JPS59227817A - Long-acting bredinin preparation for oral administration - Google Patents

Abstract

PURPOSE:To provide the titled preparation containing a slow-releasing bredinin component coated with enteric or semipermeable coating material, useful as a carcinostatic agent, and having long-acting activity and reduced side effects. CONSTITUTION:The objective drug preparation contains bredinin as an active component in the form of a slow-releasing component. The slow-releasing bredinin is obtained by coating 1pt.wt. of bredinin with 0.1-2pts.wt. of a substance which dissolves in the intestines or exhibits semipermeable property in the body (e.g. copolymer of methacrylic acid and methacrylic acid ester). When a rapidly soluble bredinin component is used in combination with the slow-releasing bredinin component at a weight ratio of 20-60:80-40, the initial concentration of bredinin in the blood can be adequately controlled, and the concentration in the blood can be maintained at a constant level.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to predenin (Bredinin: 'l
-carbamoyl/-β-D-ribofuranone-imidazolium-5-oleate, hereinafter referred to as predenine)
Bredenine, which is a long-acting oral preparation containing as an active ingredient, is a weakly acidic substance that is easily soluble in water, and the divine method is known for its production (J.

Antibiotics, , , 2 7, (/ 0
), 7 7 3 (/77g), chem. Phar
m. Bull. , ,23. 2'13 (/ri7
5), Japanese Patent Application Publication Sho Sg-33 Tag Publication, Japanese Patent Application Publication No. Sho 5g-3
9 Otsu No. 99]. In addition, as for the biological activity of predenine, it exhibits selective toxicity in particular against murine lymphoma-derived cells L-S/7gY, and also shows a survival effect on murine leukemia using L-/210. It was known to have an anticancer effect that inhibits the proliferation of cancer cells [J.

Antibiotics,, 27, (/ni l), 775
[/974t), J. An-tibiotics
, ,2g, (/O),79g (/97
Furthermore, in recent years, it has been reported that methods such as frequent administration of gredenine can improve the anticancer effect.
In other words, it was based on an administration route such as extremely frequent intraperitoneal administration of 3 grams every 3 hours or continuous oral administration for 7 days, and based on a 7-day regimen (l Japanese Patent Application Laid-Open No. 156-1989).
1111). However, this method is accompanied by an increase in the number of administrations due to injection or oral administration, which places a heavy burden on cancer patients and makes it difficult to administer the drug.

Furthermore, when gredenine is orally administered to animals, for example, even if an aqueous solution of zoredenine is orally administered to rats, it disappears quickly from the blood, and its absorption sites are presumed to be extremely limited. Deaths were observed in the high-dose group, and the effect was low in the low-dose group, requiring special attention to side effects caused by the dose.

The present inventors have developed Bredenin for oral administration, which is a water-soluble, weakly acidic substance that may have side effects depending on the amount administered, and which has good biological activity and a good anticancer effect. As a result of various studies regarding the preparation, we found that the blood concentration of gredenine can be maintained at a constant level by using a delayed-release predenine component obtained by coating gredenine with a substance exhibiting enteric properties in the body or a substance exhibiting semipermeability in the body. It has been found that the oral administration can be sustained and the number of oral administrations can be reduced as a result. It has been discovered that by stabilizing the amount of dust in the blood, side effects can be reduced and the margin of safety can be widened. In addition, by using the delayed-release bredenine component and the fast-dissolving bredenine component, the initial blood concentration of predenine can be well controlled, and the concentration in IIIJ can be stabilized and maintained for good sustained oral use. The bulletin board was launched.

The present invention was completed based on the above knowledge Q, and provides a long-acting predenine preparation characterized by containing a delayed-release bredenine component containing bredenine as an active ingredient, and a fast-dissolving bredenine component and a delayed-release bredenine component. This is a long-acting bredenine preparation containing a bredenine component.

First, Bredenine, which is the active ingredient of the long-acting oral preparation of the present invention, is obtained by the divine method, including free Bredenine, its hydrate, and pharmaceutically acceptable organic or inorganic anions. , such as maleide, p-toluenesulfonate tallate, succinate, citrate, chloride,
Anionic iopide mill with sulfate and carbonate,
It is sufficient to use a material that has been pulverized by a pulverizer such as an atomizer or a siettomizer, and is usually 300 microns or less in diameter, preferably 30 to 100 microns in diameter. A diameter of 0.00 microns may be used.

In addition, the substances exhibiting in vivo enteric properties or in vivo semipermeability used in obtaining the delayed release Bredenine component include, for example, methacrylic acid-methacrylic acid NT/I/ (for example, methyl ester, ethyl NT/I/). ) v) Copolymer (ester dimethyl ester; oy 1-
Ragit L1 Eudrakit 1-S Nirom...and...
Hass Co., Ltd.), acrylic acid-acrylic acid ester copolymer, mechacrylic acid-acrylic acid ester copolymer (Nute/I/N methi/reester; MPM-OS Tanabe M, Yakusha fM), lyric acid ester copolymer ( X Nutelv ~ Methyl F-Til; Ml) M-0 Otsu: Tanabe Seiyaku Co., Ltd.) Acrylic acid derivative type enteric polymer substance, carboxin methyl cellulose, carboxin methyl cellulose, carboxin thylethyl cellulose ( (manufactured by Koshin Co., Ltd.), cellulose acetate slate (CAP: f[] manufactured by Hikari Pure Chemical Industries, Ltd.), hydroxypropyl methyl cell O-7.7 clay) (HP-30, HP-5 S: manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxy Carboxyl group-introduced polysaccharide-based enteric polymer substances such as propyl methylcellulose acetate succinate, and other enteric polymer substances other than these enteric polymer substances, such as polymers that have carboxyl groups or nurpho groups and exhibit in vivo enteric properties. If it is a substance, it can be used,
Preferably, enteric polymer substances exhibiting an elution pH of 5 or more are used, such as methyl cellulose (manufactured by Wako Tsumugi Kogyo Co., Ltd.) and ethyl cellulose (manufactured by Wako Pure Yakuhin Co., Ltd.).
, cellulone diacetate-1-, cellulose triacetate, insoluble hydroxyfurohil cellulone [TC-5
: manufactured by Shin-Etsu Chemical Co., Ltd.), polyacrylic ester, polymethacrylic ester, polyethylene, insoluble acrylic acid-methacrylic acid-acrylic acid ester-methacrylic ester copolymer (Eudragit R8, Eudragit RL: Rohm &・Does it not dissolve in the acidic or alkaline regions of living organisms, such as Henu Co., Ltd., and has semipermeable properties? Examples of substances exhibiting this in-vivo semipermeability include shellac, waxes, and fats and oils.

Waxes and fats and oils may be derived from animals or plants, and may be in solid or liquid form, such as higher fatty acids, higher alcohols, and alcohol esters, and due to their stability, saturated compounds, hydrogenated The higher fatty acids generally have 7 carbon atoms.
Water-insoluble higher fatty acids with a carbon number of 0 or more, preferably saturated straight chain fatty acids such as capric acid, lauric acid, myristic acid, valmitic acid, stearic acid and araxic acid, and higher alcohols with a carbon number of 0 or more. The above saturated higher alcohols, for example &f. n-hexyl alcohol, n-peptyl alcohol,
n-Oly alcohol, n-nonyl alcohol, n-dodecyl alcohol, n-tetradodecyl alcohol, n-hexadecyl alcohol,
N-occudecyl alcohol and n-eicosyl alcohol are mentioned, and further alcohol esters include fatty acid esters of pro-valent alcohols, ethylene glycol, propylene glycol, chrycerin, polyethylene glycol, etc. Examples include fatty acid esters of polyhydric or trivalent alcohols, and examples of the higher-hydric alcohols include the above-mentioned saturated higher alcohols, and examples of the fatty acids include the above-mentioned higher saturated fatty acids. , Furthermore (As the alcohol Nether here, wax which is an ester of -hydric or dihydric alcohol, or oil or fat which is a trihydric alcohol ester may be used. For example, cal hair nauba wax, cotton wax, beeswax, sheep Waxes such as spermatozoa, spermaceti wax, petrolatum, cocoon oil, Gui 7' oil, nata oil, olive oil, coconut oil, camellia oil, peanut oil, cottonseed oil, mustard oil, cacao butter, lanolin fat, wood wax, beef tallow, Oils and fats such as lard and whale fat, preferably hydrogenated products of these waxes and oils, such as Rabriwatsukuno (manufactured by Freund Sangyo Co., Ltd.), which is a hydrogenated castor oil, and TP-9 +n, which is a hydrogenated oil that does not contain hatchet oil. (manufactured by Hon Yushi Co., Ltd.).

Next, a delayed-release bredenine component containing bredenine as an active ingredient is obtained, provided that predenine is substantially coated with the above-mentioned substance exhibiting in vivo enteric properties or in vivo semipermeability. However, the present invention does not require a complete coating, but only a coating that slows down the elution of predenine from the preparation. Predenine may be used as is, or may be pre-mixed with excipients such as crystalline cellulose, lactose, mannitol or hydroxyglohycellulose, lubricants such as magnesium stearate, calcium nateate, tar, binders, etc. Ehaechnol, hydroxypropyl methylcellulose solution, gum arabic solution, gelatin solution, and gelatin solution (accordingly, calcium carbonate, magnesium carbonate, sodium hydrogen carbonate, magnesium silicate, magnesium ruminate, aluminum hydroxide, synthetic aluminum silicate, etc.) are required. Bredenine granules or tablets may be formed using an acid agent as appropriate.Specifically, such Bredenine granules or tablets can be used as a fast-dissolving Bredenine component because the dissolution rate of Bredenine is not particularly controlled. Next, in order to produce a delayed-release predenine component using bredenine as it is, bredenine and the above-mentioned substance exhibiting in vivo enteric properties or in vivo semipermeability are mixed with acetone, ethanol, isopropanol, etc. It is obtained by kneading a single or mixed solution of , methylene chloride, dimethylformamide, dioxane, chloroform, etc. in a kneading machine, followed by granulation or pulverization. Excipients, antacids, and water-soluble polymeric substances such as gelatin, polyvinyl alcohol, hydroxymethylcellulose, hydroxymethylcellulose, hydroxypropylcerol, and gastric soluble polymeric substances such as cellulone acetate dibutylamino. A small amount of hydroxypropyl ether, polyvinyl acecool-diethylamine acetate, and methylaminoether methacrylate 2-methacrylic acid copolymer may be added.Furthermore, as another method, for example, a substance exhibiting in vivo enteric properties or an in vivo Prepare a homogeneous solution using a solvent that dissolves semipermeable substances, especially polymeric substances,
Predenine is added to this, and then this liquid is added in the form of droplets to the encapsulation medium liquid, and then the solvent is removed to obtain a predenine component coated with the above substance. This technique is commonly used as a microencapsulation technique, and is classified into phase separation method, in-liquid curing coating method, and in-liquid drying method depending on the solvent used, encapsulation medium, and solvent removal requirements. For example, methanol,
Solvents such as ethanol and acetone (substances that exhibit in vivo enteric properties) are dissolved in a water-soluble polymeric substance or gastric soluble polymeric substance (if necessary), and bredenine as a core substance is added thereto. A microencapsulation method based on an in-liquid drying method can be used in which this is emulsified and dispersed in an encapsulation medium such as silicone oil or liquid paraffin, and then the solvent is removed to form a coating with Bredenine as a core material. Alternatively, instead of this solvent, a hydrophobic solvent such as methylene chloride or chloroform, which can dissolve the substance exhibiting in vivo enteric properties or in vivo semipermeability, is used, and a surfactant or hydrophilic solvent is used as the encapsulation medium. A microencapsulation method using a medium containing a colloid may be used.Another method of destruction is, for example, under heating conditions of cyclohexane, a substance exhibiting in vivo enteric properties or in vivo semipermeability. The solubility of the substance may be obtained by utilizing the difference in solubility upon cooling, and then using a phase separation method in which the surface of predenine added as a core substance is coated with an e-trowel while cooling; Based on other microencapsulation technologies, delayed-release bu-V-denine granules and tablets are used that do not specifically control the elution rate of microcapsules, which are bu-V-denine as a core material. To obtain the gredenine component, a homogeneous solution of a substance exhibiting in vivo enteric properties or in vivo semipermeability is sprayed and coated using a coating device such as a centrifugal molding device or a coating pan. Alternatively, such zoledenine granules may be used as the core material of microcapsules and obtained by troweling using the microencapsulation technique described above. The bredenine component is one that contains at least bredenine as an active ingredient.
71377 per part by weight, substances exhibiting in vivo enteric properties or in vivo semipermeability 07~. 2 parts by weight, preferably from 0.5 parts by weight.

Next, the obtained delayed-release bredenin component is made into fine granules or granules as it is or with the addition of excipients, or filled into capsules using seven or more of the delayed-release bredenin components. and make it into capsules, or
This (excipients, binders, disintegrants, and other suitable additives are added and mixed to make a plastic mass, then divided and molded to make pills), or excipients, binders, disintegrants, etc. , a lubricant, and other suitable additives are added, mixed, and tableted to obtain a long-acting oral predenine preparation containing a delayed-release predenine component.

Furthermore, a rapidly dissolving gredenine component may be added to the above-mentioned delayed-release predenine component, and the resulting product may be formulated in the same manner as in the above-mentioned formulation. The rapidly dissolving bredenin component to be removed may be bredenin as it is, or may be bredenin granules exhibiting fast dissolution prepared when obtaining the above-mentioned delayed release bredenin component. At this time, the ratio of the rapidly dissolving bredenine component to the delayed release bredenine component is 20 to 60 parts by weight (gO) in terms of bredenine.
-φO parts by weight, preferably 30 to Ilo heavy moons, parts near 0
A ratio t of ~60 M parts may be used. In addition, if the usage ratio is as follows, the formulation will require a delayed-release predenine component at one end or the center, and a fast-dissolving predenine component at one or both ends and its surroundings. It may also be a hard-coated tablet or a laminated tablet.
Alternatively, a mixture of these two components may be compressed to obtain tablets, and the two components may also be used as granules, capsules, or N preparations to obtain a long-acting oral preparation.

The thus obtained long-acting oral bredenine formulation containing a delayed-release bredenine component and the long-acting oral bredenine formulation containing a rapidly dissolving bredenine component and a delayed-release bredenine component can release bredenine over a long period of time. It was an excellent preparation that could be released easily, and also showed good initial blood concentration and persistence in the blood, even in a preparation of a substance that exhibits semi-permeability in the body (due to the delayed release predenine component).

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to this.

Example / Predenine Sot, Manni) -/I/s O fi'
Color fx.

A s% TC-5R (hydroxypropyl methyl cellulose, manufactured by Shin-Etsu Chemical Co., Ltd.) solution was added to the mixture and kneaded.

This kneaded product was granulated using a cylindrical granulator (Kikusui basket granulator, diameter: 0.gmmφ), and then dried at SO° C. for 7 hours.

The dried product was crushed with a crusher (Onnlator: manufactured by Kikusui Seisakusho; 30 mesh) and Bredenin h grains <3
o-10o mesh) was obtained.

In addition, a cyclohexane solution of 15th polyisobutylene,
2oome+ko:r-chi)1. y c) Lerose (1
00 cpS) (manufactured by Wako Tsumugi Yakuhin Co., Ltd.) 57 was added to 77 [] and dissolved in a heating bath.

Into this solution, 10' of the above-mentioned predenine glue particles were dispersed by force, then allowed to cool and decanted. The residue was dried at 50° C. for 7 hours to obtain granules of the delayed release Bredenine component coated with ethyl cellulone.

Next, 200 mg of this delayed-release Bredenine component was tested with 21/00 ml of pH
This is a test tube with a stopper, and a dissolution test device, Deftist (manufactured by Nyland, Italy).
Rotate the trowel at 30 rpm at 7°C, and after 1 hour replace the test solution with a pH≠5 solution and continue rotating. exchange,
The test solutions were collected at each elution time (7 hours, 2 hours, 5 hours later), and the amount of budenine eluted in each test solution was measured. The elution rate was determined by constant loss using the absorbance of ultraviolet absorption of 2 g Onm.

As a result, the delayed-release bredenine component of the present invention exhibited a dissolution curve as shown in the figure, and the delayed-release bredenine component of the present invention exhibited sustained release over time and time t, and was good), r, bathing rate. It showed that.

In addition, this delayed-release predenine ingredient is contained in minicapsules (
・This was filled to make a preparation (hereinafter referred to as the capsule of the present invention).

In addition, a minicapsule/I/ (hereinafter referred to as bulk powder capsule IV) containing a Bredenine water bath solution and a bulk powder of Zoredenine was prepared as a 71st.

Next, each of these preparations was added to 1 (approximately 10
Bredenine (10 my/kti) was orally administered by gavage to 250-3009 weeks old, male, / ItlS mice, and 7.5 hours, 3 hours, ≠ S time, O time, g time, and 70 hours after administration. Blood was collected every hour (around 0.17ml each), and the blood was centrifuged at 3000 rpm for 75 minutes to obtain serum, which was diluted twice with distilled water, protein was removed, and 10 pl of the supernatant was used as a sample. High performance liquid chroma l-craphy [conditions: mobile phase 0, /M phosphate buffer, packing material Licrosolv RP/g (manufactured by Merck & Co., Ltd.),
Flow rate 0.7 ml, 7 minutes, time 30 minutes]? The bredenine content was measured.

As a result, as shown in Figure 2, ○−○
shows the blood concentration curve using the capsule of the present invention, △−△
indicates the blood concentration curve using bulk powder capsules, x-s indicates the blood concentration curve using predenine water bath solution,
While both the predenine aqueous solution and the bulk powder capsule as a control have a fast rate of disappearance of predenine from the blood, the capsules of the present invention show a good initial blood '/m II (2) and even after 70 hours. It was a good long-lasting preparation with a blood concentration of /γ/m14 or higher.

Example 2 The same operation as in Example 2 was performed to obtain naked granules of Bredenine.

Also, a cyclohexane solution of 75 polyisobutylene, 2
oomt', + ethylcellulose (10OCpS)
52 was added and dissolved by heating. In this liquid, naked M
After adding and dispersing the grains 3-2, the mixture was allowed to cool and filtered with decane 1-1.

This residue was dried at 50° C./hour to obtain granules [A] of the delayed release Bredenine component coated with ethyl cellulose.

Furthermore, 7% polyisobutylene Ncrohegisan M
Ethylcellulose I'l-5 cpa in 200 mg of liquid
S? The mixture was heated and dissolved. After adding and dispersing 10 g of naked granules of this liquid, the mixture was allowed to cool and decanted. This residue was dried at 50° C./hour to obtain ethylcellulose-coated pellets (13) of a delayed-release bredenine component.

The granules (A) and granules (B) containing predenine are mixed so that the ratio is 2:/e, and the mixed ingredients are filled into capsules with 10 O1 of predenine.
A long-acting oral Bredenine preparation (capsule) containing the following was obtained.

In addition, using this long-acting Bredenine preparation,
As a result of calculating the bathing rate using the same method as above, the third
As shown in Figure t, good durability was shown.

Example 3 Gredenine-S02, Avicel 10/(Asahi Kasei Corporation; Crystal Cellulone) 230? A mixture consisting of 5% T
C-5R melt was added and kneaded. This kneaded product was granulated using a cylindrical granulator (basket granulator manufactured by Kikusui Co., Ltd., diameter/mmφ), and then dried at 50° C. for 7 hours to obtain fast-acting gredenin granules.

In addition, rapid-fire Bredenine granules 1 obtained by the same operation
009 was added to a centrifugal fluid granulator (CF-3,40, manufactured by Freund Sangyo Co., Ltd.), and
% coating liquid (ethanol/I/: methylene chloride/:
Approximately 150 g of Enteric Coated Delayed Release Granules coated with Bredenine's OyF Ragit L were obtained using 50% coated Bredenine.

Q
Mix this and take 270'mg of this mixed ingredient into capsules/1/Q.
A long-acting oral preparation of Bredenine containing 100 mg of Bredenine was prepared.

Next, the dissolution rates of the fast-dissolving bredenin granules and slow-release granules were determined. As a result, the number of threads shown in Fig.
In the figure, ×-× indicates the dissolution curve of fast-dissolving Bredenin granules, 〇-〇 indicates the dissolution curve of delayed-release granules, and ◎-◎ indicates the Takeda curve of a mixture of both. The dissolution of Zoledenine Zhao granules is extremely fast, while the delayed release granules show good dissolution although no initial dissolution is observed, and the mixture of the two shows good dissolution, showing both early dissolution and delayed dissolution. It showed a large amount of eluted bacteria.

Example The following components were mixed: fast-dissolving Bredenin burnt granules obtained in Example 3, 27 parts of delayed release granules, 9 parts of Avicel 102, and 05 parts of magnesium stearate, and then tableted. 365ml/0 Bredenine per 7 tablets
A long-acting oral Bredenine tablet containing 0 mW gold was obtained.

Example S A mixture of pretinin, 2soy, mannitol, and 250g was mixed with a 5% TC-S R solution under high pressure. This kneaded product was granulated using a cylindrical granulator and then dried at SO° C. for 7 hours. This dried material was passed through a centrifugal flow device.
In addition to -3 Otsu O, Sugi-covered liquid ethyl cellulose (10% solution hair 1-: methylene chloride = /: /
) was used to obtain long-lasting bredenine granules, which were used as long-lasting bredenine granules.

Example B 30 parts of long-lasting predenine pellets obtained in the same manner as in Example 5, 7 parts of Abysse/I/102, and 05 parts of magnesium stearate were mixed and then tableted to give 7 tablets of 393 mg. A long-acting tablet containing 100 m7 of predenine was obtained.

Example 7 Bretainin soy, Lovely Watsuknu 10/(manufactured by Freund Sangyo Co., Ltd.; diurnal hydrogenated hydrogenated oil>207 Avicel 1
A mixture of ethanol and methinone chloride was vigorously kneaded into the mixture consisting of 0/2 and 7.

Dry at °C'X/hour. The obtained dried product was pulverized using a pulverizer to obtain 1 grain of il. After adding magnesium stearate/7 to the mixture, it was compressed to obtain a long-lasting tablet.

Example g Predenine 10O'i', methyl ivy acrylate/methacrylic acid copolymer (Froin l-I, Eudragi+Lloo)/3-0, Avicel 10/70
A mixture consisting of 07 (gθ% ethanol solution) was added and kneaded.

This kneaded mixture was granulated using a cylindrical granulator, and 50 parts of the mixture was crushed to obtain continuous f1 predenine powder.

Example 7 Gredenine SO'li', Lactose 157 and L-HPC
(manufactured by Shin-Etsu Chemical Co., Ltd.; low-substituted hydroxyglobil cellulose), l! Mixture powder ekoS%TC-5 consisting of
RN4 liquid was added and kneaded. This kneaded product was granulated using a cylindrical granulator and then dried at 50° C. for 7 hours.

The obtained dried product was pulverized using a pulverizer, and 05 g of magnesium nutearate was added to it, followed by tableting to obtain a fast-dissolving tablet.

This fast-dissolving tablet [this hydroxypropyl methyl cellulose phthalate l- (manufactured by Shin-Etsu Chemical Co., Ltd.: HP 33-)]
Spray FNO/1/ii dissolved in the coating pan and apply HI? -53 coated enteric-coated tablets were obtained. Next, tablets coated with this HP-55 (ratio O S part)
A mixed powder of predenine (35 parts ratio) (with a small amount of magnesium stearate added) having the same composition as the above-mentioned fast-dissolving tablet is compressed into a multi-layer tablet using a two-stage compression tableting liquid. was formed.

Sara e The tablets here are in a coating pan, TC-3R.
Inner layer e-coated HP-33 using an ethanol solution containing
A long-acting predenine tablet having an immediate-acting predenine component was obtained.

Example 10 Bretenin 100f, Mannide-w30t and L-
Mix HP C9ri7 and add this eko5chiTC-
After adding and kneading the 3-R solution, the mixture was granulated using a cylindrical granulator. After drying at 50° C. for 7 hours, the mixture was pulverized using a pulverizer, and magnesium stearate was added thereto and mixed to obtain fast-acting Bredenin granules.

Predenine 100f again? , Abysse/L/O/'s 92 and Lovely Watsuknu 10/'s 507 were mixed together, and further an O% ethanol solution was added thereto and kneaded. After granulating this mixture using a cylindrical granulator,
Dry for an hour. The obtained dried product was pulverized using a pulverizer, and magnesium stearate was further added thereto to obtain delayed-release predenine granules.

Three parts of the fast-acting granules and 7 parts of the delayed-release granules thus obtained were used in a multilayer tablet machine to obtain a long-acting predenine tablet having an upper layer, an immediate-acting portion, and a lower layer, a delayed-release portion.

Example // The same procedure as in Example 3 was carried out to obtain rapidly dissolving Bredenin granules.

Same again? The above granules thus obtained were added to a centrifugal flow granulator to obtain enteric-coated granules of Bredenine FA) coated with 30% of Eudragit L10O g% coating solution (ethanol:methylene chloride-/:/). .

Further, in the same manner as in Example 3, Eutragit L10O
Enteric-coated granules (B) of predenine were obtained which were coated 70% with the g% coating solution.

The obtained fast-dissolving m-granules, enteric-coated granules +A) and enteric-coated 11! Mix the /+ grains (■3) with the content ratio /:, 2 = 2, and fill the mixed ingredients into a capsule to create a long-lasting capsule containing L% Bretenin 1007q. obtained the drug.

Example /2 7' V de=725Of, Abysse w/O/ ノ23
After adding a bath solution of S%TC-, 5'R to the mixture consisting of 07 and 5'R, the mixture was dried at 50°C to obtain rapidly dissolving Bredenin granules.

The granules were added to a centrifugal fluid granulator, and then polyvinyl acecooled diethylamino acetate (manufactured by Sankyo Co., Ltd.,
A solution of a coating composition (ethanol:methylene chloride-l/) and ethylcellulose (AEA)
) and sprayed with 50% coated Bredenine long-acting granules.

[Brief explanation of the drawing]

Figure 1 shows the elution curve of the delayed release bredenine component obtained in Example/, Figure 2 shows the blood concentration curve, and Figure 3 shows the blood concentration curve.
The figure shows the dissolution curve of the long-acting predenine preparation obtained in Example 2, and Figure J shows the dissolution curve of the fast-dissolving predenine granules, delayed-release granules OJ, and a mixture of both obtained in Example G. show. Patent applicant: Toyo Jozo Co., Ltd. Representative Takashi 1) Tetsuo

Claims (1)

[Scope of Claims] a) A sustained oral predenine preparation characterized by containing a delayed-release gredenine component containing bredenine as an active ingredient. (2) The preparation according to claim 1, wherein the delayed-release predenine component is a component obtained by subverting predenine with a substance exhibiting whitening properties in the body or a substance exhibiting semipermeability in the body. (3) The substance exhibiting in vivo enteric properties or in vivo semipermeability is methacrylic acid-methacrylic ester copolymer, acrylic acid-acrylic ester copolymer, ivy acrylic acid-acrylic acid ester Copolymer, Entel acrylic acid-Enter acrylic acid copolymer, Carboxymethyl cellulone, Carboxyethyl cellulone, Power/Levoxymethyl leethyl cellulone, Cellerone acetate phthalate, Hydroxypro Hill methylcellulose phthalate, hydroxyprobyl methylcellulose acetate succinate), methylcellulone, ethylcellulone, cellulone cyacetate, cellulone triacetate, insoluble hydroxyprovirce! Lerone, polyacrylic acid, polymethacrylate, polyethylene, insoluble acrylic acid-methacrylic acid-acrylic acid, methacrylic acid ester copolymer, shellac, special FF R' which is wax and oil. The formulation described in Section 2 of the desired range of predenine. (4) Substance exhibiting enteric properties in vivo or semipermeability in vivo per part by weight of predenine. The preparation according to claim 2, which is a predenine component. (5) A patent claim in which the long-acting predenine preparation is in the form of fine granules, granules, pills, capsules, or tablets. The preparation according to item 1. (6) A long-acting oral preparation containing a fast-dissolving bredenine component and a delayed-release bredenine component. , 20 to Otsu O parts by weight: g O - O parts by weight (predenine equivalent amount). -40 parts by weight (in terms of bredenine) of the preparation according to claim 6. (9) The delayed-release bredenine component is a substance exhibiting in vivo enteric properties or an in vivo enteric property. The preparation according to claim 6, which is a component in which bredenine is coated with a substance exhibiting permeability. Acrylic acid ester copolymer, acrylic acid-acrylic acid ester copolymer, ivy acrylic acid-acrylic acid ester copolymer, acrylic acid ester-methacrylic acid-methacrylic acid ester copolymer, carboquine Ethyl cellulose, carboquine ethyl cellulose, carboxymethyl ethyl cellulose cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate sacunnate, methyl cellulose, ethyl hexaruron, cellulose acetate, cellulose triacetate, insoluble hydroxyglobil cellulone, polyacrylic acid ester, polymethacrylic The preparation according to item 9, which is an acid ester, polyethylene, a non-bath acrylic acid-methacrylic acid-acrylic ester-methacrylic ester copolymer, shellac, waxes and fats and oils. ) The delayed-release bredenine component is 0/-2 parts by weight of a substance exhibiting enteric properties in vivo or semipermeable in vivo per part by weight of zoredenine.
Preparations as described in section. (1) The preparation according to claim 6, wherein the sustained-acting Bredenine preparation is in the form of fine granules, granules, pills, capsules, or tablets.