Pioglitazone hydrochloride p-aminosalicylic acid eutectic crystal, preparation method, composition and application thereof

Abstract

The invention belongs to the technical field of medicine, and discloses a piolitazone hydrochloride p-aminosalicylic acid eutectic crystal, a preparation method, a pharmaceutical composition and application thereof, specifically a piolitazone hydrochloride and p-aminosalicylic acid eutectic crystal solid substance state, a preparation method of a piolitazone hydrochloride and p-aminosalicylic acid eutectic crystal solid substance sample, and application of the piolitazone hydrochloride and p-aminosalicylic acid eutectic crystal substance as an active ingredient in peparation of drugs for reducing blood sugar and blood fat and relieving or preventing diabetic nephropathy and insulin cell degeneration.

Description

technical field

[0001] The invention discloses a cocrystal of pioglitazone hydrochloride and p-aminosalicylic acid, a preparation method, a composition and an application thereof. Specifically, the present invention discloses a cocrystal formed by pioglitazone hydrochloride and p-aminosalicylic acid; a preparation method of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal; pioglitazone hydrochloride and p-aminosalicylic acid cocrystal as The application of pharmaceutical active ingredients in the preparation of medicines for lowering blood sugar, lowering blood fat, alleviating or preventing diabetic nephropathy and insulin cell degeneration belongs to the field of medical technology. Background technique

[0002] Pharmaceutical co-crystals refer to the crystals formed by intermolecular non-covalent interaction forces between active drug molecules and co-crystal formers in a certain ratio. By forming co-crystals, drugs can greatly enrich their crystalline form...

Examples

Embodiment 1

[0060] Preparation method 1 of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal:

[0061] According to the table below, take appropriate amount of pioglitazone hydrochloride and p-aminosalicylic acid (molar ratio 1:1) into a mortar, add appropriate amount of organic solvent, manually grind for an appropriate time, and dry at a certain temperature. Carry out powder X-ray diffraction analysis to it, its diffraction pattern and figure 1 Consistent, show that the obtained sample is pioglitazone hydrochloride and p-aminosalicylic acid eutectic.

[0062] Table 3 The experimental conditions example of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal preparation method 1

[0063]

[0064] Preparation method 2 of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal:

[0065] As shown in the table below, put appropriate amount of pioglitazone hydrochloride and p-aminosalicylic acid (molar ratio 1:1) into a ball mill jar, add an appropriate amou...

Embodiment 2

[0073] Solubility characteristics of pioglitazone hydrochloride and p-aminosalicylic acid co-crystal:

[0074] Pioglitazone hydrochloride belongs to the poor medicine of water solubility, uses 0.2% SDS aqueous solution to carry out experiment, solvent system has significant difference to the dissolution rate of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal and two kinds of substances of pioglitazone hydrochloride (f 2 =26.23)( Figure 6 ). Determination with reference to the solubility determination method ("Technical Guidelines for Dissolution Test of Ordinary Oral Solid Preparations (First Draft)", 2012, October Center for Drug Evaluation). Adopt high performance liquid chromatography, utilize the chromatographic peak area data of sample to calculate the concentration of sample dissolution, take time as abscissa, and solvent concentration as ordinate to draw solubility curve respectively, and data are as shown in the following table:

[0075] The dissoluti...

Embodiment 3

[0080] The absorption characteristics and plasma concentration characteristics of pioglitazone hydrochloride and p-aminosalicylic acid co-crystal in rats:

[0081] SD rats were randomly divided into groups, 5 in each group, free to drink water, and after fasting for 12 hours, the weight of the rats was weighed, according to 20 mg·kg -1 Pioglitazone hydrochloride dosage calculation, pioglitazone hydrochloride and pioglitazone hydrochloride and p-aminosalicylic acid eutectic samples are packed in the solid dispenser, and the powder is directly inserted into the stomach of rats through the oral cavity. At 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h after administration, blood was taken from the inner canthus of the eye and placed in a heparinized tube. Centrifuge at 6500rpm for 10min, and freeze in a -40°C refrigerator until testing. Precisely draw 40 μL of heparin-anticoagulated plasma, put it in a 1.5 mL centrifuge tube, add 10 μL of internal standard ...

technical field

[0001] The invention discloses a cocrystal of pioglitazone hydrochloride and p-aminosalicylic acid, a preparation method, a composition and an application thereof. Specifically, the present invention discloses a cocrystal formed by pioglitazone hydrochloride and p-aminosalicylic acid; a preparation method of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal; pioglitazone hydrochloride and p-aminosalicylic acid cocrystal as The application of pharmaceutical active ingredients in the preparation of medicines for lowering blood sugar, lowering blood fat, alleviating or preventing diabetic nephropathy and insulin cell degeneration belongs to the field of medical technology. Background technique

[0002] Pharmaceutical co-crystals refer to the crystals formed by intermolecular non-covalent interaction forces between active drug molecules and co-crystal formers in a certain ratio. By forming co-crystals, drugs can greatly enrich their crystalline form...

Examples

Embodiment 1

[0060] Preparation method 1 of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal:

[0061] According to the table below, take appropriate amount of pioglitazone hydrochloride and p-aminosalicylic acid (molar ratio 1:1) into a mortar, add appropriate amount of organic solvent, manually grind for an appropriate time, and dry at a certain temperature. Carry out powder X-ray diffraction analysis to it, its diffraction pattern and figure 1 Consistent, show that the obtained sample is pioglitazone hydrochloride and p-aminosalicylic acid eutectic.

[0062] Table 3 The experimental conditions example of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal preparation method 1

[0063]

[0064] Preparation method 2 of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal:

[0065] As shown in the table below, put appropriate amount of pioglitazone hydrochloride and p-aminosalicylic acid (molar ratio 1:1) into a ball mill jar, add an appropriate amou...

Embodiment 2

[0073] Solubility characteristics of pioglitazone hydrochloride and p-aminosalicylic acid co-crystal:

[0074] Pioglitazone hydrochloride belongs to the poor medicine of water solubility, uses 0.2% SDS aqueous solution to carry out experiment, solvent system has significant difference to the dissolution rate of pioglitazone hydrochloride and p-aminosalicylic acid cocrystal and two kinds of substances of pioglitazone hydrochloride (f 2 =26.23)( Figure 6 ). Determination with reference to the solubility determination method ("Technical Guidelines for Dissolution Test of Ordinary Oral Solid Preparations (First Draft)", 2012, October Center for Drug Evaluation). Adopt high performance liquid chromatography, utilize the chromatographic peak area data of sample to calculate the concentration of sample dissolution, take time as abscissa, and solvent concentration as ordinate to draw solubility curve respectively, and data are as shown in the following table:

[0075] The dissoluti...

Embodiment 3

[0080] The absorption characteristics and plasma concentration characteristics of pioglitazone hydrochloride and p-aminosalicylic acid co-crystal in rats:

[0081] SD rats were randomly divided into groups, 5 in each group, free to drink water, and after fasting for 12 hours, the weight of the rats was weighed, according to 20 mg·kg -1 Pioglitazone hydrochloride dosage calculation, pioglitazone hydrochloride and pioglitazone hydrochloride and p-aminosalicylic acid eutectic samples are packed in the solid dispenser, and the powder is directly inserted into the stomach of rats through the oral cavity. At 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h after administration, blood was taken from the inner canthus of the eye and placed in a heparinized tube. Centrifuge at 6500rpm for 10min, and freeze in a -40°C refrigerator until testing. Precisely draw 40 μL of heparin-anticoagulated plasma, put it in a 1.5 mL centrifuge tube, add 10 μL of internal standard ...

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