JPH07118154A - Solid dispersion and granular preparation - Google Patents

Abstract

PURPOSE:To provide a new solid dispersion improved in stability of a compound A in an acidic region and its solubility in a neutral region and a granular preparation containing it. CONSTITUTION:There are provided a solid dispersion composed of 1-(3- fluoro-6,11-dihydrodibenz[b, e] oxepin-11-yl-)-4-(3-phenyl-2propenyl)piperazine (compound A) or its acid adduct and a water-soluble polymer substance and a granular preparation produced by coating a nucleus component containing the solid dispersion with an enteric coating film.

Description

Detailed Description of the Invention

[0001]

The present invention has the following structure:
(3-fluoro-6,11-dihydrodibenz [b,
e] Oxepin-11-yl) -4- (3-phenyl-
2-propenyl) piperazine [1- (3-Fluoro-6,11-dihyd
rodibenz [b, e] oxepin-11-yl) -4- (3-phenyl-2-propenyl)
piperazine] (hereinafter referred to as “compound A”) or an acid addition salt thereof and a water-soluble polymer substance, and a pharmaceutical preparation containing the solid dispersion.

[0002]

[Chemical 1]

[0003]

BACKGROUND OF THE INVENTION Compound A and its acid addition salts are useful compounds as therapeutic agents for cerebrovascular disorders, and are disclosed in US Pat.
It can be manufactured according to the description in JP 89,858. This U.S. patent describes tablets and capsules containing an acid addition salt of compound A, but does not disclose a solid dispersion or a granular preparation containing the same.

[0004]

Compound A and its acid addition salts are known to be useful compounds as therapeutic agents for cerebrovascular disorders, but their stability in the acidic range and solubility in the neutral range are not always required. Turned out not enough.

[0005]

Therefore, the present inventors have made various studies as a solution to the above problems from the viewpoint of pharmaceuticals, and have made Compound A or its acid addition salt a solid dispersion with a water-soluble polymer substance. As a result, the solubility was improved, and it was found that acid stabilization can be achieved by coating this with an enteric coating, and the present invention was completed.

The present invention relates to a solid dispersion comprising a water-soluble polymer and compound A or an acid addition salt thereof, and a granular preparation obtained by coating the surface of a core component containing the solid dispersion with an enteric coating.

The solid dispersion of the present invention can be produced by dissolving the compound A or an acid addition salt thereof and a water-soluble polymer in a solvent, and then removing the solvent.

Examples of the acid addition salt of the compound A include salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, or salts with organic acids such as oxalic acid, malonic acid and maleic acid.

Further, as the water-soluble polymer substance, any substance used in this field can be used.
Examples thereof include polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), polyvinyl alcohol (PVA), and the like, and a mixture thereof can also be used. Particularly, PVP, HPMC, HPC and the like are suitable.

The ratio of the compound A or its acid addition salt to the water-soluble polymer in the solid dispersion is 0.5-10 parts by weight, preferably 0.75-5 parts by weight for the former 1 part for both parts.
It is selected from the range of 1 to 3 double parts, particularly preferably 1 to 3 double parts.

Examples of the solvent that dissolves both the compound A or its acid addition salt and the water-soluble polymer substance include organic solvents such as dichloromethane, ethanol and acetone, and a mixture thereof is particularly preferable. Such removal of the solvent can be carried out, for example, by using an evaporator.

It is clear from the results of X-ray analysis and thermal analysis (FIGS. 1 and 2) that the compound A or its acid addition salt in the solid dispersion does not have a crystal structure.

When water is added to a mixture of compound A or an acid addition salt thereof and a water-soluble polymer substance, and the mixture is kneaded and dried, the expected improvement in solubility is not observed.

Next, the granular preparation of the present invention will be described.
The granular preparation of the present invention can be produced by coating the surface of the core component (hereinafter sometimes referred to as the core) containing the solid dispersion with an enteric coating.

As the core component, one having an average particle size of 3 mm or less, preferably 0.1-2 mm, particularly preferably 0.15-1.5 mm is adopted.

The core component containing the solid dispersion may be particles of the solid dispersion itself, or may be granulated with other formulation ingredients, or the solid dispersion may be formed on the surface of a granular substance. May be coated.

When the core component is the solid dispersion itself, the solid dispersion is preferably crushed and sized. The core component containing other formulation ingredients can be produced, for example, by adding water to a mixture of the solid dispersion and the formulation ingredients such as lactose and starch, kneading the mixture, extruding from a sieve and granulating. The core component in which the surface of the particle substance is coated with the solid dispersion can be produced by spraying an organic solvent in which both the compound A or its acid addition salt and the water-soluble polymer substance are dissolved onto the particle substance, which is the most preferable embodiment. It is a mode.

Examples of the particulate matter include lactose, starch, crystalline cellulose, mannitol, sucrose, low-substituted hydroxypropyl cellulose, partially α-gelatinized starch, carboxymethyl starch, carboxymethyl cellulose or salts thereof, and the like. These granules may be used. In particular, commercially available particulate materials such as non-pareil (Freund Industries) and Celfia (Asahi Kasei) are conveniently used.

As the substance for forming the enteric coating, any of those commonly used in the art can be used. For example, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate ( HPMCP), and one or more selected from acrylic acid-based copolymers (for example, ethyl methacrylic acid acrylate such as Eudragit L-100 and methyl methacrylic acid methacrylate such as Eudragit S-100). .

For coating, polyethylene glycol (PEG), sucrose fatty acid ester, glycerin fatty acid ester, propylene glycol, Tween 80, Span 80, triethyl citrate, plasticizer such as monostearate stearate, talc, titanium oxide, Lubricating agents such as magnesium stearate and light anhydrous silicic acid are generally used together.

The enteric coating is coated in an amount of 0.05-4 parts by weight, preferably 0.1-2 parts by weight, particularly preferably 0.2 -1 part by weight, relative to 1 part by weight of the core component.

For the coating, a core component is charged into a fluidized bed coating device, a swirl type fluidized bed coating device, a centrifugal type coating device, etc., and an enteric film-forming substance, a plasticizer, a lubricant, etc. are dissolved or suspended therein. It can be carried out by spraying the liquid.

In the most preferred embodiment, a commercially available particulate material such as Celphia or nonpareil is charged into the coating apparatus as described above, and the compound A or an acid addition salt thereof and an organic solvent in which a water-soluble polymer material is dissolved are sprayed onto the coating apparatus. Then, it is dried to form a core component, and subsequently, the enteric coating as described above is performed in the same apparatus.

[0024]

[Effect] The solid dispersion of the present invention thus obtained is excellent in solubility in the neutral region, and the granular preparation of the present invention is excellent in solubility in the neutral region and stability in the acidic region. , As-is or in the form of capsules or tablets.

[0025]

EXAMPLES AND COMPARATIVE EXAMPLES Next, the present invention will be described more specifically with reference to Examples and Comparative Examples. In the following, the term “main drug” means the maleate salt of Compound A.

Example 1 Solid Dispersion-Manufacturing Method- 10 g of active ingredient and 30 g of water-soluble polymer substance shown in Table 1 below.
300 g of an equal volume mixture of dichloromethane and ethanol
, And the solvent was removed by an evaporator to obtain a desired solid dispersion. A solubility test was conducted on the obtained solid dispersion.

Solubility test-a solid dispersion equivalent to 500 mg of the active ingredient was added to 0.05 M at pH 6.5.
Add to 500 ml of phosphate buffer and stir (paddle; 200 rpm) according to the Japanese Pharmacopoeia test method. Take 3 ml of it at regular intervals and use a membrane filter (pore siz
e; 0.45 μm), and the concentration of Compound A in the filtrate is UV
It quantified by the method and the dissolution rate was calculated. The results are shown in Table 1.

[0028]

[Table 1] * The numbers in the table indicate the solubility (μg / ml). ** Main drug (bulk powder) itself

Further, powder X-ray diffraction and thermal analysis were performed on the solid dispersion in which the polymer substance was PVP, and the results shown in FIGS. 1 and 2 were obtained. A simple mixture of the main drug and PVP was used as a comparative control.

Example 2; Granular preparation-Formulation-

━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Main drug 1 part PVP 3 parts SELPHYA 6 parts ─────────── ───────────────── Eudragit L100 3 parts PEG6000 0.3 parts Tween 80 0.15 parts Monoglycerol stearate 0.15 parts ━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━ Total 13.6 copies

Manufacturing method: 40 g of the main ingredient and 80 g of PVP were dissolved in 800 g of an equal volume mixture of dichloromethane-ethanol, and this was sprayed onto 240 g of SELPHYA using a swirl type fluid coating apparatus, and the same mixed solution in which 40 g of PVP was dissolved was sprayed. Then, a nuclear component was prepared. Subsequently, 1200 g of an aqueous dispersion containing 120 g of Eudragit L100, 12 g of PEG, 6 g of Tween 80 and 6 g of monostearate stearate was spray-coated on the core component to obtain a granular preparation.

Example 3 Granular preparation: The target granular preparation was obtained in the same manner as in Example 2 except that HPMC was used instead of PVP.

Example 4 Granular preparation: A target granular preparation was obtained in the same manner as in Example 2 except that HPC was used instead of PVP.

Example 5 Granular formulation; Formulation-

━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Main drug 1 part PVP 3 parts Serfia 6 parts ──────────── ─────────────── CMEC 3 parts PEG6000 0.3 parts Tween 80 0.15 parts Monoglycerol stearate 0.15 parts ━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━ Total 13.6 copies

Manufacturing Method-CMEC in place of Eudragit L100,
A granular preparation was obtained in the same manner as in Example 2 except that 2400 g of an equal volume mixture of dichloromethane-ethanol was used instead of water.

Example 6 Granular formulation; Formulation-

━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Main drug 1 part PVP 3 parts Lactose 3 parts Low-substituted HPC 3 parts ───── ───────────────────── Eudragit L100 3 parts PEG6000 0.3 parts Tween 80 0.15 parts Monoglycerol stearate 0.15 parts ━━━━━━ ━━━━━━━━━━━━━━━━━━━━━━ Total 13.6 copies

Manufacturing method: 40 g of the active ingredient and 120 g of PVP were dissolved in 1200 g of an equal volume mixture of dichloromethane-ethanol, and this was dissolved in a swirl type fluid coating device to give lactose and low-substituted HP.
Sprayed on C and dried. This was transferred to a mortar, 100 ml of ethanol was added, and after kneading, extrusion granulation was performed, and after drying, particles of 0.5-1 mm were sieved. Subsequently, in the same manner as in Example 2, the enteric coating was applied to obtain a granular preparation.

Comparative Example 1 Formulation-

━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Main drug 1 part Lactose 6 parts Low-substituted HPC 2.5 parts HPC 0.5 part ─ ───────────────────────── Eudragit L100 3 parts PEG6000 0.3 parts Tween 80 0.15 parts Monoglycerol stearate 0.15 parts ━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━ Total 13.6 parts

Manufacturing method: 40 g of the active ingredient, 240 g of lactose, 100 g of low-substituted HPC and 20 g of HPC were mixed well, and 120 ml of water was added to this.
Was added, kneaded, extruded and granulated, and sized to 0.5-1 mm. Then, it was coated with an enteric coating in the same manner as in Example 2.

Dissolution test: For each of the granular preparations obtained in Examples 2-6 and Comparative Example, dissolution test of Japanese Pharmacopoeia 12th edition [first liquid (pH 1.8), second liquid (pH 6.8), Test liquid amount: 900 ml, paddle: 100 rpm, main drug amount: 10 mg as compound A] and the results of Table 2 and Table 3 were obtained. The amount of compound A and its decomposition products in the test solution was determined by measuring the test solution with a membrane filter (pore size 0.45
μm), the filtrate was subjected to high performance liquid chromatography, and then quantified by the UV method. The numbers shown in Tables 2 and 3 show the elution rate (%).

[0045]

[Table 2]

[0046]

[Table 3]

[0047]

[Brief description of drawings]

FIG. 1 shows a powder X-ray diffraction chart of a solid dispersion.

FIG. 2 shows a differential thermal curve in thermal analysis of a solid dispersion.

Claims (6)

[Claims] 1. 1- (3-Fluoro-6,11-dihydrodibenz [b, e] oxepin-11-yl) -4-
(3-phenyl-2-propenyl) piperazine (hereinafter,
A solid dispersion comprising a compound A) or an acid addition salt thereof and a water-soluble polymer substance. 2. The solid dispersion according to claim 1, wherein the weight ratio of the compound A or an acid addition salt thereof and the water-soluble polymer substance is in the range of 1: 0.5 to 10. 3. The solid dispersion according to claim 1, wherein the water-soluble polymer substance is one or more selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinyl alcohol. 4. A granular preparation obtained by coating a core component containing the solid dispersion according to claim 1 with an enteric coating. 5. The granular preparation according to claim 4, wherein the core component is obtained by coating the surface of a particle substance with the solid dispersion according to claim 1. 6. The granular preparation according to claim 4, wherein the enteric film is one kind or two or more kinds selected from carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate and methacrylic acid copolymer. .