JPH0337529B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a highly absorbable amorphous 1,4-bis[(2-methoxy-4-n-propropylphenoxy)acetyl]piperazine (hereinafter referred to as simetride) and compositions thereof. Simetride is 1,4-bis[(2-methoxy-
The generic name 4-n-propylphenoxy)acetyl]piverazine was developed by the present applicant as Patent No. 463125, and has been widely used as a non-pyrine antipyretic analgesic. The method for producing it is as described in the above patent specification, by reacting substituted phenols with N,N'-bis-haloacetylpiperazine. The cymetride obtained by this method has needle-like or plate-like crystals,
X-ray diffraction pattern peculiar to simetride (first
Time-a) is shown. These crystals are sparingly soluble in water, and many improvements have been required to increase absorption into the body and to achieve early onset of effects. With the aim of improving this solubility and absorbability, the present inventors conducted various studies, and in the case of simetride, when examining the solubility by micronization, the average particle size of 50 μm was reduced to 1.4 μm. Even if it was pulverized, its solubility was only improved by about twice as much, and it was found that there was a limit to the improvement in solubility by pulverization. Therefore, the present inventors conducted extensive research with the aim of developing cymetride with even higher solubility and absorbability.
It was discovered that after melting, it becomes amorphous when cooled and solidified. The inventors discovered that this amorphous simetride has significantly higher absorbency than conventional crystalline simetride, leading to the completion of the present invention. Although the pharmacological action of the amorphous simetride of the present invention is essentially the same as that of crystalline simetride, the improved absorption makes it possible to significantly reduce the dosage. That is, the purpose of the present invention is to contain simetride at a concentration of 0.5 to
The object of the present invention is to provide amorphous cymetride and an amorphous cymetride composition that have good absorbability by a method such as dispersing it in 10 times the amount of PVP. The highly absorbable amorphous cymetride and composition thereof of the present invention can be obtained by the method described below. i.e. 0.5 to 10 times the weight of PVP as simetride
When PVP is dissolved in ethanol, powdered (crystalline) cymetride is added and mixed, and heated to 120-130°C, cymetride PVP melts. This is cooled and solidified to obtain amorphous simetride dispersed in PVP. With this production method, amorphous cymetride can be obtained without the addition of ethanol, but adding ethanol is convenient in terms of operation because it can lower the melting temperature of cymetride and PVP. The solvent used here only needs to dissolve PVP;
It is not necessarily necessary to dissolve cymetride. In addition to the ethanol mentioned above, acetone, chloroform, methanol, water, etc. can be used as a solvent, but ethanol is most preferred from the viewpoint of the effect of residual solvent in the product on living organisms, ease of use during manufacturing, or safety. . Although this amount of solvent is not sufficient to dissolve cymetride, it is an economical amount that completely dissolves PVP and can be mixed uniformly with cymetride, and
The inventors have discovered that the melting temperature of cymetride and PVP can be lowered to below the melting point of cymetride, and this point is also a feature of the present invention. A good weight ratio of ethanol to PVP is 0.1 to 10 times, but the amount is not limited. There is no particular limit to the molecular weight of PVP used here, but if the molecular weight is too low, it will be difficult to suppress the crystallization of simetride, and if it is too high, the solubility in the solvent will be poor, so it is generally 1 to 1. A range of 160,000 is good. In addition, PVP is essential for making simetride amorphous, and simetride and PVP
The ratio is 1 part by weight of cymetride to 1 part by weight of PVP.
The amount is 0.5 to 10, preferably 1 to 5 parts by weight. PVP
If the amount used is less than 0.5 parts, it is difficult to obtain an amorphous form of simetride, and conversely, if it exceeds 10 parts, amorphous simetride can be easily obtained, but the active ingredient content in the composition decreases, and its As a result, the dose or the size of the preparation is undesirably increased. As a method for producing amorphous cymetride, in addition to the above-mentioned method of heating and melting cymetride and PVP, after dissolving both cymetride and PVP in an appropriate amount of chloroform, chloroform is distilled off under reduced pressure.
Method of forming a coprecipitate: Add excipients to a fluidized bed granulator (coating device) and mix with simetride.
A method can be used in which a hot ethanol solution containing PVP is sprayed, coated and granulated, and then dried. In addition, to form a dosage form, commonly used excipients are added to a mixture of cimetride and PVP with stirring, heated, melted, cooled and solidified, and then powdered or granulated using an appropriate means such as crushing. The preparation can be made into any form, shape, or size, such as granules, tablets by mixing with an appropriate drug, and capsules by filling into hard capsules. As is clear from Tables 1 and 2, the amorphous cymetride composition obtained as described above has 32 times the absorbability and approximately 10 times the analgesic effect compared to crystalline simetride, and has excellent absorbability and Both the analgesic effect and the acute toxicity are extremely low, making the present invention extremely useful industrially. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples. Example 1 50 g of PVP k-30 (average molecular weight 40,000) was added and dissolved in 100 ml of ethanol, 25 g of crystalline simetride was added thereto, kneaded, heated at 130°C for 60 minutes to melt, ethanol was distilled off, and the mixture was dissolved. After cooling, it was pulverized to obtain an amorphous simetride composition. A portion of this was used for the following tests. (1) X-ray diffraction, (2) Absorption test using beagle dogs, (3)
Medicinal efficacy test 1 by Randall-Selit method X-ray diffraction Measurement was performed using an X-ray diffractometer manufactured by Rigaku Denki Co., Ltd. The results are shown in Figure 1. In the figure, a shows an X-ray diffraction pattern of crystalline cymetride, with the horizontal axis showing the diffraction angle (2θ) and the vertical axis showing the intensity. As is clear from the figure, in crystalline simetride, 2θ
Many peaks with angles of =5 to 30° are seen. In the figure, b is the X-ray diffraction pattern of the powder obtained in this example, but no diffraction peak indicating crystallinity was observed, indicating that cymetride in this powder was amorphous. 2. Dog administration test The equivalent of 1.2 to 2.4 g of cimetride was orally administered to male beagle dogs, and the serum concentration was measured over time.
The pharmacokinetic parameters obtained are shown in Table 1. When comparing the area under the serum concentration curve (AUC) for 1 hour, amorphous simetride showed 32 times higher absorption than crystalline simetride.

[Table] * 0 to 7 hours 3 Drug efficacy test using Randall-Serritt method Using Wistar rats (male), Randall-Serritt method
A drug efficacy test was conducted using the Sellitz method, and the results are shown in Table 2. The analgesic effect of amorphous simetride was approximately 10 times higher than that of crystalline simetride.

[Table] Dosage Example 2 75g of the amorphous simetride powder obtained in Example 1 was
Sieve through a 30-mesh sieve to obtain 62.5 g of lactose and L-hydroxypropyl cellulose (L-HPC).
61.5 g and 1.0 g of magnesium stearate were added and tableted in a conventional manner to obtain small tablets with a diameter of 8 mm, each tablet (200 mg) containing 25 mg of cymetride. Example 3 PVP k-15 (average molecular weight
10000) and dissolve it, add 25g of crystalline simetride and 75g of lactose while stirring,
The mixture was thoroughly mixed, heated at 130° C. for 60 minutes to melt, allowed to cool, and then ground to obtain amorphous simetride. In the X-ray diffraction pattern of this powder, no peaks other than lactose were observed, indicating that cymetride was amorphous. Fill 150mg of this powder into a hard capsule No. 3,
Capsules were obtained. Example 4 30 g of PVP k-30 was added to 10 g of crystalline cymetride, pulverized and mixed in a mortar, heated to 130° C., melted, and cooled to obtain a crushed powder. This powder showed no X-ray diffraction peaks and was amorphous. 40g of this powder was sieved using a 20 mesh sieve, 10g of lactose was added and mixed, and 500mg of cymetride was
Granules containing mg were obtained. Example 5 10 g of crystalline cimetride and 40 g of PVP k-30 were dissolved in 200 ml of chloroform, and then the chloroform was distilled off under reduced pressure, and the residue was powdered. It was confirmed from the X-ray diffraction pattern that this powder was amorphous. 50 g of lactose was added to 50 g of the obtained powder and mixed to obtain granules containing 50 mg of simetride in 500 mg. Example 6 Put 425 g of lactose (80 mesh) into a fluidized bed granulator and fluidize it, and separately add 25 g of crystalline cymetride PVP k-
30 50g was dissolved in 2000ml of ethanol heated to 60°C, the solution was sprayed onto the lactose, coated and granulated, and dried to obtain fine granules. This product is a granule containing 50mg of cimetride per gram. The powder obtained here was confirmed to be amorphous from the X-ray diffraction pattern. Example 7 Add and dissolve 200 g of PVP k-30 in 400 ml of ethanol, and add crystalline simetride to the solution while stirring.
Add 100g, lactose 190g and caffeine 10g,
The mixture was mixed well, heated at 130°C for 60 minutes to melt it, allowed to cool, and then crushed into powder. In the X-ray diffraction pattern of this powder, no peaks other than lactose were observed, indicating that cymetride was amorphous. Acute toxicity test In 5 week old Wistar rats (10 rats per group),
15,250 mg/Kg (equivalent to 3,050 mg of amorphous simetride) of the preparation obtained in Example 7 was orally administered and observed for two weeks, but no deaths were observed and the toxicity of this preparation was judged to be extremely low. It was done.

[Brief explanation of drawings]

FIGS. 1a and 1b are charts showing the X-ray diffraction patterns of crystalline cymetride and amorphous cymetride.

Claims (1)

[Scope of Claims] 1 1,4-bis[2-methoxy-4-n-propylphenoxy)acetyl]piperazine (hereinafter referred to as simetride) to polyvinylpyrrolidone (hereinafter referred to as simetride)
An amorphous simetride composition obtained by dispersing it in PVP). 2. The amorphous cymetride composition according to claim 1, wherein the PVP has an average molecular weight of 10,000 to 160,000. 3. The amorphous cymetride composition according to claim 1 or 2, wherein PVP is 0.5 to 10 times the weight of cymetride. 4. Claim 1 obtained by suspending powdered simetride in PVP dissolved in a solvent, heating and cooling it.
The amorphous cymetride composition according to any one of Items 1 to 3. 5. The amorphous cymetride composition according to any one of claims 1 to 4, which is obtained by dissolving both cymetride and PVP in a solvent and then removing the solvent. 6 Claim 4 in which the solvent is ethanol
The amorphous cymetride composition according to any one of items 1 to 5. 7. The amorphous cymetride composition according to any one of claims 1 to 6, which is formulated with additives selected from ingredients that can be added as a pharmaceutical and is made into granules, tablets, or capsules.