JP6259043B2 - Sillostazol sustained-release tablets with improved dissolution rate and minimized side effects - Google Patents

Description

  The present invention relates to a sustained-release tablet of sillostazol, which is a pharmacologically active ingredient produced using a release controlling polymer, and in particular, it can be administered once a day, and silylstazole can be kept constant even with changes in pH. The present invention relates to a sustained release tablet of sillostazol, which controls the dissolution rate of the drug to reduce the side effects of sillostazol such as headache, head sensation, and tachycardia, thereby improving the convenience of taking the tablet.

  Sillostazol (6- [4- (cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H) -quinolinone, chemical 1), a quinolinone family of substances, is a phosphodiesterase type Inhibiting (phosphodiesterase type) has the effect of suppressing platelet aggregation and promoting relaxation of blood vessels. It is also known to be useful for preventing arteriosclerosis and the like by suppressing cell proliferation of vascular smooth muscle that has migrated on the vascular endothelium.

  Sillostazol suppresses the primary aggregation of platelets induced by ADP, epinephrine, etc. in platelets isolated from mice, rats, rabbits, dogs and humans, and dissociates platelet aggregates. In addition, when administered orally to beagle dogs, it suppresses platelet aggregation induced by ADP and collagen and is orally administered to patients with chronic arterial occlusion (such as Buerger's disease, obstructive arteriosclerosis, diabetic peripheral vascular disease) In this case, the aggregation of platelets induced by ADP, collagen, arachidonic acid and epinephrine is suppressed in the separated platelets. The effect of sillostazol on platelet aggregation appears rapidly after administration, and the effect is maintained even after repeated administration. Suppressed platelet aggregation at the time of discontinuation is restored to the pre-dose value as the plasma concentration decreases, and the rebound phenomenon (enhanced aggregation) does not appear.

  The mechanism of action of sillostazol is as follows. Sputum platelets inhibit serotonin release but do not affect serotonin and adenosine entering platelets. It inhibits platelet aggregation by TXA2 (thromboxane A2) without affecting the platelet arachidonic acid metabolism. This is to inhibit cAMP-PDE (cyclic AMPphosphodiesterase) activity of platelets and vascular smooth muscles, and eventually exerts antiplatelet action and vasodilatory action.

  The existing sillostazol formulation not only has the disadvantage of lowering the patient's adaptability as a formulation to be taken twice a day, but in the case of a rapid release formulation of sillostazol, rapid and uneven drug release during oral administration causes rapid blood It is known to cause an increase in medium concentration, resulting in side effects such as headache, head sensation, tachycardia (Am J Cardiol 2001; 87 (suppl): 28D-33D and US Patent Publication No. 2002/0058066). reference). Furthermore, sillostazol is not only sparingly soluble, but its absorption rate decreases as it goes to the lower part of the small intestine. Therefore, in the case of a general controlled-release preparation, the overall bioavailability may be reduced. Publication WO2000 / 57881 discloses a method of increasing the absorption rate of silostazol in the small intestine using a preparation in which fine powder form of sillostazol is dispersed and / or dissolved together with a dispersing agent and / or a solubilizing agent. Disclosure.

  Existing sillostazol tablets have side effects such as headache, head sensation, and tachycardia due to the high dissolution rate immediately after taking them, so they need to be manufactured into sustained-release tablets and simply delay the release of the drug It is necessary to develop a sustained release tablet of sillostazol that exhibits a certain dissolution rate that is not only effective for the purpose of taking 1 tablet per day.

  Accordingly, the present invention has been made to solve the above-described problems, and has the advantages of a matrix form of a water-soluble polymer used in existing sustained-release tablet formulations, and has a separate control system in the intestine. It is an object of the present invention to provide a preparation that suppresses the development of side effects by maintaining the blood concentration in the living body constant by controlling the release of the drug with constant and elaborate control.

  According to a suitable embodiment of the present invention for achieving the above object, a sustained release tablet of sillostazol containing sillostazol, a release controlling polymer, a binder, a filler and a lubricant is a release controlling polymer. As one or a mixture of two or more selected from the group consisting of hydroxypropyl methylcellulose, carbomer, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone and polyvinyl alcohol.

  According to another embodiment of the present invention, the release controlling polymer contained in the sillostazol sustained release tablet is a mixture of hydroxypropylcellulose and carbomer.

  According to another embodiment of the present invention, the mixture of hydroxypropylmethylcellulose and carbomer contained in the sillostazol sustained-release tablet is contained in an amount of 25 to 50% by weight based on the total tablet weight.

  According to still another embodiment of the present invention, the viscosity of hydroxypropyl methylcellulose, which is a release controlling polymer contained in the sillostazol sustained release tablet, is 80,000 cps to 120,000 cps.

  According to still another embodiment of the present invention, the weight mixing ratio of hydroxypropylmethylcellulose and carbomer mixture contained in the sillostazol sustained release tablet is 1: 1 to 20: 1.

  The sillostazol sustained-release tablet of the present invention has a dissolution time that can be taken once a day for convenience of administration, and minimizes the occurrence of headache, which is a side effect of the existing sillostazol preparation. Further, the sillostazol sustained-release tablet of the present invention maintains a uniform dissolution rate even in the pH change in the gastrointestinal tract.

FIG. 1 shows the dissolution test results of Formula 1 to Formula 5 of Example 1 and Comparative Example 1 of the present invention. FIG. 2 shows the dissolution test results of Formulation 6 to Formulation 9 of Example 2 of the present invention. FIG. 3 shows the dissolution test results of Formula 10 to Formula 13 of Example 3 of the present invention. FIG. 4 shows the dissolution test results of Formula 14 to Formula 17 of Example 4 of the present invention. FIG. 5 shows the results of measuring the dissolution rate depending on the pH of the formulations 6 to 9 of Example 5 of the present invention.

  The present invention relates to sustained-release tablets containing cilostazol. Specifically, absorption of the drug from the stomach to the intestine is possible by extending the elution time so that it can be taken once a day, controlling the release of the drug with a water-soluble matrix system, and adjusting the release of the drug with pH. The present invention provides a sustained release tablet of sillostazol that improves the convenience of taking for women, the elderly, and children by suppressing the expression of side effects of sillostazol by controlling the release of the drug in a constant and elaborate manner.

  The sillostazol sustained release tablet according to the present invention comprises sillostazol, a release controlling polymer, a binder, a filler and a lubricant.

  Any pharmacologically acceptable polymer can be used as the release controlling polymer, such as hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, and hydropropylcellulose. Cellulose derivatives composed of sodium carboxymethylcellulose (propylene oxide) and its derivatives, polyvinylpyrrolidone (Polyvinylpyrrolidone, molecular weight 90, trade name povidone K-90), polyethylene glycol (Polydon) Ethylene glycol, polyvinyl alcohols, polyvinyl acetate, polyvinyl acetate phthalate, polymethacrylate, and polymethacrylate (commercially polyacrylic acid, polyacrylic acid) One or a mixture of two or more selected from the group consisting of polymethacrylate derivatives (typically carbomers), glycerol monostearate and poloxamers can be used. Preferably, one or a mixture of two or more selected from the group consisting of hydroxypropylmethylcellulose, carbomer, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone and polyvinyl alcohol can be used, more preferably hydroxypropyl A mixture of cellulose and carbomer can be used.

  The ratio of the release controlling polymer contained in the sillostazol sustained release tablet according to the present invention to the total tablet weight is preferably 25% to 50%. If the ratio of the release-controlling polymer is less than 25% by weight, the release time of sillostazol is shortened and the amount of dissolution per unit time increases, causing side effects, and if it exceeds 50% by weight, the release of sillostazol is exceeded. Since the time is long and the amount of drug dissolved out per unit time is small, sufficient drug efficacy cannot be expected.

  Sustained-release tablets that delay the dissolution of pharmacologically active ingredients are produced by mixing release-controlling polymers. Generally, methylcellulose, ethylcellulose, hydroxymethylcellulose, polyvinylpyrrolidone, and the like are used as release-controlling polymers.

  The inventor of the present invention has a long dissolution time and a constant elution time when a carbomer is mixed with a general release-controlling polymer when a sustained-release tablet is produced, as compared with a case where a single-component release-controlling polymer is used. It was found to show a drug dissolution pattern. We also discovered the fact that the elution pattern can be adjusted by adjusting the weight ratio of the carbomer to the release controlling polymer other than the carbomer.

  Since rapid dissolution of sillostazol can cause tachycardia, head sensation and headache, maintaining and controlling a constant dissolution rate is also an important factor in sustained release tablets. Hydroxypropyl methylcellulose can ensure a long dissolution time by forming a matrix that prevents rapid dissolution of the pharmacologically active ingredient in the tablet. In addition, it exhibits a constant elution pattern compared to other release controlling polymers.

  In the case of a sustained-release tablet containing a pharmacologically active ingredient, the tablet exhibits swelling phenomenon upon dissolution. In this case, if the matrix of the controlled-release polymer is not solid, a phenomenon may occur in which the matrix is partially eroded and the tablet is disintegrated, which leads to rapid drug release and causes headaches in the patient. Induces and flushes. In order to solve such problems, in the present invention, a mixture of high-viscosity hydroxypropylmethylcellulose and carbomer was used as a release controlling polymer. The carbomer is a release-controlling polymer that exists in the sol state in the stomach, which is in an acidic condition, and the drug release is maintained by the hydroxypropylmethylcellulose system, and in the small intestine, which is in an alkaline condition, in the hydrogel state. To control the release of drugs. Also, when used with hydroxypropylmethylcellulose, it has the effect of hardening the matrix within the sustained release tablet, and the tablet expansion maintains the form and the tablet erosion by maintaining the tablet matrix To maintain a constant dissolution rate.

  The hydroxypropyl methylcellulose used in the present invention has a viscosity of 80,000 cps to 120,000 cps, and preferably hydroxypropylmethylcellulose having a viscosity of 90,000 cps to 110,000 cps can be used. If the viscosity is less than 80,000 cps, a large amount of hydroxypropylmethylcellulose is required, so that the size of the tablet becomes large. If the viscosity exceeds 120,000 cps, uniform mixing with sillostazol becomes difficult. Even if the viscosity is the same, a product having a good physical form (physical form) in which the degree of pulverization of particles is more constant and the dispersion is excellent is used.

  The mixing weight ratio of hydroxypropylmethylcellulose and carbomer contained in the sillostazol sustained-release tablet according to the present invention is 1: 1 to 20: 1. If the ratio is less than 1: 1, it is difficult to form a matrix in the tablet and the effect of delaying the drug release is lowered. If the ratio exceeds 20: 1, the dissolution rate of sillostazol is reduced under alkaline conditions, and the amount of sillostazol and release control is high. Uniform mixing between molecules is difficult. Preferably, a mixing of 1.5: 1 to 10: 1 is possible.

  The sillostazol sustained-release tablet according to the present invention exhibits a constant dissolution rate according to changes in pH. Orally administered sustained-release tablets stay in the human body for more than 8 hours, especially in the stomach and small intestine where they stay for a long time, because the pH changes are very large, so that the sustained-release tablets maintain a constant dissolution rate depending on the pH. There must be. The sillostazol sustained-release tablet according to the present invention maintains a uniform dissolution rate at pH 1.2 (artificial gastric juice) and pH 6.8 (artificial sputum).

  The binder used in the present invention is generally polyvinyl pyrrolidone (with a molecular weight of 30; trade name povidone K-30) or a derivative thereof (PVP), a copolymer of vinyl pyrrolidone / vinyl derivative, which can be administered orally. (co-pvp) and starches, but are not limited thereto. Polyvinyl pyrrolidone (povidone K-30) having a molecular weight of 30 or a copolymer of vinyl pyrrolidone / vinyl derivative (co-pvp) is most effective, and a mixture thereof can also be used. The binder may include 3 to 10% by weight relative to the weight of the whole tablet. When the binder is added at less than 3% by weight, the binding force becomes weak and tableting is difficult, and the amount exceeds 10% by weight. Therefore, it is difficult to adjust the dissolution rate of the drug. However, the weight ratio is not limited.

  The filler used in the present invention may contain pharmaceutically and commonly used additives. For such additives, lactose, sugar, sugar, mannitol and sorbitol can be used, or mixtures thereof can be used, optionally with stabilizers and Preservatives can be included. The filler may include 10 to 30% by weight based on the total tablet weight, but is not limited thereto.

In the lubricant used in the present invention, magnesium stearate (Magnesium stearate), silicon dioxide (SiO ₂ ), amorphous fumed silica (Amorphous fumed silica), talc or the like is added, or a mixture thereof. However, the present invention is not limited to this. Lubricants can contain 1 to 5% by weight of the total tablet weight. When lubricants are added at less than 1% by weight, tableting becomes difficult and added in excess of 5% by weight. In this case, the dissolution phenomenon of sillostazol is affected by the coating phenomenon of the lubricant granules. However, the weight ratio is not limited.

  Hereinafter, the present invention will be described in more detail through examples and comparative examples. However, the scope of the present invention is not limited to such examples.

<Elution rate experiment>

  The dissolution test was conducted according to the dissolution test method of the 7th revision of the Korean Pharmacy. In the eluate, pH 7.8 phosphate buffer was used, the paddle method was used as the elution method, the eluate was 900 ml, the stirring speed was 100 rpm, and the elution temperature was 37 ± 0.5 ° C. . At 0, 5, 10, 15, 30, 45, and 60 minutes, 5 ml of the sample was taken and the same amount of eluate was added. As analysis conditions, aceclofenac was quantified by using a liquid obtained by filtering the liquid obtained from the above elution test through a 0.45 μm membrane filter using HPLC. The analysis wavelength was 277 nm, the mobile phase was acetonitrile: pH 7.4 phosphate buffer = 68: 32 solution, the flow rate was 1.0 ml / min, and the column used was C18 ODS.

(Example 1)

  Each formulation described in the table below produced sustained release tablets using the following production method. First, a binding solution was prepared by dispersing and dissolving in povidone K-30 and carbomer (50%) ethanol. Next, silrostazole, microcrystalline cellulose, carbomer (50%), and hydroxypropylmethylcellulose were mixed well using a speed mixer, and wet granules were produced with a cylindrical granulator using a binding solution. The produced granules are dried for 12 hours or more in a drying oven (40 ° C.) and sized with a 40 mesh sieve, and then added to and mixed with hard anhydrous silicic acid and magnesium stearate to the sized products. Tableting was performed according to the weight per tablet. A certain amount of sillostazol sustained-release tablets produced from the following examples was subjected to a dissolution test according to the dissolution test method of Korean Pharmaceutical. As eluent, 0.5 W / W% sodium lauryl sulfate aqueous solution is used, elution method is paddle method, eluent is 900 ml, stirring speed is 75 rpm, elution temperature is 37 ± 0.5 ° C. did. At 15, 30, 60, 90, 120, 240, 360, 480, 600, and 720 minutes, 5 ml of the sample was taken and the same amount of eluate was added. Analytical conditions were such that the liquid obtained from the above elution test was filtered through a 0.45 μm membrane filter, and sillostazol was quantified using HPLC. The analysis wavelength was 257 nm, the mobile phase was acetonitrile: water = (40:60) mixture, and an octadecylsilylated column was used.

(Comparative Example 1)

  Each prescription described in the following table is the same as that of Example 1 except that it is manufactured with the components described in the table.

(Example 2)

  Each prescription described in the following table is the same as that of Example 1 except that it is manufactured with the components described in the table.

Example 3

  Each prescription described in the following table is the same as that of Example 1 except that it is manufactured with the components described in the table.

Example 4

  Each prescription described in the following table is the same as that of Example 1 except that it is manufactured with the components described in the table.

(Example 5)

  Dissolution tests according to pH were performed using formulations 6, 7, 8, and 9 of sillostazol sustained release tablets prepared from the above examples. As eluent, 0.5 W / W% sodium lauryl sulfate aqueous solution of pH 1.2 (artificial gastric fluid) and pH 6.8 (artificial sputum fluid) respectively described in the dissolution test method of Korean medicine is used. The paddle method was used as the method. The amount of the eluate was 900 ml, the stirring speed was 75 rpm, and the elution temperature was 37 ± 0.5 ° C. The sample collection time was based on the time that tablets generally stayed in the stomach when taking tablets, and the dissolution test was carried out on samples that had been subjected to dissolution test at pH 1.2 at pH 6.8. For sample collection, 5 ml of the sample was taken and the same amount of eluate was added. Analytical conditions were such that the liquid obtained from the above elution test was filtered through a 0.45 μm membrane filter, and sillostazol was quantified using HPLC. The analysis wavelength was 257 nm, the mobile phase was acetonitrile: water = (40:60) mixture, and an octadecylsilylated column was used.

Claims (4)

Sillostazol, a controlled release polymer containing sillostazol, a binder, a filler and a lubricant, wherein the controlled release polymer is a mixture of hydroxypropylmethylcellulose and carbomer,
The sillostazol sustained-release tablet uses an aqueous sodium lauryl sulfate solution, has an elution temperature of 37 ± 0.5 ° C., a stirring speed of 75 rpm, and the following dissolution profile by the paddle method:
(A) the sillostazol sustained release tablet releases 6.8% to 34.7% of the sillostazol after 60 minutes;
(B) The sillostazol sustained release tablet releases 15.8% to 60.7% of the sillostazol after 120 minutes; and (c) the sillostazol sustained release tablet after 20.30% to 78.78%. Releases 7% of the sillostazol;
A sustained release tablet of sillostazol. The sustained release tablet of sillostazol according to claim 1 , wherein the mixture of hydroxypropylmethylcellulose and carbomer is contained in an amount of 25 to 50% by weight based on the weight of the whole tablet. The sillostazol sustained-release tablet according to claim 1 , wherein the hydroxypropylmethylcellulose has a viscosity of 80,000 cps to 120,000 cps. 2. The sillostazol sustained-release tablet according to claim 1 , wherein the weight mixing ratio of the hydroxypropylmethylcellulose and the carbomer is 1: 1 to 20: 1.

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