KR100539584B1 - Manufacturing method of sustained release preparation containing Felodipine using Felodipine solubilization method - Google Patents

Abstract

The disclosed invention can be solubilized at relatively low temperature conditions, the operation is safe and energy-saving, and the operation is simple and simple, and does not cause problems such as precipitation or residual solvents over time. The present invention also provides a method for preparing a felodipine-containing sustained-release preparation by pelodipine solubilization, which is the same or better than the existing felodipine sustaining agent.

In order to achieve the above object, the disclosed invention is directed to felodipine as oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, caprylocaproyl macrogol-8 glycerides, and diethylene glycol monoethyl. It provides a method for producing a felodipine-containing sustained-release preparation comprising the step of solubilizing by heating to 40 to 60 ℃ while mixing with a solubilizer of one compound selected from ether.

The disclosed invention also relates to a felodipine compound of at least one compound selected from diethylene glycol monoethyl ether and oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, and caprylocaproyl macrogol-8 glycerides. It provides a method for producing a felodipine-containing sustained-release preparation comprising the step of mixing with a solubilizer in a mixture and solubilizing at room temperature.

Description

Manufacturing method of sustained release preparation containing Felodipine using Felodipine solubilization method by felodipine solubilization

The present invention relates to a process for the preparation of a felodipine-containing sustained release preparation by solubilizing felodipine useful as a calcium antagonist for the treatment of hypertension.

The present invention particularly relates to a compound in which felodipine is selected from oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, caprylocaproyl macrogol-8 glycerides, and diethylene glycol monoethyl ether. The present invention relates to a method for producing a felodipine-containing sustained-release preparation comprising the step of solubilizing by heating to 40 to 60 ℃ while mixing with a solubilizer.

In addition, the present invention is a compound in which at least one compound selected from diethylene glycol monoethyl ether and oleoyl macrogol-6 glyceride, linoleoyl macrogol-6 glyceride, and caprylocaproyl macrogol-8 glyceride It relates to a method for producing a felodipine-containing sustained-release preparation comprising the step of solubilizing at room temperature with a solubilizer in a mixture of.

In addition, the present invention comprises the steps of (a) in the solubilization step of the solubilized felodipine mixture in the hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and a conventional excipient to make granules and then drying (b) The present invention relates to a method for producing a pelodipine-containing sustained-release preparation, further comprising the step of sizing the dried granules and mixing with a lubricant. Preferably, the method for preparing the felodipine-containing sustained-release preparation of the present invention is described above. Compressing the granules mixed with the lubricants into tablets, or further comprising filling the capsule with the granules mixed with the lubricants.

Felodipine, that is, ethyl methyl 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylate (Ethylmethyl-4- (2, 3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate) is a drug that blocks calcium ion influx into cells by blocking calcium channels, which causes peripheral blood vessels to relax, myocardial contractility, coronary It is a calcium antagonist with pharmacological action such as arterial relaxation and reduction of brain damage due to thromboembolism, and is used to treat cardiovascular diseases such as arterial hypertension and ischemic heart disease.

In general, the solubility of the drug is the rate step that determines the absorption of the drug and thus has a significant impact on the bioavailability of the drug. However, felodipipine is known to be extremely poorly soluble in water and extremely low absorption of the drug in the body.

Conventional techniques for solving this problem include a solubilization method for melting at high temperatures with polymers such as polyethylene glycol and poloxamer to increase the solubility of felodipine to improve dissolution rate and to release water-soluble polymers or fat-soluble polymers that are sustained-release bases. Method to make a sustained release formulation (US Pat. No. 5,071,642 or WO 9,702,017, WO 9,623,499), and to solubilize felodipine using a nonionic surfactant such as cremophore to improve the solubility of felodipine in water ( U.S. Pat.No. 4,048,801 or 4942040), a method of making a sustained release formulation using a mixed organic solvent in the process of preparing a solid dispersion to increase the solubility of felodipine is known (National Patent No. 0315872). However, there are the following problems.

First, in the case of the solubilization method of melting at high temperature by using polymers such as polyethylene glycol and poloxamer, it is inconvenient to melt at a high temperature of about 80 ° C. or higher when used in production, and requires special attention to safety. There is this.

Second, in the case of using a nonionic surfactant, there is a problem that precipitation of felodipine is produced over time.

Third, in the case of preparing a sustained release formulation using a mixed organic solvent such as methanol, acetone, methylene chloride, isopropanor propanol, dichloromethane, chloroform in the process of preparing a solid dispersion, There are problems that require attention and that residual solvent may occur.

Fourth, most of the processes are complicated and difficult to use, so there are many difficulties in the actual production.

Therefore, a new invention for solving the above problems is required.

Disclosure of Invention An object of the present invention is to provide a method for preparing a felodipine-containing sustained-release preparation by felodipine solubilization, which has been devised to solve the above-mentioned problems and has the following effects.

First, solubilization should be performed under relatively low temperature conditions, so that the work is safe and energy-saving.

Second, the operation is simple and simple.

Third, it should not cause problems such as sedimentation over time.

Fourth, there should be no problems such as residual solvent remaining.

Fifth, the dissolution rate should be excellent.

The present invention relates to a process for the preparation of felodipine-containing sustained release preparations by solubilizing felodipine useful as a calcium antagonist for the treatment of hypertension.

The present invention is a soluble of feldipine as one compound selected from oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, caprylocaproyl macrogol-8 glycerides, and diethylene glycol monoethyl ether. It provides a method for producing a felodipine-containing sustained-release preparation comprising the step of solubilizing by heating to 40 to 60 ℃, preferably 50 ℃ while mixing with a topical agent. Preferred weight ratio of the felodipine and the solubilizer is 5: 1 to 5: 12.

In addition, the present invention comprises the steps of (a) mixing the hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and a conventional excipient in the solubilized felodipine mixture of the above solubilized to form granules and (b) the It provides a method for producing a felodipine-containing sustained-release preparation characterized in that it further comprises the step of sizing the dried granules and mixing with the lubricant. In a preferred case, the weight ratio of hydroxypropylmethylcellulose and hydroxymethylcellulose is 6: 1 to 9: 1, more preferably 8: 1. In addition, the method for preparing a felodipine-containing sustained-release preparation of the present invention further comprises the step of compressing the granules mixed with the glidants to tablets, or filling the capsule with the granules mixed with the glidants. It further comprises a step.

Detailed description of the preparation method of the felodipine-containing sustained-release preparation by pelodipine solubilization of the present invention is as follows.

1 is a flow chart of a method for preparing a felodipine-containing sustained release formulation by pelodipine solubilization according to a preferred embodiment of the present invention. As shown, the manufacturing process of the felodipine-containing sustained-release preparation by pelodipine solubilization can be largely classified into seven steps.

The first step (1) is the solubilization of felodipine. Pelodipine and Oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, caprylocaproyl macrogol-8 glycerides 8 glycerides) and a solubilizer of one compound selected from diethylene glycol monoethyl ether are weighed and placed in a binder preparation tank. In this case, the weight ratio of the preferred felodipine to the solubilizer is 5: 1 to 5:12. The above mixture is mixed at a rate of 2,500 RPM with warming to 40-60 ° C., preferably 50 ° C., to produce a solubilized felodipine-containing composition.

The second step (2) is the mixing step of the granulation part. The granulation part is composed of hydroxypropylmethylcellulose (HPMC 2910 60SH-4000), a sustained release base, hydroxypropylcellulose (L-type), and an excipient. Conventional inert excipients may be used as the excipient, in particular lactose 200 Mesh (pharmaceutical), microcrystalline cellulose (Microcrystallin cellulose) may be used. Preferred weight ratio of hydroxypropylmethyl cellulose and hydroxymethyl cellulose is 6: 1 to 9: 1, more preferably 8: 1. Weigh the ingredients corresponding to the granulation unit and mix into a high speed coalescer.

The third step (3) is an intermediate mixing step, in which the solubilized felodipine-containing composition prepared in step 1 is placed in a high speed coalescer containing the granule mixture prepared in step 2 and mixed.

The fourth step (4) is a binder liquid addition and association / granulation step. Conventional binding solutions can be used, and in particular, purified water, ethanol, a mixture of purified water-ethanol, and the like can be used. The binding solution is gradually added to the high speed coalescer containing the mixture prepared in the third step to form granules.

The fifth step (5) is a drying and establishing step. The granules formed in the fourth step are dried in a drier at 30 to 60 ° C, preferably 50 ° C, until the water content is 1.5 to 2.0%. Ordinary dryers, such as a normal dry heat dryer or a fluid bed dryer, can be used. The dried granules use particles to form particles. Preferred sizing machine is about 30 Mesh.

The sixth step (6) is a lubricant final mixing step, in which the powder established in the fifth step is placed in a suitable mixer and mixed by adding a lubricant. Conventional lubricants may be used for the lubricant, and magnesium stearate or stearic acid may be used.

The seventh step (7) is a step of molding the granules prepared in the sixth step into tablets or filling into capsules. In the case of tablet molding, it may be molded using a general rotary tablet press, and the preferred tablet weight is about 200 to 220 mg, and the preferred hardness of the tablet after molding is about 5 to 7 kp with an Erveka hardness tester. In the case of filling with a capsule, a conventional capsule charger can be used, and a preferable target content weight is 200 to 220 mg. Tablets formed as described above may be coated using a coating agent approved by the Korean Pharmacopoeia, it is also possible to use a colorant approved for granules prior to molding into tablets and capsules.

On the other hand, according to a method for preparing a felodipine-containing sustained-release preparation by pelodipine solubilization according to another preferred embodiment of the present invention, the felodipine is diethylene glycol monoethyl ether, oleoyl macrogol-6 glycerides, linoleyl Pelodipine-containing sustained-release preparations comprising mixing with a solubilizer of macrogol-6 glycerides and a mixture of one or more compounds selected from caprylocaproyl macrogol-8 glycerides and solubilizing at room temperature It provides a method of manufacturing. In a preferred case, the solubilizer is at least one selected from diethylene glycol monoethyl ether and oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, and caprylocaproyl macrogol-8 glycerides. Mixtures are used in which the compounds are mixed in a ratio of 2: 1 to 1: 2, preferably 1: 1. In this case, a preferable weight ratio of the felodipine and the solubilizer is 5: 1 to 5:12.

In addition, the present invention comprises the steps of (a) in the solubilization step of the solubilized felodipine mixture of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and a conventional excipient to make granules and then drying (b) A method for producing a felodipine-containing sustained-release preparation, characterized in that it further comprises the step of sizing the dried granules and then with a lubricant, and in a preferred case, the felodipine-containing sustained-release preparation of the present invention The manufacturing method of the present invention further comprises the step of compressing the granules mixed with the glidants into tablets, or further comprising the step of filling the capsules granules mixed with the glidants in the above-mentioned one of the present invention The same as in the embodiment.

Preparation Example 1

Furtherance Weight ratio

Solubilizer: Pelodipine 5

Oleoyl Macrogol-6 Glyceride 1 to 5

Diethylene glycol monoethyl ether 1 to 5

Granulation part: hydroxypropyl methyl cellulose 30 to 60

(HPMC 2910 60 SH-4000)

Hydroxypropyl cellulose (L-type) 5 to 10

Lactose 200Mesh 100-150

Microcrystalline cellulose 20-40

Bonding solution: water, ethanol or water-ethanol mixture

Glidant: Magnesium Stearate 1.0

① Solubilization unit composed of the above composition is weighed in the corresponding components and put into the binder preparation tank.

② The solubilized felodipine-containing composition is prepared by mixing at room temperature at a rate of 2,500 RPM.

③ Weigh the ingredients corresponding to granules and mix into a high speed coalescer for 1 minute.

④ Put the solubilized felodipine-containing composition into the high speed coalescer and mix for 1 minute.

⑤ Combine and granulate while slowly adding the binding solution to the high speed coalescing machine.

⑥ The resulting granules are dried at 40 ° C. for 12 hours using a dry heat dryer or for 40 minutes at 35 ° C. with a fluidized bed dryer.

⑦ The dried granules are formed into particles using a 30Mesh sizer.

⑧ Place the granules in the mixer and add lubricant.

⑨ Fill the capsules with the target weight of 210mg using a capsule filling machine of filling the granules after stick formation. Or a tablet is shape | molded using a rotary tablet machine. The target weight is 210 mg and the hardness of the tablets after molding is 5 to 7 kp with an Erveka hardness tester.

Preparation Example 2.

Furtherance Weight ratio

Solubilizer: Pelodipine 5.0

Oleoyl Macrogol-6 Glyceride 5.0

Diethylene glycol monoethyl ether 5.0

Granules: Hydroxypropylmethylcellulose 40

(HPMC 2910 60 SH-4000)

Hydroxypropyl Cellulose (L-Type) 5.0

Lactose 200Mesh 120

Microcrystalline Cellulose 30.0

Bonding solution: water, ethanol or water-ethanol mixture

Glidant: Magnesium Stearate 1.0

It is the same as that of the manufacture example 1 of the solubilization method of a felodipine, and the manufacturing method of a felodipine-containing sustained-release preparation by pelodipine solubilization.

Preparation Example 3

Furtherance Weight ratio

Solubilizer: Pelodipine 5.0

Linoleyl Oil Macrogol-6 Glyceride 5.0

Diethylene glycol monoethyl ether 5.0

The composition of the granule part, the binder liquid, and the lubricant was the same as in Production Example 2, and the method for producing the felodipine-containing sustained-release preparation by felodipine solubilization and felodipine solubilization was the same as in Production Example 1.

Preparation Example 4.

Furtherance Weight ratio

Solubilizer: Pelodipine 5.0

Caprylocaproyl Macrogol-8 Glyceride 5.0

Diethylene glycol monoethyl ether 5.0

The composition of the granule part, the binder liquid, and the lubricant was the same as in Production Example 2, and the same as in Production Example 1 of the method for producing pelodipine-containing sustained release preparation by felodipine solubilization.

Preparation Example 5.

Furtherance Weight ratio

Solubilization Department: Felodipine 5

Caprylocaproyl Macrogol-8 Glyceride 1 to 10

It is the same as that of the manufacture example 1 of the composition of a granule part, binder liquid, a lubricating agent, the solubilization method of a pelodipine, and the manufacturing method of the polodipine containing slow-release preparation by pelodipine solubilization.

Preparation Example 6.

Furtherance Weight ratio

Solubilization Department: Felodipine 5

Linoleoyl Macrogol-8 Glyceride 1 to 10

It is the same as that of the manufacture example 1 of the composition of a granule part, binder liquid, a lubricating agent, the solubilization method of a pelodipine, and the manufacturing method of the polodipine containing slow-release preparation by pelodipine solubilization.

Preparation Example 7.

Furtherance Weight ratio

Solubilization Department: Felodipine 5

Linoleoyl Macrogol-8 Glyceride 1 to 10

It is the same as that of the manufacture example 1 of the composition of a granule part, binder liquid, a lubricating agent, the solubilization method of a pelodipine, and the manufacturing method of the polodipine containing slow-release preparation by pelodipine solubilization.

Preparation Example 8.

Furtherance Weight ratio

Solubilization Department: Felodipine 5

Diethylene glycol monoethyl ether 1 to 10

It is the same as that of the manufacture example 1 of the composition of a granule part, binder liquid, a lubricating agent, the solubilization method of a pelodipine, and the manufacturing method of the polodipine containing slow-release preparation by pelodipine solubilization.

Preparation Example 9.

Furtherance Weight ratio

Solubilization Department: Felodipine 5

Caprylocaproyl Macrogol-8 Glyceride 1 to 5

Diethylene glycol monoethyl ether 1 to 5

It is the same as that of the manufacture example 1 of the composition of a granule part, binder liquid, a lubricating agent, the solubilization method of a pelodipine, and the manufacturing method of the polodipine containing slow-release preparation by pelodipine solubilization.

Preparation Example 10

Furtherance Weight ratio

Solubilization Department: Felodipine 5

Linoleyl Oil Macrogol-6 Glyceride 1 to 5

Diethylene glycol monoethyl ether 1 to 5

It is the same as that of the manufacture example 1 of the composition of a granule part, binder liquid, a lubricating agent, the solubilization method of a pelodipine, and the manufacturing method of the polodipine containing slow-release preparation by pelodipine solubilization.

Experimental Example 1. Results of the dissolution test in the eluate of pH 6.5 of the tablets according to Preparation Examples 2, 3, 4

Preparation of eluate: 1M sodium dihydrogen phosphate solution 260ml, 0.5M sodium dihydrogen phosphate solution 196ml, triethylammonium bromide into a 5L flask, add water to dissolve and fill the mark to make eluent. Dissolution rate was measured every 1, 4, 7 hours.

Figure 2 is a graph showing the results of the dissolution test of the tablets prepared according to Preparation Examples 2, 3, 4 and the existing product sprendil sustained tablets (Astra Korea), diropin sustained tablets (Kyungdong Pharm.) In the eluate of pH 6.5 to be. According to the experimental results, as shown, the tablets prepared according to Preparation Examples 2, 3, and 4 of the preparation method of the pelodipine-containing sustained release preparation by the present invention pelodipine solubilization were almost similar in terms of dissolution rate with existing products. The persistent dissolution pattern was shown.

Experimental Example 2 Dissolution test results in the eluate of pH 6.8 of the tablets according to Preparation Examples 2, 3, 4

Preparation of eluate at pH 6.8: 250 ml of 0.2 M potassium dihydrogen phosphate solution, 118 ml of 0.2 M sodium hydroxide solution, and water are added to make 1,000 ml. Dissolution rate was measured every 1, 4, 7 hours.

Figure 3 shows the results of the dissolution test of the tablets prepared according to Preparation Examples 2, 3, 4 and the existing product sprendil sustained tablets (Astra Korea), diropin sustained tablets (Kyungdong Pharm.) In the eluate of pH 6.8 of pH 6.8 It is a graph shown. According to the experimental results, the tablets prepared according to Preparation Examples 2, 3, and 4 of the method for preparing the pelodipine-containing sustained-release preparation by the present invention pelodipine solubilization, while meeting the criteria as a sustained-release formulation, Pelodipine persistence of 10 to 15% showed a better dissolution pattern.

Experimental Example 3. Dissolution test results in the eluate of pH 4.0 of the tablets according to Preparation Examples 2, 3, 4

Preparation of acidic solution: Dissolve 6.8g of potassium dihydrogen phosphate in 700ml of water, adjust the pH with 10v / v% phosphate diluent, adjust the pH to 1,000ml and use it as eluent. Dissolution rate was measured every 1, 4, 7 hours.

Figure 4 shows the results of the dissolution test of the tablets prepared according to Preparation Examples 2, 3, 4 and the existing product sprendil sustained tablets (Astra Korea), diropine sustained tablets (Kyungdong Pharm.) In the eluate of pH 6.8 of pH 6.8 It is a graph shown. According to the experimental results, the tablets prepared according to Preparation Examples 2, 3, and 4 of the method for preparing the pelodipine-containing sustained-release preparation by the present invention pelodipine solubilization, while meeting the criteria as a sustained-release formulation, The elution pattern was better than that of.

As described above, the preparation method of the pelodipine-containing sustained-release preparation by pelodipine solubilization of the present invention has been described in detail with reference to Examples, Preparation Examples, Experimental Examples, and the accompanying drawings. Yes, not limited to the experimental examples and drawings, various modifications can be made within the scope of the technical spirit of the invention.

According to the present invention as described in detail above, it provides a method for preparing a felodipine-containing sustained-release preparation by felodipine solubilization exhibiting the following remarkable effects compared to the prior art.

First, solubilization is performed at a relatively low temperature condition (45 to 55 ° C.) or room temperature, so that work is safe and energy is saved. That is, the feldipine is soluble in one compound selected from oleoyl macrogol-6 glyceride, linoleoyl macrogol-6 glyceride, caprylocaproyl macrogol-8 glyceride, and diethylene glycol monoethyl ether. If a topical agent is used, it is solubilized while warming to 40 to 60 ° C, and diethylene glycol monoethyl ether and oleoyl macrogol-6 glyceride, linoleyl macrogol-6 glyceride, and caprylocaproyl macrogol- Solubilizers made of a mixture of one or more compounds selected from 8 glycerides are solubilized at room temperature, which is safer, simpler and more economical than the prior art by melting or warming at a high temperature. It provides a method for producing a felodipine-containing sustained-release preparation by.

Second, the present invention provides a method for producing a felodipine-containing sustained-release preparation by simple and simple pelodipine solubilization, without special manipulation, by using a common apparatus and apparatus such as a speed mixer or a ribbon type jointer generally used in the manufacture of pharmaceuticals. .

Third, there is provided a method for preparing a felodipine-containing sustained-release preparation by felodipine solubilization that does not cause problems such as precipitation as in the prior art, even with time, due to improved solubilization. In particular, solubilizers comprising a mixture of diethylene glycol monoethyl ether and one or more compounds selected from oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, and caprylocaproyl macrogol-8 glycerides In the case of using, solubilization effect is remarkably improved and no problem of precipitation occurs.

Fourth, methanol, acetone, methylene chloride, chloroform, etc. or organic solvents mixed with them are not used, so caution is not required, and there is no problem such as residual solvent remaining. It provides a method for producing a felodipine-containing sustained-release preparation by.

Fifth, while the felodipine-containing sustained-release preparation by pelodipine solubilization can be prepared by a simple and easy method as described above, the dissolution pattern as a sustained-release formulation is superior to the conventional felodipine sustaining agent. In particular, the test results in the eluate at pH 6.8 and the eluate at pH 4.0, while meeting the elution criteria as a sustained release formulation, showed a dissolution rate of 10-15% higher than that of the conventional felodipine persistence. This means that the solubilization effect of the poorly soluble drug by the method for preparing a felodipine-containing sustained-release preparation by the present invention pelodipine solubilization is significantly improved compared to the prior art. In addition, by using a mixture of oleoyl macrogol-6 glyceride, linoleyl oil macrogol-6 glyceride, or caprylocaproyl macrogol-8 glyceride, which is a glyceride-based solubilizer, by mixing diethylene glycol monoethyl ether The solubilizing effect is increased, and the solubilizer is applied to the body at the same time as the drug to act as a fat-soluble substance, thus increasing the absorption of the drug in the small intestine, the absorption part of the drug (since the absorption effect of the fat-soluble substance is increased in the small intestine). There is a beneficial effect to it.

1 is a flow chart of a method for preparing a felodipine-containing sustained-release preparation by felodipine solubilization according to an embodiment of the present invention

Figure 2 is a graph comparing the results of the dissolution test of the tablets according to Preparation Examples 2, 3, 4 in the eluent of pH 6.5

Figure 3 is a graph comparing the results of the dissolution test of the tablets according to Preparation Examples 2, 3, 4 in the eluate of pH 6.8

Figure 4 is a graph comparing the results of the dissolution test of the tablets according to Preparation Examples 2, 3, 4 in the eluate of pH 4.0

Claims (8)

 Two compounds selected from the group consisting of diethylene glycol monoethyl ether, oleoyl macrogol-6-glycerides, linoleyl macrogol-6-glycerides and caprylocaproyl macrogol-8-glycerides Mixing with a solubilizer in a mixture of solubilizing method at 20 ~ 30 ℃ characterized in that it comprises a felodipine-containing sustained-release preparation method. The solubilizer of claim 1 wherein the solubilizing agent is a compound selected from diethylene glycol monoethyl ether, oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, and caprylocaproyl macrogol-8 glycerides. A method for producing a felodipine-containing sustained-release preparation, characterized in that the mixture has a weight ratio of 2: 1 to 1: 2, respectively.  The method of claim 1 or 2, wherein the felodipine and the solubilizing agent has a weight ratio of 5: 1 to 5:12. The method for producing a felodipine-containing sustained-release preparation according to claim 1 or 2, further comprising the following steps (a) and (b). (a) mixing the solubilized felodipine mixture with hydroxypropylmethylcellulose, hydroxymethylcellulose, a conventional excipient, and a conventional binder to form granules and drying the granules; And (b) establishing the dried granules and then mixing them with lubricants The method of claim 4, wherein the hydroxypropyl methyl cellulose and the hydroxymethyl cellulose have a weight ratio of 6: 1 to 8: 1. The method of claim 4, further comprising the step of compressing the granules mixed with the glidants into tablets. 5. The method of claim 4, further comprising the step of filling the capsule with the granules mixed with the lubricant according to the above method. delete