JPH04368330A - Sustained release preparation of pemirolast potassium - Google Patents

Abstract

PURPOSE:To provide an extremely excellent sustained release preparation of pemirolast potassium known as an antiallergic agent, capable of keeping the effective blood concentration over a long period, having high storage stability and resistant to decomposition and the change in sustained releasability even after a long-term storage. CONSTITUTION:The objective sustained release preparation of pemirolast potassium (TBX) having the above effects and applicable by peroral administration or oral cavity application contains, as essential components, (A) TBX and (B) a hydroxypropyl methylcellulose preferably having a methoxyl group substitution degree of 1.9, 1.8 or 1.4 (especially 1.8) and a hydroxy-propoxyl group substitution degree of 0.25, 0.15 or 0.20 (especially 0.25) and having a viscosity of 40-11,200cp (especially 3,000-6,000cp) as 2% aqueous solution or a carboxymethylcellulose sodium salt preferably having an ether substitution degree of 0.5-0.94, a polymerization degree of 212-1,300 and a viscosity of 15-5,410cp as 1% aqueous solution. The amounts of the components A and B are 2-30wt.% and 10-90wt.% based on the total weight of the preparation, respectively.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release preparation of an anti-allergic drug, and more particularly to a sustained-release preparation of pemirolast potassium (hereinafter referred to as TBX) that can be administered orally or orally.

0002

[Prior Art] TBX has a chemical name of 9-methyl-3-(
1H-tetrazol-5-yl)-4H-pyrido[1,
2-a] Pyrimidin-4-one potassium salt is known to suppress or prevent symptoms of allergic reactions such as allergic bronchial asthma and allergic rhinitis (Japanese Patent Publication No. 50197/1983). Allergy 3
3, No. 9, pp. 727-728 (1984), TB
The inhibitory effect of X in a type I allergic reaction model and the inhibitory effect on the release of chemical mediators such as histamine and SRS-A (a slow-reacting substance of anaphylaxis) have been described.
roenterology) Volume 88 No. 55 No. 135
4 (1985) describes the effectiveness of TBX in the treatment of gastritis and gastric inflammation based on its protective effect on gastric cells.

[0003] Further, regarding the aqueous preparation of TBX, see Japanese Patent Application Laid-Open No. 1-125321, and regarding the ointment, see Japanese Patent Application Laid-Open No. 1993-125321.
-118323, respectively. However, sustained release formulations of TBX formulations are not yet known.

0004

[Problems to be Solved] Conventionally known formulations of TBX are oral immediate-release tablets that must be taken two or three times a day. In addition, drugs that inhibit chemical mediator release must be taken continuously for at least four weeks until they begin to take effect, which is troublesome and poses a problem of decreased compliance.

For example, the 11th edition of the Japanese Pharmacopoeia (General Test Methods Section 46, B, 42
When a dissolution test was conducted in accordance with 4), TBX was 75%
The time for % elution (hereinafter referred to as T75%) was less than 5 minutes and did not exhibit sustained release properties. In addition, when this formulation is administered orally, the biological half-life is 1 hour in dogs and 4 hours in humans.
Therefore, it was desired to provide sustained release properties.

[0006] The present invention provides TB, an antiallergic drug.
The purpose of the present invention is to provide a sustained release formulation of X.

[0007] The conditions that sustained-release preparations must meet include that the number of doses per day is less than that of immediate-release preparations, and that the maximum blood concentration (hereinafter referred to as Cmax) is similar to that of immediate-release preparations. The effective blood concentration of the drug can be maintained for a long time, the release of the drug in the gastrointestinal tract is not affected by food, the bioavailability is high, and the physicochemical properties remain stable even after long-term storage. stable and with little fluctuation in release properties,
and a dosage form of a size that is easy to take.

[0008] In order to reduce the frequency of dosing, it is necessary to increase the drug content in the formulation compared to immediate release formulations.

[0009] However, if the drug is released all at once, the concentration in the blood will be high and there will be a risk of side effects occurring. Therefore, in order to increase the amount of drug and achieve a Cmax comparable to that of an immediate release formulation, the release of the drug from the formulation must be controlled.

[0010] In order to maintain the effective blood concentration of a drug over a long period of time, it is necessary that the release of the drug from the formulation be constant over a long period of time.

[0011] In order to be less affected by meals, it is necessary that the release of the drug from the preparation be constant even within the gastrointestinal tract.

[0012] In addition, in order for the relative bioavailability to have a dose relationship with that of an immediate release preparation, it is necessary that the relative bioavailability does not decrease due to sustained release, and the drug must have excellent formulation technology. It is that you are.

[0013] In order for the drug to be physically and chemically stable even after long-term storage, it is necessary that the drug does not decompose in the formulation and that the release rate of the drug does not change, ensuring efficacy and safety. It is to be done.

[0014] The size of the tablet that is easy to take is 6.5 mm in diameter.
~9 mm, preferably 7-8 mm in diameter. In the case of capsules, the size is preferably from size 2 to size 4.

[0015] In order to obtain a sustained release TBX preparation, we investigated cases in which the TBX drug substance was coated with a hydrophobic base, in the form of composite granules, in the form of dry-coated tablets, and in the form of space tabs. None of them exhibited sustained release properties or had low relative bioavailability, making it impossible to obtain satisfactory results.

Furthermore, pullulan, polyvinyl alcohol,
Single-unit gel matrix extended-release tablets using several types of gel-forming polymers such as Eudragit RS, Carbopol, and sodium alginate were investigated, but no satisfactory results were obtained in any of them.

The inventors confirmed these findings through their own experiments.

Next, when the raw material of TBX is coated, when it is made into composite granules, when it is made into dry-coated tablets, when it is made into space tabs, and when it is made into several gel-forming polymers, sodium alginate, polyvinyl alcohol, carbon Pole,
The test results are shown when Eudragit RS is used to form gel matrix tablets.

[0019] Evaluation of sustained release properties was performed according to the 11th edition of the Japanese Pharmacopoeia (
Apply the dissolution test method in General Test Methods Section 46, B, 424), use 900 ml of water as the eluent, and use 20 ml as TBX.
A sample equivalent to 100 g was added and tested using the paddle method at 100 rpm. The eluate was measured by absorbance method. To measure the TBX concentration in the blood, the equivalent of 20 mg of TBX was orally administered, a certain amount of blood was collected from a vein, and then a trace amount of TBX in the plasma was analyzed by high performance liquid chromatography fluorescence analysis.

[When the raw material is coated with a hydrophobic base] 3 to 30 g of ethyl cellulose is mixed with 50 g of dichloromethane.
It was dissolved in ~400 ml, and 10 g of TBX was added while stirring to disperse it. Next, this dispersion was dried using a spray dryer to obtain a sample. Also, Eudragit R
10 to 30 g of S was dissolved in 50 to 150 ml of dichloromethane, and 10 g of TBX was added while stirring to disperse the solution. Next, dry this dispersion using a spray dryer,
A sample was obtained.

[0021] A dissolution test was conducted on these samples, and T
When the time for 75% of BX to elute (T75%) was determined, it was all within 30 minutes, and none of these samples showed sustained release properties. The results are shown in Table 1.

[0022]

[Table 1]

[When made into composite granules] ■ When TBX is made hydrophobic as fat matrix granules Stearyl alcohol, stearic acid, magnesium stearate,
Heat-melt 1-5 g of Loveriwax, Decaglin (7s), and stearic acid monoglyceride (MGS-F-75), add 1 g of TBX, stir, cool to room temperature, and sieve through a 12-48 mesh. did.

Table 2 shows the results of a dissolution test performed on these samples. In all cases, the T75% was less than 45 minutes, indicating no sustained release properties.

[0025]

[Table 2]

■TBX as wax matrix granules
When made hydrophobic, 50 g of carnauba wax, rice wax, paraffin wax, beeswax or spermaceti wax was heated and melted, 10 g of TBX was added and mixed with stirring, and the mixture was cooled to room temperature while stirring. Next, this was pulverized and sustained release properties were evaluated using a particle size of 12 to 48 mesh.

As a result, the elution rate of the sample using paraffin wax became almost constant at 15% within 0.5 to 5 hours after the start of the test, and no further release occurred. In addition, in the case of rice wax, the elution rate was almost constant at 45% in 2 to 5 hours, and the elution rate was low, making these unsuitable as additives. For whale wax, carnauba, and beeswax, T75% is 1
．． Although the treatment was extended to 5 hours, the blood concentration Tmax was almost the same as that of the immediate release tablet, which was not a satisfactory result. The results are shown in Table 3.

[0028]

[Table 3]

[When made into dry-coated tablets] Carnauba wax 4
~10 g was heated and melted, 2 g of TBX was added thereto, and the mixture was stirred and mixed. The mixture was then sucked into a tube with a diameter of 3 mm and cooled, resulting in carnauba wax and TBX composition ratios of 2:1, 3:1, and 4.
:1, 5:1 matrices were obtained. Next, the matrix was taken out and cut into 15 mg of TBX, which was used as a core for dry-coated tablets. Crush the immediate release tablet and take TB
Take 5 mg as X and mix with immediate release tablet placebo,
A dry-coated tablet was prepared using the above matrix as a core.

In in vitro testing of these samples,
Composition ratio of carnauba wax and TBX used as core 2:
The T75% times of 1, 3:1, 4:1, and 5:1 dry-coated tablets are 2.5, 3.5, 6.5, and 9 hours, respectively, and as the wax ratio increases, the release becomes more sustained. showed that. but,
In vivo, the relative bioavailability for immediate release tablets was extremely low at 1.0, 0.9, 0.7, and 0.4, and could not be used as sustained release tablets. The results are shown in Table 4.

[0031]

[Table 4]

[In the case of space tabs] Crush these wax matrix cores, take 15 mg of TBX from the sustained release granules with a particle size of 12 to 20 mesh, and take 5 mg of TBX from the granules before compression of the immediate release tablets. An appropriate amount was taken, and 1% of a lubricant was added and mixed to obtain a space tab of 20 mg of TBX. For all these samples, the T75% time was 1.0, 1.5, 3.0, 3.5 hours, and the relative bioavailability to the immediate release tablet was 1.6, 1.4, 1.0. 0
．． 8, but if they had a high relative bioavailability, they would not exhibit sustained release properties, and if they did exhibit sustained release properties, the utilization rate would be low, and they could not be used as sustained release tablets. .

The results are shown in Table 5.

[0034]

[Table 5]

[When using other gel-forming polymers]
Weighed 10g of TBX, added pullulan as a gel-forming polymer,
Polyvinyl alcohol, Eudragit RS, Carbopol, and sodium alginate were used, and 30 g of these and 59 g of lactose were added and mixed. Next, kneading and granulating using water as kneading water and drying with a hot air blow dryer,
It was sieved using a 16 mesh sieve. Weigh out the specified amount of silicic anhydride and magnesium stearate, mix them in a polyethylene bag, and punch them into 200 tablets using an 8mm diameter punch.
It was compressed into tablets in mg. Table 6 shows the results of examining these dissolution properties.

[0036]

[Table 6]

[0037] None of these showed sustained release properties in the dissolution test, and could hardly be used as sustained release preparations.

As described above, when TBX is coated, when it is made into composite granules, when it is made into dry-coated tablets, when it is made into space tabs, and when other gel-forming polymers are used, sustained release can be achieved in vitro. Even if they showed poor persistence in vivo, their relative bioavailability was extremely low, and they could not be used as sustained-release preparations.

[0039]

[Means for Solving the Problems] In view of the above-mentioned problems, the present inventors conducted intensive research on sustained release preparations of TBX and found that hydroxypropyl methylcellulose (hereinafter referred to as HPMC) was used as a gel-forming polymer. , or carboxymethylcellulose sodium (hereinafter referred to as CMC-N)
It's called a. ), with other excipients and lubricants, showed sustained release in dissolution tests, sustained blood dynamics in dogs and humans, and maintenance of effective blood concentration. The time is more than twice that of the immediate release formulation, the Cmax is 0.7 to 0.9 times, the relative bioavailability is also good, it is not easily affected by meals, it is physicochemically stable, and the dosage They discovered that it is possible to make tablets of a size that is easy to swallow, and completed the present invention.

The gel matrix sustained release preparation of the present invention contains 2 to 30% TBX and 1% HPMC based on the total weight of the preparation.
It is preferable to contain 0 to 90% or 10 to 90% of CMC-Na.

[0041] For HPMC, preferably the degree of substitution of the methoxyl group as a substituent is 1.9, 1.8 or 1.4 and the degree of substitution of the hydroxypropoxyl group as a substituent is 0.25, 0.15 or 0.20, The viscosity of a 2% aqueous solution is 40-112
00 cp, more preferably a degree of substitution of methoxyl group of 1.8 and a degree of substitution of hydroxypropoxyl group of 0.
．． HPMC having a viscosity of 3000 to 6000 cp in a 2% aqueous solution at 25% can be used.

[0042] For example, the trade name "Metrose" manufactured by Shin-Etsu Chemical Co., Ltd.
Grade 60-SH-50, 60-SH-4000,
65-SH-400, 65-SH-50, 65-SH-
1500, 65SH-4000, 90-SH-100,
90-SH-4000, 90-SH-15000, 90
An example is SH-30000.

CMC-Na has a substitution degree of carboxymethyl group of glucose hydroxyl group in cellulose of 0.50.
~0.94, with a degree of polymerization of 212 to 1300, and 1
% aqueous solution having a viscosity of 15 to 5410 cp is preferred.

For example, grades 1120, 1130, 1140, and 115 of the product name "CMC Daicel" manufactured by Daicel Corporation
0, 1160, 1170, 1180, and 1190.

[0045] The sustained-release preparation of the present invention can be obtained into tablets by a wet method or by a direct compression method, and can be coated with a film if necessary. The sustained release preparation of the present invention can be used not only as an oral preparation but also as an oral adhesive. Alternatively, the mixture or granules before being made into tablets may be filled into capsules to form capsules, and the contents of the capsules may be sprayed into the nose using an inhaler for nasal inflammation, such as a nasal insufflator. .

Furthermore, the sustained-release preparation of the present invention does not produce decomposition products of TBX even when stored in an airtight bottle under high temperature and high humidity conditions, does not change its release properties, and has good storage stability. This is an extremely excellent sustained-release TBX preparation.

[0047]

[Function] The release properties, blood concentration behavior, and storage stability of the sustained-release preparation of the present invention are shown below.

[Release properties] TBX, HPMC (grade 6
0SH-4000), lactose, silicic anhydride, and magnesium stearate, mix them, and prepare 20 tablets per tablet.
Tablets were obtained by adjusting the concentration to 0 mg.

[0049] Furthermore, TBX, CMC-Na (grade 1
140) and lactic acid, mix them, add kneading water, dry in a hot air dryer after kneading, add predetermined amounts of silicic anhydride and magnesium stearate, and mix. Tablets were prepared to weigh 200 mg. These samples have a diameter of 8 mm, which is the most convenient size for tablets to take.

Next, these samples were subjected to dissolution tests, and the results are shown in Tables 7 and 8.

[0051]

[Table 7]

[0052]

[Table 8]

[0053] The samples in Tables 7 and 8 both showed zero-order elution patterns, and T75% was 2.5 hours or more, clearly showing sustained release properties.

[Blood Concentration Behavior] ■Blood Concentration Parameters in Beagle Dogs Table 9 shows the results of oral administration of samples 5 and 12 in Tables 7 and 8 to beagle dogs.

[0055]

[Table 9]

As shown in Table 9, the Cmax of these products is 0.7 to 0.9 times longer than that of conventional preparations, the effective concentration maintenance time is more than twice as long, and the relative bioavailability is also twice as good. Met.

■Human Blood Concentration Parameters Table 10 shows the results of comparing the human blood concentration parameters of Samples 5 and 12 in Tables 7 and 8 with those of the conventional preparation.

[0058]

[Table 10]

■Effects of Diet Sample 5 in Table 7 was orally administered to beagle dogs 30 minutes after eating, and the blood concentration parameters obtained are shown in Table 11.

[0060]

[Table 11]

[0061] As described above, the sustained release agent of the present invention was not easily influenced by diet.

[Storage stability] Samples 1 to 1 in Tables 7 and 8
2 was stored in an airtight bottle at 40°C, 75%, for 6 months, and the properties, presence or absence of decomposition products, and release properties were examined.

[0063] The properties were determined using a colorimeter, and the L and a of the tablet surface were determined using a colorimeter.
, b value was measured, and the change in storage period was expressed as color difference (ΔE). The presence or absence of decomposition products can be confirmed using thin layer chromatography (
The thin layer plate is silica gel, and the developing solvent is methanol: benzene: acetone: aqueous ammonia (5:4).
:1:1) was used. Observation was performed at 40° C., 75%, after 6 months, and TLC was also performed at that time.

[0064]

[Table 12]

[0065] As described above, in all the samples, no change was observed in the properties, no decomposition products were observed, and no change was observed in T75%, indicating that the preparations were extremely stable.

The sustained release preparation of the present invention contains 2 to 30% (w/w) of TBX and 10 to 90% of HPMC based on the total weight of the preparation.
(w/w) or CMC-Na 10 to 90% (w/w), the effective blood concentration can be maintained for a long time, no decomposition products are generated, and storage stability and sustained release properties do not change. Therefore, it is an extremely excellent formulation.

[0067] Next, production examples of sustained release preparations of the present invention will be shown, but these are not intended to limit the present invention.

[0068]

【Example】

Example 1 TBX 10g, lactose 58g, HPMC (grade 65S
H-4000), 1 g of solider, and 1 g of magnesium stearate were weighed, mixed, and then compressed into tablets with a diameter of 8 mm.
One 200 mg tablet was obtained.

Example 2 A product was produced in the same manner as in Example 1 except that the grade of HPMC in Example 1 was changed to 90SH-4000.

Example 3 TBX 10g, lactose 58g, HPMC (grade 90S
30 g of H-400), 1 g of solider, and 1 g of magnesium stearate were weighed, mixed, and then tableted to obtain 200 mg tablets each having a diameter of 8 mm.

Example 4 15 g of TBX, 42.34 g of lactose, 40 g of HPMC (grade 60SH-50), 1.33 g of solider, and 1.33 g of magnesium stearate were weighed, mixed, and then compressed into tablets of 133 mg each with a diameter of 7 mm. Got the tablets.

Example 5 15 g of TBX, 42.34 g of lactose, 40 g of HPMC (grade 65SH-4000), 1.33 g of solider, and 1.33 g of magnesium stearate were weighed, mixed, and then compressed into tablets, each having a diameter of 7 mm and weighing 133 mg. Got the tablets.

Example 6 TBX 10g, lactose 79g, CMC-Na (grade 1
140) Weigh 10g, mix it with water as a mixing solution, and then add 1
The mixture was sieved using a 2-mesh sieve and dried to obtain granules. Add to this 0.5% solider and 0 magnesium stearate.
．． After adding 5% and mixing, tablet it into 2 tablets each with a diameter of 8 mm.
00 mg tablets were obtained.

Example 7 TBX 10g, lactose 69g, CMC-Na (grade 1
130) Weigh 20g, mix it with water as a mixing solution, and then add 1
The mixture was sieved using a 2-mesh sieve and dried to obtain granules. Add to this 0.5% solider and 0 magnesium stearate.
．． After adding 5% and mixing, tablet it into 2 tablets each with a diameter of 8 mm.
00 mg tablets were obtained.

Example 8 TBX 10g, lactose 59g, CMC-Na (grade 1
150) Weigh 30g, mix it with water as a mixing solution, and then add 1
The mixture was sieved using a 2-mesh sieve and dried to obtain granules. Add to this 0.5% solider and 0 magnesium stearate.
．． After adding 5% and mixing, tablet it into 2 tablets each with a diameter of 8 mm.
00 mg tablets were obtained.

Example 9 TBX 10g, lactose 49g, CMC-Na (grade 1
160) Weigh 40g, mix it with water as a mixing solution, and then add 1
The mixture was sieved using a 2-mesh sieve and dried to obtain granules. Add to this 0.5% solider and 0 magnesium stearate.
．． After adding 5% and mixing, tablet it into 2 tablets each with a diameter of 8 mm.
00 mg tablets were obtained.

Example 10 Weighed 15 g of TBX, 42.34 g of lactose, and 40 g of CMC-Na (grade 1150), kneaded the mixture with water, passed it through a 12-mesh sieve, and dried it to form granules. I got it. To this, 0.5% solider and 0.5% magnesium stearate were added and mixed, and then tableted to obtain 133 mg tablets each having a diameter of 7 mm.

Example 11 Weighed 15 g of TBX, 42.34 g of lactose, and 40 g of CMC-Na (grade 1130), kneaded them with water, passed them through a 12-mesh sieve, and dried them to form granules. I got it. To this, 0.5% solider and 0.5% magnesium stearate were added and mixed, and then tableted to obtain 133 mg tablets each having a diameter of 7 mm.

Example 12 200 mg of the mixture of Example 1 before tableting was filled into No. 2 capsules to prepare capsules.

Example 13 100 mg of the granulated material of Example 5 before tableting was filled into No. 4 capsules to prepare capsules.

Example 14 TBX 1g, HPMC (Grade 60SH-4000)
10 g of lactose, 88 g of lactose, and 0.5 g of solider were mixed, and after mixing, 0.5 g of magnesium stearate was weighed, and after further mixing, 50 mg of the same was filled into No. 4 capsules to prepare nasal capsules.

Claims (3)

[Claims] Claim 1: Pemirolast potassium 2-30% (w/w
) and hydroxypropyl methylcellulose 10-90
% (w/w) or 10-90% (w/w) of sodium carboxymethylcellulose. 2. Degree of substitution of methoxyl group of glucose in hydroxypropyl methyl cellulose: 1.9, 1.8, 1.
4. Molar substitution degree of hydroxypropoxyl group is 0.15
, 0.25, 0.20, and the viscosity of a 2% aqueous solution is 40
The sustained release formulation according to claim 1, which has a dosage of 11,200 cp. Claim 3: Sodium carboxymethyl cellulose has a degree of ether substitution of 0.5 to 0.94 and a degree of polymerization of 212 to 13.
00, and the viscosity of the 1% aqueous solution is 15 to 5410 cp.