JP2707023C - - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a salt of a specific triazine derivative, which has a reduced water solubility in an acidic region and tends to exhibit poor absorption upon oral administration. the agent, this has been confirmed of safety, especially
The present invention relates to a new preparation for oral absorption in which a fixed water-insoluble polymer compound and a water-soluble polymer compound are blended to improve the poorly absorbable property of the main drug. 2. Description of the Related Art The solubility of water in an alkali metal salt of an organic compound known as a pharmaceutically active ingredient compound has pH dependence, and its water solubility is reduced particularly in an acidic region. Things exist. For example, the present inventors have previously developed 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,3,5 useful as an active ingredient compound for the treatment of gout. Alkali metal salts of triazine derivatives such as triazine (see EP-A-269859) become very poorly soluble in water in an acidic aqueous solution, and have very low absorption from the digestive tract. . The active pharmaceutical ingredient compound (alkali metal salt), whose water solubility is reduced in the acidic region as described above, is orally administered (administered) as a normal pharmaceutical formulation, and is affected by the pH in the digestive tract, and its absorption Decrease. This means that the bioavailability of the gastric juice varies greatly depending on whether the gastric acidity is high or low, and whether it is taken or not at the time of eating.
This is a serious problem for pharmaceuticals. [0003] As a general method for reducing individual differences in bioavailability, a technique of enteric formulation is conventionally known, but when the above-mentioned alkali metal salt is used as a main drug,
It is necessary to formulate an enteric formulation which is alkaline and soluble, and it is difficult to guarantee the stability of such a formulation over time. That is, usually enteric preparations are obtained by preparing fine granules, granules, tablets and the like, and then coating them with a coating agent. When coated with an enteric coating agent that is soluble in the alkaline region, the formulation itself becomes very unstable. [0004] In view of the above situation, the present inventors have developed a drug containing a salt of the triazine derivative as a main drug, which can avoid insolubilization of the main drug in an acidic region and improve absorption in the digestive tract. In addition, intensive studies have been made with the aim of providing a new formulation for oral administration that can guarantee excellent bioavailability irrespective of the acidity of the gastric juice, the timing of taking the drug, and the presence or absence of food intake. As a result, without the use of conventional enteric-coating technology, and thus without a complicated enteric-coating process, it is possible to simply identify
By adding and mixing the water-insoluble polymer compound and the water-soluble polymer compound described above, and then continuing the usual formulation, a surprising finding was obtained that a formulation for oral administration meeting the above-mentioned object can be obtained. The present invention has been completed based on this new finding. [0005] That is, the present invention provides a 4-hydroxy-8- (3-methoxy) having reduced water solubility in an acidic region.
C-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,3,5
-Alkali metal, calcium, magnesium and aluminum triazines;
Salt selected from the group consisting of croscarmellose sodium and low
Water-insoluble polymer compound selected from substituted hydroxypropylcellulose, and that involved in oral absorption preparation according to claim formulated together with hydroxypropyl methylcellulose as water-soluble polymer compound. According to the invention, particularly preferably the oral absorption preparation which A alkali metal salt is selected from sodium, potassium and lithium salts, the mixing ratio of the main agent and the water-insoluble polymer compound by weight The formulation for oral absorption, the main drug and croscarmellose sodium selected from the range of 1: 0.1 to 1: 3 in the ratio by weight is 1: 0.
The above-mentioned preparation for oral absorption selected from the range of 1-1: 0.5, and the compounding ratio of the main drug and the low-substituted hydroxypropylcellulose is selected from the range of 1: 0.5-1: 3 by weight. The oral absorption preparation and the oral absorption preparation wherein the compounding ratio of the main drug and the water-soluble polymer compound is selected from the range of 1: 0.01 to 1: 0.2 by weight are provided. Further, according to the present invention, there is provided a method for producing the above-mentioned preparation for oral absorption, which comprises mixing and blending the active ingredient with a water-insoluble polymer compound and a water-soluble polymer compound. [0008] The preparation for oral administration of the present invention is a compound having a low water solubility in an acidic region,
Droxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo
[1.5-a] -1,3,5-triazine alkali metal salt, calcium salt,
Using a salt selected from a gnesium salt and an aluminum salt as a main drug, it can completely eliminate the drawbacks of conventional preparations for oral administration of this type, and in particular, it can avoid insolubilization of the main drug in an acidic region, and can prevent stomach In the pH range of about 1.2 to 6.8 of the digestive tract leading to the small intestine,
Has excellent solubility and absorbability. In addition, the preparation of the present invention is used for
Regardless of the presence or absence of food intake, excellent bioavailability can always be stably guaranteed, and the variation due to the individual difference in absorbability can be significantly reduced. Therefore, it can exert a sufficient pharmacological effect by oral administration without considering individual differences between applied individuals. In addition, the preparation of the present invention has an advantage that it can be easily produced according to a usual preparation technique after simply adding and mixing a main drug and a water-insoluble polymer compound and a water-soluble polymer compound without going through a complicated enteric coating step. . Needless to say, the preparation of the present invention can be added with waxes or coated in addition to the above-mentioned usual preparation, and the release of the main drug can be controlled arbitrarily by such means. Hereinafter, the formulation of the present invention will be described in detail. The active ingredient used in the formulation of the present invention is 4 -hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo , which has reduced water solubility in an acidic region. [1,5-a] -1,3,5-triazine down alk <br/> Li metal salts, calcium salts, selected from magnesium salts and aluminum salts.
The alkali metal salt may be any of pharmacologically acceptable ordinary salts, and specific examples thereof include a sodium salt, a potassium salt, and a lithium salt . [0010] The water-insoluble polymer compound is used in combination with the above agents are not soluble in water, water absorption,
To swell, which have the property of promoting disintegration of the formulation, selected from cross carmellose sodium and low-substituted hydroxypropylcellulose. still,
As the low-substituted hydroxypropylcellulose, any of various commercially available ones can be generally used, and the degree of substitution is generally desirably in the range of about 7 to 16%. [0011] The amount of the water-insoluble polymer compound used is not particularly limited, and can be appropriately determined depending on the bioavailability of the obtained oral absorption preparation at the time of oral administration. It is good to be in the range of about 0.1 to about 3, preferably about 0.1 to 2, and more preferably about 0.2 to 1.5. Furthermore, other water-soluble polymer compound used in combination with agent of the present invention oral absorption preparation is dissolved in water at pH independent solubility of at least about 6% or more, preferably about 10 rather preferable to those having more than about percent, used hydroxypropylmethylcellulose in the present invention. The amount of the water-soluble polymer compound to be used as the main drug is not particularly limited, and can be appropriately determined depending on the bioavailability of the obtained preparation for oral absorption at the time of oral administration. About 0.2 times, preferably 0.04 to 0.2 times
The amount is preferably about twice, more preferably about 0.08 to 0.16 times. The preparation for oral absorption of the present invention is prepared by adding the above-mentioned active ingredient, water-insoluble polymer compound and water-soluble polymer compound as essential components, and if necessary, adding various commonly used additives. It is prepared in a dosage form. The above additives can be appropriately selected according to the dosage form to be prepared, and typically include excipients, colorants, lubricants, preservatives, flavors, flavors, sweeteners and the like. Preferred excipients include sugars such as lactose, sucrose, D-mannitol, starches such as potato starch, cellulose derivatives such as crystalline cellulose, and inorganic salts such as calcium hydrogen phosphate and calcium sulfate. For the colorant, for example, yellow bengalara, tar dyes, etc., for the lubricant,
For example, stearic acids such as stearic acid, magnesium stearate, calcium stearate and the like, waxes such as sucrose fatty acid esters, salami beeswax and hardened oil, talc, polyethylene glycol and the like are respectively included. The dosage form to be prepared is not particularly limited and may be any of various dosage forms similar to general oral dosage preparations, but is usually powder, fine granules, granules, capsules, tablets, pills And so on. [0015] The preparation for oral administration of the present invention can be prepared by a conventional method according to the desired dosage form. For example, tablets are prepared by mixing a base drug, a water-insoluble polymer compound and a water-soluble polymer compound, and then, if necessary, excipients, binders, disintegrants, disintegration inhibitors, absorption promoters, and humectants. Adsorbents, additives such as lubricants are mixed, and if desired, pulverized, sieved, kneaded, etc., and then prepared by tableting. These tablets are further coated with ordinary skin, such as sugar-coated tablets , Gelatin-encapsulated tablets, film-coated tablets, double tablets,
It can also be a multilayer tablet. Pills can be prepared by mixing excipients, binders, disintegrants, and the like, if necessary, with the powder after mixing, and shaping the pills into an appropriate form. Capsules are prepared by filling a mixture of the above-mentioned active ingredient, water-insoluble polymer compound and water-soluble polymer compound into a hard gelatin capsule, soft capsule or the like.
Grinding, sieving, kneading, tableting, coating, used in the preparation of each of the above dosage forms,
Each operation such as capsule filling can be performed according to a well-known ordinary method. For example, pulverization can be performed using a jet mill, a ball mill, or the like. In particular, the preparation for oral administration of the present invention is preferably prepared by kneading the above-mentioned main ingredients with waxes, and then, if necessary, further maintaining the effect of the water-insoluble polymer compound and the water-soluble polymer compound. It is suitable to mix with excipients, binders, disintegrants, etc., to lead to the desired dosage form, or to shape the mixed powder into a suitable form such as a tablet, followed by film coating to form a coated tablet. It is. As the wax used herein, various waxes that are insoluble or hardly soluble in water are used, and specific examples thereof include animal waxes such as carnauba wax and beeswax, soybean hardened oil, and castor hardened oil. Examples thereof include hardened vegetable oils such as oils, paraffins such as paraffin wax and microcrystalline wax, and these can be used alone or in combination of two or more. As the coating agent for the film coating, for example, trade names “Eudragit E” and “Eudragit L” commercially available from Rohm Pharma Co., Ltd.
And acrylic resins such as "Eudragit S", "Eudragit RS" and "Eudragit NE", and hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose, ethylcellulose and the like. Compositions for coatings containing such coating agents may further include a coloring agent such as titanium oxide, talc, yellow bellflower, a plasticizer such as triethyl citrate, glycerin fatty acid ester, polyethylene glycol, and carnauba wax, if necessary. Conventional additives such as a polishing agent can be added and blended. The coating amount of the coating composition is appropriately determined depending on the desired duration and is not particularly limited, but is generally about 0.1 to 20% by weight based on the mixed powder containing the main agent. And preferably from about 3 to 10% by weight. The coating treatment is carried out by using various general methods such as a fluidized bed coating device, a centrifugal flow type coating device, a fully automatic film coating device for tablets, and the like. In addition, for example, a phase separation method, an interfacial polymerization method, and a spray drying method. And so on. Thus, according to the present invention, the elution pattern of the desired main drug can be obtained by appropriately selecting the amounts of the main drug, the water-insoluble polymer compound, and the water-soluble polymer compound to be added or by preparing a coating preparation. And duration can be adjusted as appropriate. The preparation for oral absorption of the present invention is appropriately orally administered in an appropriate amount containing an effective amount of the active ingredient depending on the form of the preparation, whereby the intended effects of the present invention can be exhibited. That is, the preparation of the present invention is very easy to prepare itself, and in addition, it can avoid insolubilization of the main drug in the acidic range, and has an acidic pH range of the digestive tract from the stomach to the small intestine, usually about 1.2 to 6. In the pH range of 8, it exhibits excellent solubility and absorbability, and can always stably guarantee excellent bioavailability irrespective of gastric acidity, dosage time, and the presence or absence of food intake. The variation due to the difference can be remarkably reduced, and a sufficient pharmacological effect can be exhibited without taking individual differences into consideration in the administration. EXAMPLES The preparation of the present invention and its advantages will be described in more detail below with reference to examples and comparative examples. In addition, each component compound used in each example is as follows. • 4-hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl)
Pyrazolo [1,5-a] -1,3,5-triazine sodium (the main drug, hereinafter referred to as “
・ Croscarmellose sodium (water-insoluble polymer compound, manufactured by Asahi Kasei Corporation, trade name: Ac-Di-Sol) ・ Low-substituted hydroxypropylcellulose (water-insoluble polymer compound, manufactured by Shin-Etsu Chemical Co., Ltd.) , Trade name: L-HPC) ・ Hydroxypropyl methylcellulose (water-soluble polymer compound, manufactured by Shin-Etsu Chemical Co., Ltd., trade name: TC-5E) ・ Crystalline cellulose (additive, manufactured by Asahi Kasei Corporation, trade name: Avicel) Ethyl acrylate, methyl methacrylate, methacrylated trimethyl copolymer (additive, product name: Eudragg RS) ・ Hydroxypropyl methylcellulose acetate succinate (additive, product name, manufactured by Shin-Etsu Chemical Co., Ltd.) AQOAT) Example 1 Compound A (500 g) 100 g of scarmellose sodium, 80 g of hydroxypropyl methylcellulose, 100 g of lactose, 100 g of corn starch, 100 g of crystalline cellulose and 20 g of talc are mixed, and the mixed powder is filled into a No. 3 capsule to obtain a preparation for oral absorption of the present invention in the form of a capsule. Was. Table 1 shows the composition per capsule. Comparative Example 1 Compound A 500 g, hydroxypropyl methylcellulose 80 g, lactose 150
g, 150 g of corn starch, 100 g of crystalline cellulose and 20 g of talc, and the mixed powder was filled in a No. 3 capsule to obtain a capsule-type comparative preparation. 1
Table 1 shows the composition per capsule. Comparative Example 2 Compound A 500 g, croscarmellose sodium 100 g, lactose 140 g,
Mix 140 g of corn starch, 100 g of crystalline cellulose and 20 g of talc,
The mixed powder was filled into a No. 3 capsule to obtain a capsule-shaped comparative preparation. Table 1 shows the composition per capsule. [Table 1] Example 2 Compound A 500 g, low-substituted hydroxypropylcellulose 700 g, hydroxypropylmethylcellulose 80 g, lactose 600 g and corn starch 100
g were mixed and kneaded with a high-speed stirring type mixer, dried, added with 20 g of magnesium stearate, and pressed with an 8 mmφ punch to obtain a tablet-form preparation for oral absorption of the present invention. Table 2 shows the composition per tablet. Comparative Example 3 Compound A (500 g), crystalline cellulose (700 g), hydroxypropylmethyl cellulose (40 g), lactose (600 g), and corn starch (140 g) were mixed and kneaded with a high-speed stirring mixer, dried, and then added with magnesium stearate (20 g). And 8
The tablet was pressed with a mmφ punch to obtain a tablet-form comparative preparation. Table 2 shows the composition per tablet. [Table 2] Example 3 Compound A (500 g), croscarmellose sodium (120 g), hydroxypropyl methylcellulose (80 g), lactose (120 g), corn starch (50 g), and crystalline cellulose (130 g) were mixed and kneaded with a high-speed stirring mixer, extruded and granulated. (
Using a marmellaizer) to obtain granules. The granules are coated with a predetermined amount of the coating composition described in Table 3 containing an ethyl acrylate / methyl methacrylate / trimethyl methacrylate copolymer using a fluidized bed coating apparatus,
The capsule was filled in No. 2 capsule to obtain a sustained-release capsule formulation for oral absorption of the present invention. Table 3 shows the composition per capsule. [Table 3] Example 4 Compound A (500 g), croscarmellose sodium (110 g), hydroxypropyl methylcellulose (70 g), lactose (70 g), corn starch (50 g) and crystalline cellulose (130 g) were mixed and kneaded with a high-speed stirring mixer, extruded, and extruded to form a sphere. (Using a marmelizer) to obtain granules. The granules are coated with a coating composition containing 54 g of hydroxypropylmethylcellulose acetate succinate, 15 g of triethyl citrate and 16 g of talc using a fluid bed coating apparatus, and 757 g of low-substituted hydroxypropylcellulose and 18 g of magnesium stearate are further added. Then, tableting with an 8 mmφ punch was performed to obtain a sustained-release preparation for oral absorption of the present invention. Table 4 shows the composition per tablet. [Table 4] Hereinafter, the dissolution test and the oral absorption test in beagle dogs performed to confirm the effects of the present invention will be described in detail. [Test Example 1] Dissolution test 1 For the following samples, the dissolution rate of each sample after a lapse of a predetermined time under the following test conditions was determined in accordance with the dissolution test (Method 2) described in the 12th Revised Japanese Pharmacopoeia. It was measured. Sample Formulation A of the Present Invention: Capsules Obtained in Example 1 Comparative Formulation B: Capsules Obtained in Comparative Example 1 Comparative Formulation C: Capsules Obtained in Comparative Example 2 Control: Bulk Powder (4 -Hydroxy-8- (3-methoxy-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,3,5-triazine sodium salt Test conditions Test solution: 900 ml of liquid 1 (pH 1.2) Number: 100 rpm Measurement: UV 335 nm The results are shown in Fig. 1. [0036] From Fig. 1, it is clear that Formulation A of the present invention has much better dissolution than Comparative Formulations B and C. On the other hand, the dissolution property of the comparative preparation B was almost the same as that of the bulk powder, and no improvement was observed.
It is clear that the improvement effect decreases relatively quickly. Test Example 2 Dissolution Test 2 The same four kinds of samples as those used in Test Example 1 were tested under the following test conditions in accordance with the dissolution test (Method 2) described in the 12th revision of the Japanese Pharmacopoeia. After a predetermined time, the dissolution rate was measured. Test conditions Test solution: second solution (pH 6.8) 900 ml Rotation speed: 100 rpm Measurement: UV 345 nm The results are shown in FIG. FIG. 2 shows that the preparation A of the present invention has a pH of 6.8 compared to the comparative preparations B and C and the control.
Even under the condition (1), no substantial decrease in elution over time was observed, and it is clear that the composition has excellent elution. Test Example 3 Dissolution Test 3 With respect to the following samples, the time-dependent dissolution rate under the condition of pH 1.2 was measured in the same manner as in Test Example 1. Formulation D of the Present Invention—Tablets Obtained in Example 2 Comparative Formulation E—Tablets Obtained in Comparative Example 3 The results are shown in FIG. From FIG. 3, it is apparent that the dissolution property of the preparation D of the present invention is remarkably improved as compared with the comparative preparation E. Test Example 4 Dissolution Test 4 The same sample as in Test Example 3 was subjected to measurement of the time-dependent dissolution rate at pH 6.8 in the same manner as in Test Example 2. FIG. 4 shows the results. FIG. 4 also clearly shows that the preparation D of the present invention has improved dissolution properties as compared with the comparative preparation E. Test Example 5 Oral Absorption Test Five male beagle dogs (body weight: 8.4 to 11.8 kg) were fasted all day and night, and after the fasting (fasting group) or after feeding (feeding group), a sample was obtained. Of the present invention A (capsules obtained in Example 1) and Comparative Formulation B (capsules obtained in Comparative Example 1) were orally administered. After the oral administration, blood was collected over time from the epithelial vein of the forearm, and the amount of Compound A in the serum was determined as H
It was quantified by a PLC (high performance liquid chromatograph) method. Note that the samples were allocated by a crossover method. FIG. 5 (fasted group) and FIG. 6 (feed group) show the graphs of the changes in blood concentration at each time obtained as a result of the above test. The maximum blood concentration (Cmax) and the area under the blood concentration-time curve (AUC) obtained as a result of the above test are shown in Table 5 below. [Table 5] The numerical values in the above figures and tables indicate the average value ± standard error. From the above, it is evident that the oral absorption preparation of the present invention shows a remarkable improvement in absorbability as compared with the comparative preparation, and that the difference in bioavailability depending on the presence or absence of a meal can be improved. The oral absorption preparation of the present invention is based on the combined use of a specific drug and a water-insoluble polymer compound and a water-soluble polymer compound. p
It is not affected by H, does not cause a decrease in absorbability even during fasting, further reduces individual differences in bioavailability, and shows remarkably improved solubility and absorbability, and simple operation Can be easily prepared.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the dissolution rate over time at pH 1.2 of the preparation for oral absorption of the present invention determined in dissolution test 1. FIG. 2 is a graph showing the time-dependent dissolution rate at pH 6.8 of the preparation for oral absorption of the present invention determined in Dissolution Test 2. FIG. 3 is a graph showing the time-dependent dissolution rate of the preparation for oral absorption of the present invention at pH 1.2 determined in Dissolution Test 3. FIG. 4 is a graph showing the time-dependent dissolution rate at pH 6.8 of the preparation for oral absorption of the present invention determined in Dissolution Test 4. FIG. 5 is a graph (fasted group) of a change in blood concentration of a preparation for oral absorption of the present invention determined by an oral absorption test in a beagle dog after a predetermined time has elapsed. FIG. 6 is a graph (feeding group) showing a change in blood concentration of a preparation for oral absorption of the present invention determined by an oral absorption test in a beagle dog after a predetermined time has elapsed.

Claims (1)

Claims: 1. A 4-hydroxy-8- (3-methoxy) having reduced water solubility in an acidic region.
-4-phenylsulfinylphenyl) pyrazolo [1,5-a] -1,3,5-
Alkali metal, calcium, magnesium and aluminum triazines
A salt selected from the group consisting of croscarmellose sodium and low salt
Water-insoluble polymer compound selected from換度hydroxypropylcellulose, and oral absorption preparation characterized by containing a combination with hydroxypropyl methylcellulose as water-soluble polymer compound. 2. The method according to claim 1, wherein the alkali metal salt of the main drug is a sodium salt , a potassium salt or lithium.
Oral absorption preparation of claim 1, a salt or it is selected. 3. The compounding ratio of the main drug and the water-insoluble polymer compound is 1: 0,1 by weight.
The preparation for oral absorption according to claim 1, which is selected from the range of ~ 1: 3. 4. The compounding ratio of the main drug and croscarmellose sodium is 1 by weight.
: The preparation for oral absorption according to claim 1 or 3 , which is selected from the range of 0.1 to 1: 0.5. 5. the proportions the weight ratio of the agent and the low-substituted hydroxypropylcellulose 1: 0.5 to 1: oral absorption preparation of claim 1 or 3 is selected from 3 range. 6. The compounding ratio of the main drug and the water-soluble polymer compound is 1: 0.01 by weight ratio.
The preparation for oral absorption according to claim 1, which is selected from the range of ~ 1: 0.2. 7. The method for producing an oral absorption preparation according to any one of claims 1 to 6 , wherein the active ingredient is mixed with a water-insoluble polymer compound and a water-soluble polymer compound.