JPS629A - Sustained release compound unit pharmaceutical - Google Patents

Abstract

PURPOSE:The titled highly safe and effective pharmaceutical obtained by adding an elution inhibitor to a mixture containing a physiologically active substance and a specific amount or more of a unit-forming material, e.g. crystalline cellu lose, etc., granulating the resultant mixture and forming the resultant granular material into a capsule or tablet. CONSTITUTION:The titled pharmaceutical, consisting of a granular material obtained by adding an elution inhibitor, e.g. an aqueous suspension of a water- insoluble high polymer such as methacrylic acid ethyl acrylate copolymer to a mixture of a physiologically active substance, particularly 5-[2[2-(0- ethoxyphenoxy)ethylamino]propyl]-2-methoxybenzenesulfonamide-hydrochlo ride, i.e. YM-12617 and >=50wt%, particularly >=70wt%, based on the unit, unit- forming material, preferably crystalline cellulose and granulating the resultant mixture in individual unit pharmaceutical and capable of slowly releasing the physiologically active substance without disintegrating the granular material in the digestive tracts.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) This invention relates to a novel, highly safe and effective sustained release multiple unit dosage form for oral pharmaceutical use.

Pharmaceutical sustained-release individual unit % consisting of granules obtained by granulation, whose granules do not substantially disintegrate in the gastrointestinal tract, but in which physiologically active substances are gradually released.
1iYJ4L<Is Concerning complex unit preparations.

(Problems to be Solved by the Invention) When a sustained-release preparation is applied to a living body, variations within or between individuals often occur due to factors on the preparation side and the living body side. One of the biological factors is drug transit time in the gastrointestinal tract (
gastro 1ntestinal transit
However, the optimal dosage form to overcome this is the multiple-unit dosage form.
tspreparation) is known (e.g. HlBech-gaad and G, H, N1e
lsen, Drug Denel, Ind, p.
harm.

4, 53 (1978)). Solid preparations such as tablets and hard capsules disintegrate in the gastrointestinal tract to form a large number of individual units (microcapsules, microspheres, etc.),
These are the types of preparations in which the active substance elutes continuously from these units.

Hitherto, various materials and various manufacturing methods are known for obtaining the individual units (microcapsules, microspheres, etc.) containing the active substance of sustained release complex unit preparations.

For example, known materials include wax, lipids, water-insoluble polymer substances, and ion exchange resins.

In addition, the manufacturing method often requires a complicated and long process of making particles from the base agent and other materials and applying an enteric coating on top of the particles, which reduces manufacturing costs and quality such as the elution characteristics of the product. There were often gaps in terms of reproducibility.

Furthermore, crystalline cellulose (formerly known as "microcrystalline cellulose") is known to form a structure that is not easily destroyed in the gastrointestinal tract. (
Special Publication No. 45-5275). This formulation example (base ingredient BTDS)
), but enteric coatings are required to further extend the release time. Although it is described that the structure is not easily destroyed in the gastrointestinal tract, it is actually known that if the amount of crystalline cellulose is about 10 to 40%, the strength is insufficient. Also, in terms of sustained release properties of the base agent, this level of usage is generally not sufficient.

Sagen Tokukaisho, 8-9゜61-Kine Niyu, an edict stating the invention of ``Kyo. Notified air output adjustment complex unit preparation'' The ``core'' mentioned therein was developed in a rather complicated manner. manufactured and coated with an enteric material for sustained release. Although this product does not disintegrate in the stomach, it is made with disintegration accelerators added so that the coating erodes and the core itself disintegrates in the small intestine.

(Means for Solving the Problem) The present inventors have proposed an oral drug that can freely control the dissolution rate without coating with an enteric substance, has good reproducibility of dissolution behavior, and can be easily manufactured. As a result of intensive research on releasable composite unit preparations, we found that a mixture of a physiologically active substance and a unit forming material with a weight ratio of 50% or more; The present inventors have discovered that an oral preparation with excellent sustained release properties can be obtained by preparing a substance-containing unit and filling this granular material into a capsule to form a capsule, or by forming it into a tablet using a conventional method. completed.

The above-mentioned granules (active substance-containing units) of the present invention have the property of being permeable to water but not substantially disintegrating (almost not disintegrating or at least not disintegrating for more than several hours) in the gastrointestinal tract. There is. In addition, since it has high physical strength, individual units are hardly destroyed even when compressed into tablets. In addition, when producing granules (active substance-containing units), it is possible to obtain granules with desired dissolution characteristics by appropriately adjusting the type of enteric substance and the amount of the enteric substance to be blended.

A preferred unit material for use in the present invention is crystalline cellulose. In addition, chitin and chitosan can also be used. The amount of these unit molding materials used is 50% or more, preferably 70% or more by weight in the unit.

Further, the shaving agent used in the present invention includes water-insoluble polymeric substances such as acrylic acid polymers and copolymers.

Mataethylcellulose, Hydroxyglobil Methylcellulose 7 Tallate (HPMCP), Hydroxyglobil Methylcellulose Acetate Succinate) (HPM
Cellulose derivatives such as C-As) are used. These are aqueous suspension, aqueous emulsion, water-containing lylic acid/acrylic acid ethyl ester copolymer aqueous suspension), Eudragit g3oD (acrylic acid ethyl ester/methacrylic acid methyl ester copolymer aqueous suspension), Aquaco -) ECD-30 (ethylcellulose aqueous suspension)
etc., and these are fji'b? It can be used as a 1fl agent as it is or diluted with water if necessary. Also,
Low-substituted hydroxyglobil cellulose (L-RPC)
The above-mentioned -Cti/'cellulose is also used as an aqueous gel. Furthermore, these water-insoluble polymer substances can also be used as a mixed solvent solution system with a water-based organic solvent.

Note that water itself can also be used as a stwm agent.

That is, crystalline cellulose can be made into granules by adding water.

There is no particular restriction on the amount of the SM feed agent used, but an amount suitable for wet granulation may be used. 1.2 There is no particular limit to the concentration of the cape agent (as an aqueous liquid), but for example, if the blending ratio of water-insoluble polymer substances is high, the release of physiologically active substances will be slow, so the amount used should be determined depending on the purpose. (as an aqueous liquid) and concentration may be adjusted as appropriate. In addition, in order to determine the elution rate of a water-soluble polymer substance, such as a hydroxypropyl cellular substance, which is usually used as a binder,
During the production of the granules (active substance-containing units), alkaline earth metal salts (or alkali metal salts) of higher fatty acids or enteric polymeric substances may be added. These additions are effective when the physiologically active substance is a trace amount of a drug at 8%. Examples of alkaline earth metal salts or alkali metal salts of higher fatty acids include magnesium stearate and calcium stearate. In addition, as an enteric polymer substance, cellulose acetate phthalate (CA
P), hydroxypropyl methyl cellulose phthalate (HPMC-P), methacrylic acid/methacrylic acid methyl ester copolymer (Eudragi L, S), and the like. The blending amount of these is usually 1 to 15%. Note that alkali metal halides or alkaline earth metal halides such as sodium chloride, calcium chloride, etc. can also be used for the same purpose. ◎When using enteric polymeric substances such as the above-mentioned methacrylic acid/methacrylic acid methyl ester copolymer, , PE06000. tween 8
0 (Tween 80), triacetin, etc. may be used as a plasticizer. How much is used?

It is 10 to 15% based on the polymer substance (solid content).

As mentioned above, the release of physiologically active substances can be controlled by adjusting the type of binder, the amount of alkaline earth metal salts (or alkali metal salts) of higher fatty acids, and enteric-coated polymer substances; Depending on the nature of the active substance, release can also be delayed by hydrophobizing the active substance itself.

The hydrophobization treatment is carried out by microencapsulating the active substance using a wax or the like, for example by a spray concealing method. Examples of waxes include hydrogenated vegetable oils such as hydrogenated castor oil.

The physiologically active substance that can be used in the present invention is not particularly limited.

In the test examples and examples described later, Compound 5, which has relatively low solubility in water (O, about 3 to 0.5%), was used as an active substance.
-[2-r:2-(O-ethoxyphenoxy)ethylamino]propyl)-2-methoxybenzenesulfonamide hydrochloride (hereinafter abbreviated as YM-12617) was used, but in the present invention, it has a high solubility. Of course, compounds can also be used.

YM-12617 exhibits α-blocking action and is used to treat hypertension, heart failure, lower urinary tract diseases, and the like.

The sustained-release individual units of the present invention are prepared by mixing a physiologically active substance, a unit-forming substance, and, if necessary, an alkaline earth metal salt (or alkali metal salt) of a higher fatty acid or an enteric polymeric substance. Additives commonly used depending on the purpose,
For example, fillers, coloring agents, etc. can be added. Add heat to the resulting mixture &J? 111 agent, i.e. 1kMtp as mentioned above
Aqueous liquids of the various substances listed as agents or water are added to make granules. Granulation is carried out using a stirring type, rolling, centrifugal type, fluidized bed type or a combination of these types of equipment.

The particle size (diameter) is 0.1 to 1.5 mm,
Preferably it is 0.2 to 1.0 gourd.

The individual active substance-containing units obtained in this way are
It is prepared into multiple unit dosage forms, ie, tablets, capsules, granules, etc., by conventional methods.

(Effect of the invention) The active substance-containing unit obtained by the present invention has high physical strength, does not break even when made into a tablet, and maintains almost its original shape, and when administered to a living body, It separates into individual units and widely disperses within the gastrointestinal tract. Although water permeates through this product, it does not substantially disintegrate in the gastrointestinal tract and gradually releases the active substance, so that it can be maintained for a long time. In addition, there is very little variation between living organisms, and the reproducibility is excellent. Furthermore, the preparation of the present invention can be obtained by a simple and safe manufacturing method.

Next, tests on the dissolution of the active substance of the preparation of the present invention and its concentration in plasma upon administration to living organisms and the results thereof will be shown.

(1) Dissolution test 9 Dissolution test method: According to Japanese Pharmacopoeia's Sosho test method 2 paddle method, paddle rotation speed was 15 Orpm, and Japanese Pharmacopoeia's first solution (artificial gastric fluid) was 500 d as the test liquid.

Tests were conducted using the UV method or the liquid chromatography method using 500 kg of the second fluid (artificial intestinal fluid). The sample is first
Tested in WL for 1 hour, then in second liquid for 1 hour.

(+) Using the formulation obtained in each example as a UV method sample, YM-12
An amount corresponding to 61,750 square meters was weighed out and subjected to the above elution test, and the test liquid was filtered and quantified at a measurement wavelength of 278 nm.

(11) High performance liquid chromatography () (PLC method).

Using the preparations obtained in each example as samples, YM-12
An amount corresponding to 6171ffiP was taken, the above dissolution test was performed, the test solution was filtered, and the amount was quantified under the following operating conditions.

Operating conditions Detector: Ultraviolet absorption photometer (measurement wavelength 225 nm) Column: A stainless steel tube with an inner diameter of about 4 mm and a length of about 150 mm is filled with octadecylsilylated silica gel (for example, Nucleosil 5c18) of about 5 μm as a filler.

Column temperature: Approximately 35°C Mobile phase: 0.05N perchloric acid/acetonitrile mixture (7:3) Flow rate: Constant flow rate of 0.8 to 1.5 rnt/min Table 1 shows the results of 9 tests (2) Absorption test by oral administration (A) (1) The tablet obtained in Example 20 as a sample and the regular tablet obtained in Reference Example 1 as a control were used as YM-12617 and the equivalent of 1■ was measured by the crossover method. The drug was orally administered to 5 male adults, blood was collected at predetermined times, and the plasma concentration was measured using the method described below.

(11) Method for quantifying YM-12617 in plasma Plasma 1.5
After adding 0.5 μg of an internal standard aqueous solution (containing 0.5 μg of amosulalol hydrochloride) to −, a saturated aqueous solution of sodium hydrogen carbonate ITnt was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was extracted with 0.4N hydrochloric acid 2.5-. A saturated aqueous solution of hydrogen carbonate (2) was added to the hydrochloric acid layer to make it slightly alkaline, and the mixture was re-extracted with 4 rnt of ethyl acetate. The ethyl acetate layer was distilled off under reduced pressure, and 0.1M Na was added to the residue.
HC0,0,05m and danzyl chloride (500
Add 0.11 nt of an acetone solution of 1 μg) and
The reaction was allowed to proceed for 20 minutes.

After adding ether 4- to the reaction solution, the organic layer was mixed with water 5-
Washed with. The organic layer can withstand an additional 0.2Ntt57! Washed with. The organic layer was distilled off, the residue was dissolved in a mobile phase mixture of 0.05 mA' under the following operating conditions, and the entire amount was quantified by liquid chromatography under the following operating conditions.

Dansyl-YM- when the eluent flow rate was reduced to 1.4-
The retention times of 12617 and Dansilu Amosuralol were 8.1 minutes and 12.5 minutes, respectively.

Operating conditions Detector: Fluorescence photometer (excitation wavelength 365 nm, fluorescence wavelength 500 nm) Column: A stainless steel tube with an internal diameter of 4 m+ and a length of about 250 mm, with a silica gel of about 5 μm as a packing material (for example, Licrosolp SI 100 (Merck)) ).

Column temperature: Approximately 10°C Mobile phase: Benzene:methanol (Zoo:1) Flow rate:
Constant flow rate θ10 of 1.2 to 1.9 − per minute The results are shown in Tables 2 and 3 and FIG.

- As is clear from FIG. 1, the blood concentration pattern in the case of tablet administration of Example 20 was good and showed the following characteristics.

a) The ratio of Cmax:Cm1n is small and persistent.

b) Variation between individuals is small.

(B) (1) Oral administration of the tablet obtained in Example 21 as a sample and the regular tablet obtained in Reference Example 1 as YM-12617 to 5 adult males by crossover method. Blood was collected at each predetermined time and (A)
Plasma concentration was measured by method ii).

((1) The results are shown in Table 4, Table 5, and Figure 2.

As is clear from FIG. 2, the blood concentration pattern was favorable when administering the tablet of Example 21, and showed the following characteristics.

a) The ratio of Cmax:Cm1n is small and persistent.

b) Small variation between individuals.

(C) (1) The tablets obtained in Example 22 and the capsules obtained in Example n as samples and the regular tablets obtained in Reference Example 2 as YM-12617 were used as YM-12617 in plasma in a 10-section method. The concentration was measured.

(11) The results are shown in FIG.

As is clear from FIG. 3, the blood concentration pattern in the case of tablet administration in Example 4 and capsule administration in Example B was good and showed the following characteristics.

a) The ratio of Cmax:Cm1n is small.

b) Small variation between individuals.

-3) Physical strength of active substance-containing units (particles) Example 1
Tablets were prepared according to the following formulation using particles separately prepared under the same conditions as in Example 5, and the pressure during tableting was changed, and the dissolution of the active substance from them was investigated. (Quantitative determination is by HPLC method). The results are shown in Table 6.

Tablet formulation particles 4.0 ■ Lactose 62.0 Corn starch 28.5 CMC-Ca 5.0 Magnesium stearate 0.5 100 ni Table 6 As is clear from the above results, there is almost no change in elution behavior due to pressure. unacceptable. That is, it can sufficiently withstand the above-mentioned tableting pressure (individual particles are not destroyed), thereby maintaining a constant dissolution rate.

(4) Stirring intensity and dissolution properties in dissolution test The number of rotations of the paddle in the dissolution test in (1) was varied to examine the effect of stirring intensity on the dissolution rate.

The results are shown in Table 7 (quantification was done by UV method).

Table 7 As is clear from Table 7, there is no change in elution behavior depending on stirring intensity, and this is due to biological factors (
It can be seen that the formulation is not easily affected by gastrointestinal motility.

(5) Stability of elution characteristics over time The products of each example were stored under severe conditions, and before storage and after storage 1.
A dissolution test was conducted after several months. The test method was the same as in (1), and the quantitative determination was performed using the UV method.

The results are shown in Table 8.

As is clear from the upper table of Table 8, there is very little change in dissolution behavior even when stored under harsh conditions, indicating that the formulation is stable over time.

(6) Good elution reproducibility Three samples were prepared separately under the same conditions as in Example 4 and an elution test was conducted (quantification was performed using the UV method).

The results are shown in Table 9.

From Table 9, it is recognized that the elution reproducibility is good.

(Example) Example 1. (Production of active substance-containing unit) YM-1261
75 g of crystalline cellulose and 470 g of crystalline cellulose were thoroughly mixed, and to this was added 3 g of Eudragit L30D-5583 (25 g' as solid content) to make 500 g, and the mixture was granulated using a high-speed stirring granulator.

The obtained particles are spherical and have a particle size of 0.1 to 1.5 t.
ab, and the majority were 0.2 to 1.0 head.

Example 2. ~7° Active substance-containing unit 'f: Produced in the same manner as in Example 1 according to the formulation shown in Table 10.

Table 10 Example of using a centrifugal fluid granulator, 8゜YM-126175g, crystal cell #O-su 420g
and 50 g of magnesium stearate were thoroughly mixed,
To this was added Eudragit L30D-5583, 3 g (25 g as solid content) and water to make 500 g, and after kneading, the mixture was granulated using a centrifugal fluid granulator. The obtained particles are spherical and have a particle size in the range of 0.1 to 1.5, with most of them in the range of 0.2 to 1.5. It was OL+II++.

Example 9. ~11° Active substance-containing units were prepared analogously to Example 8 according to the formulations in Table 11.

Table 11 Example 12゜YM-1261720g, Crystal cell o-su 300
g and ethyl cellulose so g 2 were thoroughly mixed, and 230 g of a mixed solvent of 8:2 of ethanol and water was added thereto and granulated using a high-speed stirring granulator. Particle size etc. are the same as above.

Example 13゜ It was granulated using the same recipe as in Example 12 using an ultra-high-speed stirring granulator.

Particle size etc. are the same as above.

Example 14゜YM-1261710g, crystalline cellulose 4qog
were thoroughly mixed, 500 g of water was added thereto, and the mixture was granulated using a high-speed stirring granulator. Particle size etc. are the same as above.

Example 15. ~18° Active substance-containing units were prepared analogously to Example 14 according to the formulations in Table 12.

Table 12 Example 19゜80 g of hydrogenated castor oil was melted and used as KYM-126.
17i0g,! :Low-substituted hydroxypropyl
30g of human body was dispersed, and this was pulverized by spray concealing. 60 g of the obtained powder (YM-
12617) and crystallized O-su 44o3 were thoroughly mixed, 500 g of water was added thereto, and the mixture was granulated using a centrifugal flow granulator. Particle size etc. are the same as above.

Example addition (manufacture of combined unit preparation) To 20 g of particles (active substance-containing unit) obtained in Example 1, 44.9 g of lactose, 20 g of starch, 9.7 g of crystalline cellulose, and 5 g of CMC-Ca were added. , 0.5 g of magnesium stearate was added, and tablets were obtained in the usual manner (YM-126170,2 in 1 tablet 100.1η).
■Contains).

Examples 21-23 Composite unit preparations were prepared in the same manner as in Example 20 according to the formulations shown in Table 13.

*Q Shikyo Calyx J@c-Daheya Yoai Ebu JJ East 0 Example 24
゜40 g of particles obtained in Example 5, 24 g of lactose, 34.54 g of crystalline cellulose, 12 g of hydroxypropyl cellulose for low fit, and 3 g of corn starch were mixed, and to this was added 10% corn starch paste 4.
0 g f and granulation by a conventional method. Add hydrogenated oil 2
．． 4g of calcium stearate, and 0.06g of calcium stearate, and compressed into tablets by the usual method (YM-1261 in 120m9 of one tablet)
70,21n9).

Example 25 Y) l-126175g and crystalline cellulose 467.5g
Mix thoroughly and add Eudragit "L30D-5" to this.
583.3g (2.5g as solid content) of water and PEG6
0002.5g was added to make 500g, and the mixture was granulated using a high-speed stirring granulator. The obtained particles have a spherical shape and a particle size of 0.1 to 1.5 mm, with most of the particles having a diameter of 0.2 to 1.5 mm.
It was 1.0 mm.

Reference Examples 1 to 2 Ordinary tablets containing Sichuan and Sichuan were prepared according to the formulations shown in Table 14 in a conventional manner.

Flute table 14 By buttock fluidized bed granulation

[Brief explanation of drawings]

Plasma concentration of physiologically active substance (YM-12617) in given cases (Y~E-1261)
7) shows the change in plasma concentration over time.

Claims (9)

[Claims] (1) Each unit preparation consists of granules (particles) obtained by adding a dissolution control agent to a mixture of a physiologically active substance and a unit molding material having a weight ratio of 50% or more in the unit, and granulating the mixture. 1. A sustained-release individual or multiple unit dosage form for pharmaceutical use in which the product does not substantially disintegrate in the gastrointestinal tract but gradually releases a physiologically active substance. (2) The preparation according to claim (1), wherein the unit molded material is crystalline cellulose. (3) an aqueous suspension in which the elution control agent is a water-insoluble polymeric substance;
The formulation according to claim (1), which is an aqueous emulsion or a water-containing organic solvent solution. (4) The preparation according to claim (3), wherein the water-insoluble polymeric substance is a methacrylic acid/acrylic acid ethyl ester copolymer or ethyl cellulose. (5) The formulation according to claim (1), wherein the dissolution control agent is water. (6) The preparation according to claim (1), wherein the unit molding material is crystalline cellulose, and the dissolution control agent is an aqueous suspension, emulsion, or water-containing organic solvent solution of a water-insoluble polymeric substance. . (7) The preparation according to claim (6), wherein the water-insoluble polymeric substance is a methacrylic acid/acrylic acid ethyl ester copolymer or ethyl cellulose. (8) The physiologically active substance is 5-{2-[2-(O-ethoxyphenoxy)ethylamino]propyl}-2-methoxybenzenesulfonamide hydrochloride (YM-
Claims Nos. (1) to (12617)
7) The formulation described in section 7). (9) The preparation according to claims (1) to (8), wherein each unit is a granular material with a diameter of 0.1 to 1.5 mm.