JPH03264537A - Method for improving solubility of scarcely soluble drug - Google Patents

Abstract

PURPOSE:To remarkably improve the dissolution property of a drug by simply mixing a scarcely soluble drug to porous cellulose particles having specified specific surface area and pore volume and absorbing the drug to the particle by sublimation. CONSTITUTION:The dissolution property of a scarcely soluble drug can be improved by mixing the drug to porous cellulose particles having an average particle diameter of <=100mum and a specific surface area of >=20m<2>/g and containing 0.3-1.2cm<3>/g of pores having diameter of >=0.01mum and absorbing the drug to the particle by sublimation. The cellulose particles can be produced by dispersing fine cellulose particles (e.g. ramie, cotton linter, wood pulp or crystalline cellulose) in an organic solvent (e.g. acetone, methanol, n-hexane or benzene) and granulating and drying by spray-drying process. The drug to be used in the present process is a sublimable molecular crystal scarcely soluble in water, e.g. benzoic acid, caffeine, camphor or salicylic acid.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to a method for improving the dissolution properties of poorly soluble drugs, and more specifically, the present invention relates to a method for improving the dissolution properties of poorly soluble drugs. In particular, the present invention relates to a formulation method for improving the dissolution properties of solid formulations for internal use such as powders and tablets.

[Conventional technology]

The medicinal ingredients (drugs) in solid preparations for internal use are eluted from the preparation into body fluids within the gastrointestinal tract, absorbed, enter the systemic circulation, and exert their medicinal effects. Poorly soluble drugs have low dissolution, so
Administered drugs may be excreted from the body before they are completely eluted, resulting in insufficient medicinal efficacy. The ratio of the total amount of drug that enters the systemic circulation from a preparation to the amount of administered drug is called pyroavailability, and the problem of improving pyoherability is that the drug dissolves quickly and exerts its efficacy quickly. Due to the problem of quick effect,
Various methods have been studied to date to improve the dissolution properties of poorly soluble drugs.

For example, a method of co-pulverizing a poorly soluble drug with β-1,4 glucan powder (Japanese Patent Publication No. 53-22138), a method of kneading a poorly soluble drug with a water-soluble polymer base (Japanese Patent Publication No. 61-63614)
``Nakai, Dashi, Terada, Ichikawa, Pharmaceutical Journal, Norikai (3), 296. -299 (1985) J, etc. are known.

[Problem to be solved by the invention]

However, in the former three, the grain must be crushed for a long time until the crystallinity of the β-1,4 glucan powder disappears, and a strong shearing process must be continued for a long time with a roll mixer. Furthermore, in order to obtain a sufficient effect, it is necessary to use a solvent and further perform spray drying, which is a drawback in that it is inefficient in actual production. Further, although the sublimation adsorption method is a simple and effective method, porous glass cannot be used as a pharmaceutical product.

[Means to solve the problem]

In view of the above-mentioned situation, the present inventors have conducted extensive research and have arrived at the present invention.

That is, the present invention has a specific surface area of 2 On? /g or more, and the volume of pores with a diameter of 0.01 μm or more is 0.3 cffl/
This is a method for improving the elution property of a poorly soluble drug, which is characterized by sublimating and adsorbing the poorly soluble drug onto cellulose particles having a pore structure of 1.5 g or more. The present invention relates to a method for improving the dissolution of poorly soluble drugs, which is simple and efficient in practical production, and furthermore, can be used in pharmaceutical preparations.

The present invention will be explained below.

The porous cellulose particles used in the present invention must have a specific surface area of 20 m2/g or more and a porous structure in which the volume of pores with a diameter of 0.01 μm or more is 0.3 c+ft/g or more. If the specific surface area is less than 2 (lnf/g), the adsorption amount of the drug will not be sufficient, and if the diameter is less than 0.01
Unless the porous structure has pores of μm or more in size and a pore volume of 0.3 crfl/g or more, the pores will be blocked by the action of moisture in the atmosphere and cannot be put to practical use.

As the value of the pore volume increases, the specific surface area increases, and a more favorable effect can be obtained, but the upper limit of the pore volume is naturally determined due to constraints on the strength of the particles. The value is approximately 1.2 cffl/g. Incidentally, there are no restrictions on the size of the particles in order to obtain the desired effect of the present invention, but in terms of operability (workability) when actually manufacturing the preparation, the average particle size should be approximately 100 μm.
It is desirable that it be less than m.

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 are obtained by granulating finely divided cellulose dispersed in an organic solvent using a spray drying method.
It can be obtained by drying. Cellulose particles can be prepared using water without using an organic solvent, but the pore volume of pores with a diameter of 0.01 μm or more is extremely low or O, and the particles used in the present invention This method is inappropriate as a method for producing cellulose particles.

The organic solvent slurry of cellulose microparticles can be prepared in various ways. For example, cellulose raw materials can be treated chemically (acid hydrolysis, etc.) and/or mechanically (pulverization,
A slurry to be subjected to spray drying can be prepared by turning the cellulose particles into finely divided cellulose particles (by grinding, etc.), dispersing them in a predetermined organic solvent, and further adjusting the solid content concentration. Alternatively, since the point is that the particulate cellulose is dispersed in the organic solvent, the objective may be achieved by adding a grinding treatment to the organic solvent-substituted slurry. In this case, it is appropriate that the size of the dispersed fine particles dispersed in the aqueous solvent is 10 μm or less, preferably 1 m or less, as an intermediate raw material for the cellulose particles used in the present invention. As raw materials for cellulose, cotton linters, wood pulp, crystalline cellulose, etc. are used, and as organic solvents, one or two of acetone, methanol, ethanol, isopropyl alcohol, n-hexane, n-pentane, cyclohexane, benzene, etc. are used. More than one species is used.

Since the dispersion medium of the slurry is an organic solvent, spray drying must be carried out using a closed system with explosion protection in mind, such as a nitrogen gas circulation type spray dryer.

Furthermore, the drug used in the present invention is poorly water soluble, and
Sublimable molecular crystals, such as benzoic acid, ethenzamide, caffeine, camphor, salicylic acid, and zenacetin. By the way, "poorly soluble" here refers to the following in the table shown in General Rule 22 of the 11th revised Japanese Pharmacopoeia.
The amount of solvent (water) required to dissolve 1g of solute is 30al1
Refers to something that is more than that.

The specific operating method of the present invention is extremely simple, and it is sufficient to physically mix the cellulose particles with the drug whose dissolution properties are desired to be improved, and then leave the mixture in a closed container.

Then, the drug sublimates and is adsorbed and supported on the pore surfaces of the cellulose particles. In the case of a drug with low sublimability, the treatment time can be shortened by heating and/or reducing the pressure to an extent that it does not decompose. When the crystalline drug is completely supported on the cellulose particles, the X-ray diffractogram of the support becomes only of cellulose, and the drug peak disappears. This indicates that the drug is adsorbed in the pores of cellulose particles in an amorphous state, and this is due to changes in the crystalline state of the drug and contact with the solvent (water) due to the drug being supported on the cellulose particles. The increase in area is considered to be the reason for improving dissolution.

The amount of poorly soluble drug that can be supported on porous cellulose particles depends on the type of drug, but is generally equal to or less than the weight of the cellulose particles. If it is more than that, it is difficult to support the drug in an amorphous state, and sufficient improvement in dissolution cannot be expected.

〔Example〕

Hereinafter, the present invention will be explained in detail with reference to Examples.

In addition, prior to Examples, a method for evaluating the physical properties of cellulose particles will be explained.

<Specific surface area (po/g)> Measurement was performed using the BET method using nitrogen as an adsorbent.

Pore diameter (μm) and pore volume (cJ/g) > Pore distribution was determined by mercury porosimetry using Bore Sizer 9300 manufactured by Shimadzu Corporation, and the pore volume was expressed as the volume of mercury permeated into the particles.

<Average particle size (μm)> 50 g of sample was sieved using a JIS standard sieve (Z8801-1987) using a rotary tube sieve shaker manufactured by Yanagimoto Seisakusho.
The particles were sieved for a minute, and the cumulative particle size of 50% by weight was defined as the average particle size.

If the particle size was small and the average particle size could not be determined by the sieve method, it was measured using a microscope. For microscopy, the sample powder is mixed with water,
An appropriate amount of the particles was dispersed in a mixed solution of equal weights of ethanol and glycerin, and this was photographed using an optical microscope. The particle size of each particle in the photograph was measured, and the average was taken as the average particle size. The particle diameter was measured as the distance between two parallel lines in one arbitrary direction, and the number of samples was 20.
It was set to 0.

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

Sample A: commercially available DP pulp in a 2.4 N hydrochloric acid aqueous solution,
Hydrolyzed at 98°C for 130 minutes at a bath ratio of 100 times, neutralized the resulting acid-insoluble residue, filtered and dehydrated 3.0 kg of wet cake (water content 50%), kneaded in a 1042 kneader for about 1 hour, Grinded. This ground wet cake was dispersed in ethanol and adjusted to a solid content concentration of 8.1%.

At this time, most of the particulate cellulose was ground to 1 μm or less. When this slurry was spray-dried using a nitrogen circulating spray dryer, a powder consisting of extremely spherical particles could be obtained.

The coarse particles of 45 μm or more of the powder obtained in this way are
Cut with a standard sieve (JIS Z880145μm),
The sieved fraction was designated as sample A. The basic physical properties of sample A are
Shown in the table.

Sample B: The wet cake obtained in the same manner as Sample A was dispersed in isopropyl alcohol, filtered, dehydrated, and redispersed twice, and further processed using Gorlin Homogenizer 15M model manufactured by Shiraki Seiki Seisakusho ■ at a processing pressure of 400 kg / cffl
Dispersion treatment was carried out once, and this was spray-dried in the same manner as Sample A. The solid content concentration of the slurry before drying was 9%. The obtained sample was passed through a standard sieve (JIS Z8B0
1180 μm) to cut coarse particles of 180 μm or more, and the spherical sample of 180 μm or less was designated as Sample B. The basic physical properties of Sample B are shown in Table 1.

Sample C: Commercially available crystalline cellulose “Avicel P) l-101
J [manufactured by Asahi Kakogyo ■] 250g and pharmacopoeial acedoacunophen [manufactured by Hoei Yakuko ■] 25 finely pulverized using Pantam Mill AP-B type (screen diameter used: 2 mm) manufactured by Seiyo Iron Works ■
0g and a total of 500g using a high-speed mixing granulator N made by Hitotsubashi
Prepared in 5K250 type, stirring blade rotation speed 500 rpm
Mix well by rotating at m for 2 minutes, then
250 g of 0% ethanol aqueous solution was added and granulation was performed for 1 minute. After drying this at 50° C. for 12 hours, coarse particles were cut using a JIS standard sieve (JIS Z8801710 μm), and the sieved fraction was designated as Sample C. The basic physical properties of Sample C are shown in Table 1.

0 aUr'4 D; City ffi crystalline cellulose "Avicel P!+-101J [manufactured by Asahi Kaei Kogyo ■]" was used as a sample. The basic physical properties of the sample are shown in Table 1.

Example 1 Sample A and pharmacopoeial etenzagod [manufactured by Iwaki Pharmaceutical] (hereinafter referred to as vEZ)
) were mixed in a ratio of 9:1 and heat treated at 100'C for 2 hours. About the heat-treated sample
When line diffraction measurements were performed, no EZ diffraction peak was observed, and only a diffractogram of cellulose was obtained.

This indicates that EZ is adsorbed on the cellulose particle surface in an amorphous state. (Incidentally, when we measured the EZ content of the heat-treated sample, it was 10%. This is because the EZ diffraction peak was not observed because EZ sublimated into the air and disappeared. ) This heat-treated sample was subjected to a crude drug dissolution test using the paddle method described in the 11th edition of the Japanese Pharmacopoeia. Table 2 shows the results of the a test using Japanese Pharmacopoeia Liquid 1 as the eluate.

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

The content of Zozoic acid in the second table was 10%, and the X-ray diffraction peak of benzoic acid was clearly visible. The dissolution test results are shown in Table 3.

, Example 2 Sample B and benzoic acid [manufactured by Wako Pure Chemical Industries, Ltd., special reagent grade]
:1 ratio and heat treated at 100°C for 2 hours. When the heat-treated sample was subjected to X-ray diffraction measurement, as in Example 1, the diffraction peak of benzoic acid had completely disappeared.

(The content of benzoic acid in the sample was 10%.)
This heat-treated sample was subjected to an elution test in the same manner as in Example 1. The results are shown in Table 3.

Comparative Example 3 A test was conducted in exactly the same manner as in Example 2, except that Sample C was used in place of Sample B. Sample Safety Example 3 Sample B and benzoic acid [manufactured by Wako Pure Chemical Industries, Ltd., special grade reagent] were
: Mix at a ratio of 1, store at 50'C, and turn into powder X over time.
Linear diffraction measurements were performed.

As a result, immediately after mixing the sample, the diffraction peaks of cellulose and benzoic acid were mixed, but after 10 days of storage, the benzoic acid peak almost disappeared, and after 42 days of storage, the diffraction peaks of cellulose and benzoic acid were mixed.
After a few days, it completely disappeared.

There was a concern that benzoic acid might have sublimated into the air during the storage of the sample, so we measured the benzoic acid content of the sample after 42 days of storage and found that 93% of the sample was It was retained. This result shows that heating and/or reduced pressure are not necessarily required to sublimate and adsorb drugs onto porous cellulose particles.

〔Effect of the invention〕

According to the present invention, the dissolution properties of a drug can be significantly improved by an extremely simple operation of simply physically mixing a poorly water-soluble drug with porous cellulose particles. Moreover, the cellulose particles used as carriers are
This is a practical method that can be used immediately because the substance has been sufficiently confirmed to be safe as a pharmaceutical preparation.

Claims (1)

[Claims] Specific surface area is 20m^2/g or more and diameter 0.01μ
1. A method for improving the dissolution of a poorly soluble drug, which comprises sublimating and adsorbing the poorly soluble drug onto cellulose particles having a porous structure in which the volume of pores of 0.3 cm^3/g or more is 0.3 cm^3/g or more.