JP2010241768A - Ibuprofen-containing solid, method of production therefor, and ibuprofen formulation containing ibuprofen-containing-solid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ibuprofen-containing solid excellent in solubility, good in grindability, easy to produce, and capable of being formulated into an ibuprofen formulation. <P>SOLUTION: The ibuprofen-containing solid includes ibuprofen, a sucrose fatty acid ester, and polyethylene glycol 4000 (Fifteenth Revised Japanese Pharmacopoeia). <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an ibuprofen-containing solid material having excellent solubility, a method for producing the same, and an ibuprofen preparation comprising the ibuprofen-containing solid material.

  Ibuprofen is classified as a non-steroidal anti-inflammatory drug (NSAIDs) and is known as a poorly soluble drug having antipyretic and analgesic effects with few side effects. Many attempts have been made to promote dissolution in order to quickly develop these effects. As a current technique, a method is proposed in which ibuprofen is dissolved in a solvent together with a carrier and then the solvent is distilled off. However, this method uses a large amount of solvent and requires special equipment, which adversely affects the environment. In addition, a technique (Patent Document 1: Japanese Patent Laid-Open No. 2006-182726) for improving dissolution acceleration by co-grinding ibuprofen and L-HPC and then granulating is proposed, but a special pulverizer is required. There was a drawback that. For these reasons, there has been a demand for an ibuprofen-containing composition that is blended in an ibuprofen preparation that is excellent in solubility, good in grindability, and can be easily produced.

JP 2006-182726 A

  This invention is made | formed in view of the said situation, and it aims at providing the ibuprofen containing solid substance mix | blended with the ibuprofen formulation which is excellent in solubility, good crushability, and can be manufactured easily.

  As a result of intensive studies to achieve the above object, the inventors of the present invention have improved solubility and grindability by using ibuprofen-containing solids containing ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000. Thus, the present inventors have found that it is possible to manufacture the present invention, and have made the present invention.

Therefore, the present invention provides the following ibuprofen-containing solid, a method for producing the same, and an ibuprofen-containing preparation.
[1]. An ibuprofen-containing solid material comprising ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000 (15th Japanese Pharmacopoeia).
[2]. The mass ratio represented by sucrose fatty acid ester: ibuprofen is 0.01: 1 to 2: 1, and the mass ratio represented by polyethylene glycol 4000: ibuprofen is 0.005: 1 to 1: 1. [1] The ibuprofen-containing solid material according to [1].
[3]. The ibuprofen-containing solid material according to [1] or [2], which is a molten mixture of ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000.
[4]. The ibuprofen-containing solid material according to [1], [2] or [3], wherein the sucrose fatty acid ester is sucrose stearate.
[5]. The ibuprofen-containing solid material according to any one of [1] to [4], wherein the ratio of the monoester in the sucrose fatty acid ester is 40% by mass or more.
[6]. The ibuprofen formulation formed by mix | blending the ibuprofen containing solid substance in any one of [1]-[5].
[7]. The method for producing an ibuprofen-containing solid according to [1], wherein ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000 are heated, melted, mixed, and cooled.

  According to the present invention, it is possible to provide an ibuprofen-containing solid material that is blended into an ibuprofen preparation that is excellent in solubility, good in grindability, and can be easily produced.

Hereinafter, the present invention will be described in detail.
The ibuprofen-containing solid material of the present invention contains ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000 (15th revised Japanese Pharmacopoeia).

[Ibuprofen]
It is classified as a non-steroidal anti-inflammatory drug (NSAIDs) and is a poorly soluble drug having antipyretic and analgesic actions with few side effects, and has a melting point of 75-77 ° C. A commercially available product can be used as ibuprofen, and examples thereof include ibuprofen 70G (Albemarle), ibuprofen 20G (Albemarle), ibuprofen (BASF), ibuprofen 38 (BASF), ibuprofen 50 (BASF) and the like.

[Sucrose fatty acid ester]
As the sucrose fatty acid ester, eight hydroxyl groups of sucrose and fatty acids having 12 to 20 carbon atoms (for example, lauric acid C12, myristic acid C14, palmitic acid C16, stearic acid C18, oleic acid C18) are esters. What couple | bonded is preferable and can be used individually by 1 type or in combination of 2 or more types. When the fatty acid chain length is short, it is not solid, so that the melt-mixed product becomes liquid or viscous and is inconvenient to handle. Among these, from the viewpoint of compatibility with ibuprofen, those having 14 to 20 carbon atoms are more preferable, those having 16 or 18 carbon atoms are more preferable, and sucrose stearate in which the fatty acid is stearic acid is particularly preferable.

  The proportion of monoester in the sucrose fatty acid ester is preferably 40% by mass or more, more preferably 50% by mass or more, and further preferably 60% by mass or more. Although an upper limit is not specifically limited, 100 mass% or less is preferable and 98 mass% or less is preferable. Moreover, 10-19 are preferable and, as for HLB, 13-18 are more preferable. HLB is calculated by the Griffin method.

  As sucrose fatty acid ester, Ryoto sugar ester (Mitsubishi Chemical Foods Co., Ltd.) S-1670 (sucrose stearate, melting point 49-56 ° C., mono 75 mass%, di-tri 25 mass%, HLB16), S-1570 (sucrose stearate, melting point 49-55 ° C., mono 70% by mass, di-tri 30% by mass, HLB15), P-1670 (sucrose palmitate, melting point 40-48 ° C., mono 80% %, Di-tri 20% by mass, HLB16), O-1570 (sucrose oleate, melting point 27-43 ° C., mono 70% by mass, di-tri 30% by mass, HLB15), M-1695 (sucrose myristin Commercial products such as acid ester, melting point 27-43 ° C., mono 80% by mass, di-tri 20% by mass, HLB16) can also be used.

[Polyethylene glycol 4000 (15th revised Japanese Pharmacopoeia)]
It is an addition polymer of ethylene oxide (ethylene oxide) and water and is represented by HOCH ₂ (CH ₂ OCH ₂ ) _n CH ₂ OH. The polyethylene glycol of the present invention is polyethylene glycol 4000 listed in the 15th revised Japanese Pharmacopoeia. n is 59 to 84 or / and a mixture thereof and is solid, and has a melting point of 53 to 57 ° C. These can be used individually by 1 type or in combination of 2 or more types. Polyethylene glycol 1540 (melting point 43 to 47 ° C.) is petrolatum-like or paraffin-like, so that the product becomes a viscous body, and polyethylene glycol 6000 (melting point 56 to 61 ° C.) is not compatible with ibuprofen.

  As polyethylene glycol 4000 (15th revised Japanese Pharmacopoeia), commercially available products such as Macrogol 4000 (Asahi Denka Kogyo, Sanyo Kasei Kogyo, Nippon Oil & Fats, Maruishi Pharmaceutical) and PEG 4000 (Daiichi Kogyo Pharmaceutical) can be used.

  The content of ibuprofen with respect to the total amount of the solid containing ibuprofen is not particularly limited, but is preferably 30 to 80% by mass, and more preferably 50 to 80% by mass.

  The mass ratio represented by sucrose fatty acid ester: ibuprofen is preferably 0.01: 1 to 2: 1, more preferably 0.05: 1 to 1.5: 1, and 0.1: 1 to 0.8. : 1 is more preferable, and 0.25: 1 to 0.6: 1 is particularly preferable. If the amount of sucrose fatty acid ester is too small relative to ibuprofen, the effect of improving solubility may be insufficient. On the other hand, if the amount is too large, the stability of ibuprofen may be deteriorated, stickiness may occur, and the grindability may be deteriorated.

  The mass ratio represented by polyethylene glycol 4000: ibuprofen is preferably 0.005: 1 to 1.5: 1, more preferably 0.01: 1 to 0.6: 1, from the viewpoint of improving solubility. 0.05: 1 to 0.4: 1 are more preferable. If the amount of polyethylene glycol 4000 is too small relative to ibuprofen, the effect of improving the solubility may be insufficient. On the other hand, if the amount is too large, the stability of ibuprofen may be deteriorated, stickiness may occur, and the grindability may be deteriorated.

  As a combination of the amounts of the three components, the mass ratio represented by sucrose fatty acid ester: polyethylene glycol 4000: ibuprofen is preferably 0.01-2: 0.005-1.5: 1, and 0.1-0 .6: 0.05 to 0.6: 1 is more preferable.

  (Total amount of sucrose fatty acid ester and polyethylene glycol 4000): The mass ratio represented by ibuprofen is preferably 0.015: 1 to 3.5: 1, more preferably 0.25: 1 to 2: 1. 0.5: 1 to 1: 1 is more preferable. The mass ratio represented by sucrose fatty acid ester: polyethylene glycol 4000 is preferably 0.01: 1 to 50: 1, more preferably 0.2: 1 to 25: 1, and 0.8: 1 to 5: 1. Is particularly preferred.

  The ibuprofen-containing solid material of the present invention contains ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000 (15th revised Japanese Pharmacopoeia), and is a molten mixture of ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000. In particular, it is preferably a complex in which ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000 are dispersed. In addition, a molten mixture can mix ibuprofen, sucrose fatty acid ester, and polyethyleneglycol 4000, for example, by heating or solvent-melting.

[Production method]
As a method for producing ibuprofen-containing solids, from the viewpoint of uniform dispersibility of each component, hot melt mixing, solvent dissolution mixing, etc. are preferable. From the viewpoint of uniform dispersibility and manufacturability by not using a solvent, heat melting Mixing is more preferred.

  In the hot melt mixing, ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000 are heated and melted, mixed, and cooled to obtain a composite in which ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000 are dispersed. The temperature at the time of heating and melting is a temperature not lower than the melting point of each component, and preferably 80 ° C. or higher. The cooling is not particularly limited as long as a solid material is obtained, and the cooling may be performed to room temperature (about 25 ° C.).

  Solvent-dissolved mixing refers to a method in which ibuprofen, sucrose fatty acid ester, and macrogol 4000 are dissolved in a solvent such as methanol or acetonitrile, mixed, and then the solvent is distilled off.

[Ibuprofen formulation]
The ibuprofen-containing solid can be used for blending ibuprofen preparations. Ibuprofen-containing solids can be crushed and mixed with other powders to be used as granules and capsules, or pulverized and mixed with other powders and ingredients for tableting and use as tablets You can also

  The smaller the volume average particle diameter of the pulverized product of ibuprofen-containing solid, the better, 300 μm or less is preferable, and 100 μm or less is more preferable. In addition, the measuring method of an average particle diameter is measured using a diffuse scattering type particle size distribution measuring apparatus.

  There is no restriction | limiting in particular in content of the ibuprofen containing solid substance in an ibuprofen formulation, According to the ibuprofen compounding amount in a formulation, it can determine suitably in 10-100 mass%.

  In the ibuprofen preparation of the present invention, components blended in granules, capsules, and tablets can be blended within a range that does not impair the effects of the present invention. These components can be used individually by 1 type or in combination of 2 or more types, The appropriate quantity can be mix | blended. The following are mentioned as an arbitrary component.

  Active ingredients include naproxen, ketoprofen, acetaminophen, indomethacin, bufexamac, aspirin, diclofenac, alclofenac, fenclofenac, etodolac, flurbiprofen, ketoprofen, mefenamic, meclofenamic, piroxicam, etc. Steroid anti-inflammatory agents; antitussives such as noscapine, salbutamol, procaterol, turopterol, tranilast, ketotifen; expectorants such as bromhexine hydrochloride, guaifenesin, antihistamines such as diphenhydramine, promethazine, mequitazine, clemastine fumarate, vitamins A, vitamins B, Vitamin preparations such as vitamin D, vitamin E, vitamin K, folic acid (vitamin M); dimethicone, famotidine, lani Jin, cimetidine, nizatidine, metoclopramide, famotidine, omeprazole, sulpiride, Torepibuton, sucralfate, digestive system diseases agents such as antacids; caffeine, anhydrous caffeine, allylisopropylacetylurea, Buromuwareiru urea and the like.

  Examples of the binder include starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like. Can be used.

  Examples of excipients include disintegrants such as carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, and low-substituted hydroxypropylcellulose; lactose, corn starch, talc, crystalline cellulose (Avicel, etc.) Powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine and the like can be used.

  As the lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, sucrose fatty acid ester and the like can be used.

  As a fragrance | flavor, menthol, limonene, vegetable essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil etc.) etc. can be used, for example. As the sweetener, for example, saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like can be used. As the acidulant, for example, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition represents mass%, and the ratio represents mass ratio.

[Example 1]
10 g of sucrose fatty acid ester (S-1670, Mitsubishi Chemical Foods) and 10 g of macrogol (macrogol 4000) are melted in a 100 ° C. hot water bath, and 40 g of ibuprofen (20G, BASF) is added to the homogenizer. The mixture was melted with stirring. After the whole became liquid and mixed uniformly, the hot water bath was removed and the mixture was cooled with stirring to obtain a white solid (molten mixture).

[Example 2]
Sucrose fatty acid ester (S-1670, Mitsubishi Chemical Foods Co., Ltd.) 10 g, macrogol (macrogol 4000) 10 g, and ibuprofen (20G, BASF) 40 g were melted in a 100 ° C. hot water bath and mixed at once. A white solid (molten mixture) was obtained in the same manner as in Example 1.

[Example 3]
10 g of ethanol was added to 10 g of sucrose fatty acid ester (S-1670, Mitsubishi Chemical Foods), 10 g of macrogol (macrogol 4000) and 40 g of ibuprofen (20G, BASF), and kneaded in a mortar. Ethanol was distilled off to obtain a milky white solid (molten mixture).

[Example 4]
10 g of sucrose fatty acid ester (S-1670, Mitsubishi Chemical Foods), 10 g of macrogol (macrogol 4000) and 40 g of ibuprofen (20G, BASF) were kneaded in a mortar to obtain a mixture.

[Examples 5 to 21, Comparative Examples 1 to 6]
A solid was obtained by the production method of Example 1 except that the composition was changed to those shown in Tables 2 to 5 (only ibuprofen is indicated in%). In addition, the kind of fatty acid of sucrose fatty acid ester and the ratio (%) of monoester are shown below.

The following evaluation was performed about the obtained product. The results are also shown in the table.
(1) Contact angle measurement It measured using automatic contact angle measuring device OCA20. A result is shown by the following evaluation criteria. In addition, the contact angle of untreated ibuprofen (ibuprofen drug substance (20G, BASF)) is about 70 degrees, and the hydrophilicity (solubility in water) is improved when the contact angle is lowered by 10 degrees or more and 60 degrees or less. evaluated.
<Evaluation criteria>
: 0-30
○: 31-40
Δ: 41-60
X: 61-70

(2) Dissolution test 10 g of the sample was pulverized by performing analysis for 10 seconds 5 times with an analytical pulverizer (manufactured by Nihon Riken Kikai Co., Ltd .: R-8), and sieved with a sieve having an opening of 100 μm to obtain a powder. Obtained. This was tested by the Japanese Pharmacopoeia dissolution test paddle method, and the elution rate of ibuprofen at 3, 5, and 10 minutes after the start of the test was determined. The first solution (pH 1.2) of the Japanese Pharmacopoeia Disintegration Test Method was used as the test solution, the amount of the eluate was 900 mL, and the rotation speed of the paddle was 50 rpm. Each sample was weighed to 65 mg as ibuprofen and subjected to the test. The elution rate after 10 minutes of untreated ibuprofen (ibuprofen drug substance (20G, BASF)) was about 10%.

(3) Grindability The grindability when 10 g was ground with an analysis grinder (manufactured by Nihon Riken Kikai Co., Ltd .: R-8) was evaluated. A result is shown by the following evaluation criteria.
<Evaluation criteria>
○: Grindable

[Example 22]
The white solid obtained in Example 1 was pulverized and sieved in the same manner as in the above elution test, and 450 g of powder, 120 g of low-substituted hydroxypropylcellulose, 400 g of crystalline cellulose, and 4 g of magnesium stearate were weighed in a plastic bag. Mixed. This was tableted with a rotary tableting machine 12UK manufactured by Kikusui Seisakusho Co., Ltd. using a punch with an inner diameter of 8 mm to obtain a tablet with 243.5 mg / tablet and hardness of 4 kgf.

[Comparative Example 7]
Tablets were obtained in the same manner as in Example 22, except that the white solid obtained in Example 1 was changed to 300 g of ibuprofen drug substance (20G, BASF).

  The tablets of Example 22 and Comparative Example 7 were tested by the Japanese Pharmacopoeia dissolution test paddle method, and the ibuprofen dissolution rate after 3, 5, and 10 minutes after the start of the test was determined. The first solution (pH 1.2) of the Japanese Pharmacopoeia Disintegration Test Method was used as the test solution, the amount of the eluate was 900 mL, and the rotation speed of the paddle was 50 rpm. As a result, the elution rate after 10 minutes of Example 22 was 40%, and the elution rate of Comparative Example 7 was 8%.

Claims (7)

  An ibuprofen-containing solid material comprising ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000 (15th Japanese Pharmacopoeia).   The mass ratio represented by sucrose fatty acid ester: ibuprofen is 0.01: 1 to 2: 1, and the mass ratio represented by polyethylene glycol 4000: ibuprofen is 0.005: 1 to 1: 1. The ibuprofen-containing solid material according to claim 1.   The ibuprofen-containing solid material according to claim 1 or 2, which is a molten mixture of ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000.   4. The ibuprofen-containing solid material according to claim 1, wherein the sucrose fatty acid ester is sucrose stearate.   The ibuprofen-containing solid material according to any one of claims 1 to 4, wherein the proportion of monoester in the sucrose fatty acid ester is 40% by mass or more.   The ibuprofen formulation formed by mix | blending the ibuprofen containing solid substance of any one of Claims 1-5.   The method for producing an ibuprofen-containing solid according to claim 1, wherein ibuprofen, sucrose fatty acid ester, and polyethylene glycol 4000 are heated and melted, mixed, and cooled.