JP2011079796A - Ibuprofen-containing pharmaceutical preparation and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ibuprofen-containing pharmaceutical preparation which improves the delay of ibuprofen effect expression and the sustainability of the effect, and to provide a method for producing the same. <P>SOLUTION: There are provided the ibuprofen-containing pharmaceutical preparation containing the co-melted product of ibuprofen with cacao butter, or the ibuprofen-containing pharmaceutical preparation containing ibuprofen and cacao butter, wherein the ibuprofen is amorphous or low-crystalline; and the method for producing the same. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an ibuprofen-containing preparation that exhibits rapid antipyretic analgesic effect and is excellent in sustainability, and a method for producing the same.

The sustained-release preparation is a highly useful preparation that can maintain the effect on a drug having a short elimination half-life in vivo. As a method for gradually releasing the drug in this way, there are a method of controlling with a water-insoluble coating film such as ethyl cellulose, and a method of dispersing in an acid-resistant film agent such as enteric film agents and waxes.
However, if this technique is used to maintain the effect of ibuprofen (half-life: about 2 hours), ibuprofen is poorly water-soluble, so sufficient initial release cannot be obtained, and the onset of the effect is delayed. There was a problem. For this reason, a method has been proposed in which sustained-release particles and particles with improved solubility are blended at the same time. However, this method has a problem that workability deteriorates and is not economical.
As a technique for improving workability, a sustained-release preparation of ibuprofen (Patent Document 1: Japanese Patent No. 4078567) in which a surfactant is added to an acid-resistant film has been proposed, but it is sufficiently improved in terms of delay of effect expression. Was not.

Japanese Patent No. 4078567

  This invention is made | formed in view of the said situation, Comprising: It aims at providing the ibuprofen containing formulation which improved the delayed expression of the effect of ibuprofen, and improved durability, and its manufacturing method.

As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that ibuprofen and cocoa butter are co-melted products, which are amorphous or low crystalline ibuprofen and cocoa butter. In addition to finding that the initial solubility of can be increased and the onset of effects can be accelerated, the retention in the intestinal tract can be improved and the sustainability can be improved, and by co-melting ibuprofen and cacao butter, It has been found that ibuprofen can be easily made amorphous or low-crystallized, and the above-mentioned preparation can be obtained by a simple process, and the present invention has been made.
In addition, in this invention, that initial solubility is quick means that the pain threshold value measured by the rat Randall-Serit method mentioned later is 90% or more after 60 minutes. In the present invention, co-melting refers to a state in which two or more components including ibuprofen are uniformly melted or dissolved by heating or addition of a solvent, and these are cooled to make ibuprofen non-crystallized or low-crystallized. This mixture is called a co-melt. The composition ratio is not particularly limited. In this case, the low crystal means that the peak of the co-melt as measured by DSC (differential scanning calorimetry) is 50% or less in terms of the same mass compared to the crystal peak before co-melting. Say. Considering the production process, the method of co-melting by heating is simpler and better than the method by adding a solvent.

That is, this invention provides the following ibuprofen containing formulation and its manufacturing method.
Claim 1:
An ibuprofen-containing preparation comprising a co-melt of ibuprofen and cacao butter.
Claim 2:
An ibuprofen-containing preparation comprising ibuprofen and cacao butter, wherein ibuprofen is amorphous or low-crystalline.
Claim 3:
The ibuprofen-containing preparation according to claim 1 or 2, wherein the content of cocoa butter is 1 to 10 parts by mass with respect to 1 part by mass of ibuprofen.
Claim 4:
Furthermore, the ibuprofen containing formulation of any one of Claims 1 thru | or 3 containing the 1 type (s) or 2 or more types chosen from cacao powder, chocolate flavor, and bitter chocolate.
Claim 5:
The ibuprofen-containing preparation according to any one of claims 1 to 4, which is a chewable tablet, an orally disintegrating tablet, an orally dissolving tablet, or a troche.
Claim 6:
A method for producing an ibuprofen-containing preparation, characterized in that cacao butter and ibuprofen are heated and mixed, co-melted and then solidified.

  According to the present invention, by increasing the initial solubility of ibuprofen, it is possible to accelerate the onset of antipyretic analgesic effect and provide an ibuprofen-containing preparation excellent in sustainability and a method for producing the same. Furthermore, the ibuprofen containing formulation which improved the ingestion property can be provided by adding chocolate flavor.

[Ibuprofen]
Examples of ibuprofen include ibuprofen (2- (4-isobutyphenyl) propionic acid) and its salts, such as sodium, potassium, magnesium, calcium, ammonium, methylglucamine, and salts with amino acids such as lysine. Ibuprofen or a salt thereof is effective as an antipyretic analgesic. These can be used alone or in combination of two or more. In the case of an over-the-counter drug, the daily dose of ibuprofen is preferably 200 to 600 mg, particularly preferably 390 to 450 mg, based on the standard amount for drug approval. Although not directly related to the effects of the present invention, the ibuprofen content is preferably contained in the preparation of the present invention in an amount of 0.5 to 80% by mass, more preferably 5 to 50% by mass.

[Cocoa butter]
Cocoa butter is used for imparting sustained release to the preparation of the present invention and improving the delayed onset of antipyretic analgesic effect. Examples of the cocoa butter used in the present invention include Japanese Pharmacopoeia compatible cocoa butter. In the preparation of the present invention, the content of cocoa butter is preferably 1 to 10 parts by weight, more preferably 1.5 to 9 parts by weight, particularly 6 parts by weight or less, especially 4 parts by weight or less, relative to 1 part by weight of ibuprofen. It is preferable that If the amount is too small, the sustained effect of ibuprofen may not be sufficient. If the amount is too large, the effect at the beginning of the effect may not be sufficient.

  In the preparation of the present invention, optional components can be blended within a range not impairing the effects of the present invention. As an arbitrary component, an excipient | filler, a corrigent, a sweetener, a binder, a coloring agent, a lubricant agent etc. can be mentioned, for example. These can be used individually by 1 type or in combination of 2 or more types.

Specific examples of the excipient include erythritol, xylitol, trehalose, low-substituted hydroxypropylcellulose, mannitol, lactose, sucrose, starch, crystalline cellulose, crospovidone, silicon dioxide and the like.
As a corrigent and sweetener, cocoa powder, ascorbic acid, aspartame, acesulfame potassium, stevia, sucralose, thaumatin, sucrose, lactose, glucose, fructose, fructose glucose liquid sugar, xylitol, mannitol, erythritol, chocolate, chocolate flavor, various A powder fragrance etc. can be mentioned.
Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like.
Examples of the colorant include iron sesquioxide, yellow iron sesquioxide, black iron oxide, edible yellow No. 5 dye, edible red No. 3 dye, edible blue No. 2 dye, edible lake dye, and titanium oxide.
Examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester and the like.

[Production method]
The preparation method of the present invention is prepared by, for example, heating and mixing ibuprofen, cacao butter and the like at 80 to 90 ° C. for 10 to 30 minutes, co-melting, and then adding a sweetener, a fragrance, chocolate and the like as necessary. In addition to the method of (solidification), spray cooling, extrusion granulation, fluidized bed granulation, etc., powdered by any production method that can be co-melted by heating during the production process, excipient, disintegrant, Tablets, granules, fine granules, powders, solutions, chewable tablets, orally disintegrating tablets, orally dissolving tablets, lozenges, jelly tablets, mixed with lubricants, various flavoring agents, flavors, etc. It can be a drop or the like. In this case, additives such as optional components may be added in an appropriate process as appropriate during the production (formulation) of the present invention. However, when ibuprofen and cacao butter are added together, From the viewpoint of management, it is preferably a component that melts or dissolves together with ibuprofen and cacao butter.
Moreover, you may coat the formulation obtained from ibuprofen, cacao butter, and an arbitrary component with chocolate, a sweetener, etc. in the range which does not impair the effect of this invention. As a method of coating, it is preferable to select these chocolates, sweeteners, etc., and a film agent that disintegrates, dissolves or melts in the gastric juice and coats it by a conventional method. By these, it can be set as the chocolate formulation which suppressed the bitterness of ibuprofen and improved taking property, and is especially useful as a child's (for middle and high school students) formulations.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated more concretely, this invention is not restrict | limited to the following Example.

[Examples 1 to 4]
1,000 times the amount of ibuprofen and cacao butter listed in Table 1 were mixed, heated to 85 ° C., and co-melted. After confirmation of uniformity, it was cooled to room temperature. Then, the mortar grind | pulverized and sieved and the 250-350 micrometer fraction was evaluated.

[Comparative Examples 1-5]
1,000 times the amount of ibuprofen listed in Table 2 and each component were mixed, heated to a temperature equal to or higher than the temperature at which each component melted, and co-melted. After confirmation of uniformity, it was cooled to room temperature. Then, the mortar grind | pulverized and sieved and the 250-350 micrometer fraction was evaluated.

[Comparative Example 6]
The 100-fold amount of each component listed in Table 2 was mixed and pulverized in a mortar and sieved, and 250 to 350 μm fractions were evaluated.

[Evaluation methods]
<Crystallinity>
About 20 mg each of the samples prepared in Examples 1 to 4 and Comparative Examples 1 to 6 were measured with DSC (Differential Scanning Calorimetry: Rigaku THERMOFLEX TAS300), and the peak was compared with the ibuprofen single crystal peak. The crystallinity was evaluated in terms of the same mass.
50% or less in terms of mass is indicated as low crystal, and no peak is indicated as amorphous. The results are shown in Tables 1 and 2.

<Pain threshold>
The analgesic effect of ibuprofen was measured in the following manner according to the rat Randall-Serit method (for example, “Applied Pharmacology”, Vol. 21, No. 5, pp. 753-771, 1981).
<Experiment>
A group of 6 Wistar male rats (4 weeks old, weight 60 to 90 g) was used, and 0.1 mL of a 20% by weight brewer's yeast suspension was subcutaneously injected subcutaneously into the left hind footpad.
Next, suspension aqueous solutions each containing the components of Examples 1 to 4 and Comparative Examples 1 to 6 shown in Tables 1 and 2 were prepared so that the concentration of ibubrofen was 5% by mass, and then the dose of ibuprofen was 150 mg. / KgB. W. The footpad pain threshold after 60 minutes and 180 minutes was measured using a pressure-stimulated analgesic effect measuring device (Muromachi Kikai Co., Ltd.). The results are also shown in the table in terms of the pain threshold values obtained in terms of 100% of the pain threshold value measured 1 hour before brewer's yeast injection (before inflammation). An average pain threshold value of 90% or more was evaluated as “with antipyretic analgesic effect”. In Table 2, 10 mL of distilled water was administered after the onset of inflammation.

  In Comparative Examples 1-5, since fats and oils with a high melting point were used, the initial dissolution was delayed and the effect expression was delayed.

The raw materials used are as follows.

[Example 5]
The component A was heated and melted at 85 ° C. for 15 minutes, and after confirmation of uniformity, the component B was added and suspended to make it uniform. Then, it shape | molded and cooled and obtained the chocolate formulation (tablet).
A component (a) ibuprofen 150g
(B) Cocoa butter 300 g (blending ratio (a) / (b) = 2)
B component cacao powder 150g
150g xylitol
Aspartame 28g
Chocolate flavor 0.8g

[Example 6]
A chocolate preparation (tablet) was obtained in the same manner as in Example 5 using the following components.
A component (a) ibuprofen 150g
(B) Cocoa butter 300 g (blending ratio (b) / (a) = 2)
200g bitter chocolate
B component xylitol 160g
Aspartame 28g
Chocolate flavor 0.8g

[Example 7]
The component A was heated and melted at 85 ° C. for 15 minutes, and after confirmation of uniformity, it was pulverized by a spray cooling method (Okawara Chemical Co., Ltd.). After adding and mixing B component to this, it tableted with the tableting tester and was set as the tablet.
A component (a) ibuprofen 150g
(B) Cocoa butter 300 g (blending ratio (b) / (a) = 2)
B component silicon dioxide (Silicia 350) 10g
150 g of crystalline cellulose (Theolas PH302)
D-mannitol 150g
Hydroxypropylcellulose 30g
Crospopidone (Kollidon CL) 20g
Magnesium stearate 3g
Sucralose 1.5g
Fragrance 0.5g

  The preparations of Examples 5 to 7 were also excellent in initial solubility and sustainability as in Examples 1 to 4.

Claims (6)

  An ibuprofen-containing preparation comprising a co-melt of ibuprofen and cacao butter.   An ibuprofen-containing preparation comprising ibuprofen and cacao butter, wherein ibuprofen is amorphous or low-crystalline.   The ibuprofen-containing preparation according to claim 1 or 2, wherein the content of cocoa butter is 1 to 10 parts by mass with respect to 1 part by mass of ibuprofen.   Furthermore, the ibuprofen containing formulation of any one of Claims 1 thru | or 3 containing the 1 type (s) or 2 or more types chosen from cacao powder, chocolate flavor, and bitter chocolate.   The ibuprofen-containing preparation according to any one of claims 1 to 4, which is a chewable tablet, an orally disintegrating tablet, an orally dissolving tablet, or a troche.   A method for producing an ibuprofen-containing preparation, characterized in that cacao butter and ibuprofen are heated and mixed, co-melted and then solidified.