Patent Application
20080064713
The present invention is explained in more details below by working examples and test examples, but not limited to these examples.
A dry syrup preparation having the following composition (w/w%) and a control preparation are prepared.
According to the composition table above, a necessary amount of each material is calculated based on the manufacturing scale. Sucrose, hydroxypropyl cellulose(HPC-SSL, the viscosity of 2% aquous solution at 20° C.<3.0 mPa s) and silicon dioxide hydrate were used as a sugar, binder and lubricant, respectively.
In a case of Example 1, 20 g of loratadine and 1,958 g of sucrose were weighed and passed through a sieve with opening of 425 μm, and the resulting powder was mixed in the mixing granulator (High speed mixer Model 10, manufactured by FUKAE Powtec/aditator:300 rpm, chopper:2500 rpm) for one minute. Then, 120 g of 10 (w/w) % aquous solution of hyrdoxypropyl cellulose was added and granulated for 3 minutes, dried in the fluidized bed-granulator (Granulating Dryer WSG-5 Model, manufactured by Okawara MFG Co.Ltd., blast temperature:55° C.) and drying was terminated when the product temperature reached 45° C. After that, the product was granulated with the granulator (Powermill, P-3 Model) using a basket with opening of 1038 μm. If necessary, fine powders may be eliminated using a classifier (Vibration Separator, TMC-50-2S Model, manufactured by Tokuju Corporation)having wire gauze with opening of 154 μm. 9 g of silicon dioxide hydrate, which was a necessary amount based on the calculation according to the composition table above, was added to the resulting granulation (1,791 g) and mixed in the mixer (Mixer 8LV Model) to give the dry syrup preparation.
In a case of Control 1, necessary amounts of loratadine and sucrose are weighed and passed through a sieve with opening of 425 μm, and the resulting powder was treated in the similar way as Example 1 except that 120 g of purified water was added in place of hydroxypropyl cellulose when granulated. Control preparations 2-5 are also produced in the similar way as Example 1, but polysorbate 80 (surfactant) or silicon resin (defoaming agent) are also included in these preparations.
According to the composition table of Table 1 above, a necessary amount of each material is calculated based on the manufacturing scale. In a case of Example 1, 20 g of loratadine and 1,958 g of sucrose were weighed and passed through a sieve with opening of 425 μm, and the resulting powder was mixed in the mixing granulator (High speed mixer Model 10, manufactured by FUKAE Powtec/aditator:300 rpm, chopper:2500 rpm) for one minute. Then, 120 g of 10 (w/w) % aqueous solution of hyrdoxypropyl cellulose was added and granulated for 3 minutes. After then, it was granulated in the extrusion granulator (Cylindrical Granulator, manufactured by Yamada Iron Works Co.Ltd. dice diameter: 0.53 mm), dried in the fluidized bed-granulator (Granulating Dryer WSG-5 Model, manufactured by Okawara MFG Co. Ltd., blast temperature:55° C.) and drying was terminated when the product temperature reached 45° C. After that, the product was granulated with the granulator (Powermill, P-3 Model) using a basket with opening of 1038 μm. If necessary, fine powders may be eliminated using a classifier (Vibration Separator, TMC-50-2S Model, manufactured by Tokuju Corporation)having wire gauze with opening of 154 μm. 9 g of silicon dioxide hydrate, which was a necessary amount based on the calculation according to the composition table above, was added to the resulting granule (1,791 g) and mixed in the mixer (Mixer 8LV Model) to give the dry syrup preparation.
In a case of Control 1, necessary amounts of loratadine and sucrose are weighed and passed through a sieve with opening of 425 μm, and the resulting powder was treated in the similar way as Example 1 except that 120 g of purified water was added in place of hydroxypropyl cellulose when granulated. Control preparations 2-5 are also produced in the similar way as Example 1, but polysorbate 80 (surfactant) or silicon resin (defoaming agent) are also included in these preparations.
According to the composition table of Table 1 above, a necessary amount of each material is calculated based on the manufacturing scale. In a case of Example 1, 50 g of loratadine and 4,895 g of sucrose were weighed and passed through a sieve with opening of 425 μm, and the resulting powder was mixed in the fluidized bed granulator (Granulating Dryer WSG-5 Model, manufactured by Okawara MFG Co.Ltd.) for five minutes. Then, 1,500 g of 2 (w/w) % aquous solution of hyrdoxypropyl cellulose was sprayed (spray speed:30 g/min, spray pressure:0.15 MPa) and the it was dried until the product temperature reached 45° C. After that, the product was granulated with the granulator (Powermill, P-3 Model) using a basket with opening of 1038 μm. If necessary, fine powders may be eliminated using a classifier (Vibration Separator, TMC-50-2S Model, manufactured by Tokuju Corporation)having wire gauze with opening of 154 μm. 24 g of silicon dioxide hydrate, which was a necessary amount based on the calculation according to the composition table above, was added to the resulting granulation (e.g., 4,776 g) and mixed in the mixer (Mixer 22 LV Model) to give the dry syrup preparation.
In a case of Control 1, necessary amounts of loratadine and sucrose are weighed and passed through a sieve with opening of 425 μm, and the resulting powder was treated in the similar way as Example 1 except that 1,500 g of purified water was used as a spray solution of granulation. Control preparations 2-5 are also produced in the similar way as Example 1, but polysorbate 80 (surfactant) or silicon resin (defoaming agent) are also included in these preparations.
The preparations of example and control described above were evaluated from the five aspects of (i) sedimantation property, (ii) dispersibility, (iii) re-dispersibility, (iv) presence or absence of supernatant, and (v) defoaming property.
(i) Method for Evaluating Sedimentation Property
5 g of the dry syrup preparation was thrown into 100 mL of water in a measuring cylinder with a stopper, and the time required for the preparation to sediment below the water surface was measured. It was judged “YES” if it sedimented within one minute, and judged “NO” if it did not.
(ii) Method for Evaluating Dispersibility
5 g of the dry syrup preparation was thrown into 100 mL of water in a measuring cylinder with a stopper. After putting a stopper in the cylinder quickly, the top of the measuring cylinder was held with one hand and the bottom was held with the other hand, and it was turned upside down by rotating 180-degree around the bottom and turned back five times at a speed of two seconds for the upset and return, and left at rest. According to visual observation, it was judged Excellent, if the mixture was clouded in whole. If the mixture was not clouded, the cylinder was upset and turned back fifteen times more and left at rest. According to visual observation, it was judged Yes, if the mixture was clouded in whole, and judged No if it was not.
(iii) Method for Evaluating Re-Dispersibility
The centrifuge tubes used in the test of evaluating dispersibility were left at room temperature for a day. After then, they were judged in the same method as evaluating dispersibility described above.
(iv) Presence or Absence of Supernatant
Just after evaluating dispersibility, stoppers of the centrifuge tubes were taken off and the contents were visually observed from above. With respect to the presence or absence of supernatant, it was judged “YES” if no suspended substance is observed within one minute, and judged “N0”, if observed.
(v) Method for Evaluating Defoaming Property
With respect to the defoaming property, it was judged “YES” if bubbles are decreased and the water surface was observed within one minute after evaluation of the dispersibility, and judged “No” if not. In the present preparation, almost of bubbles disappeared within one minute even if they were about 1 cm in height above the surface just after the shaking. But, bubbles not always disappear and sometimes small bubbles may be left. Accordingly, the term, “bubbles are decreased within one minute” means that the surface is observed within one minute, includes cases that small bubbles are left on the surface, and it is preferable that all the bubbles disappeared.
The preparation of Control 1 does not include hydroxypropyl cellulose, and the preparations of Control 2-5 additionally include a surfactant and a defoaming agent; in these points the preparation of Control 1-5 are different from the present invention respectively. Thus, it is shown that the dry syrup preparation, wherein hydroxypropyl cellulose is used as a single binder, and either a surfactant or a defoaming agent is not included, may improve the dispersibility of loratadine in water.
According to the procedure described in Example 1, preparations of the compositions shown in the Table 4 below were prepared.
According to the methods described in Example 1, the homogenous dispersibilities of the preparations in Example 2-7 were evaluated. The result is shown in Table 5 below.
The results showed that maltitol, mannitol, lactose, and/or starch may be useful to improve the homogenous dispersibility in the same way.
According to the procedure described in Example 1, preparations of the compositions shown in the Table 6 below were prepared.
According to the methods described in Example 1, the homogenous dispersibilities of the preparations in Example 8-11 were evaluated. The result is shown in Table 7 below.
The result showed that the combination of hydroxypropyl cellulose with crystalline cellulose carmellose sodium, sodium alginate, methyl cellulose, and carmellose sodium might further improve the homogenous dispersibility.
The dry syrup preparation of the present invention provides a homogenous dispersion without bitter taste, and the preparation is easily taken by children who dislike a medicine or by elderly persons having difficulty swallowing. Furthermore, it is handy, and weighing and preparing divided powder of this preparation are easy. Accordingly the present invention provides a useful medicine.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2003-290052 | Aug 2003 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP04/11333 | 8/6/2004 | WO | 00 | 3/8/2006 |
