WO1993025206A1

WO1993025206A1 - ORALLY ADMINISTRABLE COMPOSITION OF PYRIDO[1,2-a]PYRIMIDINE DERIVATIVE

Info

Publication number: WO1993025206A1
Application number: PCT/JP1993/000753
Authority: WO
Inventors: Akihiro Iso; Kazumi Hayashishita; Masato Yamaguchi
Original assignee: Tokyo Tanabe Company Limited
Priority date: 1992-06-05
Filing date: 1993-06-04
Publication date: 1993-12-23
Also published as: JPH05339150A; AU4354493A

Abstract

An orally administrable composition of a pyrido[1,2-a]pyrimidine derivative represented by general formula (I), with its surface treated mechanically, wherein R represents n-propyl or allyl; A represents tetrazolyl or carboxyl; and n represents an integer of 0 to 2. The composition is excellent in long-term stability and improved in releasability and bioavailability, thus being useful as an oral antiallergic.

Description

Description Composition for oral administration of pyrido [1,2—a] pyrimidine derivative

The present invention relates to a preparation for oral administration of a pyrido [1,2-a] pyrimidine derivative having an antiallergic effect. Background art

The pyrido [1,2—a] pyrimidine derivative represented by the following general formula is disclosed in Japanese Patent Application Laid-Open Nos. Sho 62-224, 62-82, Sho 63-183, 581 and JP HirakiAkira 6 3 - a 2 4 6 3 7 compounds described in 5 JP, Anafi La carboxymethyl one slow reacting substance - strong leuco preparative Lien D ₄ is a representative active component of (SRS a) It has been reported to be useful as a therapeutic agent for type I allergic disease caused by SRS-A because of its potent inhibitory activity.

(In the formula, R represents an n-propyl group or an aryl group, A represents a tetrazolyl group or a carboxyl group, and n represents an integer of 0 to 2.)

Because allergic diseases are often associated with various parts of the body, oral drugs that absorb drugs from the digestive tract for the purpose of systemic effects have local effects. It can be said to be an effective dosage form together with aqueous preparations such as nasal drops and eye drops and aerosols for the purpose.

It is generally known that when a drug is absorbed from the gastrointestinal tract of a living body, the rate of absorption is determined by the rate of dissolution in the gastrointestinal tract fluid.The higher the dissolution rate, the higher the bioavailability. ing.

However, the solubility of pyrido [1,2-a] pyrimidine derivatives in water is extremely low. For example, 9-[(4-acetyl- 3-hydroxy-2-n-propylphenoxy) methyl] 1- (1H—Tetrazol-5-yl) — 4H—Pyrido [1,2—a] pyrimidine—4one-on (hereinafter referred to as AS-135): 4 // g / m1 there were. Therefore, when using pyrido [1,2-a] pyrimidine derivatives as oral preparations, the expected bioavailability may not be obtained without some treatment. As means for improving the solubility of a drug in water, pulverization for the purpose of increasing the surface area of the powder, addition of a surfactant, and the like are generally known. The present inventors conducted research based on these methods, but none of them yielded satisfactory results. In addition, the solid dispersion method (Sugimoto et al .: Dru. Dev. Ind. Pharm., 6_, 1337, Although the improvement of solubility was examined by 1977 7), the expected improvement in solubility could not be obtained, and lacked practicality such as the problem of residual solvent and the necessity of using a large amount of solvent. Was.

Against this background, a new formulation for oral administration of pyrido [1,2-a] pyrimidine derivatives that has improved affinity for water and improved bioavailability through new formulation processing is expected. Was rare. Disclosure of the invention The present inventors have conducted intensive studies on the above problems, and as a result, it was not enough to simply use a pyrido [1,2-a] pyrimidine derivative as a fine powder, and the pyrido [1,2 — A] A pyrimidine derivative, to which a surfactant or a mixed carrier is added, if necessary, is subjected to surface treatment by mechanical operation mainly involving impact, compression, friction, shearing, etc. The present inventors have found that a composition of a pyrido [1,2-a] pyrimidine derivative for oral administration having high solubility and improved bioavailability can be obtained, and thus completed the present invention.

The composition of the pyrido [1,2-a] pyrimidine derivative for oral administration according to the present invention is characterized in that a surfactant is added to 1 part by weight of the pyrido [1,2-a] pyrimidine derivative. , HLB 12 or more are selected and 0.005 to 10 parts by weight, preferably 0.05 to 1 part by weight, when a mixed carrier is used, 0.05 to 50 parts by weight, It is preferably obtained by blending 0.5 to 10 parts by weight and subjecting it to a mechanical treatment mainly involving impact, compression, friction, shearing and the like, followed by surface treatment.

Pyridone [1,2—a] pyrimidine derivatives include, in addition to AS-35, 9- [4-acetyl-3-hydroxy- 2-n-propyphenoxy) methyl] 1- [2- (1H—Tetrazol-5-yl) ethyl] — 4H—Pyrido [1,2-a] pyrimidine-one-one (referred to as AS-163), 9-[(4-acetyl--3 —Hydroxy-2- (arylphenoxy) methyl] 1-3— (1H—tetrazol-5—yl) 1-4H—pyrido [1,2—a] pyrimidine 1-one (AS—1688) ) And [1- (4-acetyl-2-hydroxy-2-n-propylphenoxymethyl) -1-oxo-pyridoide [1,2, -a] pyrimidine-3-yl] acetic acid (Referred to as AS-148).

As the surfactant used in the present invention, decaglyceryl monolaurate, Polyglycerin fatty acid esters such as hexaglyceryl monolaurate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monoolate; polyethylene glycol fatty acid esters such as polyoxyethylene monostearate; polyoxyethylene Polyoxyethylene alkyl ethers such as lauryl ether; polyoxyethylene castor oils such as polyoxyethylene hardened castor oil; and hydrogenated castor oils; alkyl sulfates such as sodium lauryl sulfate; sucrose stearate; Examples include sucrose fatty acid esters such as sugar palmitate, and these can be used alone or in combination of two or more.

The method of adding the surfactant used in the present invention is not particularly limited. A method of dispersing a pyrididine [1,2-a] pyrimidine derivative in a surfactant solution and drying the dispersion is described. It is preferably used.

Examples of the mixed carrier used in the present invention include cellulose such as crystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crosslinked carboxylmethylcellulose sodium and hydroxymethylcellulose and derivatives thereof, corn starch, potato starch, and hydrid. Examples thereof include starch and derivatives thereof such as loxypropyl starch and sugars such as lactose, sucrose and glucose, and these can be used alone or in combination of two or more.

The equipment used in the present invention may be any equipment intended for impact, compression, friction, and shearing. Examples thereof include rolling ball mills, vibrating ball mills, and planetary ball mills that mainly apply impact and frictional forces. Ball mills, compression milling machines such as angling mills and crushers that mainly apply compressive and frictional forces, and high-speed rotation such as hammer mills, pin mills, and disk mills that mainly apply impact and shear forces -Type impact crushers, such as roller mills and roll crushers that mainly apply compressive force Rolling mill, and a hybridizer that mainly applies an impact force.

The composition of the pyrido [1,2-a] pyrimidine derivative of the present invention may be used, if necessary, as it is or after dilution with a pharmaceutical excipient, as a powder, fine granule, granule, It can be used in the form of tablets and capsules.

Hereinafter, the present invention will be described with reference to Comparative Examples and Examples.

[Comparative Example 1]

The AS-35 lump was processed by a dit mill to obtain a fine powder of AS-35.

[Comparative Example 2]

A fine powder of AS-148 was obtained in the same manner as in Control Example 1, except that the aggregate of AS-148 was used instead of the aggregate of AS-35 in Control Example 1.

[Control Example 3]

Add sucrose stearate (125 g) to water (10 L) to dissolve, cool this solution to 5 ° C or less, and stir AS-35 (500 g) into this solution. The suspension was gradually added to obtain a suspension of AS-35. This suspension was spray-dried using a spray drier to obtain an AS-35 composition.

[Control Example 4]

A composition of AS-148 was obtained in the same manner as in Control Example 3, except that AS-148 (500 g) was used instead of AS-35 (500 g) of Control Example 3.

[Comparative Example 5]

Add AS-35 (1 g), polyethylene glycol 4000 (5 g) and sucrose stearate (0.1 g) to dimethylformamide (20 ml), and add oil at 120 ° C. Dissolved above to obtain AS-35 solution. The solvent was distilled off under reduced pressure to obtain a composition AS-35. [Comparative Example 6]

A composition of AS-148 was obtained in the same manner as in Control Example 5, except that AS-148 (1 g) was used instead of AS-35 (1 g) in Control Example 5. .

[Example 1]

A S-35 (10 g) was mixed with sucrose stearate (5 g), and the mixture was treated for 1 hour with a grinder to obtain an AS-35 composition.

[Example 2]

A composition of AS-148 was obtained in the same manner as in Example 1 except that AS-148 (10 g) was used instead of AS-35 (10 g) in Example 1. Was.

[Example 3]

The composition of AS-35 was operated in the same manner as in Example 1 except that sucrose stearate (1 g) was used instead of sucrose stearate (5 g) in Example 1. I got something.

[Example 4]

A composition of AS-148 was obtained in the same manner as in Example 3, except that AS-148 (10 g) was used instead of AS-35 (10 g) in Example 3. Was.

[Example 5]

Crosslinked sodium carboxymethylcellulose (20 g) was added to AS-35 (20 g), and the mixture was subjected to a treatment for 20 minutes with an angmill to obtain a composition of AS-35.

[Example 6]

A composition of AS-148 was obtained in the same manner as in Example 5 except that AS-148 (20 g) was used instead of AS-35 (20 g) in Example 5. Was.

[Example 7]

Instead of the crosslinked sodium carboxymethylcellulose (20 g) of Example 5, A composition of AS-35 was obtained in the same manner as in Example 5, except that carboxymethylcellulose (10 g) was used.

[Example 8]

A composition of AS-148 was obtained in the same manner as in Example 7, except that AS-148 (10 g) was used instead of AS-35 (10 g) in Example 7. Was.

[Example 9]

Add sucrose stearate (125 g) to water (10 L) to dissolve, cool this solution to 5 ° C or less, and stir AS-35 (500 g) into this solution. The suspension was gradually added to form a suspension of AS-35. This suspension was spray-dried using a spray drier and then treated for 12 hours in a ball mill to obtain an AS-35 composition.

[Example 10]

A composition of AS-148 was obtained in the same manner as in Example 9 except that AS-148 (500 g) was used instead of AS-35 (500 g) in Example 9.

[Example 11]

Sucrose stearate (50 g) was added to and dissolved in water (10 L), the solution was cooled to 5 ° C or less, and AS-35 (500 g) was added to the solution while stirring. The suspension was gradually added to form a suspension of AS-35. This suspension was spray-dried using a spray dryer, and crosslinked sodium carboxymethylcellulose (10 g) was added to 30 g of this suspension, followed by treatment for 12 hours in a ball mill to obtain an AS-35 composition. Obtained.

[Example 12]

A composition of AS-148 was obtained in the same manner as in Example 11 except that AS-148 (500 g) was used instead of AS-35 (500 g) of Example 11. . [Example 13]

Example 11 A composition of AS-163 was obtained in the same manner as in Example 11 except that AS-163 (500 g) was used instead of AS-35 (500 g). .

[Example 14]

Example 11 The procedure of Example 11 was followed, except that AS-168 (500 g) was used instead of AS-35 (500 g), to protect the composition of AS-168. Was ο

[Example 15]

The operation of AS-3 was carried out in the same manner as in Example 11 except that sodium sulphate (50 g) was used instead of the sucrose stearate (125 g) of Example 11. 5 was obtained.

[Example 16]

The composition of AS-148 was obtained in the same manner as in Example 15 except that AS-148 (500 g) was used instead of AS-35 (500 g) in Example 15.

1 Peta o

Next, the dissolution test, stability and bioavailability of the composition of the present invention thus obtained will be described in detail.

① Dissolution test

Using 900 ml of the Japanese Pharmacopoeia second liquid containing 2% polyoxyl stearate 40 as a test solution, the test was carried out by the paddle method of the Japanese Pharmacopoeia dissolution test at 150 rpm. The eluate was filtered through a 0.45 zm membrane filter, the filtrate was diluted 10-fold with dimethylformamide, and the drug concentration in the solution was measured by the absorbance method to determine the elution rate over time. Was. Table 1 shows the elution results of each composition. Table 1 Dissolution rate of each composition

As is apparent from Table 1, the dissolution rate of the fine powder and the composition of the control example was slow, and the dissolution rate was about 23 to 36% 6 minutes after the start of the test, whereas the composition of the example was 55-77% was already eluted, and it was confirmed that the compositions of the examples had excellent elution properties.

② Stability

Place the compositions of Examples 1-14 in an airtight container, 50. 1 month under condition C The samples were stored for a period of time and examined for changes in appearance and for the presence of decomposition products. Changes in appearance were visually observed, and the presence or absence of decomposition products was examined by thin-layer chromatography. All of the compositions of Examples 1 to 14 were yellowish white to grayish yellowish white powder, and no change in appearance was observed at one month after the observation. Also, at the start of storage of the compositions of Examples 1 to 14, two weeks after and one month after, no degradation products were observed.

③ Bioavailability

Using the compositions obtained in Examples 1, 7, and 11, capsules or tablets were produced according to the following formulation and used as test samples. A comparison test of the bioavailability with capsules (hereinafter referred to as control samples) manufactured using the fine powder of Control Example 1 was performed using 6 beagle dogs (body weight: 12 to 14 kg) for one week. After a drug holiday. Fasting was continued from 16 hours before administration to the end of blood collection. Blood collection was performed at 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 4 hours, 6 hours, and 8 hours after the test or control sample was orally administered with 40 ml of water. The amount of AS-35 in plasma was measured by high performance liquid chromatography.

(Prescription 1) Control sample (containing AS-352 Omg in 1 capsule)

Fine powder of Comparative Example 1 50.0 parts Lactose 49.0 parts Magnesium stearate 1.0 part

(Prescription 2) Test sample 1 (containing 20 mg of AS-35 per tablet)

Composition of Example 1 54.5 parts Lactose 12.7 parts Crosslinked carboxymethylcellulose sodium 31.8 parts Magnesium stearate 1.0 part (Formulation 3) Test sample 2 (containing 1 capsule AS-3520 mg) Composition of Example 7 54.5 parts Lactose 44.5 parts Magnesium stearate 1.0 part

(Formulation 4) Test sample 3 (containing A S-350 mg in 1 tablet)

Composition of Example 11 1 77.3 parts Corn starch 21.7 parts Magnesium stearate 1.0 part Comparison of bioavailability parameters in dogs showed that Tablets or capsules produced using the composition of the present invention have better absorption than the control sample, and have a maximum plasma concentration (Cmax) of 2.2 to 2.8 times, each with a small variation and It was confirmed that the effective utilization rate was improved. Table 2 Comparison of bioavailability parameters for each sample

Tnax Cnax AU C

(hr) (Dg / nl) (ng'hr / nl) Control sample 2.0 + 0.7 155 + 185 536 + 432 Test sample 1 1.3 + 0.4 4 392 + 85 996 + 300 Test sample 2 1 7 + 0.6 345 + 123 1250 + 411 Test sample 3 1.5 Sat 0.4 438 + 101 1374 + 395 Time to reach maximum Tnax plasma concentration in the table C window ax Maximum plasma concentration

AUC Area under the plasma concentration curve As described above, the set of pyrido [1,2-a] pyrimidine derivatives of the present invention The product is an oral preparation that has excellent stability over time, improves dissolution properties and bioavailability that cannot be obtained by conventional production methods, and at the same time reduces toxicity. I can say.

Claims

The scope of the claims

1. The following general formula

(Wherein, R represents an n-propyl group or an aryl group, A represents a tetrazolyl group or a carboxyl group, and n represents an integer of 0 to 2). — A) A composition for oral administration which has been subjected to a mechanical surface treatment of a pyrimidine derivative.

2. The composition according to claim 1, comprising a pyrido [1,2-a] pyrimidine derivative and a surfactant or a mixed carrier.

3. Pyridone [1,2—a] pyridine derivative is 9 — [(4-acetyl-1-3-hydroxy-1-2-n-propylphenoxy) methyl] —3— (1H-tetrazol-5-y 1) 4H-pyrido [1,2-a] pyrimidine 14-one, 9-[(4-acetyl-3-hydroxy-2--2-n-propylphenoxy) methyl] — 3— [2— (1H-tetrazole-5-ethyl) ethyl] — 4H-pyrido [1,2—a] pyrimidin-4-one, 9-1 [(4-acetyl-3-hydroxy-1-2-arylphenoxy) methyl] One 3 — (1 H—tetrazol-5-yl) One 4 H—pyrid [1, 2 — a] pyrimidine 14-one or [9-1 (4-acetyl-3-hydroxy-2) n-Propylphenoxymethyl) 1,4-oxo-pyrido [1,2-a] pyrimidine-13-yl] acetic acid is described in claim 1 or claim 2. Composition.