JPH0142924B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to sustained release formulations of nicomol. Nicomol has been widely used as a drug that improves lipid metabolism and peripheral circulation.
The conventional dosage form of Nicomol has been a non-coated tablet, which disintegrates and dissolves quickly. For this reason, experiments by the present inventors have revealed that the drug is rapidly absorbed after oral administration, and nicotinic acid is rapidly released. N. Svedmyr et al. reported that a sudden increase in the blood concentration of nicotinic acid induces flushing (N. Svedmyr et al.
al: Clin.Pharmacol.Therap., 10 , 559, 1969)
are doing.

Flushing is rarely seen with normal Nicomol preparations, which causes anxiety for patients taking the drug and for doctors. Therefore, there has been a demand for pharmaceutical improvements that reduce such side effects.

According to experiments conducted by the present inventors, when an aqueous solution of nicomol is orally administered to dogs, the time to reach the maximum blood concentration (Tmax) is 1/4 to 1/2 hours, whereas when administered as a powder, it is 2 to 3 hours. Also, oral administration of the powder after increasing gastric secretion shows higher blood concentrations than when no treatment is taken, and nicomol is soluble in acidic aqueous solutions but extremely difficult to dissolve in neutral aqueous solutions. These results suggest that the gastrointestinal absorption of nicomol is controlled by its dissolution or release process. Furthermore, when we look at the occurrence of flushing in humans, it often occurs 10 to 20 minutes after taking the drug and disappears after one hour, so it is thought that controlling dissolution in the stomach will lead to the reduction of flushing. Ta. However, excessive control of dissolution in the stomach leads to decreased absorption.

Additionally, the main absorption site for Nicomol is the small intestine.
Since dissolution control in the small intestine may lead to decreased absorption, it was determined that a coating agent that completely dissolves in the small intestine is desirable.

Based on the above findings, it was concluded that an enteric-coated formulation with an appropriate gastric release rate is desirable in order to maintain the absorbability of nicomol and alleviate flushing.As a result of further research, the present invention was developed. completed.

The present inventors disclosed an amorphous nicomol with improved absorbency in a previous application (Japanese Patent Application No. 132289/1989 (Japanese Patent Publication No. 51270/1983)), and this amorphous nicomol was also used in the present invention. can do.

The dispersion medium used in the practice of the present invention may be any pharmaceutically acceptable dispersion medium that is soluble in Nicomol.
Examples include sugar alcohols such as D-mannitol, D-sorbitol, and xylitol, and hydrophilic polymer compounds such as polyethylene glycol 6000.
The mixing ratio of these and Nicomol is 0.05 to 10 parts, preferably 0.1 to 4 parts, per 1 part of Nicomol.

In order to make the mixture of dispersion medium and Nicomol into a spherical shape, it is possible to apply a granulation method using a normal granulator, or to heat and melt Nicomol and at least one of the above dispersion mediums, and then cool the mixture by injection when hot. be done.
Although it is not essential that the core be spherical, it is advantageous for the core to be spherical because it allows for substantially uniform coating during the coating process and ease of handling during packaging.

The enteric coating agent used in the present invention may be one that dissolves in the pH range of 4.5 to 7.5, such as methyl methacrylate methacrylic acid copolymer (Eudragit L, Eudragit S), cellulose acetate phthalate (CAP), hydroxypropyl Methylcellulose phthalate (HP-50,
HP-55), methyl acrylate methacrylic acid
Methyl methacrylate copolymer (MPM-
05, MPM-06), etc., and any substances whose safety for humans has been established may be used, and are not particularly limited to these.

A suitable plasticizer can be added to these coating agents, and coating can be carried out by spraying with an organic solvent or water using a conventional method.

Although an ordinary fluidized bed coating device can be used for coating, a tumbling fluidized bed device Spira Coater (manufactured by Okada Seiko Co., Ltd.) is suitable.

After melting and mixing 200 parts of Nicomol and 800 parts of D-mannitol, the mixture was sprayed and cooled to create a spherical core of 28 to 48 meshes, which was then injected with Eudragit L-30D-55.
By spraying and coating with an aqueous solution, sustained release nicomol granules having the dissolution properties shown in FIG. 1 are obtained. The dissolution test method uses a dissolution test device described in the United States Pharmacopoeia/National Formulary, using a 100-mesh basket and a rotation speed.
100 rpm, Japanese Pharmacopoeia 1st liquid (PH
1.2) 1000ml was used. The amount of nicomol eluted from the granules equivalent to 200 mg of nicomol was determined using UV absorption spectroscopy.

The dissolution rate of sustained-release Nicomol granules differs depending on the coating film rate (Fig. 1), and the 1-hour dissolution rate is 100% for core granules (N), but 50% for granules (Fig. 1). A), 30% (granules B), and 5% (granules C), and the coating amounts of these granules are 20 mg/g, 40 mg/g, and 200 mg/g, respectively.
It was hot.

Figure 2 shows blood concentration curves of cyclohexanol (THC) when these sustained-release granules with different dissolution rates are administered to humans. The AUC (area under the blood concentration-time curve) was 6.9 ± 1.5 (granule A), 4.8 ± 1.5 (granule B), and 1.9 ± 0.1 (granule C) μg・hr/ml for sustained-release nicomol granules, respectively. Yes, the number of flashing occurrences calculated at the same time is 2/2, respectively.
5 (granule A), 0/6 (granule B), 0/6 (granule C)
It was hot. That is, when the coating rate of the enteric coating agent was increased, elution was suppressed for 1 hour, and granule B was able to prevent the occurrence of flashing.

However, in Granules C, which had a higher coating ratio and was completely enteric-coated, flushing could be suppressed, but the absorption rate of Nicomol decreased. In this way, Granule B is used as a sustained-release nicomol that does not cause flashing.
I got it.

These experimental results indicate that there is an optimal coating rate for sustained-release Nicomol, and in this system, the coating amount is 3-12% by weight and the dissolution amount (after 1 hour) is 20-40%. It can be said that it is desirable. Needless to say, the amount of coating varies depending on the type of dispersant, its mixing ratio, and the type of coating base.

In order to examine the effect of the dissolution pH of the enteric coating agent on absorption, HP-45 (hydroxypropyl methylcellulose phthalate), which dissolves at a lower pH, was added to the same core as Granule C (dissolution pH approximately 5.5).
PH of about 4.5) was similarly coated (granules D), and granules C and D, each having a different dissolved PH, were orally administered to beagle dogs. The AUC of blood THC was 7.5 ± 5.7 and 6.5 ± 1.9 μg・hr/ml, respectively, and there was no difference between the two, and there was no effect of dissolution PH of the coating agent on the absorption of Nicomol, and neither PH dissolution It has been found that it is also possible to use enteric-coated coating agents that exhibit sterile properties.

The present invention is the result of intensive research based on the experimental facts as described above, and has for the first time completed a sustained-release formulation of nicomol without side effects such as flushing, which has been long awaited.

The present invention can be implemented in various embodiments. For example, the particles obtained in the present invention may be made into powders, fine granules, granules, capsules filled with gelatin capsules, or tablets by mixing with other additives such as starches, lactose, etc., depending on the particle size. It can be applied to either.

EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 2400 g of D-mannitol was heated to 180° C. and melted, and 600 g of Nicomol was added and stirred well to melt and mix. This solution was sprayed from a nozzle using a spray cooling granulation device and cooled to obtain spherical particles.
Particles of 500 to 800μ were sieved and used as cores for coating. 2130g of Eudragit L30D-55 aqueous solution was added to 1600g of this coating core using a rolling fluid coating device, Spiracoater (Okada Seiko Co., Ltd.).
Coating was carried out using SP-25 type (manufactured by Co., Ltd.).
In a dissolution test of the coated granules using Japanese Pharmacopoeia First Solution (PH 1.2), the dissolution rate after 30 minutes was 20.1%, and after 60 minutes it was 34.5%. As a result of oral administration to humans, the AUC was 4.8 ± 1.5 μg・hr/
ml, and the occurrence of flushing was 0/6.

Example 2 Take 2000 g of the coating core obtained in Example 1, add Eudragit L-90 to 1600 g of ethanol,
The solution obtained by dissolving 80g of
It was coated using. In the dissolution test of the coated granules in the first solution, the dissolution rate after 30 minutes was 21.1%, and after 60 minutes it was 34.8%.

Example 3 Take 1500 g of the coating core obtained in Example 1, dissolve 75 g of HP-45 in 1500 g of ethanol,
This solution was coated using a fluidized bed coating device. The first layer of this coated granule
In the dissolution test in liquid, the dissolution rate after 30 minutes was 20.4
%, and after 60 minutes it was 35.5%.

Example 4 1600g of xylitol and 400g of nicomol
After heating to 180°C and melting and mixing, the mixture was cooled by injection from a nozzle to obtain spherical core particles. Particles of 177 to 297μ were sieved, and a solution obtained by dissolving 1800g of this core and 80g of HP55 in 1800g of ethanol was applied to a spiracoater.
Coating was performed using SP-25 type. In the dissolution test of coated granules in the first liquid, 30
Sustained-release nicomol fine granules were obtained showing a dissolution rate of 21.1% after 60 minutes and 35.2% after 60 minutes.

Example 5 500 g of D-mannitol was heated to 180° C. and melted, 2000 g of Nicomol was added thereto and melted, followed by injection cooling. 149 ~ of the obtained spherical core
Particles of 420μ were sieved and used as a core for coating. Apply 2500g of Eudragit L-30 D-55 aqueous solution to 1500g of this coating core using a spira coater.
Spray coating was performed using SP-25 model.
In the dissolution test of the coated fine particles in the first liquid, the dissolution rate after 30 minutes was 21.5%, and after 60 minutes, the dissolution rate was 21.5%.
It was 35.5%.

As a result of oral administration to humans, the AUC of blood THC was 2.6
It was ±0.7 μg·hr/ml, and the flushing incidence was 0/4.

Example 6 Nicomol 1400g, PEG6000 350g and D
- 140 g of mannitol was mixed, heated and melted, and then cooled by injection.

Spherical particles (297-590μ) were sieved and used as cores for coating.

Add 1200 g of Eudragit L-30D-55 aqueous solution to 500 g of this coating core in the same manner as in Example 5.
g was coated. The dissolution rate of the coated granules in the first solution was 19.5% after 30 minutes and 45.2% after 60 minutes.

Example 7 8250g of D-mannitol was heated and melted at 180°C,
6000 g of Nicomol was added to this and melted and mixed.
When this was spray cooled, spherical microparticles were obtained. Particles of 149 to 297μ were sieved and used as cores for coating.

Spiracoater SP-
Coated with 60 type.

The dissolution rate of the coated fine particles in the first liquid was 29.5% in 1 hour. In addition, as a result of oral administration to humans, the blood THC concentration of C _nax was 1.1 ± 0.68 μ
g/ml, _tnax is 3.0±1.0hr, AUC is 3.6±1.8μg・
hr/ml, and the incidence of flushing was 0/4.

Example 8 50 g of potato starch was added to 1000 g of coated spherical sustained-release Nicomol granules obtained in Example 5.
g, Apicel 50g mixed, Spira Coater SP-
25 was used to spray and granulate 1000 g of a 5% HPC-L aqueous solution. 0.5% of magnesium stearate was mixed with the dried granules, and the tablets were made into tablets having a diameter of 10 mm and a weight of 305 mg per tablet according to a conventional method.

In a dissolution test of this tablet in the first liquid, the dissolution rate after 30 minutes was 25.5%, and after 60 minutes it was 42.6%.

Example 9 265 mg of the fine particles obtained in Example 5 were filled into gelatin capsules to prepare sustained-release nicomol capsules.

[Brief explanation of drawings]

FIG. 1 shows the dissolution test results (dissolution rate of sustained-release nicomol granules) of granules A, B, C and core (N) with different coating amounts obtained in Example 1. FIG. 2 shows the blood THC concentration time curve after human oral administration of sustained-release Nicomol formulation (blood THC concentration after human administration of Nicomol sustained-release granules),
A, B, and C have the same meanings as in FIG.

Claims (1)

[Scope of Claims] 1. A sustained-release nicomol preparation, characterized in that an enteric coating is applied to a core in which nicomol is dispersed in a pharmaceutically acceptable dispersion medium. 2. The sustained-release nicomol preparation according to claim 1, wherein nicomol is amorphous. 3 The dispersion medium is D-mannitol, xylitol,
The preparation according to claim 1 or 2, characterized in that it is selected from D-sorbitol and polyethylene glycol. 4. The formulation according to any one of claims 1 to 3, characterized in that the core consists of 20 to 90% by weight of nicomole and the remainder a dispersion medium. 5. The preparation according to claim 3 or 4, wherein the core is substantially spherical. 6. The sustained release according to any one of claims 1 to 6, characterized in that the enteric coating agent has an elution pH selected from the range of about 4.5 to about 7.5. sexual nicomol preparation. 7.Enteric coated agent is a sustained release Nicomol formulation 3~
The sustained-release nicomol preparation according to any one of claims 1 to 6, characterized in that the amount is 12% by weight. 8. The pharmaceutical formulation according to any one of claims 1 to 7, wherein the sustained release nicomol preparation is any one of granules, fine granules, powders, gelatin capsules, and tablets.