be exemplified. The size of the capsule is not particularly limited as long as the size enables the capsule to be filled with the controlled release composition of the present invention, however, capsules No. 00 to No. 5 can be obtained as commercially available products.
The controlled release composition of the present invention may be coated by a conventional method in the pharmaceutical technical field as needed. Further, a mark or a letter for discriminating the composition, or further, a division line for dividing the composition may be provided.

(11) Use of Controlled release composition
In one aspect of the invention, there is provided a use of the controlled release composition in the treatment or prevention of the disease described above, a use of the controlled release composition in the manufacture of a medicament for the treatment or prevention of the disease described above, a method for the treatment or prevention of the disease described above comprising administering a therapeutically effective amount of the controlled release composition to a patient in need thereof. The descriptions provided above with respect to the controlled release composition are applied to such use of the controlled release composition.

(12) Medical use
The Compound A has an excellent PGI₂ receptor agonistic effect and shows various medicinal effects such as a platelet aggregation inhibitory effect, a vasodilating effect, a bronchial smooth muscle dilating effect, a lipid deposition inhibitory effect, and a leukocyte activation inhibitory effect (see, for example, PTL 1 to PTL 6).

In one embodiment of the present invention, the controlled release composition of the present invention can be used as a preventive agent or a therapeutic agent for transient ischemic attack (TIA), diabetic neuropathy (see, for example, NPL 2), diabetic gangrene (see, for example, NPL 2, a peripheral circulatory disturbance [for example, chronic arterial occlusion (see, for example, NPL 3), intermittent claudication (see, for example, NPL 4), peripheral embolism, vibration syndrome, or Raynaud's disease] (see, for example, NPL 5 and NPL 6), a connective tissue disease [for example, systemic lupus erythematosus, scleroderma (see, for example, PTL 9 and NPL 7), a mixed connective tissue disease, or a vasculitic syndrome], reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (for example, acute-phase cerebral thrombosis or pulmonary embolism) (see, for example, NPL 6 and NPL 8), hypertension, pulmonary hypertension, an ischemic disease [for example, cerebral infarction or myocardial infarction (see, for example, NPL 9)], angina pectoris (for example, stable angina pectoris or unstable angina pectoris) (see, for example, NPL 10), glomerulonephritis (see, for example, NPL 11), diabetic nephropathy (see, for example, NPL 2), chronic renal failure (see, for example, PTL 10), allergy, bronchial asthma (see, for example, NPL 12), ulcer, pressure ulcer (bedsore), restenosis after coronary intervention such as atherectomy or stent implantation, thrombocytopenia by dialysis, a disease in which fibrogenesis in an organ or a tissue is involved [for example, a renal disease {for example, tubulointerstitial nephritis (see, for example, PTL 11)}, a respiratory disease {for example, interstitial pneumonia (pulmonary fibrosis) (see, for example, PTL 11), a chronic obstructive pulmonary disease (see, for example, NPL 13)}, a digestive disease (for example, hepatocirrhosis, viral hepatitis, chronic pancreatitis, or scirrhous gastric cancer), a cardiovascular disease (for example, myocardial fibrosis), a bone or articular disease (for example, bone marrow fibrosis or rheumatoid arthritis), a skin disease (for example, postoperative cicatrix, burn cicatrix, keloid, or hypertrophic cicatrix), an obstetric disease (for example, uterine fibroid), a urinary disease (for example, prostatic hypertrophy), other diseases (for example, Alzheimer's disease, sclerosing peritonitis, type I diabetes, and postoperative organ adhesion)], erectile dysfunction (for example, diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction due to chronic renal failure, erectile dysfunction after pelvic operation for resection of the prostate, or vascular erectile dysfunction associated with aging or arteriosclerosis), an inflammatory bowel disease (for example, ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis, or intestinal ulcer associated with Behcet disease) (see, for example, PTL 12), gastritis, gastric ulcer, an ischemic eye disease (for example, retinal artery occlusion, retinal vein occlusion, or ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, an intestinal damage caused by administration of a non-steroidal anti-inflammatory agent (NSAID) (for example, diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, or celecoxib) (there is no particular limitation as long as it is a damage occurring in, for example, the duodenum, small intestine, or large intestine, however, for example, a mucosal damage such as erosion or ulcer occurring in the duodenum, small intestine, or large intestine), or symptoms (for example, paralysis, dullness in sensory perception, pain, numbness, or a decrease in walking ability) associated with spinal canal stenosis (for example, cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, coexisting cervical and lumbar spinal stenosis, or sacral spinal stenosis) (see PTL 13).

In addition, the controlled release composition of the present invention is also useful as an accelerating agent for gene therapy or angiogenic therapy such as autologous bone marrow transplantation, or an accelerating agent for angiogenesis in restoration of peripheral artery or angiogenic therapy.
Particularly, the controlled release composition of the present invention is useful as an agent for the treatment or prevention of diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance, chronic arterial occlusion, intermittent claudication, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina, glomerulonephritis, diabetic nephropathy, chronic renal failure, bronchial asthma, interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease, tubulointerstitial nephritis, inflammatory bowel disease, or symptoms associated with spinal canal stenosis.

(13) Dosage Regimen
In one embodiment of the present invention, so long as it does not inhibit the effect of the invention, the dose of the controlled release composition of the present invention may be decided taking into consideration symptoms, age, sex and the like of the subject to be administered, but is usually approximately from 0.05 mg to 5.0 mg of Compound A per adult per day in the case of oral administration, and the dose may be administered once or dividing into 2 to 4 times, preferably once in a day.
In one embodiment of the present invention, so long as it does not inhibit the effect of the invention, the controlled release composition of the present invention can be used in combination with another active ingredient for the treatment or prevention or an investigational new active ingredient described above.

(14) Controlled release preparation /Controlled release formulation
The term "controlled release composition" can be used interchangeably with the term "controlled release preparation" or "controlled release formulation". The descriptions provided above with respect to the controlled release composition are applied to such controlled release preparation and controlled release formulation.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, however, the scope of the present invention is not limited to the range of these Examples.

Table 1: Lists of formulation

Table 2: Lists of formulation

Table 3: Lists of formulation

<Preparation of Tablets shown in Table 1>
1. Tablet of Ref. 1
(1) Selexipag, microcrystalline cellulose, pregelatinized starch, hypromellose 2208, sodium carbonate, and magnesium stearate were weighed according to Table 1 and blend using a blender to obtain a mixed powder.
(2) The resulting mixed powder was compressed at 1200kgf by a rotary press to obtain tablets with diameter of 6.5mm.
(3) A coating liquid was prepared by dispersing hypromellose 2910, propylene glycol, titanium dioxide and yellow ferric oxide in purified water. The resulting coating liquid was sprayed on the tablets by using a perforated coating machine to obtain film-coated tablets.
2. Tablet of Ref. 2
(1) Selexipag, D-mannitol, hydroxypropylcellulose, polyethylene oxide, hypromellose 2208, polyethylene glycol 6000, and magnesium stearate were weighed according to Table 1 and mixed to obtain a mixed powder.
(2) The resulting mixed powder was compressed at 1200kgf by a single press to obtain tablets with diameter of 10.5mm.
3. Tablet of Ex. 1
(1) Selexipag, D-mannitol, 37.6% of total Polyvinylpyrrolidone K30 were weighed according to Table 1 and blended to obtain a mixed powder. 10％(w/w)Hydroxypropylcellulose aqueous solution was sprayed onto the resulting mixed powder by using a fluidized bed granulator to obtain granules.
(2) Polyethylene oxide, hypromellose 2208, the rest of polyvinylpyrrolidone K30, and magnesium stearate were weighed according to Table 1 and blended with the resulting granules to obtain a mixed powder.
(3) The resulting mixed powder was compressed at 1200kgf by a single press to obtain tablets with diameter of 10.5mm.

Table 4: Lists of components for Ref. 1, 2 and Ex.1

<Preparation of Tablets shown in Table 2>
(1) Selexipag, D-mannitol, cornstarch, low substituted hydroxypropylcellulose were weighed according to Table 2 and blended to obtain a mixed powder. 10％(w/w) hydroxypropylcellulose aqueous solution was sprayed onto the resulting mixed powder by using a fluidized bed granulator to obtain granules.
(2) Polyethylene oxide, hypromellose 2208, polyvinylpyrrolidone K30, and magnesium stearate were weighed according to Table 1 and blended with the resulting granules by a blender to obtain a mixed powder.
(3) The resulting mixed powder was compressed by a single press to obtain tablets.

<Preparation of tablet of Ex. 8 shown in Table 3>
(1) Selexipag, D-mannitol, cornstarch, low substituted hydroxypropylcellulose were weighed according to Table 3 and blended to obtain a mixed powder. 10％(w/w) hydroxypropylcellulose aqueous solution was sprayed onto the resulting mixed powder by using a fluidized bed granulator to obtain granules.
(2) Polyethylene oxide, hypromellose 2208, polyvinylpyrrolidone K30, and magnesium stearate were weighed according to Table 3 and blended with the resulting granules by a blender to obtain a mixed powder.
(3) The resulting mixed powder was compressed at 14kN by a rotaly press to obtain tablets with diameter of 11mm.
(4) A coating liquid was prepared by dispersing hypromellose 2910, propylene glycol, titanium dioxide and yellow ferric oxide in purified water. The resulting coating liquid was sprayed on the tablets and continuously the tablets were polished with carnauba wax by using perforated coating machine to obtain film-coated tablets.
*The rest of tablets in Table 3 were prepared by referring to the preparation of Ex. 8.

Table 5: Lists of components for Ex. 8

<Gel strength of tablets>
(1) A tablet was put on the stainless sieve (JIS Z 8801,2006, APERTURE:1mm, WIRE DIA:0.56mm), and then the set of tablet and sieve were immersed in 37℃ water. After 6 hours, the set of tablet and sieve was taken from water.
(2) The tablet on the sieve was pressed down from the top and time-dependent change of load (unit: N) was recorded in order to calculate the gel strength of the tablet.
Apparatus: Digital force gauge (IMADA, ZTA-50N) and standard type vertical motorized test stand (IMADA, MX2-500N)
Condition: Moving speed 10mm/min, sensor shape 13.3 mm diameter flat tip (IMADA, A-2-, and data sampling rate every 0.1 second
(3) Gel strength was defined as the inflection point of the load (unit: N) with respect to time. The inflection point was calculated as the minimum value of F (n) satisfying the condition (i) to (iv) below.
(i) ΔF(n)＝F(n＋1)-F(n)
(ii) ΔF(n)＞0.1 N
(iii) ΔF(n)＞2ΔF(n-1)
(iv) ΔF(n+1)＞2ΔF(n-1)
F(n) is the load measured in the n-th time.

Table 6: Gel strength of tablets

<Dissolution test>
(1) A tablet was put into the Japanese Pharmacopeia 17th edition (referred to “JP” hereinafter) basket sinker, the dissolution test was carried out by JP dissolution test method 2 (paddle method).
(2) Using 900mL JP 2nd fluid for the dissolution test, the dissolution test was carried out at a paddle speed of 200 rpm.
(3) This test was performed at a liquid temperature of 37°C.
(4) The release rate of selexipag was measured by high performance liquid chromatography.

Table 7: Release rate of selexipag from tablets

Table 8: Release rate of selexipag from tablets

<Water holding capacity>
(1) A tablet was put on the stainless sieve (JIS Z 8801,2006, APERTURE:1mm, WIRE DIA:0.56mm), and then the set of tablet and sieve were immersed in 37℃ water for 6 hours.
(2) The tablet was removed from water and then, the swelled tablet weight was measured.
(3) Water holding capacity was calculated form the following formula.
Water holding capacity (%)=Swelled tablet weight (mg) / tablet weight before test (mg) × 100

Table 9: Water holding capacity of tablets

<Disintegration>
(1) A tablet was put into the Japanese Pharmacopeia 17th edition (referred to “JP” hereinafter) basket sinker, the dissolution test was carried out by JP dissolution test method 2 (paddle method).
(2) Using 900mL JP 2nd fluid for the dissolution test, the dissolution test was carried out at a paddle speed of 200 rpm.
(3) This test was performed at a liquid temperature of 37°C.
(4) When the tablet did not maintain its shape (the tablet was dissolved, disappeared, was separated) in the dissolution test for 6 hours, it was regarded that the tablet disintegrated.

Table 10: Disintegration of tablets

<Dog in vivo study>
The test tablets were administered orally to Male beagle dogs (n = 6) fasted for 17 hours at a dose level of 0.4 mg/tablet/body together with 20 ml water.
Blood samples were collected from the cephalic vein under anesthesia into heparinized tubes after oral dosing at dose of 0.6mL each time (0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours post-dose) and the samples were immediately cooled with ice.
The tubes were centrifuged (15000 rpm, 4℃, 5 min) and the plasma was transferred to a sample tube and frozen at －20℃ until analysis.
The concentration of selexipag in the plasma sample was determined by LC-MS / MS method.

Pharmacokinetic analysis
The pharmacokinetic parameters were calculated with Phoenix WinNonlin version 7.0 (Certara Princeton, NJ).

Table 11: Result of dog in vivo study

Thus, the controlled release composition of the present invention is useful as a sustained release preparation which is required to maintain the release of the active ingredient at a constant rate for a long period of time.

Claims

A controlled release composition comprising (1) a water-soluble polymer, wherein the water-soluble polymer forms a hydrogel in water and the strength of the hydrogel is less than 10N.
The controlled release composition according to claim 1, wherein an aqueous solution of (1) the water-soluble polymer has a viscosity of 1000 mPa・s or more at a concentration of 10 weight % or less.
The controlled release composition according to claim 1, wherein (1) the water-soluble polymer is at least one selected from the group of polyethylene oxide (PEO), a cellulose derivative preferably hypromellose (HPMC), methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose (HPC), hydroxyethylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, polyvinyl alcohol (PVA), alginic acid, an alkali metal salt of alginic acid, ammonium alginate, carrageenan, xanthan gum, and Arabic gum.
The controlled release composition according to claim 1, wherein (1) the water-soluble polymer is 25 to 70 weight % based on the total weight of the composition.
The controlled release composition according to any one of claims 1 to 4, further comprising (2) a water soluble additive.
The controlled release composition according to claim 5, wherein 1 g of (2) the water-soluble additive can be dissolved in 6 ml or less of water.
The controlled release composition according to any one of claims 5 or 6, wherein (2) the water-soluble additive is at least one selected from the group of polyvinylpyrrolidone (PVP) and sugars preferably sugar alcohol.
The controlled release composition according to any one of claims 5 to 7, wherein (2) the water-soluble additive is 20 to 65 weight % based on the total weight of the composition.
The controlled release composition according to any one of claims 1 to 8, further comprising (3) an active ingredient.
The controlled release composition according to claim 9, wherein (3) the active ingredient is selexipag.
The controlled release composition according to claim 9 or 10, wherein (3) the active ingredient is 0.05 to 1 weight % based on the total weight of the composition.
The controlled release composition according to any one of claims 1 to 11, wherein (1) the water-soluble polymer and (2) the water-soluble additive in the ratio is 1:0.3 to 1:2.5.
The controlled release composition according to any one of claims 1 to 12, wherein (1) the water-soluble polymer is at least one selected from the group polyethylene oxide (PEO) and hypromellose (HPMC)
The controlled release composition according to claim 13, wherein the range of molecular weight of the PEO is 900,000 to 7,000,000, preferably 2,000,000 to 7,000,000.
The controlled release composition according to claim 13 or 14, wherein the PEO is 20 to 70 weight % based on the total weight of the composition.
The controlled release composition according to any one of claims 13 to 15, wherein the range of the viscosity of an aqueous solution of the HPMC is 3000 to 140000mP・s at a concentration of 2 weight %.
The controlled release composition according to any one of claims 13 to 16, wherein the HPMC is 5 to 20 weight % based on the total weight of the composition.
The controlled release composition according to any one of claims 5 to 17, wherein (2) the water-soluble additive is at least one selected from the group of polyvinylpyrrolidone (PVP) and D-mannitol.
The controlled release composition according to claim 18, wherein K value of the PVP is 10 to 120, preferably 20 to 40.
The controlled release composition according to claim 18 or 19, wherein the PVP is 10 to 65 weight % based on the total weight of the composition.
The controlled release composition according to any one of claims 18 to 20, wherein D-mannitol is 10 to 25 weight % based on the total weight of the composition.
The controlled release composition according to any one of claims 1 to 21, wherein the strength of the hydrogel is less than 5N.
The controlled release composition according to any one of claims 1 to 22, wherein the strength of the hydrogel is measured by rheometer with moving speed of 10 mm/min and sensor size of 13.3 mm in diameter, 6 hours after putting the composition in water of 37℃.
The controlled release composition according to any one of claims 1 to 23, wherein the controlled release composition is in a form of tablet or film coated tablet.
A controlled release composition comprising (1) a water-soluble polymer, (2) a water-soluble additive, and (3) at least one active ingredient, wherein the water-soluble polymer forms a hydrogel in water and the strength of the hydrogel is less than 10N.
The controlled release composition according to any one of claims 1 to 25, wherein the release rate of the active ingredient is 0 to 50% after 6 hours in the dissolution test and/or 70 to 100% after 24 hours in the dissolution test.
The controlled release composition according to any one of claims 1 to 26, wherein the controlled release composition has the water holding capacity of 400 to 800%.
The controlled release composition according to any one of claims 1 to 27 for use in the treatment of a disease.
The controlled release composition according to any one of claim 28, wherein the disease are at least one selected from the group of symptoms associated with diabetic neuropathy, diabetic gangrene, a peripheral circulatory disturbance, chronic arterial occlusion, intermittent claudication, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina pectoris, glomerulonephritis, diabetic nephropathy, chronic renal failure, bronchial asthma, interstitial pneumonia, pulmonary fibrosis, a chronic obstructive pulmonary disease, tubulointerstitial nephritis, an inflammatory bowel disease, and spinal canal stenosis.
Use of the controlled release composition according to any one of claims 1 to 29 for the manufacture of a medicament for the treatment of a disease.
A method of preventing and/or treating a disease comprising administration of a suitable amount of the controlled release composition according to any one of claims 1 to 29 to a subject in need thereof
A method of preparing the controlled release composition according to any one of claims 1 to 29.