JPH0319204B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method of coating ibuprofen with a pharmaceutically acceptable solid fat to obtain an ibuprofen formulation. Ibuprofen is a widely used non-steroidal anti-inflammatory drug administered orally. Since ibuprofen is insoluble in water and has a unique taste and odor that strongly irritate the tip of the tongue, it has been difficult to administer to young children in particular. In order to overcome the above-mentioned unfavorable properties of ibuprofen, methods have been proposed to include ibuprofen with cyclodextrin. However, when using cyclodextrin, it must be dissolved in water, and therefore water must be evaporated after the clathrate compound is formed, which requires a large amount of heat. Therefore, an object of the present invention is to solve the above-mentioned problems. The present inventors have conducted intensive studies to develop an easy-to-administer ibuprofen formulation that does not have the above-mentioned drawbacks, and have found that ibuprofen is mixed with solid fat, heated and melted, and then spray solidified. It has been found that an ibuprofen preparation that does not have a bitter taste and is less irritating to the gastric mucosa and wall can be obtained. The method for producing an ibuprofen preparation according to the present invention involves melting ibuprofen and a pharmaceutically acceptable solid fat at a temperature of 75 to 95°C, and then spraying and solidifying the resulting melt at an ambient temperature of 35°C or lower. It is characterized by According to the method of the invention powder coated products are obtained, to which it is also possible to add excipients, disintegrants, corrective agents, etc. These coated products can be formulated in the customary manner in the form of granules and, by addition of suitable additives, in the form of dry syrups. The ibuprofen mixed with the solid fat in the present invention has a melting point of 75-77°C. Therefore, the mixing and melting operation of ibuprofen and solid fat is carried out at a temperature higher than the melting temperature of ibuprofen, i.e.
Preferably it is carried out at 75°C to 95°C. Usually about 85
Stirring for about 30 minutes at a temperature of ~95°C followed by spray congealing at a temperature of about 85-95°C. Further, the mixing melting and spray solidification operations in the present invention may be carried out according to a conventional method using commonly used equipment. Examples of the solid fat used to produce the ibuprofen preparation in the method of the present invention include edible hydrogenated beef tallow flakes (manufactured by Miyoshi Oil Co., Ltd.);
Hydrogenated oils such as beef edible hydrogenated oil (manufactured by Miyoshi Yushi Co., Ltd.) can be mentioned. A typical example of the production of an ibuprofen preparation using the method of the present invention is as follows. Stirring time: 30 minutes Stirring temperature: 90°C Inlet temperature: 10°C Outlet temperature: 20°C Drying air: 13.6m ³ /min Sample flow rate: 200ml/min Ibuprofen used to produce ibuprofen preparation in the method of the present invention and pharmaceutically acceptable solid fat is preferably 1:2 to 1:20, especially 1:9. If the ratio of solid fat used is excessive, the ratio of solid fat to ibuprofen will be significantly large, and the weight and volume of the preparation will be too large to obtain the desired ibuprofen preparation. Conversely, if the proportion of solid fat used is too low, the bitterness suppression rate will decrease. Several tests were conducted on the ibuprofen preparation obtained according to the present invention while comparing it with ibuprofen bulk powder. <Bitterness Test> The bitterness of the ibuprofen preparation obtained according to the present invention was examined. 35 ml of water was added to the ibuprofen formulation of the invention in an amount corresponding to 0.1 g of ibuprofen, stirred for 5 minutes and then filtered off with suction. The absorbance of the obtained liquid was measured, and the inhibition rate was calculated from this absorbance using ibuprofen bulk powder as a control. The results obtained are shown in Table 1.

[Table]
As can be seen from Table 1 above, the ibuprofen preparation according to the present invention reduces the bitterness of the bulk ibuprofen powder.
Suppress by 50% or more. Therefore, by the method of the present invention,
It can be seen that the bitterness of ibuprofen can be significantly suppressed. <Stomach irritation test> The irritation of the ibuprofen preparation obtained according to the present invention to the stomach was investigated. Ten samples each of the ibuprofen preparation and ibuprofen bulk powder obtained according to the present invention were converted into ibuprofen in a pyloric ligation rat (Shay rat).
It was administered at a dose of 320 mg/Kg, and 3.5 hours later, the stomach was removed and the resulting ulcer was examined. The results are shown in Table 2.

[Table] When a t-test was performed using the Aspin-Weloh method, a significant difference was observed at the 5% significance level in both the ulcer coefficient and the number of ulcers (0.2 mm or less) for the coated product in response to direct drug stimulation. Ta. Furthermore, with the ibuprofen bulk powder, many linear ulcers of 0.2 mm or more were observed due to direct drug stimulation, whereas only petechial hemorrhagic ulcers (0.2 mm or less) were observed with the coated product.
As described above, by formulating ibuprofen according to the present invention, irritation to the gastric mucosa and stomach wall can be significantly reduced. <Blood concentration and bioavailability> Granules were prepared by adding excipients to the ibuprofen preparation obtained according to the present invention, and by a crossover method with a commercially available ibuprofen preparation, the plasma concentration of ibuprofen in humans was determined. Concentration (μg/ml)
was measured over time. Each sample was orally administered to 10 subjects at a dose of 200 mg per person in terms of ibuprofen. The results obtained are shown in FIG. In FIG. 1, the solid line represents the ibuprofen concentration in human plasma after administration of the granules prepared from the coated product of Example 4, and the dotted line represents the ibuprofen concentration in human plasma after administration of the commercially available ibuprofen granules. As can be seen from Figure 1, the solid fat in the coated product of the process of the invention has no effect on the absorption of ibuprofen, and the bioavailability of the granules prepared from the coated product of the process of the invention is commercially available. of ibuprofen granules. As mentioned above, by coating ibuprofen with solid fat, irritation to the gastric mucosa and stomach wall is significantly suppressed, and addition of solid fat does not affect absorption of the drug, and furthermore, bitterness is sufficiently suppressed. Therefore, it is thought that ibuprofen will be easier to take, especially easier to administer to infants. Hereinafter, the method of the present invention will be explained with reference to the following examples, but it should be noted that these are not intended to limit the present invention in any way. Example 1 The following ingredients: 150 g of ibuprofen and 850 g of "edible hardened beef tallow flakes" manufactured by Miyoshi Oil Co., Ltd. were mixed, heated and melted, and the temperature of the melt was adjusted to 80°C.
The temperature was maintained at around 20°C and the mixture was sprayed and solidified. As a result, a powdered product was obtained. The bitterness suppression rate of the obtained product was 65%. Example 2 The following components: Ibuprofen 200g A powdered product was obtained in the same manner as in Example 1 from 800g of "edible tallow hydrogenated oil flakes" manufactured by Miyoshi Oil Co., Ltd. The bitterness suppression rate was 60%. Example 3 The following ingredients: Ibuprofen 250g A powdered product was obtained in the same manner as in Example 1 from 750g of "Edible Hardened Beef Tallow Oil Flakes" manufactured by Miyoshi Oil Co., Ltd. The bitterness suppression rate was 55%. Example 4 The following ingredients: 100 g of ibuprofen and 900 g of "edible hardened beef tallow flakes" manufactured by Miyoshi Oil Co., Ltd. were mixed, heated and melted, and then the temperature of the melt was adjusted to 90°C.
The mixture was kept at a temperature of 17°C for spray solidification.
As a result, a powdered product was obtained. The bitterness suppression rate was 85%. Example 5 A powdered product was obtained in the same manner as in Example 4 from 150 g of ibuprofen and 850 g of "hydrogenated beef oil" manufactured by Miyoshi Oil Co., Ltd. The bitterness suppression rate was 80%. Example 6 The following components: Ibuprofen 200g A powdered product was obtained in the same manner as in Example 4 from 800g of "Cow Edible Hydrogenated Oil" manufactured by Miyoshi Oil Co., Ltd. The bitterness suppression rate was 70%. Example 7 A powdered product was obtained in the same manner as in Example 4 from 250 g of ibuprofen and 750 g of "hydrogenated beef oil" manufactured by Miyoshi Oil Co., Ltd. The bitterness suppression rate was 65%. Example 8 The following ingredients: 150 g of ibuprofen and 850 g of "hydrogenated beef oil" manufactured by Miyoshi Oil Co., Ltd. were mixed, heated and melted, and the temperature of the melt was adjusted to 85°C.
It was sprayed and solidified at an ambient temperature of 35°C. As a result, a powdered product was obtained. The bitterness suppression rate was 50%.

[Brief explanation of the drawing]

FIG. 1 is a graph showing changes over time in the average concentration of ibuprofen in human plasma.

Claims (1)

[Claims] 1. A method characterized by melting ibuprofen and a pharmaceutically acceptable solid fat at a temperature of 75 to 95°C, and then spraying and solidifying the resulting melt at an ambient temperature of 35°C or lower. A method for producing an ibuprofen preparation. 2. The manufacturing method according to claim 1, wherein ibuprofen and pharmaceutically acceptable solid fat are used in a weight ratio of 1:2 to 1:20 (former: latter).