JPH0530810B2 - - Google Patents

Description

Detailed Description of the Invention The present invention provides a long-acting oral preparation containing Bredenin (4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate, hereinafter referred to as Bredenin) as an active ingredient. Regarding.

Bredenine is a weakly acidic substance that is easily soluble in water, and various methods are known for its production [J.
Antibiotics., 27 , (10), 775 (1974), Chem.
Pharm.Bull., 23 , 245 (1975), Japanese Patent Publication No. 58-13394
Publication No. 58-39699]. In addition, as for the biological activity of Bredenine, it shows selective toxicity especially against mouse lymphoma-derived cells L-5178Y, and L-1210
It was also known to have a survival effect on murine leukemia, and also to have an anticancer effect by suppressing the growth of cancer cells in tissue culture [J. Antibiotics., 27 , (10), 775 (1974 ), J.
Antibiotics., 28 , 798 (1975)]. Furthermore, in recent years, it has been reported that the anticancer effect can be improved by methods such as frequent administration of Bredenine, such as extremely frequent intraperitoneal administration 8 times every 3 hours or continuous oral administration for 9 days. It was administered based on the route and dosing schedule (Japanese Patent Laid-Open No. 1983-1999).
Publication No. 156418). However, this method involves an increase in the number of administrations by injection or oral administration, which places a heavy burden on cancer patients and makes it difficult to schedule administration.

In addition, when bredenine is orally administered to animals,
For example, even if an aqueous bredenine solution is orally administered to rats, it disappears quickly from the blood, and the absorption sites are presumed to be extremely limited.Furthermore, cases of death were observed in the high-dose group of bredenine, and cases of death were observed in the low-dose group. However, its effectiveness was low, and special attention was required regarding side effects depending on the dose.

The present inventors conducted various studies on oral bredenine preparations, which are water-soluble, weakly acidic substances that may have side effects depending on the dose, and which exhibit good biological activity, especially anticancer effects. As a result, by using a delayed-release bredenine component and a rapidly soluble bredenine component obtained by coating bredenine with a substance that exhibits in vivo enteric properties or a substance that exhibits in vivo semipermeability, it is possible to achieve a good initial blood concentration of bredenine. We have obtained a good long-acting preparation that can be controlled and maintain a constant and sustained blood concentration.

The present invention has been completed based on the above findings, and includes a rapidly dissolving bredenin component and a delayed release bredenin component in an amount of 20 to 60 parts by weight: 80 to 40 parts by weight (in terms of bredenin), and a delayed release bredenin component. The chemical Bredenin component is 0.1 to 0.1 to 1 part by weight of a substance that exhibits in vivo enteric properties or a substance that exhibits in vivo semipermeability.
This is a long-acting oral Bredenine formulation containing the above two components in an amount of 2 parts by weight.

First, bredenine, which is the active ingredient of the sustained-release oral preparation of the present invention, can be obtained by various methods, including free bredenine, its hydrate, and medically acceptable organic or inorganic anions such as maleate. , p-toluenesulfonate, acetate, tartrate, succinate, citrate, chloride, sulfate, carbonate, and other anion salts. Bredenine is also
It is sufficient to use a material that has been made fine by a grinding device such as a speed mill, atomizer, or jettomizer, and usually has a diameter of 300 microns or less, preferably 30 to 300 microns.
It is sufficient to use one with a diameter of 200 microns.

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 esters (e.g., methyl ester, ethyl ester). Polymer (ester = methyl ester; Eudrakit L, Eudrakit S: manufactured by Rohm & Hass), acrylic acid-acrylic ester copolymer, methacrylic acid-acrylic ester copolymer (ester =
Acrylic acid derivative enteric polymers such as methyl ester (MPM-05 manufactured by Tanabe Pharmaceutical Co., Ltd.) and acrylic acid ester-methacrylic acid-methacrylic ester copolymer (ester = methyl ester; MPM-06 manufactured by Tanabe Pharmaceutical Co., Ltd.) Substances, carboxymethyl cellulose, carboxyethyl cellulose, carboxyethyl cellulose (manufactured by Kojinsha), cellulose acetate phthalate (CAP: manufactured by Wako Pure Chemical Industries, Ltd.), hydroxypropyl methylcellulose phthalate (HP-50, HP-55: manufactured by Shin-Etsu Chemical Co., Ltd.), Carboxyl group-introduced polysaccharide-based enteric polymer substances such as hydroxypropyl methylcellulose acetate succinate, and other enteric polymer substances other than these enteric polymer substances, such as polymers that have an alkyl group or a sulfo group and exhibit in vivo enteric properties. Any molecular substance can be used, preferably an enteric polymer substance with an elution pH of bredenine of 5 or more, as well as methyl cellulose (manufactured by Wako Pure Chemical Industries, Ltd.) and ethyl cellulose (manufactured by Wako Pure Chemical Industries, Ltd.). , cellulose diacetate, cellulose triacetate, insoluble hydroxypropyltcellulose (TC-5: manufactured by Shin-Etsu Chemical Co., Ltd.), polyacrylic ester, polymethacrylic ester, polyethylene, insoluble acrylic acid-methacrylic acid-acrylic ester-meth Substances that do not dissolve in the acidic or alkaline regions of the body and exhibit semipermeability in the body, such as acrylic acid ester copolymers (Eudragit RS, Eudragit RL: manufactured by Rohm & Hass) Examples include shellac, waxes, and fats and oils. Waxes and fats and oils may be derived from animals or plants, and may be solid or liquid.
Examples include higher fatty acids, higher alcohols, and alcohol esters, and saturated compounds and hydrogenated products thereof are preferred from the viewpoint of stability.The higher fatty acids are generally water-insoluble higher fatty acids having 10 or more carbon atoms, preferably saturated. Straight chain fatty acids such as capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid are mentioned, and higher alcohols are preferably saturated higher alcohols having 6 or more carbon atoms, such as n-
hexyl alcohol, n-peptyl alcohol,
n-octyl alcohol, n-nonyl alcohol, n-dodecyl alcohol, n-tetradodecyl alcohol, n-hexadecyl alcohol, n
- Octadecyl alcohol, n-eicosyl alcohol, n-hexacosyl alcohol, etc., and alcohol esters include fatty acid esters of higher monohydric alcohols, dihydric or trihydric alcohols such as ethylene glycol, propylene glycol, glycerin, and polyethylene glycol. Examples of the higher monohydric alcohols include the above-mentioned saturated alcohols, and examples of the fatty acids include the above-mentioned higher saturated fatty acids. As the alcohol ester, wax which is an ester of monohydric or dihydric alcohol, or oil or fat which is an ester of trihydric alcohol may be used, such as carnauba wax,
Waxes such as cotton wax, beeswax, wool wax, spermaceti wax, petrolatum, sesame oil, soybean oil, rapeseed oil,
Olive oil, coconut oil, camellia oil, rattan oil,
Oils and fats such as cottonseed oil, castor oil, cacao butter, lanolin fat, wood wax, beef tallow, lard, and whale fat, preferably hydrogenated products of these waxes and fats, such as Labrywatus (Freund Sangyo Co., Ltd.), which is a hydrogenated oil of castor oil. (manufactured by Nihon Yushi Co., Ltd.) and TP-9 (manufactured by Nihon Yushi Co., Ltd.), which is a hydrogenated oil of rapeseed oil.

Next, a delayed-release bredenine component containing bredenine as an active ingredient is obtained, but it is sufficient if bredenine is substantially coated with the above-mentioned substance exhibiting in vivo enteric properties or in vivo semipermeability. However, the present invention does not require complete coating, but any coating that delays the elution of bredenine from the preparation is sufficient. First, in manufacturing this delayed release Bredenine component,
Bredenine may be used as is or it may be pre-mixed with excipients such as crystalline cellulose, lactose, mannitol or hydroxypropyl cellulose, lubricants such as magnesium stearate, calcium stearate or talc, binders such as ethanol, hydroxypropyl cellulose, etc. Bredenin is prepared using methylcellulose solution, gum arabic solution, gelatin solution, and, if necessary, antacids such as calcium carbonate, magnesium carbonate, sodium bicarbonate, magnesium aluminate metasilicate, aluminum hydroxide, and synthetic aluminum silicate. It may also be used in the form of granules or tablets. In particular, 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 bredenine component using bredenine as it is, bredenine and the above-mentioned substance exhibiting in vivo enteric property or in vivo semipermeability are mixed with acetone,
It is obtained by kneading in a kneader using a single or mixed solvent such as ethanol, isopropanol, methylene chloride, dimethylformamide, dioxane, chloroform, etc., followed by granulation or pulverization. At this time, excipients and antacids may be added as necessary, as well as water-soluble polymeric substances such as gelatin,
A small amount of polyvinyl alcohol, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or gastric soluble polymer substances such as cellulose acetate dibutylamino hydroxypropyl ether, polyvinyl acetal-diethylamino acetate, dimethyl amino ether methacrylate-methacrylic acid copolymer May be added. Another method is to prepare a homogeneous solution using a solvent that dissolves, for example, a substance that exhibits enteric properties in vivo or semipermeable in vivo, especially a polymeric substance, and then adds bredenine to this solution. Then, this liquid is added in the form of droplets to the encapsulation medium liquid, and then the solvent is removed to obtain a Bredenine component coated with the above substance. This technology is
It 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, and these methods can be used. . For example, substances that exhibit in vivo enteric properties in solvents such as methanol, ethanol, and acetone;
Further, if necessary, it is dissolved using a water-soluble polymeric substance or a gastric-soluble polymeric substance, furthermore, bredenine as a core substance is added thereto, and this is emulsified and dispersed in an encapsulating medium liquid such as silicone oil or liquid paraffin. A microencapsulation method using an in-liquid drying method can be used in which the solvent is then removed and a coating is formed using bredenine as a core material. In addition, instead of the above-mentioned solvent, a hydrophobic solvent such as methylene chloride or chloroform that can dissolve a substance exhibiting in vivo enteric properties or an in vivo semipermeable substance is used, and a surfactant or a hydrophilic colloid is used as an encapsulation medium. A microencapsulation method using a medium containing . Another coating method is to use the solubility of a substance exhibiting in vivo enteric properties or in vivo semipermeability under heating conditions of cyclohexane, for example, by utilizing the difference in solubility upon cooling. Bredenine added as a core material may be obtained using a phase separation method in which bredenine is precipitated and coated on the surface of the core material under cooling, or based on other microencapsulation techniques, delayed release bredenine containing bredenine as a core material may be obtained. Component microcapsules may also be obtained. Furthermore, when obtaining a delayed-release bredenine component using bredenin granules or tablets whose dissolution rate is not particularly controlled as described above, it is important to ensure that the substance exhibiting in vivo enteric properties or in vivo semipermeability is homogeneous. The solution may be sprayed and coated using a coating device such as a centrifugal flow granulator or a coating pan, or such bredenine granules may be used as the core material of microcapsules and applied to the microencapsulation technique described above. It may also be obtained by coating. Furthermore, the delayed-release bredenine component obtained in this manner contains at least bredenine as an active ingredient, and per 1 part by weight of bredenin, 0.1 to 2 parts of a substance exhibiting in vivo enteric properties or in vivo semipermeability are contained.
Part by weight, preferably 0.5 to 1 part by weight.

The obtained delayed release Bredenine component is then:
Using one or more types of delayed-release Bredenin components, one or more types of retarded release Bredenine components can be used as is, or with the addition of excipients to form fine granules or granules, or this can be filled into capsules to form capsules, or this can be filled with excipients. Add excipients, binders, disintegrants, and other appropriate additives and mix to form a plastic mass, then divide and mold to make pills, or excipients, binders, disintegrants, and lubricants. , and other suitable additives are added thereto, mixed and compressed into tablets to obtain a sustained-release oral bredenine preparation containing a delayed-release bredenine component.

Furthermore, a rapidly dissolving bredenine component may be added to the above-mentioned delayed release bredenine component to formulate a formulation in the same manner as the above formulation. The rapidly dissolving bredenin component used in this case 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 fast-dissolving bredenine component to the delayed-release bredenine component is as follows:
20-60 parts by weight as Bredenine equivalent amount: 80-40
It may be used in parts by weight, preferably in a ratio of 30 to 40 parts by weight: 70 to 60 parts by weight. Furthermore, if such a usage ratio is used, a dry-coated tablet is prepared in which one end or the center is laminated with a delayed-release bredenin component, and one or both ends and the surrounding area are laminated with a rapidly dissolving bredenin component. Alternatively, it may be made into a laminated tablet, or a mixture of these two components may be compressed to obtain a tablet, and both components may be further combined into granules,
Depot oral Bredenine formulations may be obtained as capsules or pills.

The sustained oral bredenine preparation containing the fast-dissolving bredenine component and the delayed-release bredenine component thus obtained was a good preparation capable of releasing bredenine over a long period of time.

Next, the present invention will be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 A 5% TC-5R (hydroxypropyl methyl cellulose: manufactured by Shin-Etsu Chemical Co., Ltd.) solution was added to a mixture consisting of 50 g of bredenine and 50 g of mannitol and kneaded. This mixture was granulated using a cylindrical granulator (Kikusui basket granulator, diameter: 0.8 mm), and then dried at 50°C for 1 hour.

The obtained dried product was pulverized with a pulverizer (oscillator: manufactured by Kikusui Seisakusho; 30 mesh) to obtain naked granules of Bredenine (30-100 mesh).

Further, 5 g of ethyl cellulose (100 cps) (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 200 ml of a 1.5% polyisobutylene solution in cyclohexane, and dissolved by heating. To this solution, 10 g of the bare granules of bredenine mentioned above were added and dispersed, and then allowed to cool and decanted. This residue was heated at 50℃ for 1 hour.
to obtain granules of delayed release Bredenine component coated with ethyl cellulose.

Then, 200mg of this delayed release Bredenine component
was placed in a test tube with a stopper along with 100 ml of the test solution (PH1.2), set in a dissolution test device Diftest (manufactured by Ueland, Italy), and heated at 37°C.
Rotate at 30 rpm and adjust the pH of the test solution after 1 hour.
4.5 Interact with the solution and continue the rotational movement, and then part 1
After the time, the test solution was replaced with a PH6.9 solution and rotated to elute.The test solution was collected according to each elution time (1 hour, 2 hours, 4 hours, 8 hours later), and each The amount of Bredenine eluted into the test solution was determined by the absorbance of ultraviolet absorption at 280 nm to determine the elution rate.

As a result, the dissolution curve as shown in FIG. 1 was shown, and the delayed release bredenine component of the present invention exhibited sustained release over a long period of time and a good dissolution rate.

Furthermore, this delayed-release bredenine component was filled into minicapsules to prepare a formulation (hereinafter referred to as the capsule of the present invention).

As a control, minicapsules (hereinafter referred to as bulk powder capsules) containing an aqueous solution of bredenine and bulk powder of bredenine were prepared.

Next, each of these preparations was orally administered by force to Wistar rats (approximately 10 weeks old, approximately 250 to 300 g, male, 5 animals per group) at a dose of 10 mg/Kg of Bredenine, and the administration was administered at 1.5 hours, 3 hours, and 4.5 hours after administration. Collect blood (approximately 0.4 ml each) every 6 hours, 8 hours, and 10 hours.
This blood was centrifuged at 3000 rpm for 15 minutes to obtain serum, which was diluted 2-fold with distilled water, protein removed, and 10μ of the supernatant was used as a sample for high performance liquid chromatography [conditions: mobile phase 0.1M] phosphate buffer,
Filler Licrosolp RP18 (manufactured by Merck), flow rate 0.7
ml/min, time 30 minutes] and the bredenine content was quantified.

The results are as shown in Figure 2, and in Figure 2, ○-○ indicates the blood concentration curve using the capsule of the present invention, and △-△ indicates the blood concentration curve using the bulk powder capsule. , ×-× indicate blood concentration curves using a bredenine aqueous solution.While the bredenine aqueous solution and bulk powder capsules as controls both have a fast bredenine disappearance rate in the blood, the capsules of the present invention have a good rate of disappearance from the blood. Indicates initial blood concentration, and
It was a good long-lasting preparation with a blood concentration of 1γ/ml or more even after 10 hours.

Reference Example 2 The same operation as in Reference Example 1 was performed to obtain naked granules of Bredenine.

Further, 5 g of ethyl cellulose (100 cps) was added to 200 ml of a 1.5% polyisobutylene solution in cyclohexane and dissolved by heating. After adding and dispersing 5 g of bare granules of Bredenin to this liquid, the mixture was allowed to cool and decanted. This residue was dried at 50°C for 1 hour to produce granules of delayed-release Bredenin component coated with ethyl cellulose.
I got (A). Furthermore, 5 g of ethyl cellulose (45 cps) was added to 200 ml of a 1% polyisobutylene solution in cyclohexane and dissolved by heating. 10 g of naked Bredenine granules were added to this solution to decompose it, and then the solution was allowed to cool and decanted. This residue was dried at 50° C. for 1 hour to obtain granules (B) of a delayed release Bredenine component coated with ethyl cellulose.

The obtained granules (A) and granules (B) are mixed so that the bredenine content ratio is 2:1, and the mixed components are filled into capsules, and the delayed-release oral bredenine containing 100 mg of bredenine is prepared. A preparation (capsule) was obtained.

Further, the dissolution rate of this long-acting Bredenine preparation was determined in the same manner as in Reference Example 1, and the result was as shown in FIG. 3, indicating good sustainability.

Example 1 5.
%TC-5R solution was added and kneaded. This kneaded product was granulated using a cylindrical granulator (basket manufactured by Kikusui Co., Ltd.) to obtain fast-acting Bredenin granules.

In addition, 100 g of rapidly dissolving Bredenin granules obtained in the same manner were added to a centrifugal flow granulation device (CF-360, manufactured by Freund Sangyo), and
Approximately 150 g of enteric-coated delayed release granules coated with Eudragit L of Bredenine coated with 50% coating using an 8% coating solution of L100 (ethanol:methylene chloride = 1:1) were obtained.

The obtained fast-acting bredenine granules and delayed-release bredenine granules were mixed so that the bredenine content ratio was 3:7, and 270 mg of this mixed ingredient was filled into capsules to form a sustained-release oral capsule containing 100 mg of bredenine. A Bredenine formulation was obtained.

Next, using the above-mentioned fast-dissolving Bredenin granules, slow-release granules, and a mixture containing both, the dissolution rate was determined by the above-mentioned Reference Example 1 and the agitation dissolution test method. The results are as shown in Figure 4, and in Figure 4, ×-× indicates the dissolution curve of fast-dissolving bredenin granules, ○-○ indicates the dissolution curve of delayed-release granules, and ◎-◎ indicates both dissolution curves. The results show that the fast-dissolving bredenin granules elute very quickly, the delayed-release granules show good dissolution although no initial dissolution is observed, and the mixture of both It showed both elution and delayed elution, indicating a good elution pattern.

Example 2 Rapidly dissolving Bredenin granules 6 obtained in Example 1
1 part, 21 parts of delayed release granules, 9 parts of Avicel 102, and 0.5 parts of magnesium stearate were mixed, and this was then compressed to form a long-acting oral Bredenine tablet containing 100 mg of Bredenine per 365 mg tablet. Obtained.

Reference Example 3 A 5% TC-5R solution was added to a mixture consisting of 250 g of bredenine and 250 g of mannitol and kneaded. This kneaded product was granulated using a cylindrical granulator and then dried at 50°C for 1 hour. This dried material is transferred to a centrifugal fluidizer TC-360.
In addition, delayed-release Bredenin granules were obtained which were coated with a 10% coating solution of ethyl cellulose (acetone: methylene chloride = 1:1), and these were used as delayed-release Bredenine granules.

Reference Example 4 30 parts of delayed-release bredenin granules obtained in the same manner as in Reference Example 3, 9 parts of Avicel 102, and 0.5 part of magnesium stearate were mixed, and then tableted to give 395 mg of bredenin per tablet. Delayed release tablets containing 100 mg were obtained.

Reference Example 5 A mixture of ethanol and methylene chloride was added to a mixture consisting of 50 g of Bredenine, 20 g of Lovely Wax 101 (manufactured by Freund Sangyo Co., Ltd., Japan Hydrogenated Hydrogenated Oil), and 29 g of Avicel 101 and kneaded.

After granulating this mixture using a cylindrical granulator, it was heated to 50°C.
It was dried for 1 hour. The obtained dried product was pulverized using a pulverizer to obtain granules. After adding 1 g of magnesium stearate to the mixture, the mixture was compressed to obtain delayed-release tablets.

Reference example 6 Bredenine 100g, methyl methacrylate.
150g of methacrylic acid copolymer (Freund Sangyo, Eudragit L100), 100g of Avicel 101
An 80% ethanol solution was added to the mixture and kneaded.

This kneaded product was granulated using a cylindrical granulator and then dried at 50°C for 1 hour. The obtained dried product was pulverized using a pulverizer to obtain retarded release Bredenin powder.

Example 3 A 5% TC-5R solution was added to a powder mixture consisting of 50 g of Bredenine, 15 g of lactose, and 24.5 g of L-HPC (manufactured by Shin-Etsu Chemical Co., Ltd.; low substituted hydroxypropyl cellulose) and kneaded. This kneaded product was granulated using a cylindrical granulator and then dried at 50°C for 1 hour. The obtained dried product was pulverized with a pulverizer, 0.5 g of magnesium stearate was added thereto, and then tableted to obtain a fast-dissolving tablet.

Hydroxypropyl methyl cellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd.; HP-
Enteric-coated tablets coated with HP-55 were obtained by spraying an ethanol solution containing HP-55) in a coating pan. Next, using this HP-55 coated tablet (ratio 6.5 parts) as a core, a mixed powder of bredenine (ratio 3.5 parts) having the same composition as the above-mentioned fast-dissolving tablet was added.
part) (added a small amount of magnesium stearate)
was compressed using a two-stage compression tableting solution to form a multilayer tablet.

Furthermore, this tablet is coated with TC-
HP on the inner layer using an ethanol solution containing 5R
-55 coated tablets and long-acting Bredenine tablets having an immediate-acting Bredenine component in the outer layer were obtained.

Example 4 Bredenine 100g, Mannitol 50g and L
- Mix 99g of HPC and add 5% TC-5R
After adding and kneading the solution, it was granulated using a cylindrical granulator. After drying at 50° C. for 1 hour, the mixture was pulverized using a pulverizer, and magnesium stearate was added thereto and mixed to obtain fast-acting Bredenin granules.

Further, 100 g of Bredenin, 49 g of Avicel 101, and 50 g of Lovely Wax 101 were mixed together, and an 80% ethanol solution was added thereto and kneaded. This kneaded product was granulated using a cylindrical granulator and then dried at 50°C for 1 hour. The obtained dried product is crushed with a crusher,
Furthermore, magnesium stearate is added to this,
Delayed release Bredenine granules were obtained.

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 bredenine tablet having an immediate-acting portion in the upper layer and a delayed-release portion in the lower layer.

Example 5 The same procedure as in Example 1 was carried out to obtain rapidly dissolving Bredenin granules.

In addition, enteric-coated granules of Bredenine (A) were obtained by adding the above granules obtained in the same manner to a centrifugal fluid granulator and coating them at 30% with Eudragit L100 8% coating solution (ethanol: methylene chloride = 1:1). I got it.

Further, in the same manner as in Example 1, the Eudragit
Enteric-coated granules (B) of Bredenine were obtained which were coated 70% with an 8% coating solution of L100.

The obtained fast-acting granules, enteric-coated granules (A), and enteric-coated granules (B) were mixed at a content ratio of 1:2:2, and the mixed components were filled into capsules containing 100mg of budenine. A long-lasting capsule containing the following was obtained.

Example 6 A 5% TC-5R solution was added to a mixture of 250 g of Bredenine and 250 g of Avicel 101 and kneaded.
After granulating this mixture using a cylindrical granulator, it was heated to 50°C for 1 hour.
After drying for an hour, quickly dissolving Bredenin granules were obtained.

The granules were added to a centrifugal fluid granulator, and a mixture of polyvinyl acetal diethylamino acetate (manufactured by Sankyo Co., Ltd., AEA) and ethyl cellulose in a ratio of 4:1 was added to a centrifugal fluid granulator.
An 8% solution of a coating composition (ethanol: methylene chloride = 4:1) was sprayed to obtain a 50% coated bredenine granule.

[Brief explanation of the drawing]

Figure 1 shows the dissolution curve of the delayed-release bredenine component obtained in Reference Example 1, Figure 2 shows the blood concentration curve, and Figure 3 shows the dissolution curve of the long-acting bredenine preparation obtained in Reference Example 2. FIG. 4 shows Example 2.
Figure 2 shows the dissolution curves of fast-dissolving Bredenin granules, delayed-release granules, and a mixture of both obtained in .

Claims (1)

[Scope of Claims] 1. The fast-acting bredenine component and the delayed-release bredenine component are 20 to 60 parts by weight: 80 to 40 parts by weight (in terms of bredenine), and the delayed-release bredenine component is 1 part by weight of bredenine. Substances exhibiting enteric properties or semipermeable properties in vivo
A long-acting oral Bredenine preparation containing 2 parts by weight of the above two components. 2. The preparation according to claim 1, wherein the rapidly dissolving bredenine component and the delayed release bredenine component are 30 to 40 parts by weight: 70 to 60 parts by weight (in terms of bredenine). 3. The substance exhibiting in vivo enteric property or in vivo semipermeability is a methacrylic acid-methacrylic ester copolymer, an acrylic acid-acrylic ester copolymer, a methacrylic acid-acrylic ester copolymer, etc. combination, acrylic ester-methacrylic acid-methacrylic ester copolymer, carboxymethyl cellulose, carboxyethyl cellulose, carboxymethyl ethyl cellulose,
Cellulose acetate phtate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, methyl cellulose, ethyl cellulose, cellulose diacetate, cellulose triacetate, insoluble hydroxypropyl cellulose, polyacrylic acid ester, polymethacrylic acid ester, polyethylene, insoluble acrylic acid The preparation according to claim 1, which is a methacrylic acid-acrylic ester-methacrylic ester copolymer, shellac, wax/oil. 4. The formulation according to claim 1, wherein the sustained-acting oral Bredenine formulation is a fine granule, granule, pill, capsule, or tablet.