US2008311212A1PendingUtilityA1
Crystalline isoxazole derivative and pharmaceutical preparation thereof
Assignee: DAINIPPON SUMITOMO PHARMA COPriority: Mar 27, 2001Filed: Aug 20, 2008Published: Dec 18, 2008
Est. expiryMar 27, 2021(expired)· nominal 20-yr term from priority
A61P 5/14A61P 7/04A61P 37/02A61P 7/06A61P 37/08A61P 29/00A61P 25/28A61P 3/10C07D 261/14A61P 19/02A61P 21/04A61P 17/06A61P 11/00A61P 1/04A61P 17/12A61P 19/06A61K 31/5377A61P 1/16A61P 13/12C07D 413/12
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Claims
Abstract
Crystalline 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}-isoxazole that exhibits the following angle of diffraction (2θ) and relative intensity in a powder X-ray diffraction pattern, is very easy to handle and stable in a process of its formulation into a pharmaceutical preparation. 2θ (°) Relative intensity (%) 6.1 100 14.1 55 16.0 74 18.5 36 20.0 43 25.4 39
Claims
exact text as granted — not AI-modified1 . A pharmaceutical preparation comprising crystalline 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}isoxazole that exhibits the following angle of diffraction (20) and relative intensity in a powder X-ray diffraction pattern:
2θ (°)
Relative intensity (%)
6.1
100
14.1
55
16.0
74
18.5
36
20.0
43
25.4
39
2 . A pharmaceutical preparation according to claim 1 , which is a therapeutic or prophylactic agent for autoimmune diseases or inflammatory diseases.
3 . A process for producing crystalline 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}isoxazole by crystallizing 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}isoxazole from a mixed solvent of a hydrophilic solvent and water.
4 . A production process according to claim 3 , wherein the hydrophilic organic solvent is 2-propanol, methanol or acetone.
5 . An oral pharmaceutical preparation comprising crystalline 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}isoxazole according to claim 1 , a water-soluble excipient in an amount of 2.5 times or more the weight of the crystalline isoxazole derivative, a derivative, a disintegrating agent and a water-soluble binder.
6 . An oral pharmaceutical preparation according to claim 5 , wherein the contents of the ingredients are the following percentages by weight:
the crystalline 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}isoxazole: 25% or less, the water-soluble excipient: 35 to 90%, the disintegrating agent: 1 to 40%, the water-soluble binder: 1 to 5%.
7 . An oral pharmaceutical preparation according to claim 5 , wherein the water-soluble excipient is lactose, mannitol, erythritol, xylitol, or a mixture thereof.
8 . An oral pharmaceutical preparation according to claim 5 , wherein the disintegrating agent is sodium croscarmelose, sodium carboxymethyl starch, crospovidone, calcium carmelose, low-substituted hydroxypropyl cellulose, starch, or a mixture thereof.
9 . An oral pharmaceutical preparation according to claim 5 , wherein the water-soluble binder is hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, or a mixture thereof.
10 . An oral pharmaceutical preparation according to claim 5 , which is tablets.
11 . A pharmaceutical preparation according to claim 5 , which is a therapeutic or prophylactic agent for autoimmune diseases or inflammatory diseases.
12 . A process for producing an oral pharmaceutical preparation according to claim 5 by the following steps:
(1) mixing the water-soluble excipient and the disintegrating agent to prepare a mixture, (2) dispersing crystalline 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}isoxazole that exhibits the following angle of diffraction (20) and relative intensity in a powder X-ray diffraction pattern:
2θ (°)
Relative intensity (%)
6.1
100
14.1
55
16.0
74
18.5
36
20.0
43
25.4
39
in an aqueous solution of the water-soluble binder to prepare a suspension,
(3) spraying the suspension of (2) on the mixture of (1) to prepare granules, and
(4) compression-molding the granules of (3).
13 . A process for producing an oral pharmaceutical preparation according to claim 5 by the following steps:
(1) mixing crystalline 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}isoxazole that exhibits the following angle of diffraction (20) and relative intensity in a powder X-ray diffraction pattern:
2θ (°)
Relative intensity (%)
6.1
100
14.1
55
16.0
74
18.5
36
20.0
43
25.4
39
the water-soluble excipient and the disintegrating agent to prepare a mixture,
(2) preparing an aqueous solution of the water-soluble binder,
(3) spraying the aqueous solution of (2) on the mixture of (1) to prepare granules, and
(4) compression-molding the granules of (3).
14 . A process for producing an oral pharmaceutical preparation according to claim 5 by the following steps:
(1) mixing the water-soluble excipient and the disintegrating agent to prepare a mixture, (2) dispersing crystalline 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}isoxazole that exhibits the following angle of diffraction (20) and relative intensity in a powder X-ray diffraction pattern:
2θ (°)
Relative intensity (%)
6.1
100
14.1
55
16.0
74
18.5
36
20.0
43
25.4
39
in an aqueous solution of the water-soluble binder to prepare a suspension and which is in a grounded state and has an undersize particle D50% particle size of 10 μm or less,
(3) spraying the suspension of (2) on the mixture of (1) to prepare granules, and
(4) compression-molding the granules of (3).
15 . A process for producing an oral pharmaceutical preparation according to claim 5 by the following steps:
(1) mixing crystalline 3-[(1S)-1-(2-fluorobiphenyl-4-yl)ethyl]-5-{[amino(morpholin-4-yl)methylene]amino}isoxazole that exhibits the following angle of diffraction (20) and relative intensity in a powder X-ray diffraction pattern:
2θ (°)
Relative intensity (%)
6.1
100
14.1
55
16.0
74
18.5
36
20.0
43
25.4
39
the water-soluble excipient and the disintegrating agent to prepare a mixture and which is in a grounded state and has an undersize particle D50% particle size of 10 μm or less,
(2) preparing an aqueous solution of the water-soluble binder,
(3) spraying the aqueous solution of (2) on the mixture of (1) to prepare granules, and
(4) compression-molding the granules of (3).
16 . An oral pharmaceutical preparation according to claim 6 , wherein the water-soluble excipient is lactose, mannitol, erythritol, xylitol, or a mixture thereof; the distintegrating agent is sodium croscarmelose, sodium carboxymethyl starch, crospovidone, calcium carmelose, low-substituted hydroxypropyl cellulose, starch, or a mixture thereof; and the water-soluble binder is hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, or a mixture thereof.
17 . An oral pharmaceutical preparation according to claim 15 , which is tablets.Join the waitlist — get patent alerts
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