JP6439503B2 - Solid preparation - Google Patents

Description

  The present invention relates to a solid preparation containing loxoprofen or a salt thereof and carbocysteine.

Currently, in over-the-counter drugs, preparations containing a plurality of medicinal ingredients are widely used. For example, the common cold medicine contains many components such as antipyretic analgesics, antitussive expectorants and rhinitis drugs. These drugs need to be excellent in stability as a preparation from the viewpoint of effectiveness and safety.
Loxoprofen or a salt thereof is a non-steroidal antipyretic analgesic that has a proven track record as an ethical drug. This component has a feature such that side effects such as gastric disorders are relatively light and is widely used.

  On the other hand, carbocysteine is an expectorant action in diseases such as upper respiratory tract inflammation (pharyngitis, laryngitis), acute bronchitis, bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, and drainage action in diseases such as chronic sinusitis It has a high track record in medical use as a highly safe expectorant.

  Solid formulations containing loxoprofen and carbocysteine are known, and interaction occurs when these are added, so as a method to suppress the interaction by adding tranexamic acid so far and mixing Have been reported (Patent Documents 1 and 2).

JP 2011-246441 A JP 2011-246437 A

  However, according to this method, in order to suppress the interaction between loxoprofen and carbocysteine, it was necessary to add tranexamic acid, which is a pharmaceutical active ingredient. Further, the present inventors have found that in the case of a preparation containing loxoprofen and carbocysteine, the interaction is particularly prominent when tableted into tablets.

In view of such circumstances, the present inventors have conducted various studies on the stabilization of pharmaceutical preparations containing loxoprofen and carbocysteine. As a result, it is surprising that the above problem can be solved by adding a specific fluidizing agent. The headline and the present invention were completed.
That is, the present invention
(1) (a) loxoprofen or a salt thereof, (b) carbocysteine, and (c) a light anhydrous silicic acid and / or calcium silicate,
(2) The solid preparation according to (1), wherein the solid preparation is a tablet, granule, powder, capsule or pill,
It is.

  The pharmaceutical preparation of the present invention can suppress the interaction between loxoprofen and carbocysteine. Therefore, it is possible to provide a solid preparation containing loxoprofen and carbocysteine in which the preparation is prevented from being colored and consolidated for a long time.

  Loxoprofen or a salt thereof used in the solid preparation of the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate with water, alcohol and the like. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium dihydrate.

  The carbocysteine used in the solid preparation of the present invention is L-carbocysteine described in the 16th revised Japanese pharmacopoeia and can be produced by a known method or commercially available.

  The content of loxoprofen or a salt thereof in the solid preparation of the present invention is not particularly limited as long as it shows the medicinal effect, but is 5 to 30 in terms of loxoprofen sodium anhydride relative to the total mass of the solid preparation. Mass% is preferred.

  The carbocysteine content in the solid preparation of the present invention is preferably 20 to 50% by mass relative to the total mass of the solid preparation.

  The specific fluidizing agent of the present invention means light anhydrous silicic acid and / or calcium silicate shown as component (c).

Light anhydrous silicic acid is a known compound described in the 16th revised Japanese Pharmacopoeia (JP16), such as Aerosil manufactured by Nippon Aerosil Co., Ltd. is there.

  Calcium silicate is a known compound that is known as an excipient with a high oil absorption and is widely used in pharmaceuticals and cosmetics. Examples include Fluorite R manufactured by Tomita Pharmaceutical and Fluorite RE manufactured by Eisai Food Chemical. is there.

  Moreover, 0.5 mass%-30 mass% are preferable with respect to the solid formulation total mass, and, as for content of (c) component in the solid formulation of this invention, More preferably, it is 1-25 mass%.

The dosage form of the solid preparation of the present invention includes powders, fine granules, granules, pills, tablets (including film-coated tablets, sugar-coated tablets, laminated tablets), capsules, dry syrups, lozenges, etc. Examples include parenteral preparations such as drugs, but granules, powders, capsules, pills or tablets are particularly preferable. What is necessary is just to manufacture by arbitrary usual methods according to the dosage form. Examples of the granulation method include a fluidized bed granulation method, an extrusion granulation method, a rolling granulation method, and a spray granulation method, and preferably a stirring granulation method. A) component, (b) component, and (c) component are mixed and manufactured. Moreover, after mixing (a) component, (b) component, and (c) component, it granulates and manufactures. Moreover, the granulated material containing (a) component and the granulated material containing (b) component are manufactured separately, and after mixing these, (c) component is added and manufactured. In that case, the granulated product containing the component (a) or the granulated product containing the component (b) may contain the component (c). In that case, after mixing the granulated product, Addition is not essential.
After manufacturing in this way, these may be coated. Moreover, if an active ingredient and a conventional additive are mix | blended suitably and it compresses, a tablet can be obtained.

  In addition to loxoprofen or a salt thereof and carbocysteine and light anhydrous silicic acid or calcium silicate, other known additives such as excipients, disintegrants, binding agents are included in the pharmaceutical preparation of the present invention. Agents, lubricants, antioxidants, coating agents, colorants, flavoring agents, surfactants, plasticizers and the like can be blended.

  Below, this invention is demonstrated further in detail based on an Example and a comparative example. In addition, the manufacturing method of the solid formulation of this invention is not limited to the formulation example described in the Example.

(Examples 1-2 and Comparative Examples 1-3)
Manufacturing method of formulation Each component and the amount shown in Table 1 are weighed and weighed and mixed, and 400 mg of the obtained pharmaceutical composition is weighed, and 12 kN using a tabletop simple tablet molding machine (trade name: HANDTAB; manufactured by Ichibashi Seiki Co., Ltd.). Tableting was performed to obtain a tablet having a tablet diameter of 11 mm.

Example 3
Preparation Method of Formulation Each component and the amount of each component (A) and (B) shown in Table 2 are weighed and mixed uniformly, and then each obtained mixed powder is granulated by wet stirring granulation method, Granule A and granulated product B were obtained. After mixing the obtained two types of granules, 13.5 g of light anhydrous silicic acid, 81 g of low-substituted hydroxypropyl cellulose, and 13.5 g of magnesium stearate, a rotary tableting machine (trade name: VIRGO519SS1AZ; Kikusui Seisakusho Co., Ltd.) And tableting with a tablet diameter of 9 mm was obtained.

(Example 4)
Preparation Method of Formulation The C component and the amount shown in Table 3 were weighed and granulated in the same manner as in Example 3 to obtain a granulated product. The obtained granulated product was mixed with 54 g of light anhydrous silicic acid, 90 g of low-substituted hydroxypropylcellulose and 9 g of magnesium stearate, and then tableted in the same manner as in Example 3 to obtain tablets with a tablet diameter of 9 mm.

(1) Appearance evaluation About the tablet obtained by Examples 1-3 and Comparative Examples 1-3, the solidification state was observed visually by two special panelists. Evaluations were as follows: Examples 1 to 3 and Comparative Examples 1 to 3 were samples stored for 3 days under the condition of 65 ° C. The evaluation was performed by comparison and evaluated in the following four stages. The evaluation results are shown in Table 4.
<Evaluation criteria>
-: No consolidation +: Slight aggregation is observed ++: Consolidation is recognized +++: Clear consolidation is recognized

(2) Color difference measurement About the tablet obtained in Examples 1-3 and Comparative Examples 1-3, the color difference measurement of the sample preserve | saved for three days on 65 degreeC conditions was implemented for the tablet immediately after that as a control. For the measurement, a spectral color difference meter (trade name: SE6000; Nippon Denshoku Industries Co., Ltd.) was used, and the following [Equation 1] was used for calculation. The color difference is measured for each sample, and the smaller ΔE * (ab), the less the color tone changes.

ΔL ^* = 65 ℃ 3 days storage goods L ^* value - immediately after product L ^* value (L ^*: lightness + white direction, - the black direction)
Δa ^* = 65 ℃ 3 days storage goods of a ^* value - immediately after the goods of a ^* value (a ^*: chromaticity + red direction, - green direction)
Δb ^* = 65 ℃ 3 days storage goods a b ^* value - immediately after article b ^* value (b ^*: Chromaticity + Huang direction, - the blue direction)

  As is apparent from the test results, the preparation containing loxoprofen and carbocysteine (Comparative Example 1) solidified, and ΔE * (ab) showed a high value, and it was observed that the color changed significantly. On the other hand, no solidification was observed in the preparation containing calcium silicate (Example 1) and light anhydrous silicic acid (Examples 2 to 4), and ΔE * (ab) was lower than that of Comparative Example 1. The discoloration could be suppressed. On the other hand, the formulation to which magnesium metasilicate aluminate (Comparative Example 2) as another fluidizing agent was added showed a low value of ΔE * (ab), but spots were confirmed and talc (Comparative Example 3) was added. It was revealed that neither the caking nor the discoloration was suppressed in the added preparation.

(Example 5 and Comparative Examples 4 to 5)
(1) Manufacturing method of formulation Each component and quantity shown in Table 5 were weighed and mixed to obtain a formulation. The obtained preparation was sealed in a glass bottle and stored for 1 week at 65 ° C., and then the appearance of the preparation was evaluated.
(2) Appearance evaluation About the preparation obtained in Example 5 and Comparative Examples 4-5, the appearance evaluation by 2 expert panelists was implemented. The solidification state and discoloration of the sample stored for 1 week under the condition of 65 ° C. were evaluated by the relative comparison with Comparative Example 4 in the following four stages. The results are shown in Table 6.
<Consolidation state criteria>
-: No change +: Slight aggregation is observed ++: Solidification is recognized +++: Clear solidification is recognized <Discoloration criteria>
-: No change +: Slight discoloration is recognized ++: Discoloration is recognized +++: Obvious discoloration is recognized

  As is clear from Table 6, discoloration and significant caking were observed in the mixture of loxoprofen and carbocysteine alone (Comparative Example 4). In contrast, discoloration and caking were suppressed in the solid preparation to which light silicic acid was added (Example 5). On the other hand, the preparation to which magnesium metasilicate aluminate, which is another fluidizing agent, was able to suppress caking, but could not suppress discoloration, and the whole color changed to brown.

  According to the present invention, it is possible to suppress the interaction with loxoprofen or a salt thereof and carbocysteine. Therefore, it is possible to provide a solid preparation containing loxoprofen or a salt thereof and carbocysteine having excellent storage stability.

Claims (2)

A solid preparation comprising (a) loxoprofen or a salt thereof, (b) carbocysteine, and (c) light anhydrous silicic acid and / or calcium silicate. The solid preparation according to claim 1, wherein the solid preparation is a tablet, granule, powder, capsule or pill.