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Amorphizing agent, amorphous composition comprising an amorphousizing agent, and use thereof

A shape-forming agent and composition technology, applied in the field of amorphous composition and amorphizing agent, can solve the problems of undisclosed, limited compound quality, and taking too much time

Active Publication Date: 2022-07-01
POLA PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] It is known that compounds represented by general formula (1) such as luliconazole or lanoconazole have high crystallinity and excellent antifungal activity, but on the other hand, their crystallization is also relatively high, and they are difficult to obtain in the preparation process. processing characteristics
In addition, in terms of stability, its light stability is also poor, so if too much time is spent in the process of manufacturing or formulation, the production amount of its analogue may increase (for example, see Patent Documents 1 to 2)
In addition, these patent documents also disclose that in preparations, instant crystallization can inhibit the migration into the living body, and the development of means for crystallization inhibition is also a technical problem in the preparation of the compound represented by the general formula (1)
In addition, these patent documents also disclose that α-hydroxy acids such as lactic acid inhibit the instant crystallinity of the compound represented by the general formula (1), but the mechanism by which this instant crystallinity is inhibited is completely unclear. was made public
[0005] As a technique for suppressing such crystallization, for example, a technique of forming a liquid viscous film by excessively using a plasticizer such as polyoxyethylene polyoxypropylene is known (for example, refer to Patent Document 3). However, this technique has the following disadvantages : The mass of the compound represented by the general formula (1) that can be contained in the film is limited
[0007] On the other hand, for the compound represented by the general formula (1), although the monoclinic crystal system is known, the amorphous solid is still completely unknown.

Method used

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  • Amorphizing agent, amorphous composition comprising an amorphousizing agent, and use thereof
  • Amorphizing agent, amorphous composition comprising an amorphousizing agent, and use thereof
  • Amorphizing agent, amorphous composition comprising an amorphousizing agent, and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Prepare an ethanol solution containing 1 mass % luliconazole and an ethanol solution containing 1 mass % luliconazole and 0.1 mass % polyvinylpyrrolidone, and drop them on a glass slide. After the addition, the mixture was stored at room temperature for 4 hours, after the dropwise addition, at room temperature for 1 day, and after the dropwise addition at room temperature for 4 days, and then the properties were observed under a microscope. Microscopic observation was carried out by ordinary light microscope and polarized light microscope. The result is as figure 1 shown. From this, it can be seen that differences are observed in crystallization due to the amorphousizer of the present invention, and it is known that polyvinylpyrrolidone acts as an amorphousizer. As described above, even when crystalline and amorphous coexist, a substance that should be only in a crystalline state can coexist with an amorphous (appearance of an amorphous structure) by containing the am...

Embodiment 2

[0089] For the pharmaceutical composition 1 having the following formulation, the coating formulation was prepared by the following steps.

[0090] [Table 1]

[0091]

[0092] Luliconazole and ethanol were mixed, heated and stirred at 70°C to dissolve, then lactic acid and polyvinylpyrrolidone were added, and the mixture was heated and stirred at 70°C. After confirming dissolution, the remainder of the solvent component was added for dilution and the mixture was stirred. Dissolved, after confirming dissolution, stirring and cooling to room temperature, a pharmaceutical composition 1 was obtained.

[0093]

[0094] 1 mL of the pharmaceutical composition 1 was taken into a tube, 100 µL of a solution obtained by dissolving 10 mg of neutral red in 200 µL of methanol was added to the tube, and after stirring well, it was dropped onto a glass slide, and at room temperature, passed The process of solvent volatilization and film formation was observed under microscope (400 times...

Embodiment 3

[0096]According to the sequence shown in Example 2, pharmaceutical compositions 2 and 3 (film formulations) of the formulations shown in Table 2 below were prepared. Furthermore, according to the method described in Example 2, the film formation process was observed by a microscope (400 times). Similar to the pharmaceutical composition 1, in the pharmaceutical compositions 2 and 3, an amorphous film in which the micellar structure was uniformly dispersed in the continuous phase structure was observed, and the amorphization effect was confirmed.

[0097] [Table 2]

[0098]

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PUM

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Abstract

An object of the present invention is to provide a technique for amorphizing the compound represented by the general formula (1) and / or a salt thereof. The object of the present invention is to provide an amorphous agent for the compound represented by the general formula (1) and / or its salt, which is formed from one or more selected from water-soluble polymers and acids.

Description

technical field [0001] The present invention relates to an amorphous-forming agent for the compound represented by the following general formula (1) and / or a salt thereof, an amorphous composition containing the amorphous-forming agent, and use thereof. [0002] [Chemical formula 1] [0003] Background technique [0004] Compounds represented by the general formula (1), such as luliconazole or lanoconazole, are known to have high crystallinity and excellent antifungal activity, but on the other hand, they have high crystal precipitation properties and are difficult to prepare in the production process. processing characteristics. In addition, in terms of stability, its photostability is also poor, so if too much time is spent in the process of manufacturing or formulation, the production volume of its analogs may increase (for example, see Patent Documents 1 to 2) . In addition, these patent documents disclose that immediate crystallization inhibits migration into the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/32A61K31/4178A61K47/12A61K47/38A61K47/46A61P31/10
CPCA61K47/12A61K47/32A61K47/38A61K47/46A61K31/4178A61P31/10A61K9/0019A61K9/08
Inventor 增田孝明藤井香穗梨小林浩一
Owner POLA PHARMA