TW201707703A - Soft capsule preparation - Google Patents

Abstract

Provided is a soft capsule preparation that shows an excellent content stability of Nalfurafine or an acid addition salt thereof. The soft capsule preparation consists of a capsule core comprising Nalfurafine or an acid addition salt thereof, a hydrophobic oily base and propyl gallate, and a capsule coating comprising sodium thiosulfate.

Description

Soft capsule

The present invention relates to a soft capsule containing neferac or an acid addition salt thereof.

Nalfurafine, as a selective opioid κ receptor agonist, shows a strong antipruritic effect on the central itching of the opioid system intervention (Patent Document 1). Further, a soft capsule containing nafuralin hydrochloride is marketed as an orally pruritus improving agent.

However, naleraram is chemically unstable to heat, light, oxygen, and moisture. It must be stored at a low temperature, light-shielded, or inert gas.

Therefore, a capsule containing nalfural or an acid addition salt thereof is prepared by formulating sodium thiosulfate as a water-soluble antioxidant in water and polyethylene glycol (Patent Document 2).

However, when a hydrophilic polyethylene glycol is used as a base, it is easy to cause the soft capsules due to moisture to adhere to each other and dent. Therefore, the strict moisture management of the soft capsule is required, and the drying step tends to become complicated. Further, it is considered that since hydrophilic polyethylene glycol is used as a base, the stability of the content of nalofyramine and the formation of a decomposition product are caused by water contained in the polyethylene glycol.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent No. 3531170

[Patent Document 2] Japanese Patent No. 3743449

The present invention relates to a soft capsule which provides nalfororphan or an acid addition salt thereof which is excellent in content stability.

The inventors of the present invention have conducted an effort to repeatedly study a soft capsule containing nafuraphine or an acid addition salt thereof, and as a result, found that a hydrophobic oily base is used in the contents of the capsule, and contains nefurac or an acid thereof. The content of the addition salt and the propyl gallate, and the content of the nalfuralin or the acid addition salt thereof in the soft capsule containing sodium thiosulfate in the film are good and stable.

That is, the present invention is the following 1) to 3).

1) A soft capsule comprising a flavonoid or an acid addition salt thereof, a hydrophobic oily base and propyl gallate, and a sodium thiosulfate in a capsule film.

2) The soft capsule according to 1), which contains 400 to 200,000 parts by mass of a hydrophobic oily base and 150 to 20,000 parts by mass of a propyl gallate relative to 1 part by mass of nalufuraphine or an acid addition salt thereof. .

3) The soft capsule according to 1) or 2), which contains 150 to 20,000 parts by mass of sodium thiosulfate with respect to 1 part by mass of naloforphan or a salt thereof.

By using the present invention, it is possible to produce a capsule containing stable nafuraphine or an acid addition salt thereof which is excellent in stability of the content of the nalofylatone or an acid addition salt thereof and which inhibits the formation of a specific decomposition product. The drying step can be simplified by eliminating the need for tight moisture management during the manufacturing steps of the capsule.

In the present invention, "nafural" means (2E)-N-[(5R,6R)-17-(cyclopropylmethyl)-4,5-epoxy-3, as described below. 14-dihydroxymorphine-6-yl]-3-(furan-3-yl)-N-A Propyl-2-enamine hydrochloride).

The acid addition salt of nalufuradine is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include a hydrochloride, a sulfate, a nitrate, a hydrobromide, a hydroiodide, and a phosphoric acid. Inorganic acid salts such as salts, acetates, lactates, citrates, oxalates, glutarates, malates, tartrates, fumarates, mandelic acid salts, maleates, benzoic acid An organic sulfonate such as an organic carboxylate such as a salt or a phthalic acid salt, a methanesulfonate, an ethanesulfonate, a besylate, a p-toluenesulfonate or a camphorsulfonate; Hydrobromide, phosphate, tartrate, maleate, methanesulfonate are preferred.

A hydrophobic oily base is used as a base in the above soft capsule containing nafuralin or an acid addition salt thereof.

Examples of the hydrophobic oily base include medium chain fatty acid triglyceride, trioctyl, hexanoic acid, octanoic acid, oleic acid, linoleic acid, linoleic acid, and vegetable oil. Here, examples of the vegetable oil include coconut oil, olive oil, rapeseed oil, peanut oil, corn oil, soybean oil, cottonseed oil, grape oil, and safflower oil. These may be used alone or in a mixture of two or more. Among them, a glyceride of a medium-chain fatty acid having 8 to 12 carbon atoms is preferred, and a tricaprylin, tris(octanoic acid, decanoic acid) glyceride or the like is suitable.

The amount of the hydrophobic oil-based base is 400 parts by mass or more, preferably 1,000 parts by mass or more, more preferably 10,000 parts by mass or more, and further preferably 10,000 parts by mass or more, more preferably 1 part by mass of the nalfural or an acid addition salt thereof. It is 40,000 parts by mass or more, preferably 200,000 parts by mass or less, more preferably 150,000 parts by mass or less, and still more preferably 120,000 parts by mass or less. Again The amount is preferably from 400 to 200,000 parts by mass, more preferably from 10,000 to 150,000 parts by mass, and further preferably from 40,000 to 120,000 parts by mass in consideration of the capsule size.

In the present invention, the propyl gallate is added as a stabilizer, and the amount thereof is preferably 150 parts by mass or more, preferably 300 parts by mass based on 1 part by mass of the naloforol or an acid addition salt thereof. The amount is more preferably 500 parts by mass or more, more preferably 20,000 parts by mass or less, still more preferably 2,000 parts by mass or less, still more preferably 1,500 parts by mass or less. Further, it is preferably from 150 to 20,000 parts by mass, more preferably from 300 to 2,000 parts by mass, still more preferably from 500 to 1,500 parts by mass.

In the present invention, sodium thiosulfate is formulated in a capsule film. By dissolving sodium thiosulfate in the capsule film, the formation of the decomposition product can be suppressed.

The sodium thiosulfate may be an anhydrous salt or an aqueous salt, preferably sodium thiosulfate pentahydrate.

The content of the sodium thiosulfate is preferably 150 parts by mass or more, more preferably 300 parts by mass or more, still more preferably 500 parts by mass or more, and more preferably 20,000 parts by mass based on 1 part by mass of the naloforate or an acid addition salt thereof. The amount is preferably 2,000 parts by mass or less, more preferably 1,500 parts by mass or less. Further, it is preferably from 150 to 20,000 parts by mass, more preferably from 300 to 2,000 parts by mass, still more preferably from 500 to 1,500 parts by mass.

In the soft capsule of the present invention, in addition to the above components, for example, a solubilizing agent, a solubilizing agent, a preservative, a surfactant, a coloring agent, etc. may be added to the content in the soft capsule of the present invention, and the film may be applied to the film. The medium is formulated, for example, a film base, a plasticizer, a colorant, a preservative, and the like.

Examples of the co-solvent herein include ethanol, propylene glycol, polyethylene glycol, sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, oleic acid glyceride, and myristic acid glycerin. Ester, polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl ether, glycerin, and the like.

Examples of the solubilizer include cyclodextrin and the like.

Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl paraben, and benzalkonium chloride.

Examples of the surfactant include polysorbate 80, castor oil polyoxyl ester 35, and the like.

Examples of the coloring agent include titanium oxide, yellow ferric oxide, edible yellow No. 4, edible yellow No. 5, edible red No. 3, edible red No. 102, edible red No. 105, edible red No. 106, and ferric oxide. Wait.

Examples of the film base agent include gelatin, amber gelatin, starch, amylopectin, polyvinyl alcohol copolymer, and polyethylene glycol.

Examples of the plasticizer include concentrated glycerin, sugar alcohol, and the like.

The content of the soft capsule of the present invention can be prepared, for example, by dissolving nalfural or an acid addition salt thereof and propyl gallate in a cosolvent such as ethanol, and formulating it into a hydrophobic oily group. The mixture was prepared by mixing and stirring.

The film of the soft capsule of the present invention can be produced, for example, by dispersing a base, a plasticizer, and sodium thiosulfate in water, dissolving it at 60 to 90 ° C, and then performing vacuum defoaming.

The soft capsule of the present invention can be prepared by using a soft capsule previously used, for example, by punching a rotary automatic soft capsule molding machine, placing contents between two gelatin sheets, and compressing from both sides by using a mold. The content is filled in a film by a flat method or a dropping method using a double nozzle (seamless capsule or the like), and the like, and molded and dried.

The soft capsule obtained as described above has the stability of the content of the naloformine or its acid addition salt as an active ingredient as shown in the following examples, and suppresses the formation of a specific decomposition product.

[Examples]

The present invention will be described in detail by the following examples, but the invention is not limited thereto.

Example 1 Preparation of Soft Capsules

The specific amount of nalfluoran hydrochloride and propyl gallate shown in Table 1 below was dissolved in a specific amount of ethanol and mixed with a specific amount of medium chain fatty acid triglyceride [three ( Capsule-filled composition was prepared by stirring in octanoic acid/capric acid glyceride (manufactured by BASF Corporation). Stirring was carried out to disperse a specific amount of gelatin, amber gelatin, concentrated glycerin, D-sorbitol solution, sodium thiosulfate and titanium oxide shown in Table 1 below in an appropriate amount of purified water, and stirred at 60 ° C to dissolve. Thereafter, vacuum defoaming was carried out to prepare a gelatin film. The capsule filling composition and the gelatin film described above were used, and a soft capsule was prepared by a punching method using a rotary automatic soft capsule molding machine.

Further, 2.5 μg of REMITCH capsules (2.5 μg of nalofyloporine hydrochloride (manufactured by Toray Industries, Inc.)) was used as a comparative product in one capsule. The blending ingredients of the comparative products are shown in Table 2.

Example 2 Stability Test

The soft capsule prepared in Example 1 was placed in a glass bottle and stored at 80 ° C for 1 week in a plugged state. After the storage time was completed, the content and decomposition product of the nalofyramine hydrochloride in each soft capsule were measured by HPLC (high performance liquid chromatography). The measurement results are shown in Tables 3 and 4.

According to Table 3, it can be confirmed that the present invention has the residual of nalofyramine hydrochloride compared with the comparative product. The rate is high and shows significant content stability. Further, according to Table 4, it is clear that the product of the present invention has no increase in the 10?-OH form visible in the comparative product, and exhibits a remarkable inhibitory effect on the 10?-OH body which is a decomposition product of nalfural.

Example 3 Preparation of Soft Capsules

Soft capsules were prepared in the same manner as in Example 1 in the specific amounts shown in Table 5 below.

Further, in the same manner as in Example 1, 2.5 μg of REMITCH capsules (2.5 μg of nalofyramine hydrochloride (manufactured by Toray Industries, Inc.) in one capsule) was used as a comparative product.

Example 4 Stability Test

The soft capsule prepared in Example 3 was subjected to PTP (Press Through Packaging)/puppet packaging and stored at 40 ° C, 75% RH for 6 months. After 1 month, 3 months, and after the storage time, the content of the nalofylopin hydrochloride and the decomposed product in each soft capsule were measured by HPLC. The measurement results are shown in Tables 6 and 7.

As is clear from Table 6, the residual ratio of the nalofyllalin hydrochloride of the present invention was higher than that of the comparative product, showing a remarkable content stability. Further, according to Table 7, it is clear that the product of the present invention has no increase in the decomposition product visible in the comparative product, and exhibits a remarkable inhibitory effect on the decomposition product of nalfural.

Claims (3)

A soft capsule comprising a flavonoid or an acid addition salt thereof, a hydrophobic oily base and a propyl gallate, and a sodium thiosulfate in the capsule film. The soft capsule of claim 1, which contains 400 to 200,000 parts by mass of a hydrophobic oily base and 150 to 20,000 parts by mass of a propyl gallate with respect to 1 part by mass of naluforphine or an acid addition salt thereof. The soft capsule of claim 1 or 2, which contains 150 to 20,000 parts by mass of sodium thiosulfate with respect to 1 part by mass of naloforphan or a salt thereof.