JPH0688899B2 - Persistent tablets - Google Patents

Description

TECHNICAL FIELD The present invention relates to a sustained-release tablet and a method for producing the same. More specifically, by controlling the disintegration property of the tablet, the drug is released from the tablet continuously and at a substantially constant rate, whereby the drug effect is maintained over a long period of time. The present invention relates to a sustained-release tablet comprising disintegrating granules containing molecules and waxes, and a method for producing the same.

Formulations in which the drug is continuously released and the drug effect is sustained for a long period of time have a constant blood concentration of the drug such that toxicity and side effects increase when the drug is taken less frequently or when the blood concentration of the drug exceeds a certain level. It is a useful preparation that has been studied in the past for the purpose of controlling below the value.

b Conventional Technology As conventional technology developed for such a purpose,
There are those in which granules containing a drug are coated, and those in which the drug is dispersed in a continuous matrix (matrix tablet). In these, the film or matrix is made of an insoluble or sparingly soluble substance in an aqueous body fluid, and the drug release is controlled by resistance as the drug diffuses in the film or matrix. Further, in these cases, the granules to be coated or the first granules used for tableting the matrix tablet are characterized in that they are as hard to disintegrate as possible.

The drug elution mode of the drug product provided by the conventional techniques as described above uses a drug concentration gradient generated by water permeation as a driving force (diffusion-controlled). The elution rate decreases due to the decrease of the gradient or the increase of the diffusion distance, and the elution amount is approximately proportional to the square root of time.

In addition, examples of sustained-release preparations other than these include enteric-coated preparations. The release of the drug is delayed by applying a film that dissolves in the intestine and then dissolves in this formulation. The rate is determined by the rate of gradual elimination of the formulation from the stomach to the intestine. . By combining such an enteric-coated portion with a portion that is normally dissolved in the stomach, the release of the drug can be sustained.

c Problems to be Solved by the Invention The drawbacks of the above-described prior art are as follows.

i) When the release rate is controlled by diffusion-controlling the drug from the formulation, there is a drawback that the release rate gradually slows down with time. Further, when it is applied to a poorly soluble drug, its dissolution is extremely low, which is not practical.

ii) The one using an enteric-coated preparation has a problem in that its release is controlled by pH.

The pH value in the gastrointestinal tract varies with the site, there is also diurnal variation, and also with the mental state of the patient, so that the release may be affected by such variations and may not always reach its intended purpose. May not be. Further, in the case of anoxic acid that is often seen in the elderly, there is a risk that even the enteric-coated portion is dissolved in the stomach and a large amount of drug is released at a time. Furthermore, since it is controlled by the rate of gastric emptying, it is an important factor such as plants present in the stomach at the time of taking, but the patient does not always take according to the usage, so the intended purpose is There are cases where it cannot be reached.

In addition, not only enteric-coated preparations, but the properties (eg, solubility) of the drug itself change depending on the pH value of the aqueous solvent, so that the release rate is affected by the change in pH value even in the preparation by diffusion control.

As described above, the conventional techniques have the drawback that the release rate of the drug becomes slower with the passage of time and the drawback that it depends on the pH value of the elution portion, which makes it difficult to control the blood concentration. It was

The present invention aims to solve these problems, and the drug release rate is almost constant (zero-order release), and the stirring strength and
It is intended to provide a preparation having a small change in drug release rate due to a change in pH value and a method for producing the same.

As a solution to these problems,
Immediately disintegrating granules containing the main drug are coated with a film consisting of waxes, water-soluble polymer and nonionic surfactant with HLB of 9 or less, and then the coated granules are compressed to give sustained release. The technology to obtain the drug is provided (Japanese Patent Publication Sho
No. 57-53763), the surfactant used here is to avoid use as much as possible from the viewpoints of irritation and safety to human body, stability of preparation itself, and the like. Further, in this method, since there are many factors to control the release, when applying this method to a certain drug, it is considered that it is difficult to determine specific components and blending ratios.

As described in detail below, the present invention is composed of disintegrating granules and waxes containing a main drug, and a simpler method of attaining the purpose is to achieve the object by a method. Is also an improvement.

d. Means for Solving Problems The sustained-release tablet of the present invention comprises disintegrating granules and waxes containing a main drug, or disintegrating granules and waxes containing a main drug and a water-soluble polymer, For example, it is produced by applying waxes to the surface of disintegrating granules containing such a main drug and then tableting.

The disintegrating granules containing the main drug include a main drug, a disintegrant [for example, various starches (for example, corn starch,
Potato starch, rice starch, α-starch, carboxymethyl starch, etc.), gums (eg gum arabic), cellulose derivatives (eg carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl cellulose sodium,
Etc.), various ion exchange resins (eg potassium polymethacrylate), etc.], excipients (eg lactose, sucrose,
Mannitol, etc.) and additives usually used in this field are made into granules by a conventional method.

The amount of the disintegrant used in the production of granules is preferably 10 to 60% by weight as a ratio in the granule component, but is not necessarily limited to this, and may be appropriately selected depending on the properties of the main drug used, the intended duration, etc. Also, several kinds of disintegrants may be mixed and used.

Disintegrating granules containing a main drug and a water-soluble polymer include a main drug, a water-soluble polymer [eg, a cellulose derivative (eg, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, etc.), a synthetic water-soluble polymer] (Eg, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyethylene oxide, etc.), polysaccharides (eg, pullulan,
Dextran, etc.), etc.], and the above-mentioned disintegrants, excipients, additives generally used in this field, etc., are made into granules by a conventional method.

In this case, the preferable amount of the disintegrant used is 10 to 60% by weight as a ratio in the granule component, as in the previous case,
It is not necessarily limited to this.

The amount of the water-soluble polymer used is preferably 2.5 to 45% by weight (more preferably 5 to 30% by weight) as a ratio in the granule component, but it is not necessarily limited to this, and the nature and purpose of the main drug to be used and It is appropriately selected depending on the duration of time and the like, and several kinds of water-soluble polymers may be mixed and used.

As described above, the present invention is characterized in that the main drug, or the granule containing the main drug and the water-soluble polymer, is made disintegrating.

Here, if the main drug to be used is extremely poorly soluble and it is considered that absorption into blood is insufficient if used as it is, after leading the main drug into a readily soluble dosage form such as a solid solution in advance, Granules may be manufactured. This solid solution is produced, for example, by uniformly dispersing the main drug in a water-soluble polymer (for example, hydroxypropylmethyl cellulose).

The granules produced as described above are subjected to wax treatment.

Waxes used herein include all types of waxes that are insoluble or sparingly soluble in water, such as vegetable or animal waxes (eg, carnauba wax, beeswax, etc.), various hardened oils (eg, soybean). Hydrogenated oil, hydrogenated castor oil, etc.), paraffins (eg, paraffin wax, microcrystalline wax, etc.) and the like. Further, these waxes may be mixed and used.

The wax treatment can be performed by kneading the above granules in molten wax, then drying and sieving.
The method is not necessarily limited to this. The amount of waxes used is appropriately selected depending on the properties of the main drug to be used and the intended duration, etc., but is usually 20 to 65% by weight, more preferably 30 to 65% by weight in the total components of the tablet.
55% by weight. The type of wax used is appropriately selected depending on the properties of the main agent used, the amount of wax used, the intended duration, and the like.

After the wax has been applied to the surface of the granules in this manner, a lubricant such as magnesium stearate is added and the mixture is compressed according to a conventional method to produce the sustained-release tablet of the present invention.

e Example Hereinafter, the present invention will be described in accordance with an example.

The chemical names and structural formulas of the main drugs used in the examples are shown below.

1) Names in Examples: Dihydropyridine A substance (vasodilator) Chemical name: 6-cyano-5-methoxycarbonyl-2-methyl-4
-(3-Nitrophenyl) -1,4-dihydropyridine-
Isopropyl ester of 3-carboxylic acid Structural formula: 2) Names in Examples: Cephalosporin A substance (antibacterial agent) Chemical name: 7- [2- (2-aminothiazol-4-yl) -2-
Carboxymethoxyiminoacetamide] -3-vinyl-3-cephem-4-carboxylic acid (syn isomer) Structural formula: 3) Names in Examples: Chloropyridine substance (treatment agent for vascular disorders) Chemical name: β-cyclodextrin inclusion compound of 2-nitrooxymethyl-6-chloropyridine (molar ratio 1: 1) Structural formula: 2- Nitrooxymethyl-6-chloropyridine is a compound having the following structural formula.

Example 1 Dihydropyridine A substance (20 g) and hydroxypropylmethylcellulose (viscosity: 6 cps; 60 g) were dissolved in a 1: 1 mixed solution of ethanol and methylene chloride, and then this solution was mixed with low-substituted hydroxypropylcellulose (90 g). Add lactose (30 g) evenly mixed and knead. The kneaded product is dried at 60 ° C. for 4 hours and then crushed using a crusher to obtain 32 mesh passing particles. (At this stage, dihydropyridine A substance-containing solid solution granules are prepared.) 110 g of the granules thus produced is taken and cooled to room temperature while being kneaded with molten soybean hydrogenated oil (110 g), and then passed through 20 mesh (Wax-treated granules).

200 g of the wax-treated granules are taken and mixed with magnesium stearate (0.4 g), followed by tabletting to obtain a sustained-release tablet.

The outer diameter of this tablet is 7 mm, and each tablet has the following composition.

Dihydropyridine A substance 8.0 mg Hydroxypropyl methylcellulose (viscosity: 6 cps) ^* 2
4.0 mg Low-substituted hydroxypropyl cellulose 36.0 mg Lactose 12.0 mg Soybean hydrogenated oil 80.0 mg Magnesium stearate 0.3 mg 160.3 mg ^* cps: centipoise (same units will be used below)
(The viscosity of a substance is closely related to its molecular weight, and the higher the viscosity representing the degree of viscosity, the higher the molecular weight.) Example 2 As in Example 1, per tablet A tablet having the following composition is obtained.

Dihydropyridine A substance 8.0 mg Hydroxypropyl methylcellulose (viscosity: 6 cps) 24.
0 mg Low-substituted hydroxypropylcellulose 24.0 mg Lactose 24.0 mg Soybean hydrogenated oil 80.0 mg Magnesium stearate 0.3 mg 160.3 mg Example 3 In the same manner as in Example 1, tablets having the following composition per tablet are obtained.

(1) Dihydropyridine A substance 8.0 mg Hydroxypropyl methylcellulose (viscosity: 6 cps) 24.
0mg Low-substituted hydroxypropylcellulose 19.2mg Lactose 28.8mg Soybean hydrogenated oil 53.3mg Magnesium stearate 0.3mg 133.6mg (2) Dihydropyridine A substance 8.0mg Hydroxypropylmethylcellulose (viscosity: 6cps) 24.
0 mg Low-substituted hydroxypropylcellulose 36.0 mg Lactose 12.0 mg Carnauba wax 40.0 mg Paraffin wax 40.0 mg Magnesium stearate 0.3 mg 160.3 mg Example 4 Cephalosporin A substance (purity: 89.4%) (20 g) and low-substituted hydroxypropyl cellulose After uniformly mixing cellulose (6.7 g), 10.8 ml of a 5 (weight / volume)% aqueous solution of hydroxypropylmethyl cellulose (viscosity: 6 cps) is added and kneaded. After kneading, it is dried at 50 ° C. for 4 hours and then made into 32 mesh passing particles.

24 g of the granules thus produced is taken and cooled to room temperature while being kneaded with molten carnauba wax (16 g) to obtain 20-mesh passing particles (wax-treated particles).

The wax-treated particles are tableted by a conventional method to give a sustained-release tablet having the following composition per tablet.

Cephalosporin A substance (Purity: 89.4%) (125 mg titer)
139.8mg Hydroxypropyl methylcellulose (viscosity: 6cps) 3.8
mg Low-substituted hydroxypropylcellulose 46.6 mg Carnauba wax 126.8 mg Magnesium stearate 0.6 mg 317.6 mg Example 5 In the same manner as in Example 4, tablets having the following composition per tablet are obtained.

Cephalosporin A substance (Purity: 89.4%) (84.3mg titer) 94.3mg Hydroxypropylmethylcellulose (viscosity: 6cps) 6.7
mg Low-substituted hydroxypropylcellulose 67.4 mg Castor hydrogenated oil 101.0 mg Soybean hydrogenated oil 67.4 mg Magnesium stearate 0.7 mg 337.6 mg Example 6 Tablets having the following composition per tablet are obtained in the same manner as in Example 4.

(1) Chloropyridine substance 58.4mg Hydroxypropyl methylcellulose (viscosity: 6cps) 16.
2mg Low-substituted hydroxypropylcellulose 87.6mg Castor hydrogenated oil 64.9mg Soybean hydrogenated oil 43.3mg Magnesium stearate 0.5mg 270.9mg (2) Chloropyridine substance 58.4mg Hydroxypropylmethylcellulose (viscosity: 6cps) 16.
2 mg Low-substituted hydroxypropyl cellulose 87.6 mg Castor hydrogenated oil 97.3 mg Soybean hydrogenated oil 64.9 mg Magnesium stearate 0.6 mg 325.0 mg Example 7 Cephalosporin A substance (purity: 89.4%) (14 g), low-substituted hydroxypropyl cellulose (8.5g) and hydroxypropyl methylcellulose (viscosity: 4000cps) (2.25
After uniformly mixing g), 2.5 (weight / volume)% hydroxypropylmethylcellulose (viscosity: 4000 cps) aqueous solution (10 ml) is added as an engaging agent, and the mixture is kneaded.
Then, it is dried at 60 ° C. for 4 hours and then sieved to obtain 32 mesh passing particles.

Take 20 g of the granules made in this way, cool to room temperature while kneading with a mixture of melted castor hydrogenated oil (16 g) and melted soybean hydrogenated oil (4 g), and obtain 20 mesh passing particles (wax treated particles ).

The wax-treated granules are tableted by a conventional method to give a sustained-release tablet having the following composition per tablet.

Cephalosporin A substance (Purity: 89.4%) (83.3mg titer) 93.2mg Hydroxypropyl methylcellulose (viscosity: 4000cps)
16.6 mg Low-substituted hydroxypropylcellulose 56.6 mg Castor hydrogenated oil 133.2 mg Soybean hydrogenated oil 33.3 mg Magnesium stearate 0.7 mg 333.6 mg Example 8 In the same manner as in Example 7, tablets having the following composition per tablet are obtained.

(1) Cephalosporin A substance (Purity: 89.4%) (83.3m
g titer) 93.2mg Hydroxypropyl methylcellulose (viscosity: 400cps) 1
6.6 mg Low-substituted hydroxypropyl cellulose 56.6 mg Castor hydrogenated oil 133.2 mg Soybean hydrogenated oil 33.3 mg Magnesium stearate 0.7 mg 333.6 mg (2) Cephalosporin A substance (purity: 89.4%) (83.3m
g titer) 93.2mg Hydroxypropyl methylcellulose (viscosity: 50cps) 1
6.6mg Low-substituted hydroxypropylcellulose 56.6mg Castor hydrogenated oil 133.2mg Soybean hydrogenated oil 33.3mg Magnesium stearate 0.7mg 333.6mg (3) Cephalosporin A substance (Purity: 89.4%) (83.3m
(g titer) 93.2 mg Hydroxypropyl methylcellulose (viscosity: 6 cps) 16.
6 mg Low-substituted hydroxypropyl cellulose 56.6 mg Castor hydrogenated oil 133.2 mg Soybean hydrogenated oil 33.3 mg Magnesium stearate 0.7 mg 333.6 mg Example 9 Tablets having the following composition per tablet are obtained in the same manner as in Example 7.

(1) Chloropyridine substance 58.4mg Hydroxypropyl methylcellulose (viscosity: 4000cps)
16.2mg Low-substituted hydroxypropylcellulose 87.6mg Castor hydrogenated oil 64.9mg Soybean hydrogenated oil 43.3mg Magnesium stearate 0.5mg 270.9mg (2) Chloropyridine substance 58.4mg Hydroxypropylmethylcellulose (viscosity: 400cps) 1
6.2mg Low-substituted hydroxypropylcellulose 87.6mg Castor hydrogenated oil 64.9mg Soybean hydrogenated oil 43.3mg Magnesium stearate 0.5mg 270.9mg (3) Chloropyridine substance 58.4mg Hydroxypropylmethylcellulose (viscosity: 50cps) 1
6.2 mg Low-substituted hydroxypropylcellulose 87.6 mg Castor hydrogenated oil 64.9 mg Soybean hydrogenated oil 43.3 mg Magnesium stearate 0.5 mg 270.9 mg Example 10 In the same manner as in Example 7, tablets having the following composition per tablet are obtained.

(1) Chloropyridine substance 58.4mg Polyvinylpyrrolidone (Molecular weight: 3.6 × 10 ⁵ ) 16.2mg Low-substituted hydroxypropylcellulose 87.6mg Carnauba wax 54.1mg Paraffin wax 54.1mg Magnesium stearate 0.5mg 270.9mg (2) Chloropyridine substance 58.4mg Polyvinylpyrrolidone (Molecular weight: 1.6 × 10 ⁵ ) 16.2 mg Low-substituted hydroxypropylcellulose 87.6 mg Carnauba wax 54.1 mg Paraffin wax 54.1 mg Magnesium stearate 0.5 mg 270.9 mg (3) Chloropyridine substance 58.4 mg Polyvinylpyrrolidone (Molecular weight: 4.0 × 10 5) ⁴ ) 16.2mg Low-substituted hydroxypropyl cellulose 87.6mg Carnauba wax 54.1mg Paraffin wax 54.1mg Magnesium stearate 0.5mg 270.9mg (4) Chloropyridine substance 58.4mg Polyvinylpyrrolidone (molecular weight: 1.0 × 10 ⁴ ) 16.2mg Low-substituted hydroxy Propyl cellulose 87. 6 mg Carnauba wax 54.1 mg Paraffin wax 54.1 mg Magnesium stearate 0.5 mg 270.9 mg Example 11 In the same manner as in Example 1, the dihydropyridine A substance was blended with hydroxypropylmethyl cellulose (viscosity: 6 cps) to form a solid solution, and then Example 7 In the same manner as above, a tablet having the following composition per tablet is obtained.

(1) Dihydropyridine A substance 8.0 mg Hydroxypropyl methylcellulose (viscosity: 6 cps) 24.
0 mg Low-substituted hydroxypropyl cellulose 36.0 mg Lactose 12.0 mg Pullulan (molecular weight: 3.0 × 10 ⁵ ) 8.9 mg Soybean hydrogenated oil 88.9 mg Magnesium stearate 0.4 mg 178.2 mg (2) Dihydropyridine A substance 8.0 mg Hydroxypropyl methylcellulose (viscosity: 6cps) 24.
0 mg Low-substituted hydroxypropyl cellulose 36.0 mg Lactose 12.0 mg Pullulan (molecular weight: 2.0 × 10 ⁵ ) 8.9 mg Soybean hydrogenated oil 88.9 mg Magnesium stearate 0.4 mg 178.2 mg (3) Dihydropyridine A substance 8.0 mg Hydroxypropyl methylcellulose (viscosity: 6cps) 24.
0 mg Low-substituted hydroxypropyl cellulose 36.0 mg Lactose 12.0 mg Pullulan (molecular weight: 1.0 × 10 ⁵ ) 8.9 mg Soybean hydrogenated oil 88.9 mg Magnesium stearate 0.4 mg 178.2 mg f Effect of the invention In the tablets produced by the present invention, water is used. Penetration is limited to the surface layer of the tablet, and the disintegrant in the inner granules (wax-treated particles during tableting) present in the surface layer gradually swells and eventually breaks the surrounding wax wall. Fall off the tablet surface. Since the inner granules are made disintegrating, the inner granules that have fallen off the tablet surface immediately disintegrate, thereby releasing the main drug. Then, by repeating this over time and at a substantially constant rate, the main drug is released from the tablet at a continuous and substantially constant rate.

In other words, the rate-determining step in the release of the main drug from this tablet is the disintegration (or loss) of the internal granules present in the tablet surface layer from the tablet.
This feature gives the tablet the characteristics that the dissolution pattern is linear and that the dissolution pattern and dissolution rate are not easily affected by changes in stirring strength, pH of the aqueous medium, and the like.

Usually, the method of disintegrating the tablet is used for releasing the active ingredient from the tablet quickly, but in comparison with this, the present invention has a remarkable feature.

For this reason, the sustained-release tablet according to the present invention can be called a "gradual disintegrating tablet".

In the present invention, the disintegration (in other words, dropping) of the inner granules from the tablet can be carried out by adjusting the kinds and amounts of the disintegrant and waxes.

Furthermore, when a water-soluble polymer is blended in the inner granules, finer adjustment can be performed by adjusting the molecular weight of the water-soluble polymer used.

As described above, since the disintegration step of the inner granules from the tablet is the rate-determining step, the release of the main drug can also be controlled by adjusting the above-mentioned factors.

Typical test results will be given below to show the effects obtained by the present invention.

Test tablet Test tablet A: Tablet disclosed in Example 1 (containing 8.0 mg of dihydropyridine A substance per tablet) Test tablet B: Tablet disclosed in Example 2 (8.0 mg of dihydropyridine A substance per tablet) Test tablet C: tablet disclosed in Example 4 above (containing 125 mg of cephalosporin A substance per tablet) Test tablet D: tablet disclosed in Example 5 above (cephallot per tablet) 84.3 mg of Sporin A substance) Dissolution / disintegration test test method (1) Japanese Pharmacopoeia (10th revision) disintegration test method (1st liquid, 15cpm, 9)
00ml) (2) Japanese Bureau (10th revision) Dissolution test method Paddle method (1st liquid,
(200 rpm, 900 ml) (3) Japanese Bureau (10th revision) Dissolution test method Paddle method (1st liquid,
(100 rpm, 900 ml) (4) Japanese Bureau (10th revision) Dissolution test method Paddle method (2nd liquid,
(100 rpm, 900 ml) (5) Improved disintegration test method (1st liquid, 15 cpm, 10 ml) (6) Sartorius method (1st liquid, 100 ml) (7) Sartorius method (2nd liquid, 100 ml) (By dissolution test method) The test solution used was the same as the test solution used in the disintegration test method, and in each case, the experiment was conducted at 37 ° C.) [I] Elution conditions (stirring strength, pH of test solution) In order to examine the effect of the difference on the elution pattern, the elution rate was measured with time under several conditions.

[II] A disintegration test was conducted under two conditions in order to observe the influence of the difference in liquid amount on the disintegration rate.

Blood Concentration Test Test 1 Four male Beagle dogs (weight 8 to 12 kg) fasted overnight were given 100 g of Lab.Chow (trademark: Purina Taiyo Pet Foods Co., Ltd.) 30 minutes before administration of test tablets, and then dihydropyridine. 8.0 mg was administered as a substance A per animal. Immediately after the administration, 40 ml of water was forcibly administered, and water was given freely thereafter. After administration of the test tablets, the plasma concentration of the dihydropyridine A substance was measured over time by ECD gas chromatography.

As the test tablets, the above-mentioned test tablets A and B and a control tablet having the following composition per tablet were used.

(Composition of control tablet) Dihydropyridine A substance 8.0 mg Hydroxypropyl methylcellulose (viscosity: 6 cps) 24.
0 mg Low-substituted hydroxypropylcellulose 24.0 mg Lactose 24.0 mg Magnesium stearate 0.2 mg 80.2 mg This control tablet is a solid solution tablet that is readily soluble.

Test Results Plasma concentrations (ng / ml) at each time point are shown in the table below as the mean value ± standard error of 4 Beagle dogs.

Test 2 Six male Beagle dogs (weight 8 to 12 kg) fasted overnight were given 100 g of Lab.Chow (trademark: Purina Taiyo Pet Food Co., Ltd.) 30 minutes before administration of the test tablets, and then cephalosporin A substance 250 mg per animal was administered. Water immediately after administration 4
0 ml was forcibly administered and water was given freely thereafter. After administration of the test tablets, the serum concentration of the cephalosporin A substance was measured over time by liquid chromatography.

The test tablet C was used as the test tablet, and the aqueous solution containing the cephalosporin A substance was used as the control.

(Preparation of Control Aqueous Solution) The cephalosporin A substance was dissolved in a phosphate buffer of pH 6.0 to prepare a 1.25 (weight / volume)% aqueous solution. At the time of the test, 20 ml of this aqueous solution (25 mg as cephalosporin A substance)
0 mg) was administered.

Test Results The following table shows the serum concentration (μg / ml) at each time point as the average value ± standard error of 6 Beagle dogs.

Dissolution test results When the results of test methods (1) to (3) in Table 1 are compared, the dissolution pattern is almost linear in all cases, and there is no significant difference between the dissolution rates. I understand. The results in Table 2 also show that the elution pattern is almost linear.

From the above, the tablet in the present invention has a substantially linear elution pattern even when the stirring method and stirring strength are changed (that is, the dissolution rate is close to constant), and the dissolution rate is affected by the change in conditions. It has become clear that it has the feature of being small.

Further, when the results of the test methods (3) and (4) in Table 1 are compared with the results of the test methods (6) and (7) in Table 3, the elution pattern is also linear in this case. It can be seen that the elution rates are almost the same.

From this, it is clear that the dissolution pattern and dissolution rate of the tablet according to the present invention are hardly affected even if the pH value of the eluate changes.

The cephalosporin A substance has a carboxy group or an amino group in the molecule, so the solubility changes depending on the pH of the eluate, but the results in Table 3 show that almost the same elution pattern is obtained in solutions with different pH. It became clear to have.

Therefore, it became clear that applying the present invention to a drug whose solubility varies depending on the pH of the solution is extremely effective. (Test solution 1st solution has a pH of about 1.2, 2nd solution has a pH of about 6.8. Also, the solubility of the cephalosporin A substance is 1.9 mg / ml in the 1st solution, and in the 2nd solution. 400 mg / ml or more.) Disintegration test results From the results in Table 4, the disintegration rate changes almost linearly with time regardless of whether the liquid is present in a large amount or in a small amount. The speed is almost the same. Since the disintegration stage of the tablet of the present invention is rate-determining, the same can be said for elution. Since the water content in the digestive tract tends to fluctuate depending on the site and time, it can be said that this tablet is a practical one that can adapt to such environmental changes.

Furthermore, it was found from the results of the blood concentration test that the sustained blood concentration as expected from the results of the dissolution test and the disintegration test was obtained. It was also clarified that the time to reach the maximum blood concentration can be controlled by changing the composition (that is, the types and amounts of the disintegrants and waxes as described above).

As described above, the sustained release tablet according to the present invention has excellent effects, and the dissolution rate and the duration of dissolution can be easily controlled by adjusting the types and amounts of disintegrants and waxes. It solves the drawbacks of the various preparations provided by the prior art.

By the way, as described above, the sustained-release tablet according to the present invention may contain a water-soluble polymer (that is, may be composed of disintegrating granules and waxes containing a main drug and a water-soluble polymer). ).

In this case, the duration of the main drug release can be controlled more delicately by adjusting the molecular weight of the water-soluble polymer used. However, even in this case, it goes without saying that such control can be performed by adjusting the above-mentioned factors (that is, the types and amounts of the disintegrant and the waxes).

In order to show the effect obtained by adjusting the molecular weight of the water-soluble polymer, typical test results will be given below.

Test tablet Test tablet E: Tablet disclosed in Example 7 above Test tablet F: Tablet disclosed in Example 8 (1) above Test tablet G: Tablet disclosed in Example 8 (2) above Test tablet H : Tablets disclosed in Example 8 (3) above (each test tablet contains 8 cephalosporin A substances per tablet)
Test method (dissolution test) Test method X: JP (10th revision) Dissolution test paddle method (1st)
Liquid, pH1.2, 100 rpm, 900 ml, 37 ° C) Test method Y: Japan Bureau (10th revision) Dissolution test method Paddle method (2nd)
Liquid, pH6.8, 100rpm, 900ml, 37 ℃) Test results From the test results, it can be seen that the dissolution rate changes almost linearly with time. That is, it can be seen that the characteristic feature of the sustained-release tablet according to the present invention that the dissolution rate is almost constant even if the molecular weight of the water-soluble polymer changes is retained.

Comparing the results of test methods X and Y for test tablets E and G, it can be seen that there is almost no difference in the dissolution pattern and dissolution rate. In other words, even if the molecular weight of the water-soluble polymer changes, the elution pattern and elution rate
It can be seen that the characteristic that it is hardly affected by the change in pH is retained.

The test results also show that the higher the viscosity of the water-soluble polymer (that is, the higher the molecular weight), the longer the elution duration.

As described above, in the sustained-release tablet according to the present invention, by adjusting the molecular weight of the water-soluble polymer, the dissolution rate is close to constant, and the dissolution pattern does not depend on the pH of the eluate. Properties such as elution duration and elution rate can be controlled without loss.

Therefore, by combining the control of the type and amount of the disintegrant, the control of the type and amount of the wax, and the control of the molecular weight of the water-soluble polymer, it becomes possible to more finely control the characteristics of the tablet.

As described above, the sustained-release tablet according to the present invention, which comprises disintegrating granules containing the main drug and waxes, and the sustained-release tablet according to the present invention, which comprises disintegrating granules containing the main drug and a water-soluble polymer and waxes. Both of the tablets have extremely excellent effects, and are extremely useful because they solve various problems that the prior art had.

Claims (10)

[Claims] 1. A sustained-release tablet comprising disintegrating granules containing a main drug and waxes. 2. The sustained-release tablet according to claim 1, wherein the disintegrating granule contains a main drug and a disintegrating agent. 3. A disintegrating granule containing a main drug and a disintegrating agent, which is produced by applying waxes to the surface of the granule and then tableting to produce the disintegrating granule. A sustained-release tablet as described. 4. The disintegrant is selected from the group consisting of starches, gums, cellulose derivatives and ion exchange resins,
The sustained-release tablet according to claim (3), wherein the waxes are selected from the group consisting of vegetable or animal waxes, hydrogenated oils and paraffins. 5. The method according to claim 3, wherein the amount of the disintegrant is 10 to 60% by weight as a ratio in the granule component, and the amount of wax is 20 to 65% by weight as a ratio in all components of the tablet. The sustained-release tablet according to the item. 6. A sustained-release tablet comprising disintegrating granules and waxes containing a main drug and a water-soluble polymer. 7. The sustained-release tablet according to claim 6, wherein the disintegrating granule contains a main drug, a water-soluble polymer and a disintegrating agent. 8. A method for producing a disintegrating granule containing a main drug, a water-soluble polymer and a disintegrating agent, applying waxes to the surface of the granule, and then tableting the tablet. The sustained-release tablet according to item (7). 9. The disintegrant is selected from the group consisting of starches, gums, cellulose derivatives and ion exchange resins,
Claims wherein the water-soluble polymer is selected from the group consisting of cellulose derivatives, synthetic water-soluble polymers and polysaccharides, and the waxes are selected from the group consisting of vegetable or animal waxes, hydrogenated oils and paraffins. The sustained-release tablet according to item (8). 10. The amount of disintegrant in the granule component is 10 to 60% by weight, the amount of water-soluble polymer is 2.5 to 45% by weight in the granule component, and the amount of wax is the tablet. The sustained-release tablet according to claim (8), which has a proportion of 20 to 65% by weight in all components.