JPS62221626A - Formulating composition of 1,4-dihydropyridine compound - Google Patents

Abstract

PURPOSE:A composition, obtained by blending CV-159 with a water-soluble high polymer base and, as desired, a surfactant, and capable of improving the bioavailability, sustaining the effective blood concentration and exhibiting long remedial effect while moderating the action and useful for a hypotensive agent. CONSTITUTION:A composition obtained by blending 6-(5-phenyl-3-pyrazolyloxy)- hexyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbony-l-pyridine-5- carboxylate (CV-159) with a water-soluble high polymer base, e.g. polyvinylpyrrolidine or hydroxypropyl cellulose or a high polymer base capable of dissolving depending on pH, e.g. methacrylic acid-methyl methacrylate copolymer or hydroxypropylmethyl cellulose phthalate, and, as desired, further a surfactant. The blending weight ratio of the CV-159 to the base is 1:0.2-1:10, preferably 1:0.5-1:5.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 1,4-dihydro-2,6-dimedylene-4-(3-nitrophenyl)-, which is a type of 1,4-dihydropyridine compound having a blood pressure lowering effect. 3-methoxycarbonyl-pyridine-5-carboxylic 16-(5-phenyl-3-pyrazolyloxy)-hexyl ester (hereinafter C
It is called V-159. ).

Conventionally, nifedipine, nicardipine, etc. are well known as 1,4-dihydropyridine compounds, and their bioavailability is improved by appropriately blending them with hydrophilic or poorly soluble polymeric bases, surfactants, etc.
Various pharmaceutical compositions aimed at improving bioavailability (bioavailability) are known.

On the other hand, CV-159, which is the medicinal ingredient of the composition of the present invention, is a new type of 1,4 that has a long-lasting antihypertensive effect.
- A patent application has been filed by the present applicant as a dihydropyridine compound (compound described in Production Example 1 in JP-A-58-131982), but it has a rough texture due to insufficient absorption from the gastrointestinal tract upon oral administration. The present applicant filed a patent application for an amorphous single powder formulation of CV-159 with improved bioavailability (Japanese Patent Application Laid-open No. 1983-1993).
139688). However, no literature has been published regarding a pharmaceutical composition for CV-159.

Problems to be resolved When a suspension of amorphous and crystalline CV-159 is suspended in an aqueous solution of carboxymethyl cellulose, methyl cellulose, etc., is orally administered, the amorphous form has higher bioavailability; Experiments conducted by the present inventors revealed that bioavailability of ordinary formulations prepared using amorphous CV-159 using ordinary formulation additives is 175 to 1/10 lower than that of suspensions. . Generally, pharmaceutical preparations such as tablets, capsules, and granules that are easy to take are preferred. Therefore, in order to develop CV-159 as a drug, it is desired to have a pharmaceutical composition that does not reduce its bioavailability even if it is prepared into a regular formulation, but rather improves it and maintains its efficacy.

The purpose of the present invention is to improve the bioavailability of CV-159, a new type of 1,4-dihydropyridine compound, to maintain effective blood concentrations, and to maintain long-lasting effects while mitigating the effects. The object of the present invention is to provide a pharmaceutical composition that exhibits a therapeutic effect.

The present inventors have developed a composition containing CV-159, a water-soluble polymer base, and optionally a surfactant (referred to as composition A), and a composition containing CV-159 and a polymer that dissolves depending on the pH. A composition containing a base (hereinafter referred to as a pH-dependent base) and, if desired, a surfactant (hereinafter referred to as composition B), and a composition containing a mixture of composition A and composition 8 (composition C). We have completed the present invention by discovering that even ordinary preparations made by adding conventional excipients have excellent absorption and persistence when administered orally to animals. Both Composition A and Composition 8 are highly absorbent, especially Composition A is fast absorbing and Composition 8 is slow absorbing.
Composition C, which is a mixture of B and B, is expected to have excellent medicinal efficacy in terms of both absorption and persistence. Therefore, if you want immediate effect, use Composition A, if you want slow effect, use Composition B, and if you want long-lasting effect by taking advantage of both characteristics, use Composition C. Therefore, the composition of the present invention can be said to be an ideal pharmaceutical composition as a pharmaceutical composition. The CV-159 used is Japanese Patent Application Publication No. 1986-
Not only the amorphous powder described in the publication No. 139688@, but also the crystalline powder can provide the same effect.

The pharmaceutical composition of the present invention is prepared by dissolving CV-159, a water-soluble polymer base or a pH-dependent base, and optionally a surfactant in a solvent, and drying the resulting solution under reduced pressure.
The solvent can be removed by freeze drying, spray drying, etc. to form granules or powder, or small particulate excipients can be spray coated, or a solution can be kneaded with excipients and then dried to form granules. It can be made into a thing. In addition, it can be made into a solid material by heating and melting, and if necessary, pulverized to form a powder. Therefore, this powdered or granular composition can be formulated into conventional preparations such as tablets, capsules, granules, pills, powders, etc. using conventional pharmaceutical additives.

The water-soluble polymer base of the present invention includes polyvinylpyrrolidone, hydroxypropylcellulose, droxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyethylene glycol (molecular weight 2,000 or more), carboxylic polymer, hydroxyethylcellulose, vinylpyrrolidone/vinyl acetate. Copolymers and the like may be used alone or in combination of two or more.

Examples of pH-dependent bases include weak to alkaline aqueous solutions and organic solvents (limited to solvents that dissolve CV-159).
In particular, methacrylic acid/methyl methacrylate copolymer, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, cellulose acetate phthalate 1-1, methacrylic acid/ethyl acrylate copolymer, cellulose acetate-1 ~N,N-di-n-butylaminopropyl ether, cellulose propione-1-phthalate, cellulose acetate-1-maleate, polyvinyl alcohol phthalate-1-, styrene-acrylic acid copolymer, carboxymethylethyl cellulose preferable. In addition, as surfactants, sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene sorbitan monooleate 1~, glyceryl monostearate, glyceryl monooleate, polyoxyethylene monostearate, polyoxyethylene cetyl ether, It is preferable to use one type or a combination of two or more types of hardened polyoxyethylene, mustard oil, sucrose fatty acid ester, soybean lecithin, polyoxyethylene/polyoxypropylene block polymer, and the like.

Next, a method for producing the pharmaceutical composition of the present invention will be explained.

(Production method of compositions A and B) Crystalline or amorphous CV-159, a water-soluble polymer base or an OH-dependent base, and a surfactant if necessary are dissolved in a solvent. The solvent may be any solvent as long as it can dissolve CV-159 and the base used; for example, methanol, ethanol, isopropanol, acetone, chloroform, dichloromethane, ethyl acetate, etc. may be used alone or in appropriate combinations.

The mixing ratio (weight ratio) of CV-159 and the water-soluble polymer base or pH-dependent base is 1:0.2 to 1:10, preferably 1:0.5 to 1:5, and is used Determined from time to time depending on the characteristics of the base material. There are no particular restrictions on the amount of surfactant used, but it is preferably 15% or less based on the weight of the drug and base.

The solution containing the CV-159 thus obtained, a water-soluble polymer base or l) H-dependent base, and optionally a surfactant is dried under reduced pressure, freeze-dried, spray-dried, etc. It can be made into granular or powdered form by removing it and crushing it if necessary, or it can be made into granular or powdered form, or it can be made into granules or powder,
Fluid bed coating method, centrifugal fluid coating method, small particle core of common excipients such as cellulose and starch
It is formed into granules by spray coating using a pan coating method or by kneading the solution and excipient and then drying. Also, crystalline or amorphous CV-1
59 and a low melting point base such as polyethylene glycol are heated and melted and cooled to form a solid, which can be pulverized as necessary to form a powder.

(Method for producing composition C) Composition C is obtained by appropriately selecting powdered or granular composition A and composition B produced by the above method and mixing them. Composition A is rich in fast absorption properties, and Composition 8 is rich in slow absorption properties, so they can be prepared depending on the purpose, but if the mixing ratio of compositions A and 8 is 1.
; Both effects can be efficiently exhibited in the range of 1 to 1:10.

Compositions A, B, and C thus obtained can be made into oral preparations such as tablets, capsules, granules, powders, and the like using commonly used pharmaceutical additives.

Additives for formulations include cellulose, lactose, sucrose, mannitol, sorbitol, starches (potato, corn, rice, wheat, etc.), gelatin, 1-lagant gum, polyvinylpyrrolidone, carboxymethylcellulose boxymethylcellulose sodium tilcellulose calcium Magnesium phosphate, calcium stearate, synthetic aluminum silicate, polyethylene glycol, polysorbate, etc. are used as appropriate depending on the dosage form.

Esai: In order to confirm the effects and characteristics of the pharmaceutical composition of the present invention, the blood concentration was measured over time using Peagle dogs.

Tablets, capsules, or granules containing 30η equivalent of CV-159 produced in the Examples described below are orally administered to Peagle-sized animals weighing 8 to 12 to 9 who have fasted overnight.
3, 4, 6.8 hours t. :a[6cV-159(
7) Blood concentration was measured. As a comparative formulation, amorphous CV
-159 suspension (A), amorphous CV-159 ordinary preparation (Japanese), and crystalline CV-159 ¥! ! ! Clouding agent (c)
was prepared as described below, and an amount equivalent to 30 mg of CV-159 was orally administered.

To measure blood concentration, plasma was pretreated and CV-159 was extracted, and then ODS (octadecylsilylated packing material) was used.
It was carried out by high performance liquid chromatography using a column.

Comparative formulation (a) Amorphous CV-159 of 801119 was added to 0. A suspension was prepared by suspending it in 100 d of 5X methylcellulose aqueous solution.

Comparative formulation (oral) 1 g of amorphous CV-159 was mixed with 10 g of lactose and 0.0 g of carboxymethyl cellulose calcium magnesium. 0559 in an agate pot to prepare tablets containing 30 m3 of CV-159.

Comparative Formulation (c) A suspension was prepared by suspending 601Q crystalline CV-159 in 100 rnl of a 0.5% methylcellulose aqueous solution.

Blood concentrations and parameters at each elapsed time are shown in the table below.

(*1) Tmax: Time to reach maximum blood concentration (hr) (
*2) Cmax: Maximum blood concentration (ng/rnl) (
13) AUG: Area on blood concentration time curve (ng-hr/
ml ) (*4) ND: Not detectable
tcctable) Effects of the Invention From the above results, the following can be seen.

■ Composition A using a water-soluble polymer base (Example 1.5)
and 7) reached the maximum blood concentration in a short time and were excellent in concentration and total drug absorption (AUG).

■ Composition B using a pH-dependent base (Examples 2, 4.
8 and 10) had a slow time to reach the maximum blood concentration, 6 hours;
The blood concentration remained high even after 8 hours.

■ Composition C, which is a mixture of compositions A and 8 (Example 3.
6 and 9) efficiently expressed the characteristics of both. Therefore,
By changing the mixing ratio of compositions A and 8, the characteristics of either composition can be strongly brought out.

■ In the composition of the present invention, CV-159 is crystalline,
There was no difference in absorbency characteristics regardless of the amorphous type.

■ All preparations prepared from the composition of the present invention have amorphous C.
Conventional formulation of V-159 [Comparative formulation (Sun Moon and Crystalline CV
-159 suspension [comparative formulation (c)] was significantly superior in maximum blood concentration and overall drug absorption, and significantly improved in bioavailability. In addition, amorphous CV-15
9 suspension [Comparative formulation (a) 1 has rapid absorption into the composition,
Composition 8 was clearly inferior in its slow absorption properties and Composition C in its durability.

■ As mentioned above, Composition A is fast absorbing, so when immediate action is required, Composition B is slow absorbing, so slow action is required.
Composition C can be preferably used when sustainability is required while taking advantage of both characteristics.

Next, the method for producing the composition of the present invention and its common formulation will be explained with examples. Amorphous CV-1 used in the examples
No. 59 was manufactured by the method disclosed in Japanese Patent Application Laid-open No. 60-199688.

Example 1 140 (140 g of crystalline CV-159, 420 g of polyvinylpyrrolidone (PVP K-30, manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.) and 42 g of Tucor-0-1O1 manufactured by Nikko Chemicals Co., Ltd. in polyoxyethylene sorbitan monooleate) was added to acetone. 1
The resulting solution was spray-dried onto 420 (l) of crystalline lactose in a fluidized bed coating apparatus under heating at 60°C to obtain 1 q of granules.

Next, 219 g of the above granules, 75 g of lactose, 35 g of corn starch, 17.5 g of carboxymethylcellulose calcium, and 3.5 g of magnesium stearate.
Mix 5g thoroughly and compression mold to make 30m of CV-159.
A tablet having a weight of 3 bOmg was obtained.

Example 2 20 g of crystalline CV-159, two types of methacrylic acid/methyl methacrylate copolymer [Eudragit (
Polyoxyethylene (Eudragit) L and S10-M & Haas Co., Ltd.
60)rI! Irized castor oil (Chive D-/LztlCO
-60, Nikko' (manufactured by MICALS) 0.40 was dissolved in 150 d of ethanol.

Separately, 400 g of corn starch and 60 g of hydroxypropyl cellulose were mixed in a high-speed stirring mixer,
The previously prepared solution was added and thoroughly kneaded.

This kneaded product was taken out and granulated using an extrusion granulator, and further dried with ventilation at 40°C for 2 hours to obtain CV-159 of 4'X@
Granules with a diameter of 11M1 were obtained. 30mFI CV-1
59 corresponds to a granule of 750 mFI.

Example 3 18 g of the granules obtained in Example 1 and 1 q of the granules 25017 obtained in Example 2 were mixed to obtain 268 g of granules.

To this, 1300 ml of corn starch and 2.0 J of magnesium stearate were added, mixed thoroughly, and this mixture was filled into capsules at 960 ffiff.CV-
Capsules containing 30η of 159 were prepared.

Example 4 25 g of crystalline CV-159, 125 g of hydroxypropyl methylcellulose phthalate (IIP-55, manufactured by Shin-Etsu Chemical Co., Ltd.), polyoxyethylene (60) hydrogenated castor oil 15Q were mixed with 300 rni of a mixed solvent of dichloromethane-ethanol (4:1). This solution was dried under reduced pressure, and the resulting dried product was pulverized to obtain 155 g of a powder.

Next, capsules containing 66 g of the obtained powder, 124 g of lactose, and 10 (l) of talc were thoroughly mixed and filled into capsules in 60 hyy portions to give 30 my of CV-159.

Example 5 15 g of amorphous CV-159, 60 g of hydroxypropylcellulose, and 6 g of sucrose fatty acid ester (O ester F-140, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) were mixed with 36 g of ethanol.
It was dissolved in 0rIJ1, the solution was dried under reduced pressure, and the resulting dried product was pulverized to obtain a powder 78Q.

Next, 1 q of powdered material 36.5 CI, lactose 75.
Mix 80 and 3.7g of talc thoroughly and put 51 into a capsule.
Capsules containing 3 qmg of CV-159 were prepared by filling 5 capsules each.

Example 6 79 g of powder obtained in Example 4 and powder 1 obtained in Example 5
6g was mixed to obtain 950 powder.

Add 209 g of lactose and 160 g of talc to this mixture,
After thorough mixing, this mixture was filled into capsules at 640/Q each to prepare capsules containing 3ON of CV-159.

Example 7 10 g of amorphous CV-159 and polyethylene glycol (intermolecular e, ooo) ioog were placed in a glass container, mixed with molten TiN on a 70°C water bath, and the molten liquid was sucked up into a Teflon tube with an inner diameter of 5 m. After cooling and solidifying at air temperature, the tube was cut open to obtain a rod-shaped solid. This solid material, 330#2J, was ground into a powder and then filled into capsules to prepare capsules containing 30 mg of CV-159.

Example 8 140g of crystalline CV-19, cellulose acetate-1
~ Phthalate (CAP, Wako Tsumugi Co., Ltd.) 11200 was dissolved in 9.61% of a mixed solvent of acetone-ethanol (1:1), and this solution was added to 420 g of crystalline lactose in a fluidized bed coating device at 60°C. Granules were obtained by spray drying under heat.

Next, 3 eog of the above granules, 60 g of lactose, 25 g of corn starch 50Q carboxymethylcellulose, and 5 g of magnesium stearate were thoroughly mixed and compression molded to form 500ffi containing 3 qmg of CV-159.
j9 tablets were obtained.

Example 9 The solid obtained in Example 7 was pulverized to produce a powder of 33(II), and this was mixed with 180 g of the granules obtained in Example 8 to obtain 213 g of a mixture.

213 g of this mixture, 63 g of corn starch (],
Synthetic aluminum silicate 15 (l) and talc (9 g) were thoroughly mixed and compression molded to produce 500 m5 tablets containing 30 mFi of CV-159.

Example 10 700 (J amorphous CV-159, methacrylic acid/methyl methacrylate copolymer (Eudragitsu l-1)
525 () and polyoxyethylene (40) monostearate, 15 g of Tucor IIYs-40 (manufactured by Nikko Chemicals Co., Ltd.) was dissolved in 9 ml of ethanol, and this solution was added to crystalline lactose 2.1 g in a fluidized bed coating device. 3 to 80
Granules were obtained by spray drying under heating at .degree.

Subsequently, 145 g of the above granules, 80 g of lactose, 12 g of cross-linked sodium carboxymethyl cellulose, and 2.40 g of magnesium stearate were thoroughly mixed, and then C.
Tablets containing 301 Fl of V-159 and weighing 240 mg were prepared.

Claims (8)

[Claims] (1), 1,4-dihydro-2,6-dimethyl-4-(
3-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 6-(5-phenyl-3-pyrazolyloxy)-hexyl ester (hereinafter referred to as CV-159) and a water-soluble polymer base or pH 1. A pharmaceutical composition for CV-159, which comprises a polymer base that dissolves depending on pH (hereinafter referred to as a pH-dependent base) and, if desired, a surfactant. (2) The composition according to claim (1), characterized in that CV-159, a water-soluble polymer base, and optionally a surfactant are blended. (3) The composition according to claim (1), characterized in that CV-159 is blended with a pH-dependent base and, if desired, a surfactant. (4) The water-soluble polymer base is one or more selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, and polyethylene glycol (molecular weight 2,000 or more). A composition according to claim (1). (5), a group in which the pH-dependent base consists of methacrylic acid/methyl methacrylate copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate, cellulose acetate phthalate, methacrylic acid/ethyl acrylate copolymer, and carboxymethylethylcellulose; Claim No. (1) which is one or more selected from
Compositions as described in Section. (6), 1,4-dihydro-2,6-dimethyl-4-(
3-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 6-(5-phenyl-3-pyrazolyloxy)-hexyl ester (hereinafter referred to as CV-159) and a water-soluble polymer base, if desired. is a composition containing a surfactant, a polymer base that dissolves depending on CV-159 and pH (hereinafter referred to as a pH-dependent base), and optionally a surfactant. A pharmaceutical composition of CV-159, which is obtained by mixing the following compositions: (7) The water-soluble polymer base is one or more selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, and polyethylene glycol (molecular weight 2,000 or more). A composition according to claim (6). (8), a group in which the pH-dependent base consists of methacrylic acid/methyl methacrylate copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate, cellulose acetate phthalate, methacrylic acid/ethyl acrylate copolymer, and carboxymethylethylcellulose; Claim No. (6) which is one or more selected from
Compositions as described in Section.