JP2000128779A - Controlled release medicine type preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation having a proper lag time from the administration of the medicine to the release of the medicine in the inside of the body, rapidly finishing the release of the medicine after the lag time, and useful in a medical field for efficient absorption or the like of the medicine by covering a specific tablet with a specified film for controlling the release of the medicine. SOLUTION: This preparation is obtained by covering (A) a tablet comprising (i) a medicine such as acetaminophen and (ii) a water-swellable material selected from a starch, a croscarmellose sodium, a carmellose calcium and a hydroxypropylcellulose having a low substitution degree, with (B) a film for controlling the release of the medicine comprising (i) 100 pts.wt. ethylcellulose and (ii) 75-1,500 pts.wt. water-insoluble powdery material (preferably talc, magnesium stearate or the like), preferably having 0.1-100 μm average particle diameter. The preparation can control a lag time with good repeatability by regulating the thickness of the component B, and the kind and the added amount of the component (ii) of the component B.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug release-controlled preparation, and more particularly, to a drug (medicinal component) which is administered in a body for a considerable period of time (lag time). And to provide a formulation that rapidly releases the drug. Furthermore, by combining these controlled-release preparations with different lag times, it is also possible to provide a preparation that releases the drug continuously while keeping the drug concentration constant, or that releases the drug intermittently at fixed time intervals. It is an object of the present invention. This type of preparation is advantageously used in the pharmaceutical field to efficiently absorb a drug, maintain drug efficacy for a long time, and suppress the occurrence of side effects.

[0002]

2. Description of the Related Art As for the prior art related to the present invention,
JP-A-4-338323, JP-A-4-273816, JP-A-62-30709, JP-A-52-64420, JP-B-44-2
It is described in 6315 gazette and the like.

[0003] And, relates to a preparation for controlling the drug to release sigmoidally after lag time, and relates to a preparation for controlling to gradually release the drug after lag time.

[0004] The methods for forming a drug release controlling film are different from each other. The method is based on a hot melt coating method, the method is a compression (nucleated tableting) method, and the method is a film coating method. It has drawbacks due to the law.

[0005] The drug release mechanism is swelling of the film and the contents of the formulation due to moisture entering from the outside, and accompanying leaching of the active ingredient out of the system. The drug dissolution shows a sigmoid type, and the dissolution rate after the lag time is lower than before the application of the drug release controlling film. When a high-melting substance is used as a coating material for forming a drug release control film, the drug may be deteriorated during film formation. On the other hand, when the coating material is a low-melting substance, the drug release control film may be softened and deformed during storage to change the release characteristics.

[0006] The drug release mechanism is swelling of the inner core tablet due to moisture entering from the outside and accompanying leaching of the medicinal component out of the system by destruction of the drug release controlling powder layer. The lag time is adjusted by changing the thickness of the powder layer for controlling drug release, but it is difficult to accurately position the core tablet, and the thickness of the powder layer for controlling drug release varies, resulting in good reproducibility. Cannot be formed, and the lag time varies greatly. The drug release control layer formed by the compression method is porous and is much thicker than a dense drug release control film formed by the coating method, so that the preparation becomes large and it may be difficult to take it.

The mechanism of drug release is rupture of the drug release control film due to expansion of the contents of the preparation due to moisture entering from the outside, and release of the medicinal component from the opening of the film to the outside of the system. Since the polymer that is the base of the drug release control film has flexibility, the swelling force of the contents of the formulation is also used for the deformation of the film, etc., and does not work efficiently as a film rupture force. Cannot be large, and the drug release rate is reduced. The lag time is adjusted by changing the film thickness of the drug release control film and adjusting the moisture penetration rate.Thus, if the film is thickened to extend the lag time, the film strength increases and it is difficult to burst, so the lag can be adjusted. Time range is narrow.

The mechanism of drug release is rupture of the drug release control film due to swelling of the contents of the preparation due to water entering from the outside, and release of the medicinal component from the opening of the film to the outside of the system. In order to gradually release the drug, an additive that becomes a gel or colloid by water absorption is blended into the inner core, and rapid opening of the drug is not possible because the film opening is small.

[0009] In the preparations (granules, tablets) or dry coated tablets provided with the above-mentioned drug release controlling film, no clear lag time is observed, or even if it is observed, the reproducibility is low. The rate of drug release after the lag time is lower than the rate of drug release in the inner core due to the small rupture and opening of the film. In addition, there are other drawbacks, such as difficulty in taking the drug due to the large size of the preparation, requiring special equipment for its manufacture, and low productivity.

[0010]

The main problems of the present invention are:
By providing a controlled-release drug preparation that has a considerable time (lag time) from the administration of a drug to the start of drug release in the body, and then rapidly completes drug release, Is to control the drug release lag time and drug release rate of the formulation by the structure of the formulation. Other applications or development subjects are to provide a formulation corresponding to a specific drug release pattern, for example, a pattern that releases the drug continuously while keeping the drug concentration constant, a pattern that releases the drug intermittently at regular time intervals, and the like. This is specifically described below.

[0011] 1) A drug having a short half-life can be sustained.

In general, a drug having a shorter half-life requires a longer-lasting effect. In the prior art, there are two methods of sustained release: a method of sustained release and a method of combining a gastric-soluble portion and an enteric portion. The method of sustained release is not suitable for a drug having an extremely short half-life because the first-pass effect is greatly affected and the bioavailability is greatly reduced. on the other hand,
In the case of a preparation combining a gastric-soluble part and an enteric part, the gastric-soluble part first dissolves in the stomach and rapidly releases the drug, and the enteric part stays in the stomach without dissolving for a certain time (lag time). 2 which dissolves into the intestine and releases the drug rapidly
It shows a step release and the drug release in each step is fast, so that a decrease in bioavailability can be prevented. However, since there is a great difference between individuals in the stomach retention time, there is a drawback that there is an individual difference in the drug release time of the enteric portion. In patients with low acidity in the stomach, such as anoxia or hypoxia, the enteric portion dissolves in the stomach almost at the same time as the gastric soluble portion, resulting in excessive blood levels and side effects. And there is a drawback that it does not show long-lasting effect. The object of the present invention is to reduce the bioavailability by speeding up drug release, and to reduce individual differences because lag time is not affected by the acidity in the digestive tract, and to provide a multistage preparation. That is, to maintain the medicinal effect.

2) The drug is released in the body at a specific time.

For example, it has been reported that in a hypertensive patient, the blood pressure drops after going to bed and the blood pressure starts rising early in the morning. An object of the present invention is to administer a drug before going to bed, to set a lag time so that the drug is not released for a certain period of time during which blood pressure is low after going to bed, and the drug is released at a time when blood pressure starts to rise. .

3) Release the drug at a specific gastrointestinal site.

For example, when a drug is a peptide, it is decomposed by an enzyme in the gastrointestinal tract. Therefore, it is desirable to release the drug at a gastrointestinal site (for example, large intestine) where the enzyme is small, but it has been difficult in the prior art. An object of the present invention is to provide an enteric coating on the surface of a preparation, so that the preparation is transferred to the small intestine and, after the enteric coating is dissolved, a lag time is set so that the drug is released when the preparation reaches a desired gastrointestinal site. Is to set.

4) Obtain various drug release characteristics.

Conventional drug release curves are mostly controlled release preparations based on parabolic type or two-step release preparations using a combination of gastric and enteric components, and the lag time can be changed. Therefore, there is a limit in controlling drug release characteristics. An object of the present invention is to obtain various drug release characteristics by variously combining formulations having different lag times.

[0019]

According to the present invention, a water-swellable substance is added to a drug to produce a core tablet.
On the surface of the core tablet, a drug release controlling film containing ethyl cellulose as a main component is formed.

A core tablet made by adding a water-swellable substance to a drug absorbs water penetrating through the drug release control film and swells, thereby reliably destroying the drug release control film covering the surface, thereby producing a drug. Release. By the time the drug release control film ruptures (corresponding to almost the lag time), the core tablet is swollen by the intruding water, so that the drug is released rapidly after the film ruptures. Finish in a short time. When the formulation has the above-described configuration, a formulation that reliably controls the lag time and speed of drug release can be manufactured.

The application or development of the invention naturally accompanies the solution of the main problem of the present invention, but the solution of these problems can be solved without much difficulty after the solution of the main problem.

For example, if it is necessary to prepare a drug which starts drug release after a certain period of time after drug administration and maintains drug release at a substantially constant concentration for a certain period of time, several types having different lag times are suitable for the purpose. It can be prepared in combination in any ratio. In addition, if a formulation that performs drug release intermittently is required, the purpose can be achieved by combining several types of tablets of the present invention having greatly different lag times into capsules to form capsules. . Furthermore, if the conventional preparation and the preparation of the present invention having a certain lag time are combined and filled into a capsule to form a capsule, the conventional preparation is administered in a single administration, and after a certain period of time, the preparation of the present invention is obtained. It is also possible to prepare a formulation that ensures release of the drug.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION The main embodiment of the controlled-release drug preparation of the present invention is a drug-release controlled film layer comprising ethyl cellulose containing a water-insoluble powdery substance on the surface of a core tablet comprising a drug and a water-swellable substance. Is a tablet formed. The core tablet contains a drug and a water-swellable substance as essential components, and may further contain excipients, binders, lubricants and the like which are added in ordinary pharmaceutical preparations. The drug as an essential component is not particularly limited. At present, the drug may be a commonly used drug, or a new medicinal active ingredient as long as it meets the normal conditions of use. FIG. 1 shows an example of the preparation according to the present invention, and FIG.
2 and FIG. 3 show the disintegration process of the preparation.

From the viewpoint of its function, the water-swellable substance suitable for use in the present invention may be any substance that absorbs water when contacted with water and swells and can be added to a pharmaceutical preparation. However, starch, croscarmellose sodium, carmellose calcium, hydroxypropyl starch or low-substituted hydroxypropylcellulose are most suitable for use in the present invention.

Excipients suitable for use in the present invention include, for example, lactose, sucrose, mannitol, sorbitol, crystalline cellulose, calcium phosphate and the like. Examples of the binder include hydroxypropylcellulose, polyvinyl alcohol, macrogol, gelatin, polyvinylpyrrolidone, starch paste and the like. Further, examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, light anhydrous silicic acid and the like.

The ratio of the water-swellable substance is usually about 5 to 70 parts by weight with respect to the drug, and if necessary, an excipient, a lubricant, a disintegrant and the like are added to the tablet, and tableting is carried out.

The core tablet of the present invention may be produced by mixing the above-mentioned components and following a commonly used tablet production method.
The size of a core tablet is usually 4 to 20 mm in diameter.

The drug release controlling film of the preparation of the present invention is obtained by adding a water-insoluble powdery substance to ethyl cellulose.
75 to 1500 parts by weight with respect to 100 parts by weight,
It can be formed by a commonly used film coating method by spray coating. Dissolve the water-insoluble polymer serving as the film base material in a solvent, add a water-insoluble powdery substance and, if necessary, a plasticizer, a lubricant, etc. to prepare a coating solution, and dry the spray while spraying the solution on core tablets. , To form a film.

The main component of the water-insoluble polymer is ethylcellulose. In some cases, methylcellulose, shellac, polyvinyl acetate, polymethylstyrene, polydiethylaminomethylstyrene, polyethylene oxide, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, etc. are partially used. You may use together. When used in combination, for example, up to 20% by weight, preferably up to 10% by weight, of ethylcellulose can be replaced with the substance used in combination. That is, ethyl cellulose: the combined substance is 80:20 to 100: 0 (weight ratio),
Preferably, it can be 90:10 to 100: 0 (weight ratio).

As the solvent, water, lower alcohol (ethanol, propanol, isopropanol, butanol, etc.), lower alkanone (eg, acetone, methyl ethyl ketone, etc.) dichloromethane, dichloroethane or a mixture thereof may be used.

Examples of the water-insoluble powdery substance include talc, stearic acid and its salts, palmitic acid, silicon dioxide, silicic anhydride, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, aluminum hydroxide gel, calcium carbonate , Calcium lactate, bentonite, magnesium aluminate metasilicate, calcium hydrogen phosphate, starch, cellulose, chitin, chitosan, polylactic acid, polyglycolic acid, hardened oil, wax (eg, carnauba wax,
Etc., but talc, magnesium stearate, hydrogenated oil or carnauba wax is advantageously used in the present invention.

The average particle size of the water-insoluble powdery substance added to the film for rupture of the drug release controlling film and for widening the rupture of the film is 0.1 to 200 μm, preferably 0.1 to 100 μm.

The amount of the water-insoluble powdery substance to be added to the film is 75 to 1500 parts by weight, preferably 100 to 1000 parts by weight, based on 100 parts by weight of ethyl cellulose. When the amount of the water-insoluble powdery substance is 75 parts by weight or less based on 100 parts by weight of ethylcellulose, the rupture of the film is observed but the lag time is not observed in the preparation having a small film thickness, and the lag time is not observed in the preparation having a large film thickness. Rupture is not observed, and only rapid release of the drug is not observed. The amount of the water-insoluble powdery substance is 150 per 100 parts by weight of ethylcellulose.
If the amount is more than 0 parts by weight, the balance between the water-insoluble powdery substance and ethylcellulose will be lost, and the strength of the drug release controlling film will decrease, making it impossible to control the core tablet coating.

The total weight of the drug release controlling film can be arbitrarily adjusted to obtain a desired lag time, but is usually 0.5 to 80 parts by weight based on 100 parts by weight of the core tablet.

A plasticizer (eg, triethyl citrate, triacetin, macrogol, glycerin fatty acid ester, propylene carbonate, etc.) usually used in this field may be added to the drug release controlling film.

The components of the second drug release controlling film include:
For example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, carboxymethyl ethyl cellulose, cellulose acetate phthalate, acrylic acid methyl methacrylate copolymer, acrylic acid ethyl methacrylate copolymer, shellac, etc. In the present invention, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and dimethylaminoethyl methacrylate-methyl methacrylate copolymer are advantageously used.

The second controlled drug release film may contain a plasticizer usually used in this field (eg, triethyl citrate, triacetin, macrogol, polyethylene glycol,
Glycerin fatty acid ester, propylene carbonate, etc.).

The preferred size of the thus-produced controlled-release tablet of the present invention is 4 to 20 mm in diameter.

In order to produce capsules, controlled-release capsules are produced by filling the capsules with the controlled-release tablets produced by the above-mentioned processes using a capsule filling machine.

As the capsule, a usual gelatin capsule, hydroxypropylmethylcellulose capsule or starch capsule (for example, a hard capsule in Japanese Pharmacopoeia) can be used.

As described above, the controlled-release drug preparation of the present invention has various excellent effects and solves the problems of the prior art.

Hereinafter, the present invention will be specifically described with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto. NG-150 type agitation granulator manufactured by Daiwa Kakoki as a granulation device, P-18 type rotary tableting machine manufactured by Hata Iron Works as a tableting device, and Hicoater mini-type fluidized bed manufactured by Freund Sangyo as a coating device. Each coating machine was used.

[0043]

The present invention will be described in more detail with reference to the following examples. The configuration of the tablets obtained in Examples 1 to 7 is shown in FIG.
FIG. 5 shows the structure of the tablet obtained in Example 8, and FIG.
The structures of the capsules obtained in the above are shown in FIG.

Example 1 Core tablets and talc-containing coated tablets (test preparations A to D) (1) 180.0 g of nifecarane hydrochloride, 47.5 g of croscarmellose sodium and 148.0 g of fumaric acid were mixed, and 4.0 g of hydroxypropyl cellulose was added to ethanol. While the solution dissolved in 80.0 g was dropped, the mixture was kneaded and granulated using a stirring granulator, dried at 40 ° C. for 1 hour, and passed through a 20-mesh standard sieve to obtain granules for producing core tablets. After taking 350.0 g of granules and adding and mixing 1.8 g of magnesium stearate, the diameter is 5.
Using a tableting machine with a 0 mm mortar and a 4.0 mm R concave punch, the rotation speed was 3
Tableting was performed under the conditions of 0 r.pm, a preload of about 100 kg / punch, and a main pressure of about 350 kg / punch to obtain a core tablet (test preparation A) weighing 53.0 mg. (2) 300.0 g of the obtained core tablet is put in a coating device,
Ethyl cellulose 64.8 g, talc 64.8 g, glycerin fatty acid ester 8.0 g, ethanol 1720.0 g, dichloromethane 3
20.0 g of a solution is spray-coated, and a film having a film thickness of 2.1 parts by weight of ethyl cellulose and 2.1 parts by weight of talc is formed on the surface of the core tablet with respect to 100 parts by weight of the core tablet. Formulation B) was obtained. Similarly, a preparation (test preparation C) in which a film having a film thickness of 4.0 parts by weight of ethyl cellulose and 4.0 parts by weight of talc was applied to the surface of the core tablet, and 6.4 parts by weight of ethyl cellulose and 6.4 parts by weight of talc A controlled release formulation (Test Formulation D) in which a film having a thickness of 5 parts was applied to the surface of the core tablet was obtained.

Example 2 Tablets with modified talc content (test preparation E) 300.0 g of core tablets obtained in the same manner as in Example 1 were placed in a coating apparatus, and 32.4 g of ethyl cellulose, 64.8 g of talc,
A drug formed by spray-coating a solution consisting of 4.0 g of glycerin fatty acid ester, 860.0 g of ethanol and 160.0 g of dichloromethane, and forming a film composed of 8.3 parts by weight of ethyl cellulose and 22.4 parts by weight of talc on the surface of the core tablet with respect to 100 parts by weight of the core tablet. Controlled release tablets were obtained.

Example 3 Tablets with modified talc content (test preparation F) 300.0 g of core tablets obtained in the same manner as in Example 1 were placed in a coating apparatus, and 24.3 g of ethylcellulose, 85.1 g of talc,
Hydroxypropyl cellulose 2.7 g, glycerin fatty acid ester 3.0 g, ethanol 645.0 g, dichloromethane 120.
A solution consisting of 0 g was spray-coated to obtain a drug-release controlled tablet in which a film having a film thickness of 6.4 parts by weight of ethyl cellulose and 22.5 parts by weight of talc was formed on the surface of the core tablet with respect to 100 parts by weight of the core tablet.

Example 4 Tablets with modified talc content (test preparation G) 300.0 g of core tablets obtained in the same manner as in Example 1 were placed in a coating apparatus, and 18.8 g of ethyl cellulose, 94.0 g of talc,
2.0 g of hydroxypropylcellulose, 2.4 g of triethyl citrate, 500.0 g of ethanol, spray-coating with a solution consisting of 93.0 g of dichloromethane, a film having a thickness of 4.0 parts by weight of ethyl cellulose and 20.0 parts by weight of talc for 100 parts by weight of core tablets. Was obtained on the surface of a core tablet to obtain a controlled-release tablet.

Example 5 Tablets with modified talc content (test preparation H) 300.0 g of core tablets obtained in the same manner as in Example 1 were placed in a coating apparatus, and 20.3 g of ethyl cellulose and 203.0 g of talc were added.
g, hydroxypropylcellulose 2.3 g, glycerin fatty acid ester 2.3 g, ethanol 537.5 g, dichloromethane
A solution consisting of 100.0 g was spray-coated, and 6.4 parts by weight of ethyl cellulose and 64.
A drug release controlled tablet having a film having a thickness of 0 parts by weight formed on the surface of the core tablet was obtained.

Example 6 Carnauba wax-containing coated tablet (test preparation I) 300.0 g of a core tablet obtained in the same manner as in Example 1 was placed in a coating apparatus, and 24.4 g of ethylcellulose and polishing wax-103 (Carnauba wax: trademark, Freund ( Co., Ltd.) 48.8 g, spray coating with a solution consisting of glycerin fatty ester 3.0 g, ethanol 612.0 g, dichloromethane 153.0 g, and a coating consisting of ethyl cellulose 3.6 parts by weight and carnauba wax 7.2 parts by weight per 100 parts by weight of core tablet Was obtained on the surface of a core tablet to obtain a controlled-release tablet.

Example 7 Magnesium stearate-containing coated tablet (test preparation J) 300.0 g of core tablets obtained in the same manner as in Example 1 were placed in a coating apparatus, and 32.4 g of ethyl cellulose, 64.8 g of magnesium stearate, and glycerin fatty acid ester were used. 4.0g,
Spray coated with a solution consisting of 860.0 g of ethanol and 160.0 g of dichloromethane, 4.0 parts by weight of ethyl cellulose and 100 parts by weight of core tablet, and magnesium stearate
A drug-release controlled tablet having a coating of 8.0 parts by weight formed on the surface of the core tablet was obtained.

Example 8 Tablet Having a Second Controlled Drug Release Layer (Test Formulation K) To the controlled drug release type tablet obtained in the same manner as in Example 3, 20.0 g of Eudragit L100, 4.0 g of talc, Macrogol 6000R 2.0g, ethanol 200.0g and purified water 53.0g
A solution consisting of spray-coated with a solution consisting of 4.9 parts by weight of Eudragit L100 based on 100 parts by weight of the core tablet was formed on the surface of the core tablet to obtain a drug-release controlled tablet having a second drug-release control layer. .

Example 9 Three-stage Drug Release Capsule (Test Formulation L) A core tablet obtained in the same manner as in Example 1 and Example 2
Capsules prepared by filling a gelatin hard capsule (Nippon Elanco Co., Ltd., No. 2) into three tablets each having a small film amount and a tablet having a large film amount, obtained in the same manner as described above. Obtained.

Example 10 Core tablets and talc-containing coated tablets (test preparations M and N) (1) 180.0 g of acetaminophen, 47.5 g of croscarmellose sodium, and 148.0 g of lactose were mixed, and the mixture was stirred using a stirring granulator. A solution prepared by dissolving 4.0 g of hydroxypropyl cellulose in 80.0 g of ethanol was dropped and granulated, and this was heated to 40 ° C.
After drying for 1 hour, the mixture was passed through a 20-mesh standard sieve to obtain granules for producing core tablets, 350.0 g of the granules were taken, 1.8 g of magnesium stearate was added and mixed, and a 5.0 mm diameter die and a 4.0 mm R Using a tableting machine with a concave punch, the rotation speed is 30 r.p.
m., tableting under the conditions of a preload of about 100 kg / punch and a main pressure of about 350 kg / punch,
A core tablet (test preparation M) weighing 53.0 mg was obtained. (2) 300.0 g of the obtained core tablet is put in a coating device,
32.4 g of ethyl cellulose, 32.4 g of talc, 4.0 g of glycerin fatty acid ester, 900.0 g of ethanol, spray-coated with a solution composed of 100.0 g of purified water, and a film thickness of 5.8 parts by weight of ethyl cellulose and 5.8 parts by weight of talc based on 100 parts by weight of core tablets. A drug release controlled tablet (test preparation N) having a film formed on the surface of the core tablet was obtained.

Comparative Example 1 Talc (water-insoluble powdery substance)
Example of not using 300.0 g of core tablets obtained in the same manner as in Example 1 was placed in a coating apparatus, and was composed of 32.4 g of ethylcellulose, 4.0 g of glycerin fatty acid ester, 860.0 g of ethanol, and 160.0 g of purified water. Spray-coats the core tablets with the additive-free solution, and coats the film with a film thickness of 2.1 parts by weight of ethyl cellulose (test preparation O) and 4.0 parts by weight (test preparation P) with respect to 100 parts by weight of the core tablets, respectively. The formed controlled-release tablet was obtained.

Comparative Example 2 Talc (water-insoluble powdery substance)
Example in which the amount of used is less than the lower limit of the present invention. 300.0 g of a core tablet obtained in the same manner as in Example 1 was placed in a coating apparatus, and 32.4 g of ethyl cellulose and 16.2 of talc were added.
g, glycerin fatty acid ester 4.0 g, ethanol 860.0
g, purified water 160.0 g, spray-coated the core tablets, 2.1 parts by weight of ethyl cellulose and 1.1 parts by weight of talc (test preparation Q) and 4.0 parts by weight of ethyl cellulose and 2.0 parts by weight of talc with respect to 100 parts by weight of the core tablets. Controlled-release tablets were obtained in which a coating of test formulation R) was formed on the surface of each core tablet.

In order to show the effect of the present invention, the results of the dissolution test and the results of the measurement in blood concentration are shown below.

Dissolution test Test preparation: The following preparations were used in the dissolution test. Test preparation A; core tablet of Example 1 (1) Test preparation B; tablet of Example 1 (2) Test preparation C; tablet of Example 1 (2) Test preparation D; Example 1 (2) ) Tablet Test Formulation E; Tablet of Example 2 Test Formulation F; Tablet of Example 3 Test Formulation G; Tablet of Example 4 Test Formulation H; Tablet of Example 5 Test Formulation I; Tablet of Example 6 Test Formulation J: tablet of Example 7 Test formulation K; tablet of Example 8 Test formulation L; Capsule of Example 9 Test formulation M; Core tablet of Example 10 (1) Test formulation N; Example 10 (2) ) Tablet Test formulation O; Tablet of Comparative example 1 Test formulation P; Tablet of Comparative example 1 Test formulation Q; Tablet of Comparative example 2 Test formulation R; Tablet of Comparative example 2

Test method: The dissolution test method II (paddle method) according to the thirteenth revised Japanese Pharmacopoeia (hereinafter, Japanese Pharmacopoeia) was used.

Test solution: JP First Solution or JP Disodium Hydrogen Phosphate / Citrate Buffer pH 6.0 Test conditions: Temperature 37 ° C., test solution volume 900 ml, rotation speed 100 rpm. These are shown in FIGS. 7 to 12 below.

FIG. 7 shows the elution curves of the three drug release-controlled tablets having different amounts of talc and ethyl cellulose and having different film thicknesses (correlated with the film amount). In formulation B, the lag time is about 1 hour and the time required for drug release is less than 1 hour. In formulation C, the lag time is about 2 hours and the time required for drug release is less than 1 hour. In formulation D, the lag time is about 3 hours. The time required for drug release is less than one hour,
No lag time is observed in the control (core tablet, formulation A), and the drug is rapidly released within one hour. It can be seen that all of the controlled-release formulations release the drug rapidly after a certain lag time. The lag time increases as the film thickness of the controlled release tablet increases, and the rupture property of the film of the controlled release tablet does not deteriorate even when the thickness increases.

FIG. 8 shows the dissolution curves of the controlled-release tablets in which the amount of talc was 300, 350, 500 and 1000 parts by weight based on 100 parts by weight of ethylcellulose. The lag time of Formulation E is about 5.5 hours, the time required for drug release is within 1 hour,
The lag time of Formulation F is about 3 hours, the time required for drug release is within 1 hour, the lag time of Formulation G is about 2 hours, the time required for drug release is within 1 hour, and the lag time of Formulation H is about 1.5 hours. The time required for drug release is less than one hour, and the drug is released rapidly after the lag time.
Although lag time is observed even when the amount of the water-insoluble powdery substance is increased, the drug is still rapidly released, but the length of the lag time varies depending on the film formulation. It can be seen that the length of the lag time can be adjusted by changing not only the film thickness but also the addition ratio of the water-insoluble powdery substance.

FIG. 8 shows the dissolution curves of the tablet in which the water-insoluble powdery substance is carnauba wax and the tablet in which the water-insoluble powdery substance is magnesium stearate. Formulation I has a lag time of about 4.5 hours and a drug release time of about 1 hour.
The time required for drug release is about 3.5 hours with a lag time of about 3.5 hours for Formulation J, and the drug is released rapidly after a certain lag time even if the type of water-insoluble powdery substance is changed. .

FIG. 9 shows an elution curve of a preparation (test preparation K) in which the controlled-release tablet of the present invention is provided with an enteric coating as a second controlled-release coating. The drug was not released in the Japanese Pharmacopoeia first solution (pH 1.2) used in place of gastric juice, and about 2 hours of lag in the Japanese Pharmacopoeia disodium hydrogen phosphate / citrate buffer pH 6.0 used in place of intestinal fluid. After the time, the drug is released rapidly within one hour. By adjusting the lag time of the first drug release controlling film and the dissolution pH of the enteric film which is the second drug releasing controlling film, the drug can be rapidly released from the small intestine to a desired site in the large intestine. This method is also useful for oral administration of peptides.

The release curve of a preparation (formulation L) in which two tablets (formulation D and preparation E) each having a different lag time are taken from a core tablet and a controlled-release tablet, each of which is filled in a capsule, is shown. It is shown in FIG. This capsule shows a multi-stage drug release that rapidly releases the drug immediately after administration, about 3 hours and about 5 hours later, and by combining a plurality of tablets with different drug contents and lag times, Release rate and release pattern can be controlled freely. In addition, by combining the preparations of the present invention having various lag times, the blood concentration of the drug can be maintained for a certain period of time. This has the advantage that when applied to a drug having a large first-pass effect, a decrease in bioavailability due to the prolonged release can be minimized.

FIG. 11 shows elution curves of a control (core tablet, test preparation M) using acetaminophen as a drug and a controlled-release tablet (test preparation N). While no lag time was observed in the control and the drug was released rapidly within 1 hour, the test formulation N released the drug rapidly within 1 hour after a lag time of about 3 hours,
The effect of the present invention is recognized even if the type of drug changes.

FIG. 12 shows the elution curves of the 0 part and 50 parts by weight preparations, respectively, in which the amount of the water-insoluble powdery substance (talc) with respect to the amount of ethylrose is smaller than that of the controlled release drug preparation of the present invention. In the preparations provided with the talc-free coating (Comparative Preparations O and P), no rupture was observed regardless of the thickness of the film, and the drug was gradually (10-38 hours).
%), But no rapid drug release is obtained. In the case of a preparation in which a coating of 50 parts by weight of talc was applied, rupture of the coating was observed but no lag time was observed in the preparation Q having a small thickness, whereas rupture of the coating was observed in the preparation R having a large thickness. Only rapid release of the drug (78% in 7 hours) without rapid drug release.

Absorption test Test method: Test preparations A, G and D were given as nifecalane hydrochloride to three beagle dogs (body weight: about 12 kg) fasted overnight.
Each dose was 2.6 mg. After administration, blood was collected from the forelimb vein with time, and after centrifugation, the concentration of nifecaran hydrochloride in the plasma was measured by high performance liquid chromatography. Test results: The test results are shown in FIG. 13 below. The plasma concentration was shown as an average of three animals.

This plasma concentration well reflects the results of the dissolution tests obtained in FIGS. 7 and 8. That is, since the drug is rapidly released from the core tablet (test preparation A) which does not control drug release, the blood concentration also shows a rapid increase after administration of the drug, whereas the drug release-controlled tablet (test preparation G) does not release the drug. No drug concentration was detected until 1.5 hours after administration, and a rapid increase in blood concentration was observed due to rapid drug release that occurred thereafter, and reached a maximum at 2.5 hours. In the case of a controlled-release tablet (Test Formulation F), plasma concentration was hardly detected until 2.5 hours after administration, and a rapid increase in plasma concentration was observed due to rapid drug release that took place thereafter, and 3.5 hours was observed. The maximum value was shown. From these results, it is understood that the controlled-release drug preparation of the present invention rapidly releases the drug even in vivo after a lag time equivalent to that observed in the dissolution test.

[0069]

The technical findings obtained by the present invention are as follows:
It is as follows.

By covering the core tablet with the drug release controlling film, a lag time occurs before the elution of the drug starts, and the lag time is determined by the thickness of the drug releasing controlling film and the water-insoluble powder in the drug releasing controlling film. That it can be controlled with good reproducibility by adjusting the type and amount of substance added,
The drug can be released by controlling the drug release control film to break after a certain period of time after the water swellable substance in the core tablet swells, and a large amount of water-insoluble powdery substance is added to the drug release control film As a result, the film breaks and opens widely or separates into two or more, so that the film does not block the swelling and disintegration of the core tablet, the drug is released rapidly, and by combining formulations with different lag times, The drug must be released, and it can be manufactured using only pharmaceutical equipment that is widely used in the manufacture of pharmaceuticals.

At the time of drug release, the drug release control film ruptures, and since the film rupture portion opens largely, it does not hinder drug release, and even if the film thickness is increased to extend the lag time, the rupturability is impaired. As a result of the completion of the technology of applying a dense and thin drug release control film to the core tablet by the ordinary film coating method without any problems, the lag time can be easily adjusted and the drug can be rapidly released, which was not achieved with the conventional technology. Controlled release medicines to be released were completed.

[Brief description of the drawings]

FIG. 1 is an external view of a controlled-release tablet of the present invention.

FIG. 2 is a schematic view of a drug release control film that has been ruptured and opened greatly like a shell cap.

FIG. 3 is a schematic view of a ruptured (separated) clam-like controlled release coating.

FIG. 4 is a schematic cross-sectional view of the drug release controlled tablets of Examples 1 to 7. Is a core tablet, and is a controlled release coating.

FIG. 5 is a cross-sectional view of a controlled-release tablet of Example 8. Is a core tablet, is a drug release controlling film, and is an enteric film.

FIG. 6 is a schematic cross-sectional view of the controlled-release capsule of Example 9; Is a core tablet, and both are controlled-release tablets, is a cap part of a hard capsule, and is a body part of a hard capsule.

FIG. 7 shows dissolution curves of Formulation A, Formulation A, Formulation B, Formulation C and Formulation D, respectively, in the dissolution tests of Formulations A to D.

FIG. 8 shows E in the dissolution test of Formulations E to J, F is Formulation F, G is Formulation G, H is Formulation H, I is Formulation E.
Shows the dissolution curve of Formulation I, and J shows the dissolution curve of Formulation J.

FIG. 9 shows the dissolution curve of K-1 in the dissolution test of Formulation K in the first solution of JP, and K-2 in the dissolution test of disodium hydrogen phosphate / citrate buffer pH6.0 in JP. The elution curves are shown respectively.

FIG. 10 shows a dissolution curve of a dissolution test of Formulation L.

FIG. 11 shows M in the dissolution test of Formulations M and N.
Indicates an elution curve of the preparation M, and N indicates an elution curve of the preparation N.

FIG. 12 shows dissolution curves of Formulations O to R in the dissolution test of Formulations O to P, P to Formulation P, Q to Formulation Q, and R to Formulation R, respectively.

FIG. 13 shows S in the dog oral administration experiment of the preparation.
Indicates the change in blood concentration of Formulation A, T indicates the change in blood concentration of Formulation G, and U indicates the change in blood concentration of Formulation F.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Yunori Hanada 1900-1, Togo, Mobara City, Chiba Prefecture Inside Mitsui Pharmaceutical Industry Co., Ltd. (72) Inventor Hiroshi Shinozaki 1900-1, Togo, Mobara City, Chiba Prefecture Mitsui Pharmaceutical Industry Co., Ltd. F-term (reference) FF34 FF67 GG14 GG16

Claims (12)

[Claims] A core tablet comprising a drug and a water-swellable substance,
A tablet containing a water-insoluble powdery substance and coated with a drug release controlling film mainly composed of ethyl cellulose, wherein the core tablet is selected from the group consisting of starch, croscarmellose sodium, carmellose calcium and low-substituted hydroxypropylcellulose. Containing a water swellable substance, and the drug release controlling film is ethyl cellulose 100.
A controlled-release tablet containing 75 to 1500 parts by weight of a water-insoluble powdery substance per part by weight. 2. The drug release controlled tablet according to claim 1, wherein the water-insoluble powdery substance is a substance selected from the group consisting of talc, magnesium stearate, hydrogenated oil and carnauba wax. 3. A drug release control wherein a second drug release control film which dissolves depending on pH is further provided on the surface of the drug release control film of the drug release control type tablet according to claim 1 or 2. Shaped tablets. 4. The method according to claim 3, wherein the second drug release controlling film is selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and dimethylaminoethyl methacrylate-methyl methacrylate copolymer.
2. The controlled-release tablet of claim 1. 5. A controlled-release tablet comprising the controlled-release film of the controlled-release tablet of claim 1 and a layer containing the same drug further provided on the surface of the controlled-release film. 6. A controlled-release drug-containing capsule prepared by filling two or more kinds of the controlled-release tablet according to claim 1 with each other. 7. A drug-release-controlled capsule formed by filling two or more kinds of the drug-release-controlled tablets according to claim 1 having different times (lag times) from the administration of the drug to the start of drug release. Agent. 8. The controlled drug release capsule according to claim 7, which is filled with two or more kinds of the controlled drug release tablets according to claim 1 or 2 having different lag times. 9. The method according to claim 7, wherein the controlled-release tablet according to claim 1 or 2 and the controlled-release tablet according to claim 3 or 4 are filled in two or more kinds. Controlled release capsules. 10. The controlled drug release capsule according to claim 7, which is filled with two or more kinds of the controlled drug release tablets according to claim 3 or 4 having different lag times. 11. A drug-release controlled capsule prepared by filling a drug-free drug formulation and at least one drug-release-controlled tablet according to claim 1. 12. The drug release-controlled capsule according to claim 11, wherein the preparation that does not control drug release is a tablet, a powder or a granule.