A kind of oral solid preparation and its application

A technology of solid preparation and disintegrant, which is applied in the field of pharmaceutical preparations to achieve the effects of improving druggability, strong hygroscopicity and improving bioavailability

Active Publication Date: 2021-08-27
WUHAN LL SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The oral solid preparation of the present invention disintegrates rapidly, improves its dissolution rate, thereby improving bioavailability, and can especially solve the problem of using conventional disintegrants for active substances (active ingredients) that are highly hygroscopic and will become viscous after absorbing moisture. The problem of not being able to disintegrate effectively

Method used

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  • A kind of oral solid preparation and its application
  • A kind of oral solid preparation and its application
  • A kind of oral solid preparation and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Embodiment 1: the preparation of formula (A) compound

[0108] Dissolve the compound of formula (B) (1.0g) in dichloromethane (5ml), stir at room temperature to form a solution, add potassium phthalimide (0.27g) to the solution, keep the reaction for 4h, cool to -50 °C, filtered, and the solvent was spin-dried to obtain a solid that was the compound of formula (A) (amorphous).

[0109] Melting point: 135-145°C.

[0110] MS / HRMS m / z: 717[M+H] + ;677[M-K] - .

[0111] 1 H-NMR (400MHz, DMSO-d 6 )δ: 1.44(t, 3H), 1.46(t, 3H), 2.38(s, 3H), 2.41(s, 3H), 2.44(s, 3H), 4.64(q, 2H), 5.29(d, 1H ), 5.32(d, 1H), 5.52(d, 1H), 5.56(d, 1H), 6.86(q, 1H), 6.90(d, 2H), 7.18(m, 2H), 7.22(d, 2H) , 7.33 (m, 1H), 7.36 (m, 1H), 7.46 (d, 1H), 7.52 (dd, 1H), 7.75 (d, 1H).

[0112] 1 H-NMR spectrum and X-ray powder diffraction spectrum are shown in Figure 5 with Image 6 .

Embodiment 2

[0113] Embodiment 2: Antihypertensive efficacy test of formula (A) compound on spontaneously hypertensive rats

[0114] Spontaneously hypertensive rats aged 12 weeks (hereinafter referred to as SHR, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were anesthetized by intraperitoneal injection of 2.5% sodium pentobarbital. The blood pressure sensing catheter was inserted into the abdominal aorta, the implant was fixed on the abdominal wall, and the postoperative daily care was performed after suturing. Animals whose systolic blood pressure exceeded 160mm Hg were selected into groups, with 8 animals in each group, 3 groups in total. The matched group is given 0.5% sodium carboxymethylcellulose (hereinafter referred to as CMC-Na); formula (B) compound group and formula (A) compound group adopt 0.5% CMC-Na to dissolve, and dosage is all at 1mg / kg A Zisartan effective dose meter, the administration volume is 4mL / kg, all are administered by intragastr...

Embodiment 3

[0125] Embodiment 3: the preparation of crystal form I

[0126] (1) Take 15 mg of the compound of formula (A), add 0.2 ml of ethanol / isopropyl ether (volume ratio 1:5) mixed solution to obtain a suspension, stir at room temperature for 1 day, filter, and dry to obtain crystal form I. See the attached XRD detection pattern figure 1 ; DSC: 184°C. According to the same method, use ethanol / n-heptane (volume ratio of 1:5) mixed solution, isopropanol / n-heptane (volume ratio of 1:5) mixed solution, or tetrahydrofuran / n-heptane (volume ratio of 1:5) mixed solution was also prepared to obtain the crystal form I.

[0127] (2) Dissolve 15 mg of the compound of formula (A) in 0.1 ml of methanol to obtain a clear solution, add 1.0 ml of isopropyl ether under stirring, and precipitate a solid, continue stirring, filter, and dry to obtain crystal form I. In the same way, use good solvent ethanol / antisolvent isopropyl ether, good solvent ethanol / antisolvent methyl tert-butyl ether, good so...

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Abstract

The invention discloses an oral solid preparation, which contains any one, two or more mixtures of crystal forms I, II, III, and IV of the compound represented by formula (A): the oral solid preparation of the present invention rapidly Disintegrate, increase its dissolution rate, thereby improving bioavailability, and especially solve the problem of active substances (active ingredients) that are highly hygroscopic and become viscous after absorbing moisture, which cannot be effectively disintegrated by conventional disintegrants question. The present invention further relates to the application of the oral solid preparation in the preparation of angiotensin II receptor antagonist, or the application in the preparation of drugs for preventing and / or treating hypertension, chronic heart failure and diabetic nephropathy.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to an oral solid preparation and its application. Background technique [0002] In general, the absorption rate of oral solid preparations depends on the dissolution (release) speed of the active substance (active ingredient) from the solid preparation, and the dissolution (release) speed of the active ingredient often depends on the disintegration speed of the solid preparation, so basically It can be considered that the disintegration rate of the oral solid dosage form is the determining step for the absorption rate of the active ingredient by the body. Most disintegrants have good water absorption and swelling properties. The role of disintegrants in oral solid preparations is to eliminate or destroy the bonding force caused by adhesives or high compression, so that they can be rapidly broken in the dissolution medium. into fine granular substances, so that the active ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/20A61K31/497C07D413/14A61K47/26A61K47/38A61K47/12A61K47/02A61P9/12A61P9/04A61P13/12A61P3/10
CPCA61K9/2009A61K9/2013A61K9/2018A61K9/2054A61K31/497C07D413/14C07B2200/13A61K31/42A61K31/45A61K31/501A61P9/00A61P9/12A61K9/0053
Inventor 梁雷陈永凯胡柳冯伟王朝东
Owner WUHAN LL SCI & TECH DEV
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