JPH0215027A - Novel probucol solid preparation - Google Patents

Abstract

PURPOSE:To obtain a solid preparation having enhanced solubility and remarkably improved bioavailability and useful as a serum lipid improving drug by preparing a powder composition obtained by pulverizing a specific gastric or enteric high polymer compound and probucol together. CONSTITUTION:The aimed solid preparation obtained by pulverizing a gastric high polymer compound selected from an aminoalkylmethacrylate copolymer E and polyvinylacetaldiethylaminoacetate or enteric high polymer compound selected from methacrylic acid copolymer L, acetic acid phthalic acid acetate and hydroxypropylmethylcellulosephthalate and probucol together and preparing the obtained fine powder composition into a solid agent for internal use, e.g., inhalt, subtilized granule, granule or capsule by a conventional preparation method. The high polymer compound is preferably used at an amount of 0.5-10 times in weight based on the probucol.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a solid preparation of probucol useful as a pharmaceutical. More specifically, the present invention provides a formulation with improved bioavailability of probucol, a poorly water-soluble pharmaceutical substance, by increasing its solubility using a special formulation technology. It is something.

[Conventional technology]

Probucol has been put into practical use as a serum lipid-improving drug in North America since 1977 and in Japan since 1985 because it shows an ameliorating effect on hypercholesterolemia induced in animals. Clinical trial results in Japan have confirmed that this drug has a superior effect on lowering serum total cholesterol compared to over-the-counter drugs.

However, since probucol is sparingly soluble in water, conventional formulation techniques for making solid preparations, such as adding excipients and making them into granules or tablets, are difficult to dissolve from the prepared preparation. As a result, rapid absorption from the gastrointestinal tract cannot be expected. In general, the means to improve the dissolution of poorly soluble pharmaceutical substances are (a) converting the substance into a soluble derivative and using that derivative;

(b) During formulation, a solubilizing agent such as a surfactant is added.

The following methods have been adopted and widely used; however, in the case of probucol, satisfactory results have not yet been obtained by these commonly employed methods.

More specifically, in the case of probucol, soluble derivatives have not been put to practical use so far, and the purpose can be achieved by mere micronization, and furthermore, it is generally used as a solubilizing agent. polysorbate 8
Even when using surfactants such as 0, sodium lauryl sulfate, and polyoxyl stearate 40, the elution effect is small, and some of these have been experimentally shown to achieve this effect by using large amounts. Although there are some, there are difficulties in putting them into practical use. Another possibility is to dissolve it in a dissolving agent such as polyethylene glycol 400 or propylene glycol and then make it into soft capsules, but this method has the disadvantage of increasing the size of the dosage form (large capsules, etc.). tablets are difficult to swallow).

[Disclosure of the invention]

As a result of intensive research into improving the dissolution properties of solid preparations of probucol, the present inventors found that aminoalkyl methacrylate copolymer E1 methacrylic acid copolymer L1 cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate, polyvinyl By using one or more gastric-soluble or enteric-coated polymeric compounds selected from the group consisting of acetal diethylaminoacetate and hydroxypropyl methylcellulose phthalate, and co-pulverizing these polymeric compounds and probucol, fine particles can be obtained. By forming a powder composition into a formulation, we have succeeded in providing a solid preparation of probucol with significantly improved dissolution properties.

That is, the present invention provides a gastric soluble polymer selected from the group consisting of aminoalkyl methacrylate copolymer E1 methacrylic acid copolymer L1 cellulose acetate heptatalate, hydroxypropyl methyl cellulose acetate, polyvinyl acetal diethylamino acetate, and hydroxypropyl methyl cellulose phthalate. Alternatively, the present invention provides a solid preparation of probucol, which is characterized by co-pulverizing one or more enteric polymer compounds with probucol and formulating the resulting fine powder composition.

The present invention will be explained in detail below.

The gastric soluble polymer compound used in the solid preparation of the present invention is
A compound selected from the group consisting of aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate, and the enteric polymer compound is methacrylic acid copolymer L1 cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinimate and hydroxypropyl It is a compound selected from the group consisting of methylcellulose phthalate.

These polymer compounds can be used alone or in combination of two or more, and the amount used is 0.1 times or more, preferably 0.1 times or more based on the weight of probucol.
It is used in an amount of 5 times to IO times, and is made into a fine powder composition by co-pulverizing with probucol.

In preparing this fine powder composition, water-soluble sugars or sugar alcohols such as glucose, fructose, mannitol, sorbitol, xylitol, maltose, lactose, and sucrose can be added as excipients. This results in
The co-grinding process becomes easier to operate. Further, in this co-pulverization process, the type of crushing equipment and the crushing time are not particularly limited.

The fine powder composition thus obtained is prepared into various solid dosage forms using conventional solid dosage formulation methods. That is, excipients, disintegrants, binders, lubricants, etc. are further added to this fine powder composition, and powders, fine granules, granules, capsules, tablets, etc. are prepared by conventional formulation methods. It can be prepared into a solid dosage form for internal use.

According to the preparation of the present invention prepared by the production method based on co-grinding treatment as described above, the solubility of probucol can be increased and the bioavailability can be significantly improved. Furthermore, as a result, probucol formulations can be provided as small capsules or tablets.

Examples of the present invention are shown below along with test examples and comparative examples,
The present invention will be explained more specifically.

Hereinafter, "parts" in the examples represent "parts by weight."

Comparative Example 1 A commercially available product containing 250 mg of probucol in one tablet was crushed in a mortar to form granules.

Example 】 The following prescription ingredients were used.

Probucol 10 parts Lactose 10 parts Carboxymethyl cellulose 3 parts Magnesium stearate 1 part Probucol, lactose and aminoalkyl methacrylate copolymer E were thoroughly mixed and then co-milled for 30 minutes with a vibrating rod mill (Model TI-200 manufactured by Heiko Seisakusho). After forming a fine powder composition with an average particle size of 10 μm or less, carboxymethylcellulose and magnesium stearate are added to this fine powder composition,
After thorough mixing, dry granulation was performed to form granules.

Example 2 The following regional components were used.

Probucol 10 parts milk
Sugar 10 parts Methacrylic acid copolymer L 10 parts Carboxymethylcellulose 3 parts Magnesium stearate 1 part Probucol, lactose and methacrylic acid copolymer L were thoroughly mixed and then co-pulverized for 30 minutes in a vibrating rod mill to obtain particles with an average particle size of 10 μm or less. After forming a fine powder composition, carboquine methylcellulose and magnesium stearate were added to the fine powder composition, thoroughly mixed, and then dry granulated to form granules.

Example 3 The following prescription ingredients were used.

Probufur 10 parts milk
Sugar 10 parts Cellulose acetate phthalate 10 parts Carboxymethylcellulose 3 parts Magnesium stearate 1 part After thoroughly mixing probucol, lactose and cellulose acetate phthalate, co-pulverize for 30 minutes with a vibrating rod mill to obtain a fine powder with an average particle size of 10 μm or less. After forming a composition, carboxymethyl cellulose and magnesium stearate are added to this fine powder composition,
After thorough mixing, dry granulation was performed to form granules.

Test Example 1 (Solubility Test) Sample ■ Probucol Fine Powder Probucol was ground in a vibrating rod mill for 1 hour to form a fine powder with an average particle size of 10 μm or less.

Sample ① Co-pulverized fine powder composition of probucol and lactose Equal amounts of probucol and lactose were mixed and then co-pulverized for 1 hour in a vibrating rod mill to obtain a fine powder composition with an average particle size of 10 μm or less.

Sample■ Equal amounts of probucol, lactose, and aminoalkyl methacrylate copolymer E are mixed into a large pulverized fine powder composition. After mixing equal amounts of the three components, they are co-pulverized in a vibrating rod mill for 1 hour to obtain a fine powder composition with an average particle size of 10 μm or less. It became a thing.

Sample ■ Co-pulverized fine powder composition of probucol, lactose and methacrylic acid copolymer L. After mixing equal amounts of the three components, co-pulverization was carried out in a vibrating rod mill for 1 hour to form a fine powder composition with an average particle size of 10 μm or less. did.

Trial M ■ A co-pulverized fine powder composition of probucol, lactose and cellulose acetate phthalate. After mixing equal amounts of the three components, co-pulverization was carried out in a vibrating rod mill for 1 hour to form a fine powder composition with an average particle size of 10 μm or less. did.

For each of samples ■, ■, ■, ■, and ■, accurately weigh the amount corresponding to 20 mg of probucol, add purified water to make exactly 100 m (2), and place in a shaking constant-temperature water bath (
Atvanchik Lab Thermo/Nieker TS-30G
) for 1 hour at 37°C (horizontal reciprocating shaking 90 to 100 times per minute). This dispersion was filtered through a membrane filter with a pore size of 0.45 μm, and the filtrate had a wavelength of 240
Absorbance was measured at the maximum wavelength of absorption near nm to determine the amount of probucol dissolved (μg/mQ). The results are shown in Table 1.

Table 1: Solubility Test As is clear from Table 1, the fine powder composition used in the formulation of the present invention has an extremely high dissolution amount compared to the pulverized product of probucol alone and the co-pulverized product of probucol and lactose. shows.

Test Example 2 Using 4 domestic colored rabbits weighing around 3 by, each of the granules of Comparative Example 1 and Examples 1, 2, and 3 was orally administered in an amount corresponding to 1 g of probucol per rabbit. Time plasma concentration (μ97mQ), maximum plasma concentration (Cm
ax (μg/m12)) and the area under the plasma concentration-time curve (AUC (μ9·hr/m12)).

The results are shown in Table 2.3 and Figure 1.

Table 3 Maximum plasma concentration, area under the plasma concentration/time curve As is clear from Table 2.3 and Figure 1, the solid preparation of the present invention has a higher plasma concentration than the comparative preparation. shows.

As described above, the solid preparation of the present invention has high probucol dissolution and significantly improved bioavailability.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the test results in the animal test described in Test Example 2 herein. 1←Comparative Example 1 Time (hr)

Claims (1)

[Claims] A gastrosoluble or enteric polymeric compound selected from the group consisting of aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetal diethylaminoacetate, and hydroxypropylmethylcellulose phthalate. co-pulverizing one or more of the following and probucol,
A solid preparation of probucol, which is obtained by formulating the obtained fine powder composition.