JP2859919B2 - Method for improving dissolution of poorly soluble drugs - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to a method for improving the dissolution of a poorly soluble drug, and more particularly, to a method of sublimating and adsorbing a poorly soluble drug to porous cellulose particles. The present invention relates to a method for improving the dissolution of a solid preparation for internal use such as a powder or a tablet.

[Conventional technology]

The medicinal component (drug) in the solid preparation for internal use elutes from the preparation into the body fluid in the digestive tract, is absorbed, enters the systemic blood, and exerts its medicinal effect. Since poorly soluble drugs have low dissolution properties, the administered drug may be excreted outside the body before dissolution, and may not be able to exhibit sufficient drug efficacy.
Bioavailability refers to the ratio of the total amount of drug entering the systemic blood from the preparation to the amount of drug administered, and this problem of improving bioavailability, the drug is eluted quickly, and the drug exerts its efficacy immediately Because of the problem of rapid action, various methods have been studied to date for improving the dissolution of poorly soluble drugs.

For example, a method of co-milling a poorly soluble drug with β-1,4 glucan powder (Japanese Patent Publication No. 53-22138), a method of kneading and kneading with a water-soluble polymer base (Japanese Patent Application Laid-Open No. 61-63614). A method of adsorbing and supporting on the surface of processed starch (Japanese Patent Application Laid-Open No. 63-101333), and a method of sublimating and adsorbing on porous glass [Nakai, Yamamoto, Terada, Ichikawa, Pharmaceutical Magazine, 105 (3), 296-299 (198)
5) is known.

[Problems to be solved by the invention]

However, the former three methods require that the β-1,4 glucan powder be subjected to grinding for a long time until the crystallinity disappears, and that a strong shear must be continuously applied with a roll mixer for a long time. Further, in order to obtain a sufficient effect, a solvent must be used and spray drying must be further performed. Further, the sublimation adsorption method is a simple and effective method, but porous glass cannot be used as a pharmaceutical.

[Means for solving the problem]

The present inventors have made intensive studies in view of the above situation, and have reached the present invention.

That is, the present invention has a specific surface area of 20 m ² / g or more, and a diameter
This is a method for improving the solubility of a poorly soluble drug, which comprises sublimating and adsorbing a poorly soluble drug to cellulose particles having a porous structure with a pore volume of 0.01 μm or more and 0.3 cm ³ / g or more.
The present invention relates to a method for improving the dissolution of a poorly soluble drug, which is simple, efficient in practical production, and can be used as a pharmaceutical preparation.

 Hereinafter, the present invention will be described.

The porous cellulose particles used in the present invention must have a specific surface area of 20 m ² / g or more and have a porous structure in which the volume of pores having a diameter of 0.01 μm or more is 0.3 cm ³ / g or more. If the specific surface area is less than 20 m ² / g, the amount of adsorbed drug is not sufficient, and if the pores having a diameter of 0.01 μm or more do not have a porous structure having a pore volume of 0.3 cm ³ / g or more, the action of moisture in the atmosphere Therefore, the pores are closed, so that it cannot be used practically. The pore volume increases the specific surface area as its value increases,
Although a more favorable effect can be obtained, the upper limit is naturally determined due to restrictions on the strength of the particles. Its value is about 1.2 cm ³ / g. Incidentally, the size of the particles is not limited in obtaining the intended effect of the present invention, but in actual manufacture of the preparation, from the viewpoint of operability (workability), the average particle size is about 100 μm or less. Desirably.

The cellulose particles used in the present invention can be produced, for example, by the following methods, but are not limited to these methods.

The cellulose particles used in the present invention can be obtained by granulating and drying particulate cellulose dispersed in an organic solvent by a spray drying method. Without using an organic solvent, cellulose particles can be prepared using water, but the pore volume of pores having a diameter of 0.01 μm or more is extremely low or becomes zero, and the cellulose used in the present invention is used. It is not suitable as a method for producing particles.

The organic solvent slurry of cellulose fine particles can be prepared by various methods. For example, a cellulose raw material is formed into fine cellulose particles by chemical treatment (acid hydrolysis or the like) and / or mechanical treatment (pulverization, milling or the like), dispersed in a predetermined organic solvent, and furthermore, the solid content concentration is adjusted. Thus, a slurry to be subjected to spray drying can be prepared. Alternatively, since the essential point is that the particulate cellulose is dispersed in the organic solvent, the purpose may be achieved by subjecting the slurry of the replacement with the organic solvent to a grinding treatment. In this case, the size of the dispersed fine particles dispersed in the organic solvent is 10 μm or less, preferably 1 μm or less, which is suitable as an intermediate material for the cellulose particles used in the present invention. As the cellulose raw material, ramie, cotton linter, wood pulp, crystalline cellulose, or the like is used. As the organic solvent, one or two of acetone, methanol, ethanol, isopropyl alcohol, n-hexane, n-pentane, cyclohexane, benzene, and the like are used. More than seeds are used. Since the dispersion medium of the slurry is an organic solvent, the spray drying must be performed using a closed system, for example, a nitrogen gas circulation type spray dryer in consideration of explosion proof.

The drug used in the present invention is a poorly water-soluble, and is a sublimable molecular crystal, for example, benzoic acid,
Ethenzamide, caffeine, camphor, salicylic acid, phenacetin and the like. By the way, the term "poorly soluble" as used herein means a solvent (water) amount required for dissolving 1 g of the solute is 30 ml or more in the table shown in the general rule 22 of the 11th revised Japanese Pharmacopoeia.

The specific operation method of the present invention is extremely simple, and it is only necessary to physically mix the drug whose dissolution property is desired and the cellulose particles and leave it in a closed container. Then, the drug sublimates and is adsorbed and carried on the pore surfaces of the cellulose particles. In the case of a drug having a low sublimation property, heating and / or
Alternatively, the processing time can be reduced by reducing the pressure. When the crystalline drug is completely supported on the cellulose particles, the X-ray diffractogram of the support becomes cellulose only, and the drug peak disappears. This indicates that the drug is adsorbed in the amorphous state in the pores of the cellulose particles. The change in the crystal state of the drug and the contact between the drug and the solvent (water) due to being carried by the cellulose particles. The increase in area is considered to be the reason for improving the dissolution.

The amount of the poorly soluble drug that can be supported on the porous cellulose particles depends on the type thereof, but is generally equal to or less than the weight of the cellulose particles. If it is more than this, it is difficult to carry the drug in an amorphous state, and it is not possible to sufficiently improve the dissolution.

〔Example〕

Hereinafter, the present invention will be described in detail with reference to examples. In addition,
Prior to the examples, a method for evaluating physical properties of cellulose particles will be described.

<Specific surface area (m ² / g)> It was measured by the BET method using nitrogen as an adsorbing substance.

<Pore diameter (μm) and pore volume (cm ³ / g)> Pore distribution was determined by mercury porosimetry using Shimadzu Corporation's Pore Cider 9300. expressed.

<Average particle size (μm)> A sample of 50 g was sieved for 30 minutes using a JIS standard sieve (Z8801-1987) with a low tap type sieve shaker manufactured by Yanagimoto Seisakusho, and the particle size at a cumulative 50% by weight was defined as the average particle size. . When the average particle diameter was not determined by the sieving method due to the small particle diameter, the measurement was performed using a microscope. Microscopy involves dispersing an appropriate amount of a sample powder in a mixed solution of equal weights of water, ethanol and glycerin, taking a photograph with an optical microscope, measuring the particle size of each particle in the photograph, and averaging the average particle size. Was used as the average particle size. The particle diameter was arbitrarily determined as a distance between two parallel lines in one direction, and the number of samples was 200.

The cellulose particle samples used in Examples and Comparative Examples were prepared by the following method.

Sample A: Commercial DP pulp in 2.4N hydrochloric acid aqueous solution, bath ratio 1
Hydrolysis at 98 ° C. for 30 minutes at 00 ×, the resulting acid-insoluble residue was neutralized, filtered and dehydrated, wet cake (50% water content) 3.
0 kg was kneaded and milled in a 10 kneader for about 1 hour. This milled wet cake was dispersed in ethanol to adjust the solid content to 8.1%. At this time, most of the particulate cellulose was in a state of being ground to 1 μm or less. When this slurry was spray-dried with a nitrogen circulation type spray dryer, it was possible to obtain a powder composed of extremely spherical particles. The coarse particles having a size of 45 μm or more of the powder thus obtained were cut with a JIS standard sieve (JIS Z8801 45 μm). Table 1 shows the basic physical properties of Sample A.

Sample B: The wet cake obtained in the same manner as in Sample A was dispersed in isopropyl alcohol, filtered, dehydrated and re-dispersed twice, and further processed with a Gaulin homogenizer 15M manufactured by Nippon Seiki Seisaku-sho at a processing pressure of The dispersion treatment was performed once at 400 kg / cm ² , and this was spray-dried in the same manner as in Sample A. The solid content of the slurry before drying was 11.9%. The obtained sample was cut using a standard sieve (JIS Z8801 180 μm) to remove coarse particles of 180 μm or more, and the spherical sample of 180 μm or less was used as Sample B. Table 1 shows the basic physical properties of Sample B.

Sample C: 250 g of commercially available crystalline cellulose "Avicel PH-101" (manufactured by Asahi Kasei Kogyo Co., Ltd.) and pulverized acetaminophen pulverized with a bantam mill AP-B type (used screen diameter: 2 mm) manufactured by Hosokawa Iron Works [Hoei Pharmaceutical Co., Ltd.] 250 g and 500 g in total are charged into a high-speed mixing granulator NSK250 manufactured by Gohashi Seisakusho, and mixed well by rotating the stirring blade at a rotation speed of 500 rpm for 2 minutes, followed by 50% ethanol. 250 g of an aqueous solution was added, and granulation was performed for 1 minute. After drying at 50 ° C. for 12 hours, the coarse particles were cut with a JIS standard sieve (JIS Z8801 710 μm). Table 1 shows the basic physical properties of Sample C.

Sample D: Sample D was commercially available crystalline cellulose “AVICEL PH-101” (manufactured by Asahi Kasei Corporation). Table 1 shows the basic physical properties of Sample D.

Example 1 Sample A and Ethenzamide Pharmacopoeia [Iwaki Pharmaceutical Co., Ltd.] (hereinafter abbreviated as EZ) were mixed at a ratio of 9: 1 and heated at 100 ° C. for 2 hours. When an X-ray diffraction measurement was performed on the heat-treated sample, no diffraction peak of EZ was observed, and only a diffractogram of cellulose was obtained. this is
This indicates that EZ is adsorbed on the surface of the cellulose particles in an amorphous state. (By the way, when the EZ content of the heat-treated sample was measured, it was 10%. This is because the EZ diffraction peak was not observed because the EZ sublimated into the air and disappeared. This heat-treated sample was subjected to the dissolution test of the main drug by the paddle method described in the Japanese Pharmacopoeia 11th Edition. The first solution of the Japanese Pharmacopoeia was used as the eluate. The test results are shown in Table 2.

Comparative Example 1 A test was performed in exactly the same manner as in Example 1 except that Sample D was used instead of Sample A. Table 2 shows the dissolution test results. (The EZ content of the sample was 10%, and the X-ray diffraction peak of EZ was clearly apparent.) Comparative Example 2 The EZ bulk powder was subjected to a dissolution test in the same manner as in Example 1. Table 2 shows the results.

Example 2 Sample B and benzoic acid (reagent grade, manufactured by Wako Pure Chemical Industries, Ltd.) were mixed at a ratio of 9: 1, and heated at 100 ° C. for 2 hours. When the X-ray diffraction measurement was performed on the heat-treated sample, the diffraction peak of benzoic acid completely disappeared as in the case of Example 1. (The content of benzoic acid in the sample was 10%.) The heat-treated sample was subjected to a dissolution test in the same manner as in Example 1. Table 3 shows the results.

Comparative Example 3 A test was performed in exactly the same manner as in Example 2 except that Sample C was used instead of Sample B. The benzoic acid content of the sample was 10%, and the X-ray diffraction peak of benzoic acid was clearly visible. Table 3 shows the results of the dissolution test.

Example 3 Sample B and benzoic acid (reagent grade, manufactured by Wako Pure Chemical Industries, Ltd.) were mixed at a ratio of 9: 1, stored at 50 ° C., and subjected to powder X-ray diffraction measurement over time.

As a result, immediately after the sample was mixed, the diffraction peaks of cellulose and benzoic acid were in a mixed state, but the peak of benzoic acid almost disappeared after 10 days of storage, and completely disappeared after 42 days of storage.

There was concern that benzoic acid may have sublimed into the air during storage of the sample, so the benzoic acid content of the sample 42 days after storage was measured, and 93% of the charge was retained. I was This result indicates that heating and / or depressurization is not necessarily required to cause the drug to sublimate and adsorb to the porous cellulose particles.

〔The invention's effect〕

ADVANTAGE OF THE INVENTION According to this invention, the dissolution property of a drug can be remarkably improved by the very simple operation of simply mixing physically poorly water-soluble drugs with porous cellulose particles. Moreover, the cellulose particles used as a carrier are substances that have been sufficiently confirmed as "safety" as pharmaceutical preparations, and are therefore a practical method that can be used immediately.

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Claims (1)

(57) [Claims] (1) a specific surface area of 20 m ² / g or more and a diameter of 0.01 μm;
A method for improving the dissolution property of a poorly soluble drug, which comprises sublimating and adsorbing a poorly soluble drug to cellulose particles having a porous structure with a pore volume of 0.3 m ³ / g or more.