HK1172255B - Extended release preparation - Google Patents

Description

Sustained release preparation

Technical Field

The present invention relates to a sustained-release preparation which controls the release of an active ingredient from the preparation and achieves stable and sustained release.

Background

Sustained-release preparations are useful preparations capable of reducing the frequency of administration and controlling the concentration of the agent in the blood so as to maintain the drug efficacy. For example, the frequency of administration of a medicament such as ibuprofen (half-life: 2 hours) or phenylpropanolamine hydrochloride (half-life: 4 hours) can be reduced from three times a day (usually the number of times necessary) to twice a day using a sustained release formulation. Further, the use of a sustained-release preparation makes it possible to control the concentration of a medicinal agent such as theophylline in blood so as to achieve reduction in side effects and long-term efficacy, wherein the medicinal agent has a narrow concentration range in which the efficacy is exerted or side effects occur. As one method for obtaining such sustained-release preparations, hydrogel matrices using water-soluble polymers as sustained-release matrices have been proposed (patent documents 1 to 4).

4-bromo-6- [3- (4-chlorophenyl) propoxy ] -5- (3-pyridylmethylamino) -3(2H) -pyridazinone (hereinafter abbreviated as "compound a") or a pharmaceutically acceptable salt thereof is a compound having an inhibitory effect on phosphodiesterase III enzyme, and has been shown to have a far greater prospect as a therapeutic drug for diseases such as asthma (patent document 5). However, this compound is greatly affected by the first pass effect through the liver and has a very short half-life of about 1.5 hours in plasma. Moreover, since phosphodiesterase III enzymes are well known to be present in many internal organs, it is necessary to appropriately control the concentration of a compound in plasma in order to simultaneously obtain its activity and avoid the occurrence of side effects. Therefore, preferably, the sustained-release formulation for compound a or its pharmaceutically acceptable salt lowers the maximum plasma concentration (Cmax) of compound a and maintains the effective concentration in plasma for a long time.

On the other hand, a pharmaceutically acceptable salt of compound a decreases its solubility in water at a pH range of about 4.0 or higher and becomes rather poorly soluble at about a neutral pH range similar to the intestinal environment. Therefore, the following problems arise: the formulation containing the pharmaceutically acceptable salt of compound a is poor in dissolution after oral administration and low in absorbability to dogs, i.e., bioavailability in a fasted state is about 10%. In order to improve such poor solubility and absorbability, it has been found that the presence of an organic acid such as citric acid, tartaric acid, malic acid, fumaric acid, malonic acid, succinic acid or maleic acid together with a pharmaceutically acceptable salt of compound a gives a preparation which achieves immediate release (patent document 6). It has also been found that when an organic acid such as citric acid, tartaric acid, malic acid, fumaric acid, malonic acid, succinic acid or maleic acid is present together with a pharmaceutically acceptable salt of compound a, and a hydrogel matrix such as a carboxyvinyl polymer is mixed therewith, the dissolution of compound a from the formulation can be controlled independently of pH (patent document 7). However, the preparation thus obtained only delays the time to reach the maximum plasma concentration (T) of Compound A_max) The property necessary in sustained-release preparations, i.e., C_maxIs insufficient in terms of reduction of (d) and maintenance of an effective concentration in plasma.

Reference list

Patent document

[ patent document 1] JP 63-215620A

[ patent document 2] JP 62-120315A

[ patent document 3] WO 1998/041210

[ patent document 4] JP 06-330524A

[ patent document 5] WO 1991/016314

[ patent document 6] JP 10-273440A

[ patent document 7] WO 2007/023729.

Disclosure of Invention

Technical problem

It is an object of the present invention to provide sustained release formulations that exhibit pH independent dissolution of compound a. It is another object of the present invention to provide sustained-release preparations capable of controlling C of Compound A_maxTo an appropriate amount and thus capable of maintaining the level of compound a in plasma to a level at which drug efficacy can be expected for a long time.

Means for solving the problems

Surprisingly, the present inventors have found that the above problems can be solved by mixing a pharmaceutically acceptable salt of compound a with hypromellose.

That is, the present invention provides the following:

(1) an extended release preparation characterized in that the extended release preparation comprises a pharmaceutically acceptable salt of 4-bromo-6- [3- (4-chlorophenyl) propoxy ] -5- (3-pyridylmethylamino) -3(2H) -pyridazinone and hypromellose, and an organic acid in an amount of less than 1 mass% is contained in the extended release preparation;

(2) the sustained-release formulation according to claim 1, characterized by further comprising a pharmaceutically acceptable inert carrier;

(3) the sustained-release formulation according to claim 1 or 2, characterized in that the pharmaceutically acceptable salt of 4-bromo-6- [3- (4-chlorophenyl) propoxy ] -5- (3-pyridylmethylamino) -3(2H) -pyridazinone is a hydrochloride;

(4) the sustained-release preparation according to any one of claims 1 to 3, characterized by containing the organic acid in an amount of 0.5 mass% or less based on the total preparation; or

(5) The sustained-release preparation according to any one of claims 1 to 4, characterized by not containing an organic acid.

Advantageous effects of the invention

The sustained-release formulation of the present invention successfully dissolves compound a independently of pH, although compound a has pH-dependent solubility. Furthermore, when the formulation of the present invention is administered orally, Compound A C_maxIs controlled to an appropriate amount, and the level of compound a in plasma can be maintained to a level at which the drug effect can be expected for a long time.

Drawings

Fig. 1 shows the results of dissolution testing of the sustained release formulation of example 1 (mean ± SD, n = 3).

Fig. 2 shows the results of dissolution test of the sustained-release formulation of comparative example 1 (mean ± SD, n = 3).

Fig. 3 shows the results of dissolution testing of the formulation of comparative example 2 (mean ± SD, n = 3).

Fig. 4 shows the results of dissolution test of the sustained-release formulation of comparative example 3 (mean ± SD, n = 3).

Fig. 5 shows the results of dissolution test of the sustained-release formulation of comparative example 4 (mean ± SD, n = 3).

Fig. 6 shows the results of dissolution test of the sustained-release formulation of comparative example 5 (mean ± SD, n = 3).

Fig. 7 shows the results of dissolution test of the sustained-release formulation of comparative example 6 (mean ± SD, n = 3).

Fig. 8 shows the results of dissolution test of the sustained-release formulation of comparative example 7 (mean ± SD, n = 3).

Fig. 9 shows the results of dissolution test (mean ± SD, n =3) of the sustained release formulations of example 7, example 8, and comparative example 10.

Fig. 10 shows the results of dissolution test (mean ± SD, n =3) of the sustained-release formulations of comparative examples 11 to 15.

Fig. 11 shows the results of dissolution testing (mean ± SD, n =3) of the sustained-release formulations of examples 9-11.

Fig. 12 shows the results of dissolution testing (mean ± SD, n =3) of the sustained-release formulations of examples 12 to 14.

Fig. 13 shows the plasma concentration profile of compound a after oral administration to dogs of the sustained release formulations of examples 2 or 3 or the general formulation of comparative example 8 (mean ± SD, n = 8).

Fig. 14 shows the plasma concentration profile of compound a after oral administration to dogs of the sustained release formulations of examples 4, 5 or 6 or the general formulation of comparative example 9 (mean ± SD, n = 8).

Detailed description of the preferred embodiments

The sustained-release preparation of the present invention comprises a pharmaceutically acceptable salt of compound a, which is an active ingredient. The pharmaceutically acceptable salt of compound a is not particularly limited, but is preferably an inorganic acid salt, more preferably a strong inorganic acid salt, further preferably a hydrochloride, sulfate or nitrate, and most preferably a hydrochloride. In addition to the pharmaceutically acceptable salt of compound a, the sustained release formulation of the present invention comprises hypromellose as the hydrogel matrix (which generally represents a water-swellable polymer).

In the present invention, "hypromellose" and hydroxypropyl methylcellulose are synonymous and are mixed ethers of methyl ether and hydroxypropyl ether of cellulose. In the present invention, hypromellose having various degrees of substitution for methoxy and hydroxypropyl groups may be used. Typical examples of hypromellose are substitution degree types of 1828, 2208, 2906 and 2910 (see, for example, japanese pharmacopoeia 15 th edition, page 887), any of which may be used for the sustained-release preparation of the present invention, but substitution degree types of 2208 or 2910 are preferable. Also, hypromellose having various viscosities may be used, but hypromellose having a viscosity of 50 to 10,000mPa · s is preferable.

In the present invention, the content of hypromellose in the sustained-release preparation is preferably 10 to 90 mass%, more preferably 50 to 70 mass%. The amount of hypromellose may vary with the viscosity of the matrix. For example, when the hypromellose has a viscosity of 50 to 100 mPas, its amount is preferably 40 to 90 mass%, and when the hypromellose has a viscosity of 4,000 to 100,000 mPas, its amount is preferably 10 to 40 mass%.

Preferably, the sustained release formulation of the present invention comprises substantially no organic acid. Compound a or a pharmaceutically acceptable salt thereof has very poor solubility in water, approximately at a pH range similar to that of the intestinal environment. However, surprisingly, the sustained-release formulation of the present invention achieves the desired solubility and absorbability without adding organic acids such as citric acid, tartaric acid, malic acid, fumaric acid, malonic acid, succinic acid and maleic acid, which is effective for improving the solubility expectation. Herein, "substantially not containing an organic acid" means that the organic acid is not contained in such an amount that the above-mentioned compound a or a pharmaceutically acceptable salt thereof allows to achieve improved solubility. Although it is preferable that no organic acid is contained at all, the organic acid may be contained in such a small amount that the solubility of compound a or a pharmaceutically acceptable salt thereof is not affected. When the organic acid is contained in a small amount, the amount is preferably less than 1% by mass, more preferably 0.5% by mass or less, based on the sustained-release preparation.

In the present invention, an inert carrier may be optionally added to the sustained-release preparation, and may be provided as a granulated drug, a powdered drug, an encapsulated drug, a tablet, or the like by a conventional method. In the present invention, "inert carrier" means a component which is contained in the preparation together with the agent, except for hydrogel matrix, but does not show efficacy. For example, inert carriers include excipients, lubricants, disintegrants, binders, antioxidants, coating agents, pigments, flavoring agents, surfactants, plasticizers, and the like.

As the excipient used in the present invention, for example, the following may be used alone or in combination of two or more selected from the group consisting of: lactose, crystalline cellulose, sucrose, powdered sugar, granulated sugar, glucose, mannitol, sorbitol, corn starch, acacia, dextrin, amylopectin (pulullan), light anhydrous silicic acid, low substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, synthetic aluminum silicate, and aluminum magnesium silicate (aluminum magnesium silicate).

As the lubricant used in the present invention, for example, the following may be used alone or in combination of two or more selected from the group consisting of: magnesium stearate, calcium stearate, stearic acid, talc (talc), light anhydrous silicic acid, colloidal silicon dioxide, synthetic aluminum silicate, magnesium aluminum silicate (magnesium aluminum metasilicate), calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate.

The mode of administering the sustained-release preparation of the present invention is not particularly limited. In addition to oral administration, parenteral agents such as suppositories, aerosols and the like can be appropriately selected as necessary. Oral administration is preferred.

The sustained-release preparation of the present invention can dissolve compound a independently of pH, although compound a has pH-dependent solubility. Thus, when the formulation is orally administered to a patient, the dissolution rate of the agent is not altered by the properties of the digestive fluids in the digestive tract, and thus variability in the concentration of the agent in the plasma in and between individuals can be minimized.

Furthermore, when the formulation is administered orally, Compound A C_maxCan be controlled to an appropriate amount. If C is present_maxRising to an unnecessary level, the risk of side effects increases. As a side effect due to compound a, an increase in pulse rate and the like are expected. Therefore, it is preferable to maintain the concentration in plasma in which such side effects do not occur and only drug efficacy can be expected.

Moreover, when the preparation of the present invention is orally administered, the effective concentration in plasma can be maintained for a long period of time. Since compound a tends to be broken down by metabolism, it has been expected that maintaining the concentration in the plasma for a long period of time by the sustained-release preparation of the present invention is difficult. However, surprisingly, according to the invention, good absorbability of the organism of compound a can be obtained.

Examples

(examples 1 to 3)

Tablets having a weight of 130 mg/tablet and a convex (convex) diameter of 7mm were prepared by compression molding the formulation (each tablet) shown in table 1 using a direct compression method. Herein, METOLOSE 90SH-100SR (Shin-Etsu Chemical Co., Ltd.) having a degree of substitution 2208 is used as hypromellose, FLOW LAC100(Meggle Japan Co., Ltd.) is used as lactose hydrate, Adsolider 101(Freund Corporation) is used as light anhydrous silicic acid, and one produced by Taihei Chemical industry Co., Ltd. is used as magnesium stearate.

[ Table 1]

Components	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)
					Example 1	Example 2	Example 3
Compound A (hydrochloride)	8	8	6
				Hydroxypropyl methylcellulose (2208, 100 mPa. s)	72	73	70
Lactose hydrate	48	47	52
				Light anhydrous silicic acid	0.7	0.7	0.7
Magnesium stearate	1.3	1.3	1.3
				Total of	130	130	130

(examples 4 to 6)

As shown in table 2, a formulation (tablet) was produced by using hypromellose in the same manner as in examples 1 to 3 except that compression molding was performed to prepare a tablet having a flat beveled edge (flat measured) with a diameter of 6 mm. As hypromellose, methose 60SH-50 (Shin-Etsu Chemical co., Ltd.) with a degree of substitution 2910 was used in example 4, and METHOCEL K100CR (The Dow Chemical Company) with a degree of substitution 2208 was used in examples 5 and 6. As crystalline cellulose, CEOLUS 101 (Asahi Kasei Chemicals Corporation) was used in example 4 and CEOLUS 301 (Asahi Kasei Chemicals Corporation) was used in example 5. As lactose hydrate, FLOW LAC100(Meggle Japan co., Ltd.) was used; as the anhydrous methacrylic acid copolymer LD, Eudragit L100-55 (Evonik Degussa Japan co., Ltd.) was used; as the light anhydrous silicic acid, AEROSIL 200 (Nippon AEROSIL co., Ltd.) was used; and as magnesium stearate, one produced by Taihei Chemical Industrial co.

[ Table 2]

Components	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)
					Example 4	Example 5	Example 6
Compound A (hydrochloride)	4	4	4
				Hydroxypropyl methylcellulose (2910, 50 mPa. s)	50	-	-
Hydroxypropyl methylcellulose (2208, 100 mPa. s)	-	50	30
				Crystalline cellulose	32.5	34.5	-
Lactose hydrate	-	-	54.5
				Anhydrous methacrylic acid copolymer LD	10	10	10
Light anhydrous silicic acid	0.5	0.5	0.5
				Magnesium stearate	1.0	1.0	1.0
Total of	98	100	100

Comparative examples 1 to 4

As shown in table 3, a formulation (tablet) was produced in the same manner as in example 1 except that hydroxypropyl cellulose, methyl cellulose, pregelatinized starch and polyethylene oxide were used instead of hypromellose used in examples 1 to 3. HPC-M (Nippon Soda co., Ltd.) was used as hydroxypropyl cellulose; METOLOSE SM-100 (Shin-Etsu Chemical Co., Ltd.) was used as methylcellulose; SWELSTAR MX-1 (Asahi Kasei Chemicals Corporation) was used as the pregelatinized starch; and Polyox WSR N750-LEO (the Dow Chemical company) as polyethylene oxide.

[ Table 3]

Components	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)
						Comparative example 1	Comparative example 2	Comparative example 3	Comparative example 4
Compound A (hydrochloride)	8	8	8	8
					Hydroxypropyl cellulose	72	-	-	-
Methyl cellulose	-	72	-	-
					Pregelatinized starch	-	-	72	-
Polyethylene oxide	-	-	-	72
					Lactose hydrate	48	48	48	48
Light anhydrous silicic acid	0.7	0.7	0.7	0.7
					Magnesium stearate	1.3	1.3	1.3	1.3
Total of	130	130	130	130

Comparative example 5

As shown in table 4, a formulation (tablet) was produced in the same manner as in example 1 except that carboxyvinyl polymer was used instead of hypromellose used in example 1. As carboxyvinyl polymer, CARBOPOL 974P (Lubrizol) was used.

[ Table 4]

Components	Mixing quantity (mg/tablet)
			Comparative example 5
Compound A (hydrochloride)	8
		Carboxyvinyl polymer	72
Lactose hydrate	48
		Light anhydrous silicic acid	0.7
Magnesium stearate	1.3
		Total of	130

Comparative examples 6 and 7

As shown in table 5, a formulation (tablet) was produced in the same manner as in example 1, except that citric acid hydrate was added in comparative example 6, and the free compound of compound a was used in comparative example 7 instead of the hydrochloride of compound a used in example 1. Citric acid hydrate was obtained from Iwata Chemical co., ltd., milled in a mortar, passed through a sieve with 500 μm openings, and then used.

[ Table 5]

Components	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)
				Comparative example 6	Comparative example 7
Compound A (hydrochloride)	8	-
			Compound A (free Compound)	-	7.4
Hydroxypropyl methylcellulose (2208, 100 mPa. s)	72	72
			Lactose hydrate	33	48.6
Citric acid hydrate	15	-
			Light anhydrous silicic acid	0.7	0.7
Magnesium stearate	1.3	1.3
			Total of	130	130

(comparative examples 8 and 9: ordinary tablets)

Compound a (hydrochloride), crystalline cellulose, citric acid hydrate, hypromellose (metholose TC-5R, Shin-Etsu Chemical co., Ltd.), and low-substituted hydroxypropyl cellulose (LH-31, Shin-Etsu Chemical co., Ltd.) were mixed and wet granulated according to the formulation of each tablet shown in table 6. Further, magnesium stearate was added thereto and compression molding was performed to obtain a tablet having a weight of 150mg and a convex surface with a diameter of 7.5mm (comparative example 8) and a tablet having a weight of 75mg and a convex surface with a diameter of 6mm (comparative example 9). The general formulation (tablet) was obtained by film-coating the tablet with Opadry AMB (Colorcon Japan, LLC) and further by glossing with carnauba wax and light anhydrous silicic acid.

[ Table 6]

(ordinary tablet)

Components	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)
				Comparative example 8	Comparative example 9
Compound A (hydrochloride)	4	2
			Crystalline cellulose	Proper amount of	Proper amount of
Citric acid hydrate	15	7.5
			Hydroxypropyl methylcellulose (2910, 6 mPa. s)	4.5	2.25
Low-substituted hydroxypropyl cellulose	15	7.5
			Magnesium stearate	0.6	0.3
Opadry AMB	7.5	5.0
			Carnauba wax	Micro-scale	Micro-scale
Light anhydrous silicic acid	Micro-scale	Micro-scale
			Total of	157.5	80.0

(examples 7 and 8 and comparative example 10)

As shown in table 7, a formulation (tablet) was produced in the same manner as in example 1, except that citric acid hydrate was added in examples 7, 8 and comparative example 10. Citric acid hydrate was obtained from Iwata Chemical co., ltd., milled in a mortar, passed through a sieve with 500 μm openings, and then used.

[ Table 7]

Components	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)
					Example 7	Example 8	Comparative example 10
Chemical combinationSubstance A (hydrochloride)	8	8	8
				Hydroxypropyl methylcellulose (2208, 100 mPa. s)	72	72	72
Lactose hydrate	47.87	47.35	46.7
				Citric acid hydrate	0.13	0.65	1.3
Light anhydrous silicic acid	1.3	1.3	1.3
				Magnesium stearate	0.7	0.7	0.7
Total of	130	130	130

Comparative examples 11 to 15

As shown in table 8, a formulation (tablet) was produced in the same manner as in example 1 except that tartaric acid, DL-malic acid, fumaric acid, succinic acid or maleic acid was added. Tartaric acid was obtained from Dainippon Sumitomo Pharma co., ltd., DL-malic acid was obtained from Fuso Chemical co., ltd., fumaric acid and succinic acid were obtained from Nippon Shokubai co., ltd., and maleic acid was obtained from Wako Pure Chemical Industries, ltd. Each of these acids was ground in a mortar, passed through a sieve having 500 μm openings, and then used.

[ Table 8]

Components	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)
							Comparative example 11	Comparative example 12	Comparative example 13	Comparative example 14	Comparative example 15
Compound A (hydrochloride)	8	8	8	8	8
						Hydroxypropyl methylcellulose (2208, 100 mPa. s)	72	72	72	72	72
Lactose hydrate	35	35	35	35	35
						Tartaric acid	13	-	-	-	-
DL-malic acid	-	13	-	-	-
						Fumaric acid	-	-	13	-	-
Succinic acid	-	-	-	13	-
						Maleic acid	-	-	-	-	13
Light anhydrous silicic acid	1.3	1.3	1.3	1.3	1.3
						Magnesium stearate	0.7	0.7	0.7	0.7	0.7
Total of	130	130	130	130	130

(examples 9 to 11)

As shown in table 9, a formulation (tablet) was produced in the same manner as in example 1 except that the amount of hypromellose was changed in examples 9 to 11.

[ Table 9]

Components	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)
					Example 9	Example 10	Example 11
Compound A (hydrochloride)	8	8	8
				Hydroxypropyl methylcellulose (2208, 100 mPa. s)	58.5	91	97.5
Lactose hydrate	61.5	29	22.5
				Light anhydrous silicic acid	1.3	1.3	1.3
Magnesium stearate	0.7	0.7	0.7
				Total of	130	130	130

(examples 12 to 14)

As shown in table 10, a formulation (tablet) was produced in the same manner as in example 1 except that the substitution type, viscosity and amount of hypromellose were changed in examples 12 to 14. As hypromellose, methoose 60SH-50 with substitution 2910 was used in example 12; METOLOSE 65SH-4000(Shin-Etsu Chemical Co., Ltd.) with a degree of substitution 2906 was used in example 13; and METOLOSE 90SH-100000SR (Shin-Etsu Chemical Co., Ltd.) with a degree of substitution 2208 was used in example 14.

[ Table 10]

Components	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)	Mixing quantity (mg/tablet)
					Example 12	Example 13	Example 14
Compound A (hydrochloride)	8	8	8
				Hydroxypropyl methylcellulose (2910, 50 mPa. s)	117	-	-
Hydroxypropyl methylcellulose (2906, 4000 mPa. s)	-	19.5	-
				Hydroxypropyl methylcellulose (2208, 100000 mPa.s)	-	-	13
Lactose hydrate	3	100.5	107
				Light anhydrous silicic acid	1.3	1.3	1.3
Magnesium stearate	0.7	0.7	0.7
				Total of	130	130	130

Test example 1 (dissolution test)

The dissolution test was carried out according to japanese pharmacopoeia method No. 2, 15 edition (paddle method). As the test liquids, liquid 1 (pH: 1.2) and liquid 2 (pH: 6.8) prescribed in Japanese pharmacopoeia 15 edition were each used in an amount of 900 ml. In the test, a settler was used and the test was performed at a paddle rotation speed of 50rpm and a temperature of 37 ℃.

In the present invention, the judgment of whether the dissolution of the sustained-release preparation is dependent or independent of pH is made by referring to the following documents: yakushokushinsa, number 1124004, 24.2006, Director, Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health and Welfare "guidelines for Bioequaluation Test of Generic Drugs". In particular, when the dissolution properties of one formulation in liquid 1 and liquid 2 satisfy the "similarity judgment criterion" described below, the dissolution of the sustained-release formulation is judged to be pH independent.

(similarity judgment Standard)

a. When the average dissolution rate of liquid 1 of the formulation became 80% or more after 20 hours from the start of the dissolution test, the f2 value was 42 or more.

b. When the average dissolution rate of liquid 1 of the formulation became 50% or more but less than 80% after 20 hours from the start of the dissolution test, the f2 value was 46 or more.

c. When the average dissolution rate of liquid 1 of the formulation did not reach 50% after 20 hours from the start of the dissolution test, the f2 value was 53 or greater.

Here, the value of f2 is represented by the following formula

Where Ti is the average dissolution rate of liquid 2 of the formulation when comparing the average dissolution rates, Ri is the average dissolution rate of liquid 1 of the formulation when comparing the average dissolution rates, and n is the number of time points in which the average dissolution rates are compared.

The time point at which the average dissolution rates were compared was determined by the following criteria.

(1) When the average dissolution rate of the liquid 1 became 80% or more after 15 minutes to 30 minutes from the start of the dissolution test, the time points were 15 minutes, 30 minutes, and 45 minutes.

(2) When the average dissolution rate of liquid 1 became 80% or more after 30 minutes to 20 hours from the start of the dissolution test, the time points were Ta/4, 2Ta/4, 3Ta/4 and Ta, wherein Ta is a suitable time point in which the average dissolution rate of liquid 1 became 80%.

(3) When the average dissolution rate of liquid 1 of the formulation did not reach 80% after 20 hours from the start of the dissolution test, the time points were Ta/4, 2Ta/4, 3Ta/4 and Ta, where Ta is a suitable time point at which the average dissolution rate of liquid 1 became 80% of the value determined 20 hours after the start of the dissolution test for liquid 1.

For example, for the formulation of example 1 shown in fig. 1, the similarity judgment criterion "a" was employed because the average dissolution rate of liquid 1 of the formulation was 80% or more after 20 hours from the start of the dissolution test. Also, since the time point at which the average dissolution rate of liquid 1 of the formulation reached 80% was 6 hours after the start of the dissolution test (Ta = 6 hours), the f2 value was calculated at four points at which the time points at which the average dissolution rates were compared were 1.5, 3, 4.5, and 6 hours.

Fig. 1-12 show the results up to 10 hours after the start of the dissolution test.

As shown in fig. 1, in the formulation of example 1, immediate dissolution of compound a was inhibited and a stable zero-order release was achieved. Since the difference between liquid 1 and liquid 2 was difficult to identify in terms of the dissolution rate of compound a and the f2 value was 42 or greater, it was found that dissolution was independent of pH.

As shown in fig. 9, in the formulations of examples 7 and 8, immediate dissolution of compound a was inhibited and a stable zero-order release was achieved. Since the difference between liquid 1 and liquid 2 was difficult to identify in terms of the dissolution rate of compound a and the f2 value was 42 or greater, it was found that dissolution was independent of pH.

As shown in fig. 11, in the formulations of examples 9, 10 and 11, immediate dissolution of compound a was suppressed and a stable zero-order release was achieved. Since the difference between liquid 1 and liquid 2 was difficult to identify in terms of the dissolution rate of compound a and the f2 value was 42 or greater, it was found that dissolution was independent of pH.

As shown in fig. 12, in the formulations of examples 12, 13 and 14, immediate dissolution of compound a was inhibited and a stable zero-order or primary (primary) release was achieved. Since the difference between liquid 1 and liquid 2 was difficult to identify in terms of the dissolution rate of compound a and the f2 value was 42 or greater, it was found that dissolution was independent of pH.

In the formulation of comparative example 2 shown in fig. 3, immediate dissolution cannot be inhibited. Further, the f2 value by which the pH dependence was judged could not be calculated.

As shown in fig. 2 and 4 to 8, in the formulations of comparative examples 1, 3, 4, 5, 6 and 7, sustained release was achieved but the f2 value was below the norm (less than 42 in comparative examples 1, 4, 6 and 7, and less than 46 in comparative examples 3 and 5), and thus it was found that dissolution was highly pH dependent.

As shown in fig. 9, in the formulation of comparative example 10, sustained release was achieved but the f2 value was less than 42, and thus it was found that dissolution was highly pH dependent.

As shown in fig. 10, in the formulations of comparative examples 11, 12, 13, 14 and 15, sustained release was achieved but the f2 values were all less than 42, and thus it was found that dissolution was highly pH dependent.

Test example 2 (dog BA test 1)

Tablets of the formulation of example 2 or example 3 or the general formulation of comparative example 8 were orally administered to each of eight beagle dogs who had fasted for 16 hours. After administration, blood was collected from the cutaneous vein on the radial side of the forelimb and centrifuged. The concentration of compound A (free compound) in plasma was determined by LC/MS/MS method using a mass spectrometer AP14000 (produced by Applied Biosystems/MDS SCIEX). And, calculating pharmacokinetic parameters C obtained by pharmacokinetic analysis_maxAnd T_maxAnd the area under the plasma concentration-time curve (AUC) and is shown in table 11. Relative bioavailability (relative BA) was calculated by the following method: using comparative example 8 as a control, the ratio of the AUC from examples 2 and 3 to the AUC of comparative example 8, and further assuming that the doses are the same as each other.

From FIG. 13 and Table 11, it was found that the sustained-release tablets of examples decreased C compared to the conventional tablet of comparative example 8_maxWithout decreasing AUC and maintaining plasma concentrations over a long period of time.

[ Table 11]

Drug delivery preparation	Dosage (mg/dog)	Cmax(ng/mL)	Tmax(hr)	AUC(ng·hr/mL)	Relative BA (%)
						Comparative example 8	4	3.34±2.05	0.688±0.579	4.16±1.74	100
Example 2	8	1.35±0.346	2.69±1.75	7.54±2.51	90.6
						Example 3	6	1.23±0.597	1.88±1.09	5.21±1.35	83.5

Test example 3 (dog BA test 2)

Comparative oral administration in the same manner as in test example 2The general tablet of example 9 and each of the sustained release formulations of examples 4, 5 and 6. The plasma concentration profile is shown in figure 14 and the pharmacokinetic parameters are shown in table 12. From FIG. 14 and Table 12, it was found that the sustained-release tablets of examples reduced C compared with the conventional tablets of comparative example 9_maxWithout decreasing AUC and maintaining plasma concentrations over a long period of time.

[ Table 12]

Drug delivery preparation	Dosage (mg/dog)	Cmax(ng/mL)	Tmax(hr)	AUC(ng·hr/mL)	Relative BA (%)
						Comparative example 9	2	1.18±0.141	0.656±0.297	1.34±0.220	100
Example 4	4	0.671±0.237	2.88±2.17	2.93±1.21	109.3
						Example 5	4	0.669±0.318	2.81±2.17	3.56±1.98	132.8
Example 6	4	1.07±0.350	2.00±1.07	3.02±1.72	112.7

Industrial applicability

According to the present invention, it becomes possible to provide a sustained-release preparation which can dissolve a medicinal agent independently of pH, although the medicinal agent has a solubility depending on pH. Furthermore, by oral administration, it becomes possible to provide a sustained-release preparation which can lower the maximum plasma concentration of the agent compared with the ordinary preparation and can maintain the effective concentration of the agent in the plasma for a long period of time.

Claims (5)

1. A sustained-release preparation characterized in that the sustained-release preparation comprises a pharmaceutically acceptable salt of 4-bromo-6- [3- (4-chlorophenyl) propoxy ] -5- (3-pyridylmethylamino) -3(2H) -pyridazinone and hypromellose, an organic acid is mixed in an amount of less than 1% by mass in the sustained-release preparation, and the content of hypromellose in the sustained-release preparation is 10 to 90% by mass.

2. The sustained-release formulation according to claim 1, characterized by further comprising a pharmaceutically acceptable inert carrier.

3. The sustained-release formulation according to claim 1 or 2, characterized in that the pharmaceutically acceptable salt of 4-bromo-6- [3- (4-chlorophenyl) propoxy ] -5- (3-pyridylmethylamino) -3(2H) -pyridazinone is a hydrochloride salt.

4. The sustained-release preparation according to claim 1 or 2, characterized in that the organic acid is mixed in an amount of 0.5 mass% or less based on the total preparation.

5. The sustained-release preparation according to claim 1 or 2, characterized by not containing an organic acid.