Avantrombopag maleate pharmaceutical preparation as well as preparation method and application thereof

Abstract

The invention discloses an atavalopag maleate pharmaceutical preparation as well as a preparation method and application thereof, relates to the technical field of medicines, and aims to solve the problems that the atavalopag maleate is poor in dissolution rate and is not suitable for large-scale production of pharmaceutical preparations. The crystal form of the acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike acicular or rodlike The preparation method is used for preparing an atavalopag maleate pharmaceutical preparation. The acavalopag maleate pharmaceutical preparation as well as the preparation method and the application thereof provided by the invention are used for producing an acavalopag maleate solid preparation.

Description

technical field

[0001] The invention relates to the technical field of medicine, in particular to a drug of avatrombopag maleate and a preparation method and application thereof. Background technique

[0002] The chemical name of Avatrombopag Maleate Tablets is 1-(3-Chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazine-1- Base)-1,3-thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid, is a chronic liver disease developed and developed by AkaRx Inc. A drug for adult patients with associated thrombocytopenia with the following structural formula:

[0003]

[0004] Clinically, as a small molecule thrombopoietin (TPO) receptor (c-Mpl) agonist, avatropopa maleate can stimulate platelet production and increase platelet count by mimicking the biological effects of TPO. However, avatrombopag maleate belongs to BCS class II or IV and is a low-soluble crystalline drug with low solubility and almost insoluble in the pH range of 1-9. Based on this, avatrombopa...

Examples

preparation example Construction

[0044] like image 3 As shown, the preparation method of the pharmaceutical preparation of avatrombopag maleate also provided by the present invention comprises:

[0045] Step 301: Mix and sieve avatrombopag maleate and auxiliary materials to obtain a first premix. The first premix can be obtained by mixing avatrombopag maleate with the auxiliary materials, and then sieving by means of rotary granulation. During the sieving process, the aperture of the screen can be a screen with a diameter of 1.2 mm to 0.8 mm. Since the average aspect ratio of avatrombopag maleate is (2-10):1, the particle size distribution is D90≤20μm, and the adhesion degree is low when D50≤10μm, it is not easy to generate electrostatic adsorption during the sieving process , thereby reducing the probability of blocking the screen holes of the screen or getting stuck in the screen holes.

[0046] Step 302: Dry granulating and sieving the first premix to obtain a second premix.

[0047] Step 303: The sec...

Embodiment 1

[0055] The embodiment of the present invention provides a pharmaceutical oral preparation of avatrombopag maleate, the selected active ingredient is avatrombopag maleate, the particle size distribution is D50: 10 μm, D90: 20 μm; shape or rod; the average aspect ratio is 10:1; the crystal form is C type. The specification of the pharmaceutical preparation of avatrombopag maleate in the embodiment of the present invention is 20 mg, and Table 2 shows the composition ratio table of the oral pharmaceutical preparation of avatrombopag maleate at 20 mg in the embodiment of the present invention.

[0056] Table 2 Composition ratio table of avatrombopag maleate pharmaceutical oral preparation in 20mg of Example 1

[0057]

[0058]

[0059] Due to the good oral absorption of avatrombopag maleate and the stable supply of avatrombopag maleate in mass production such as industrial production It exists in the form of popa, therefore, when recording the mass of avatropopa maleate, cho...

Embodiment 2

[0065] The particle size distribution of avatrombopag maleate is D50: 8μm, D90: 15μm; the crystal habit is needle-like or rod-like; the average aspect ratio is 8:1; the crystal form is C type. The specification of the pharmaceutical preparation of avatrombopag maleate of the embodiment of the present invention is 20 mg, and Table 3 shows the composition ratio table of the oral pharmaceutical preparation of avatrombopag maleate of the embodiment of the present invention at 20 mg.

[0066] Table 3 The composition ratio table of the oral preparation of avatrombopag maleate in 20mg of embodiment two

[0067]

[0068] The preparation method of avatrombopag maleate oral pharmaceutical preparation provided in the embodiment of the present invention comprises the following steps:

[0069] In the first step, avatrombopag maleate is mixed with excipients lactose monohydrate SuperTab 11SD, microcrystalline cellulose Vivapur101, colloidal silicon dioxide, talc and crospovidone SH-SL10 ...

technical field

[0001] The invention relates to the technical field of medicine, in particular to a drug of avatrombopag maleate and a preparation method and application thereof. Background technique

[0002] The chemical name of Avatrombopag Maleate Tablets is 1-(3-Chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazine-1- Base)-1,3-thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid, is a chronic liver disease developed and developed by AkaRx Inc. A drug for adult patients with associated thrombocytopenia with the following structural formula:

[0003]

[0004] Clinically, as a small molecule thrombopoietin (TPO) receptor (c-Mpl) agonist, avatropopa maleate can stimulate platelet production and increase platelet count by mimicking the biological effects of TPO. However, avatrombopag maleate belongs to BCS class II or IV and is a low-soluble crystalline drug with low solubility and almost insoluble in the pH range of 1-9. Based on this, avatrombopa...

Examples

preparation example Construction

[0044] like image 3 As shown, the preparation method of the pharmaceutical preparation of avatrombopag maleate also provided by the present invention comprises:

[0045] Step 301: Mix and sieve avatrombopag maleate and auxiliary materials to obtain a first premix. The first premix can be obtained by mixing avatrombopag maleate with the auxiliary materials, and then sieving by means of rotary granulation. During the sieving process, the aperture of the screen can be a screen with a diameter of 1.2 mm to 0.8 mm. Since the average aspect ratio of avatrombopag maleate is (2-10):1, the particle size distribution is D90≤20μm, and the adhesion degree is low when D50≤10μm, it is not easy to generate electrostatic adsorption during the sieving process , thereby reducing the probability of blocking the screen holes of the screen or getting stuck in the screen holes.

[0046] Step 302: Dry granulating and sieving the first premix to obtain a second premix.

[0047] Step 303: The sec...

Embodiment 1

[0055] The embodiment of the present invention provides a pharmaceutical oral preparation of avatrombopag maleate, the selected active ingredient is avatrombopag maleate, the particle size distribution is D50: 10 μm, D90: 20 μm; shape or rod; the average aspect ratio is 10:1; the crystal form is C type. The specification of the pharmaceutical preparation of avatrombopag maleate in the embodiment of the present invention is 20 mg, and Table 2 shows the composition ratio table of the oral pharmaceutical preparation of avatrombopag maleate at 20 mg in the embodiment of the present invention.

[0056] Table 2 Composition ratio table of avatrombopag maleate pharmaceutical oral preparation in 20mg of Example 1

[0057]

[0058]

[0059] Due to the good oral absorption of avatrombopag maleate and the stable supply of avatrombopag maleate in mass production such as industrial production It exists in the form of popa, therefore, when recording the mass of avatropopa maleate, cho...

Embodiment 2

[0065] The particle size distribution of avatrombopag maleate is D50: 8μm, D90: 15μm; the crystal habit is needle-like or rod-like; the average aspect ratio is 8:1; the crystal form is C type. The specification of the pharmaceutical preparation of avatrombopag maleate of the embodiment of the present invention is 20 mg, and Table 3 shows the composition ratio table of the oral pharmaceutical preparation of avatrombopag maleate of the embodiment of the present invention at 20 mg.

[0066] Table 3 The composition ratio table of the oral preparation of avatrombopag maleate in 20mg of embodiment two

[0067]

[0068] The preparation method of avatrombopag maleate oral pharmaceutical preparation provided in the embodiment of the present invention comprises the following steps:

[0069] In the first step, avatrombopag maleate is mixed with excipients lactose monohydrate SuperTab 11SD, microcrystalline cellulose Vivapur101, colloidal silicon dioxide, talc and crospovidone SH-SL10 ...

Images