JPS6248618A - Slow-releasing drug preparation and production thereof - Google Patents

Abstract

PURPOSE:To obtain a slow-releasing drug preparation, by coating a slow- releasing granule composed of a drug having remedying effect and a release- retarding substance of said drug with a release-controlling substance and compression-molding the coated granules. CONSTITUTION:A drug having remedying effect (e.g. nifedipin, propranolol, furosemide, etc.) is mixed uniformly with a release-retarding substance such as water-soluble, enteric and inert polymers (e.g. hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc.), aliphatic compounds, waxes, etc., or their mixture to obtain alow-releasing granule. The slow-releasing granule is coated with a water-soluble polymeric substance or an enteric polymeric substance either by spraying a solution of the substance in water or proper organic solvent to the granule or by mixing the granule with fine powder of the polymeric substance. the coated granules are compression-molded to obtain the objective slow-releasing drug. EFFECT:The process can be applied to a wide variety of drugs including a pH- dependent drug and pH-independent drug.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention is characterized in that upon administration, the granules are gradually released or granulated from the surface regularly over a long period of time. Either a dissolution rate that releases the drug at a constant rate per unit time, that is, a dissolution rate close to the zero-order dissolution rate, or a slow release rate that can increase the dissolution rate after a certain period of time [using raw granules] The present invention relates to a sustained-release preparation whose dissolution pattern can be adjusted by adjusting the dissolution pattern, and a method for producing the same.

[Prior Art] Many sustained-release preparations have been used for the purpose of improving the effectiveness or reducing side effects when administering therapeutically effective drugs.

Conventional sustained release formulations include semi-permeable coatings around particles or tablets, or dispersion of drug in a continuous matrix consisting of an aqueous medium and insoluble or sparingly soluble substances; There are known drugs in which a drug is dispersed in a continuous matrix made of a chemical substance.

However, it is also known that all of them tend to have a large number of eluted feet in the early stage and a decrease in the number of eluted particles in the later stage.

In the case of sustained-release formulations that utilize diffusion control, the dissolution rate depends on the diffusion distance, and in the case of sustained-release formulations that utilize erosive properties, the dissolution rate depends on the effective surface area for dissolution. There is a marked tendency for the dissolution rate of drugs to slow down over time.

In order to maintain the drug concentration in the body fluid where the drug product is present or in the blood at a certain predetermined value in a steady state, the release rate of the drug from the drug product should ideally be constant (zero-order). It is known.

In addition, it is generally known that the absorption rate of drugs decreases in the lower gastrointestinal tract, and when drugs are released over a long period of time, such as with sustained-release preparations, it is difficult to maintain a constant blood concentration. It is also considered necessary to increase the dissolution rate after a certain period of time.

JP-A-56-92816 and JP-A-58-17
Publication No. 4311e describes a continuous matrix preparation consisting of a water-soluble polymer, hydroxypropylcellulose or hydroxypropylmethylcellulose, and a drug. However, in such sustained release preparations, since the effective surface area of the matrix in contact with the aqueous medium gradually changes, it is impossible in principle for the release rate to be zero-order throughout.

Japanese Patent Publication No. 57-53763 describes a sustained release II preparation in which instantly disintegrating particles are coated with a coating agent consisting of waxes, water-soluble polymer substances, and nonionic surfactants, and then compression molded. has been done.

However, the method disclosed in the publication has the disadvantage that it is not practical in terms of production since it is necessary to strictly specify the coating agent for the grains.

In addition, Japanese Patent Application Laid-open No. 58-39618 discloses that since the amount of drug absorbed in the lower part of the gastrointestinal tract decreases, in order to increase the dissolution rate after a certain period of time, two or three layers using waxes are used.
Stacking of layers has been described. However, the method disclosed in the publication has the disadvantage that the operation is complicated and that depending on the drug to be applied, the preparation is very large.

[Problems to be solved by the invention] Most conventional sustained-release preparations utilize osmotic pressure, diffusion control, erodibility, etc., but in principle, they do not allow zero-order elution until complete elution. is known to be impossible. Even if it is possible, it requires special and complicated processing,
It was unrealistic in terms of manufacturing.

Furthermore, it is generally known that the absorption rate of drugs decreases in the lower part of the gastrointestinal tract, and in sustained release preparations with long drug release durations, it is necessary to increase the dissolution rate after a certain period of time.

With conventional sustained release formulations, it has been impossible to achieve these problems with a single formulation.

The present invention seeks to solve these problems by controlling the rate of granulation from the matrix surface using a single slow release granule.

[Means for Solving the Problems] The present inventors investigated various means for achieving the objective of controlling release, and as a result, the present inventors coated slow-release granules with a water-soluble polymeric substance or an enteric-coated polymeric substance. It was surprisingly found that granules were gradually released from the surface of the compression-molded matrix, and drug elution occurred almost zero-orderly.

Surprisingly, the inventors have discovered that the elution rate of a drug can be freely controlled by controlling the granulation rate of the matrix, and have completed the present invention.

That is, the present invention provides a sustained-release preparation in which delayed-release granules comprising a therapeutically effective drug and a release-retarding substance are coated with a water-soluble polymeric substance or an enteric-coated polymeric substance, and then compression molded, or A sustained-release preparation with improved dissolution properties, which is obtained by blending a swelling substance into coated granules and compression molding, and a delayed-release granule obtained from a therapeutically effective drug and a release-retarding substance; The present invention relates to a method for producing a sustained-release preparation, which is characterized in that granules are coated with a release-controlling substance and then compression-molded.

To produce the preparation of the present invention, first, a therapeutically effective drug and a water-soluble, enteric-coated, or inert polymeric substance, or a release-retarding substance such as an aliphatic substance or a wax, alone or in a mixture, are uniformly mixed. Mix to obtain slow release granules. Further, known excipients may be added as appropriate. This homogeneous mixture is made into slow-release granules by a wet granulation method or a dry granulation method.

By spraying a solution prepared by dissolving a water-soluble polymeric substance or an enteric polymeric substance in water or an appropriate solvent, or by mixing a finely powdered polymeric substance into the slow-release granules, Perform coating. The coated granules can be formulated by compression molding into tablet form.

Here, slow-release granules refer to drugs with therapeutic effects, water-soluble, enteric-coated, inert polymeric substances, or one type selected from fatty acids, fatty acid esters, hydrogenated vegetable oils, other waxes, etc. Comprised of two or more types of granules, the elution of the drug from the granules is delayed to some extent. However, since the formulation of the present invention is in the form of a tablet, the initial effective area is small, and the dissolution rate can also be adjusted by adjusting the granulation rate, so the dissolution rate from slow-release granules is strictly controlled. There is no need to be controlled by This is one of the major advantages of the formulation according to the invention.

In the delayed-release granules in the formulation of the present invention, the release-retarding substances include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, gelatin, gum arabic, gum tragacanth, Water-soluble polymer substances such as pectin and locust bee gum, or hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, methyl methacrylate, etc.
Enteric polymeric substances such as methacrylic acid copolymer, ethyl methacrylate/methacrylic acid copolymer, sodium alginate, and shellac are used alone or in combination with insoluble polymeric substances such as ethyl cellulose and methacrylic acid ester copolymer. . In addition to these polymeric substances, fatty acids and their esters, vegetable hydrogenated oils, and other waxes can also be used for the purpose of delaying release.

The blending amount of these release-retarding substances can be freely set within the range of 1 to 80%. Further, known additives such as crystalline cellulose, lactose, starch, etc. are added as necessary.

In order to gradually release slow-release granules from the matrix surface of the formulation in the present invention, after coating the above-mentioned slow-release granules with a granule release-controlling substance such as a water-soluble polymeric substance or an enteric-coated polymeric substance, This is accomplished by compression molding.

The water-soluble polymer substances used here include diroxypropylcellulose, hydroxypropylmethylcellulose carboxymethylcellulose sodium vinylpyrrolidone, polyvinyl alcohol, polyethylene glycol,
Gelatin, gum arabic, and pullulan are used alone or in combination.

In addition, the enteric polymer substances include hydroxypyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acedate phthalate, carboxymethyl ethyl cellulose, methyl methacrylate-1-methacrylic acid copolymer,
Ethyl methacrylate/methacrylic copolymer and sodium alginate are used alone or in combination.

The blending amount can be freely set within the range of 1 to 60 (% by weight). Also, the coating method may be to spray a solution in which the release control substance is dissolved or dispersed in water or an appropriate organic solvent, or This is done by combining a finely powdered release controlled substance with granules in its powder form.

The elution rate of the drug from the formulation in the present invention is determined by the balance between the elution rate of the drug from the slow-release granules and the release rate of the granules from the matrix, that is, the granulation rate. The elution rate of the drug from slow-release granules is controlled by the type of release-retarding substance and the compounding port, and the granulation rate can be controlled over a very wide range by changing the amount of coating of the polymeric substance.

The speed of granulation can also be adjusted by adding a swelling substance/material to the coated slow-release granules and then compression molding.3 In this case, the swelling substance is carboxylic acid. Methylcellulose calcium, low-substituted hydroxypropylcellulose, polyvinylpolypyrrolidone, crystalline cellulose, starch, and starch derivatives are used alone or in combination. Its blending amount is 0.1~
It is 35 (W/buttock)%.

When mixing granules and powder, there is a possibility that the phenomenon of separation may occur, so it is necessary to effectively prevent the phenomenon of separation by dispersing a swelling substance in the polymer coating liquid for coating the slow-release granules. I can do it.

The therapeutically effective drug applicable to the present invention may be any orally administrable drug, such as nifedipine,
Cardiovascular agents such as propranolol, furosemide, clonidine, and pentoxifylline; psychoneurotic agents such as oxazolam, diazepam, and heroberidol; antipyretic, anticancer, and antiinflammatory agents such as ibuprofen, indomethacin, and diclofenac sodium; and hormones such as dexamethasone and hydrocortisone. oral antidiabetic agents such as glibenclamide,
Antibiotics such as cef7rexin and amoxicillin, antitussives such as salbutamol and terbutaline, and antineoplastic agents such as 5-[U] are included.

[Effect] When the preparation of the present invention is orally administered, in the stomach or intestine,
The controlled-release substances, i.e., water-soluble (raw polymeric substances and enteric polymeric substances) whose matrix is disintegrated by each body fluid, gradually dissolve into compression-molded slow-release granules, which are gradually released at a constant rate. The therapeutically effective drug is released from the released granules at an excessive rate controlled by the release retarding substance.

In other words, the matrix obtained by coating slow-release granules with a polymeric substance and then compression molding is a discontinuous matrix separated by partitions and walls of polymeric substances with different dissolution rates, and the granules gradually form from this surface. The phenomenon is a useful controlled release system for zero-order dissolution of matrix-type sustained release formulations. The formulation of the present invention has 0
Since it exhibits elution close to the next level, it has a good utilization rate and can maintain the blood concentration at a predetermined level for a long time even for drugs with a narrow therapeutically effective concentration range.

In this way, in order to achieve two-stage drug release using both the release-controlling substance and the release-retarding substance, by selecting and formulating the components of each release-controlling substance and release-retarding substance,
It becomes easy to design a wide variety of arbitrary sustained release formulations.

In other words, the formulation of the present invention can increase the dissolution rate after a certain period of time by adjusting the rate of granulation from the matrix using the same coated granules. Effective for release formulations.

In addition, the formulation of the present invention can be designed to be either I)H-dependent or pH-independent depending on the physical properties of the drug, and can be applied to a wide range of drugs, regardless of whether they are easily soluble or poorly soluble [crude drugs]. It is possible.

[Examples] Examples of the present invention will be described in detail below, but the present invention is not limited to these Examples.

Example 1 Diclofenac sodium 400g vegetable hydrogenated oil aoog crystalline cellulose
100g of the above ingredients were mixed, 70% (V/V) of ethanol solution containing 15% of ethyl cellulose was added, and after kneading, a screen of 8mm diameter was passed through an extrusion granulator. used to produce slow-release granules.

70 (V
/V)% isopropyl alcohol solution (880 m) was coated using a flow coater (Freund Sangyo).

Add 2 g of magnesium stearate to the jq radish-coated granules to form a tablet of 240 m (1 (diclofenac sodium 50 m! II)).

The dissolution amount of diclofenac sodium from the formulation of this example was investigated using the rotating basket method in Method 1 under the diurnal cycle (X>dissolution test).The results are shown in FIG.

Further, the elution amount of the slow-release granules alone used in the formulation of this example is as shown in FIG.

It was found that in the formulation of this example, the drug was released in constant amounts over a long period of time.

Example 2 Slow release granules 28 obtained by the same method as Example 1
0 (116.8 g of hydroxypropylcellulose per liter,
Add 3.2g of magnesium stearate, 250 tablets per tablet
mg <diclofenac sodium 50 mg) tablets.

Example 3 Delayed release granules 28 obtained by the same method as in Example 1
84.80 g of hydroxypropyl methylcellulose acetate succinate and 3.2 g of magnesium stearate are added to 0 g to form a tablet of 230 ma (diclofenac sodium 50 mg).

Example 4 Diclofenac sodium 320 (] Vegetable hydrogenated oil 640tj Sucrose fatty acid ester (Hu37) 128g The above components were mixed,
Slow-release granules are made using a soft granulator using an 18-mesh sieve.

Add 81,136 g of hydroxypropyl methylcellulose acetate tsukushine and 40 magnesium stearate to the obtained slow-release granules 340 (240 + nc) per tablet.
+ (diclofenac sodium 50 mg) tablets.

The amount of diclofenac sodium eluted from the formulation and slow-release granules of this example was measured in the same manner as in Example 1 above. The results are shown in FIGS. 2 and 6, respectively.

In the case of the preparation of this example as well, it is clear that the drug is released in a constant amount over a long period of time.

Example 5 Theophylline 500 (350 g of crystalline cellulose)
After adding 750 g of a 0 (V/V)% ethanol solution and kneading, the mixture is made into slow-release granules using an extrusion granulator using a screen with a diameter of 0.8 mff1.

123 g of hydroxypropyl methyl cellulose acetate succinate and 4.5 g of magnesium stearate were added to 300 g of the obtained slow-release granules to make one tablet 285 m9.
(Theophylline 100mg) tablets.

The amount of theophylline eluted from the preparation of this example was measured in the same manner as in Example 1 above. The results are shown in Figure 3, and it is clear that the drug is released in constant amounts over a long period of time.

Example 6 Indomethacin 350 (] Eudragit RS ” 2[>g Hydroxypropylcellulose 50g Starch
330 g of the above ingredients were mixed, 70 (V/V cormorant ethanol solution 500 ml was added, kneaded, and then slow-released using an extrusion granulator using a screen with a diameter of 0.8 mm [made into bovine granules).

To 150 g of the obtained slow-release granules, 53 g of hydroxypropyl methyl cellulose acetate succinate and 2 g of magnesium stearate were added to make one 220 mg tablet (indomethacin 701n (J)).

The dissolution a of the formulation and slow-release granules of this example was measured in the same manner as in Example 1 above.

The results are shown in FIGS. 4 and 7, respectively.

In the case of the preparation of this example, a relatively large amount of the drug is released at a substantially constant rate within 2 to 6 hours after administration.

Example 7 Delayed release granules 27 obtained by the same method as Example 6
8 (IJ/
After dispersing 18 g of cornstarch in 1000 d of a 60 (V/V)% isopropyl alcohol solution containing W)%, coating was performed using a flow coater. Add 3.6 g of magnesium stearate to the jqed granules to form tablets of 205 ma (indomethacin 70 mg).

Example 8 Barium sulfate 250 (1) Vegetable hydrogenated oil 100 g After uniformly mixing the above components, ethyl cellulose: 1.35 (W/
W) % Contains t Le95 (V/V)% Ethanol/-Le liquid 2
Add 30 Inl, knead, and use an extrusion granulator to make 1.0 m
Slow release granules are made using a m diameter screen.

Add 22.5 g of hydroxypropyl methyl cellulose acetate succinate and 2.5 g of magnesium stearate to 200 g of the obtained slow-release granules to make one tablet 450n+
c+ (232.6 mg of barium sulfate) tablets.

This preparation did not disintegrate for more than 2 hours in the diurnal disintegration test of (X) I solution h) H1, 2), and was completely granulated in 4 to 5 hours in solution (1) H6, 8).

One tablet of this preparation was administered lightly with 50 d of water to a fasted Peagle dog, and observations were made using X-ray imaging.

X-ray radiation is 0.5.1.1.5, 2°2, 5.3.3
．． 5.4. Abdominal decoy imaging was performed every 7 hours. X-rays show that this preparation does not form granules in the stomach and is excreted by the stomach) I! ! It was confirmed that granulation started gradually after 1 hour and continued until it reached the colon 7 hours later.

[Effects of the Invention] As described above, the slow release preparation of the present invention and the method for producing the same use a single granule and control the granulation rate and drug release rate using a release controlling substance and a release delaying substance. By adjusting the amount, it is possible to easily design a sustained-release preparation that exhibits near-zero-order dissolution up to complete dissolution, or a sustained-release preparation that increases the amount of dissolution after a certain period of time. The effect is better than the conventional one, and it can be used for one use.

[Brief explanation of the drawing]

Figures 1 to 4 are diagrams showing the results of the drug elution test for the formulation of the present invention. Figure 1 is the tablet of Example 1, Figure 2 is the tablet of Example 4, and Figure 3 is the tablet of Example 4. Figure 4 is a diagram showing the results of the drug dissolution test for the tablet of Example 5, and Figures 5 to 7 are diagrams showing the results of the drug dissolution test for the tablet of Example 6. FIG. 5 is a diagram showing the results; FIG. 5 shows the slow-release granules used in Example 1, FIG. 6 shows the slow-release granules used in Example 4, and FIG. 7 shows the slow-release granules used in Example 6. FIG. 3 is a diagram showing the results of a drug elution test for sex granules.

Claims (1)

[Scope of Claims] 1) A sustained-release preparation characterized in that slow-release granules comprising a therapeutically effective drug and a substance that delays the release of the drug are coated with a release-controlling substance and compression molded. . 2) The substance that delays the release of drugs with therapeutic effects is water-soluble synthetic or natural polymeric substances, enteric-coated synthetic or natural polymeric substances, insoluble polymeric substances, fatty acids, fatty acid esters, and hydrogenated vegetable oils. , 1 selected from waxes
The sustained release preparation according to claim 1), which comprises one or more species. 3) Claim 1) wherein the release-controlled substance of the slow-release granules is a water-soluble polymeric substance or an enteric-coated polymeric substance.
Sustained-release preparations as described in Section. 4) The sustained-release preparation according to claim 1, wherein the release-controlled substance of the slow-release granules comprises either a water-soluble polymeric substance or an enteric-coated polymeric substance and a swellable substance. 5) A patent in which the water-soluble polymeric substance is one or more selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, gelatin, gum arabic, and pullulan. The sustained release preparation according to claim 3) or 4). 6) Enteric polymer substances include hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, carboxymethylethylcellulose, methyl methacrylate/methacrylic acid copolymer, ethyl methacrylate/methacrylic acid copolymer, and sodium alginate. The sustained release preparation according to claim 3) or 4), which comprises one or more selected from the following. 7) The swelling substance is composed of one or more selected from carboxymethyl cellulose calcium, low substituted hydroxypropyl cellulose, polyvinyl polypyrrolidone, crystalline cellulose, starch, and starch derivatives, and the amount thereof is 0. The sustained release preparation according to claim 4), which has a content of 1 to 35 (W/W)%. 8) Production of a sustained-release preparation, characterized in that delayed-release granules are obtained from a therapeutically effective drug and a release-retarding substance, the delayed-release granules are coated with a release-controlling substance, and then compression molded. Law.