JP6131379B1 - Formulation containing 4,5-epoxymorphinan derivative - Google Patents

Abstract

The present invention provides a preparation having improved light resistance and oxidation resistance of a 4,5-epoxymorphinan derivative (especially NAL-F), an oral pruritus ameliorating drug. SOLUTION: (a) 4,5-epoxymorphinan derivative or neutralized salt thereof with pharmacologically acceptable acid as component (a), polyethylene glycol as component (b), and naphthol as component (c) A coated preparation comprising at least one dye selected from a azo dye or a xanthene dye, and tocopherol as component (d). [Selection figure] None

Description

  The present invention relates to a stable preparation containing a 4,5-epoxymorphinan derivative. More specifically, the present invention relates to (a) a 4,5-epoxymorphinan derivative, (b) polyethylene glycol, and (c) a naphthol-based azo. It is related with the stable formulation excellent in light resistance and oxidation resistance containing a pigment | dye, a xanthene pigment | dye, or copper chlorophyllin sodium, and (d) tocopherol.

で表される４，５−エポキシモルヒナン誘導体（ＩＵＰＡＣ名は、（２Ｅ）−Ｎ−［（５Ｒ，６Ｒ）−１７−（Ｃｙｃｌｏｐｒｏｐｙｌｍｅｔｈｙｌ）−４，５−ｅｐｏｘｙ−３，１４−ｄｉｈｙｄｒｏｘｙｍｏｒｐｈｉｎａｎ−６−ｙｌ］−３−（ｆｕｒａｎ−３−ｙｌ）−Ｎ−ｍｅｔｈｙｌｐｒｏｐ−２−ｅｎａｍｉｄｅ ｍｏｎｏｈｙｄｒｏｃｈｌｏｒｉｄｅ）（以下「ＮＡＬ−Ｆ」という）は、そう痒症改善剤であり、オピオイドκ受容体に対する選択性の高い作動薬として、血液透析患者及び慢性肝疾患患者に於ける経口そう痒症改善薬「レミッチ（登録商標）カプセル２．５μｇ」の商品名で知られている。 Chemical formula (XIV):

(IUPAC name is (2E) -N-[(5R, 6R) -17- (Cyclopropylmethyl) -4,5-epoxy-3,14-dihydroxymorphinan-6 yl] -3- (furan-3-yl) -N-methylprop-2-enamide monohydrochloride (hereinafter referred to as “NAL-F”) is a pruritus ameliorating agent and has high selectivity for opioid κ receptors. As an agonist, it is known under the trade name of “Remich (registered trademark) capsule 2.5 μg”, an oral pruritus ameliorating drug in hemodialysis patients and chronic liver disease patients.

  This NAL-F is an amorphous powder that is easily soluble in water and has high hygroscopicity, and is widely known to have characteristics that are easily subjected to photoisomerization and oxidative decomposition in a solution state. For this reason, in order to achieve light stability and storage stability, “REMITCH (registered trademark) capsule 2.5 μg” is sold as a soft capsule for the purpose of light-shielding and oxygen-blocking properties. Sodium sulfate hydrate is blended, and a titanium oxide colorant is blended in the gelatin film of the capsule as a light-shielding agent (Non-patent Document 1).

  Patent Document 1 has an object to provide a stable pharmaceutical composition and a stabilization method of a 4,5-epoxymorphinan derivative. As a means for solving the problem, as a means for solving the problem, a 4,5-epoxymorphinan derivative and the following ( 1), (2), (3), (4) or pharmaceutical composition comprising at least one substance selected from (5) is disclosed: (1) sodium sulfite, sulfite Water-soluble antioxidant selected from sodium hydrogen, sodium pyrosulfite, Rongalite, sodium nitrite, L-ascorbic acid, erythorbic acid, sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, oxyquinoline sulfate, (2) gallic acid Propyl acid, butylhydroxytoluene, butylhydroxyanisole, tocopherol, ascorbyl pal A fat-soluble antioxidant selected from tate, ascorbic acid stearate, nordihydroguaiaretic acid, mercaptobenzimidazole, (3) a synergist selected from EDTA or a salt thereof, citric acid or a salt thereof, and lecithin (ie, oxidation) Food additives such that the antioxidant effect becomes stronger when used in combination with an inhibitor), (4) saccharides selected from D-mannitol, D-sorbitol, xylitol, glucose, and fructose; and (5) sesquiskies. A surfactant selected from sorbitan oleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate, polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether.

  Among these substances, Patent Document 1 specifically describes, in the Examples, stabilizers that have demonstrated a stabilizing effect on NAL-F: (1) Thiosulfuric acid as a water-soluble antioxidant Sodium, (2) propyl gallate and tocopherol as fat-soluble antioxidants, (3) citric acid or salts thereof as synergists, (4) D-mannitol, D-sorbitol, xylitol and glucose as sugars, and (5) Sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate, polyoxyethylene nonylphenyl ether as a double-sided activator.

  However, the light stability and storage stability of 4,5-epoxymorphinan derivatives including NAL-F are still not sufficient, and there is a demand for more stable and diverse preparations.

JP 2005-247866 A JP 05-031352 A Special republication WO 04/017958

Pharm. Tech. Jpn. 2011, 27 (13), 2607

  The subject of this invention is providing the formulation which is excellent in the light stability and oxidation stability of a 4, 5- epoxy morphinan derivative, and has the outstanding storage stability in view of the above-mentioned situation.

The present inventors diligently tried to solve the above-mentioned problems and repeated various trials and errors. Surprisingly, the combination of a specific dye and an antioxidant is a light of 4,5-epoxymorphinan derivative. The present inventors have found that a coated preparation excellent in stability and oxidative stability is provided, and reached the present invention.

［式中、Ｒ^１は水素又はヒドロキシを表し、Ｒ^２は水素又はヒドロキシを表し、Ｒ^３は−Ｎ（Ｄ）−（Ｄは水素又は炭素数１〜６のアルキルを表す）又は−Ｏ−を表し、Ｒ^４はメチレン又はカルボニルを表し、Ｒ^５は水素、炭素数１から６のアルキル、炭素数１〜４の２−アルキルビニル、２−フェニルビニル、又は２−（３−フラン）ビニルを表す。］で表される４，５−エポキシモルヒナン誘導体又はその薬理学的に許容される酸との中和塩と、
（ｂ）成分として、ポリエチレングリコールと、
（ｃ）成分として、化学式（ＩＩ）：

［式中、Ｘは置換１−ナフトール基を表し、Ｙは置換フェニル基又は置換１−ナフチルを表す。」で表されるナフトール系アゾ色素、キサンテン色素、化学式（ＩＩＩ）：

で表される青色１号、及び化学式（ＩＶ）：

で表される銅クロロフィリンナトリウム、
から選択される少なくとも一つの色素と、
（ｄ）成分としてトコフェロールとを、含有する製剤に関するものである。 That is, the present invention provides [1] (a) component as chemical formula (I):

[Wherein, R ¹ represents hydrogen or hydroxy, R ² represents hydrogen or hydroxy, R ³ represents —N (D) — (D represents hydrogen or alkyl having 1 to 6 carbon atoms) or —O— R ⁴ represents methylene or carbonyl, R ⁵ represents hydrogen, alkyl having 1 to 6 carbons, 2-alkylvinyl having 1 to 4 carbons, 2-phenylvinyl, or 2- (3-furan) vinyl. Represents. And a neutralized salt with a pharmacologically acceptable acid thereof,
(B) As a component, polyethylene glycol;
As component (c), chemical formula (II):

[Wherein, X represents a substituted 1-naphthol group, and Y represents a substituted phenyl group or substituted 1-naphthyl. Naphthol-based azo dyes, xanthene dyes, chemical formula (III):

Blue No. 1 represented by the formula (IV):

Copper chlorophyllin sodium represented by
At least one dye selected from
(D) It relates to a preparation containing tocopherol as a component.

で表される１７−（シクロプロピルメチル）−３、１４β−ジヒドロキシ−４、５α−エポキシ−６β−［Ｎ−メチル−トランス−３−（３−フリル）アクリルアミド］モルヒナン塩酸塩（「ＮＡＬ−Ｆ」）である、［１］に記載の製剤に関するものである。 Furthermore, the present invention provides
[2] The 4,5-epoxymorphinan derivative has the chemical formula (V):

17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamide] morphinane hydrochloride (“NAL-F It is related with the formulation as described in [1].

Furthermore, the present invention provides
[3] The pharmaceutical preparation according to [1] or [2], wherein the preparation is a coated tablet, a hard capsule, a soft capsule, or a seamless capsule.

で表される赤色１０２号、化学式（ＶＩＩ）：

で表される赤色２号、化学式（ＶＩＩＩ）：

で表される赤色４０号、及び化学式（ＩＸ）：

で表される黄色５号から選択される少なくとも一つのナフトール系アゾ色素、及び／又は、化学式（Ｘ）：

で表される赤色３号、化学式（ＸＩ）：

で表される赤色１０４号、化学式（ＸＩＩ）：

で表される赤色１０５号、及び化学式（ＸＩＩＩ）：

で表される赤色１０６号から選択される少なくとも一つのキサンテン系色素である、［１］〜［３］のいずれか一つに記載の製剤に関するものである。 Furthermore, the present invention provides
[4] The component (c) is in the film, and the dye is represented by the chemical formula (VI):

Red No. 102 represented by the chemical formula (VII):

Red No. 2 represented by the chemical formula (VIII):

Red No. 40 represented by the chemical formula (IX):

At least one naphthol-based azo dye selected from yellow No. 5 and / or chemical formula (X):

Red No. 3 represented by the chemical formula (XI):

Red No. 104 represented by the chemical formula (XII):

Red No. 105 represented by the formula (XIII):

It relates to the preparation according to any one of [1] to [3], which is at least one xanthene pigment selected from Red No. 106 represented by formula (1).

Furthermore, the present invention provides
[5] The preparation according to [4], wherein the naphthol-based azo dye is Red No. 102.

Furthermore, the present invention provides
[6] The present invention relates to the preparation according to any one of [1] to [5], further having a titanium oxide in the coating part .

  The present invention provides a preparation having excellent storage stability due to excellent light stability and oxidation stability of a 4,5-epoxymorphinan derivative, preferably NAL-F. Examples of the preparation of the present invention include coated tablets, hard capsules, soft capsules, and seamless capsules.

The comparison of the effect of the kind of dye (red No. 3, red No. 102 dye and blue No. 1 dye) on the stability of NAL-F in a nitrogen environment is shown (tocopherol is not added). Each of these dyes is contained in the film at a solid content of 0.1 wt%, and the nuclear liquid contains 17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl- Trans-3- (3-furyl) acrylamide] morphinan hydrochloride ("NAL-F") is included. The effect of the dye (red No. 102) and the effect of the antioxidant tocopherol on the stability of NAL-F in the atmospheric environment, and the combined effect of applying the present invention are shown. The pigment is contained in the capsule film, and tocopherol is contained in the nuclear fluid together with NAL-F. Comparison of the effect of red No. 106 dye, yellow No. 5 dye, red No. 2, red No. 40 and red No. 3 dye in the film on the stability of NAL-F hydrochloride in the atmospheric environment to which the present invention is applied Represents. The content of the pigment is 0.4 wt% in the solid content of the film. The pigment is contained in the film, and tocopherol is contained in the nuclear fluid together with NAL-F. The effect of combined use of Blue No. 1 and Red No. 102 dye in the film and the effect of using copper chlorophyllin sodium on the stability of NAL-F in the atmospheric environment to which the present invention is applied is shown. Titanium oxide is contained in the film, and in addition to the above, each of the above dyes is contained. The nuclear fluid contains 0.75 wt% of the antioxidant tocopherol together with NAL-F. The effect of the dye and tocopherol on the stability of NAL-F in the seamless capsule to which the present invention is applied is shown. (Tocopherol combined use; under atmospheric environment)

  Hereinafter, embodiments for carrying out the present invention will be described more specifically.

  The component (a) represented by the chemical formula (I), which is an active ingredient used in the present invention: 4,5-epoxymorphinan derivative can be produced, for example, by the method described in Japanese Patent No. 2525552. .

で表される化合物（「ＮＡＬ−Ｆ」）である。 The component (a) is preferably 17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamide] morphinan hydrochloride. (Hereinafter sometimes abbreviated as “NAL-F”), 17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (phenyl) acrylamide] morphinan Hydrochloride (may be abbreviated as “NAL-P”), and 17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (n-propyl) ) Acrylamide] morphinan hydrochloride, particularly preferred is the chemical formula (V):

("NAL-F").

  The amount of the component (a), which is a medicinal component in the preparation according to the present invention, depends on the disease state of the patient and the dosage form of the preparation, but may be any amount as long as it has a therapeutic effect, for example, 0.01 to The range can be 10,000 mg / formulation, but usually the range of 0.1-1000 mg / formulation is preferred. More specifically, in the case of a capsule preparation containing NAL-F as the component (a), 0.1 to 100 μg / capsule, preferably 0.5 to 50 μg / capsule, more preferably 1.0 to The amount is 10 μg / capsule, and an appropriate amount can be determined in consideration of the disease state and safety of the corresponding patient. Incidentally, the “Remitch (registered trademark) capsule 2.5 μg” formulation currently on the market has a blending amount of 2.5 μg / capsule.

  The polyethylene glycol as the component (b) according to the present invention is used as a solvent for the 4,5-epoxymorphinan derivative as the component (a). It can also be used as a mixed solvent with water. The molecular weight of polyethylene glycol is not particularly limited as long as it is liquid in the formulation step, and is usually about 200 to 9000, preferably about 200 to 4000. For example, commercially available products such as Macrogol 200 and Macrogol 400 are available. Product can be used. The amount of polyethylene glycol used is not particularly limited and can be varied depending on the type of preparation, but is usually sufficient to dissolve NAL-F to dissolve and disperse fillers such as citric acid as tocopherol and synergist. It is selected in consideration of the sufficient amount, and further, it is selected in consideration of the necessary dilution amount corresponding to the viscosity required in the preparation process. For example, in the case of a capsule preparation, 30 to 99.99 wt% per capsule, preferably 35 to 90 wt%.

［式中、Ｘは置換１−ナフトール基を表し、Ｙは置換フェニル基又は置換１−ナフチルを表す。］で表されるナフトール系アゾ色素が挙げられる。好ましいナフトール系アゾ色素としては、赤色２号、赤色１０２号、赤色４０号、及び黄色５号、好ましいキサンテン色素は、赤色３号、赤色１０４号、赤色１０５号、赤色１０６号が挙げられるが、特に赤色１０２号が好ましい。 The pigment of component (c) according to the present invention functions as a light stabilizer for the 4,5-epoxymorphinan derivative of component (a). These dyes include chemical formula (II):

[Wherein, X represents a substituted 1-naphthol group, and Y represents a substituted phenyl group or substituted 1-naphthyl. Naphthol azo dyes represented by the formula: Preferred naphthol-based azo dyes include Red No. 2, Red No. 102, Red No. 40, and Yellow No. 5, and preferred xanthene dyes include Red No. 3, Red No. 104, Red No. 105, and Red No. 106. Red No. 102 is particularly preferable.

Examples of the dye of component (c) include Blue No. 1 and copper chlorophyllin sodium in addition to the naphthol-based azo dye.
These dyes can be used alone as the dye of component (c), or a plurality of them can be used in any combination.

  The combination part of a pigment | dye can be mix | blended in any location of a formulation. For example, blending with 4,5-epoxy morphinan derivative, which is the active main ingredient, or blending into the external film of 4,5-epoxy morphinan derivative blending part, etc. You can choose. Considering that the function of the dye is to improve light resistance, blending into the outer surface part of the preparation, for example, the coating part of the outer surface of a tablet, or blending into the capsule film part of a capsule Is more effective.

  In a preferred embodiment of the present invention, the preparation is a capsule preparation, the pigment of component (c) is in the film, and the pigment is a naphthol-based azo pigment of red 102, red 2, red 40, or yellow No.5. Among these, Red No. 102 is particularly preferable.

  The blending amount of the dye is not particularly limited as long as the light resistance effect can be significantly confirmed. The amount depends on the kind of the preparation. For example, when it is contained in the capsule film, it is usually 0.0001 to 0.5 wt%, preferably 0.01 to 0.4 wt%, preferably 0.00. 02 to 0.3 wt%.

  The tocopherol which is the component (d) of the present invention functions as an antioxidant for the 4,5-epoxymorphinan derivative. As the tocopherol, any of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, or a mixture thereof can be used. The amount of tocopherol blended is not particularly limited as long as the antioxidant effect can be confirmed to be superior. There are no particular limitations on the location of tocopherol, and it can be added in the bulk of the preparation or in the film, but it is usually mixed in the same location as the 4,5-epoxymorphinan derivative. For example, in the case of a capsule preparation, it is blended in a nuclear fluid. The blending amount of tocopherol should just be more than the quantity which can confirm the antioxidant effect significantly. For example, in the case of a capsule preparation, the amount of tocopherol is 0.01 to 30.0 wt%, preferably 0.1 to 25.0 wt% of the core liquid.

  Furthermore, in the present invention, it is preferable to further mix titanium oxide, and it is particularly preferable to blend in the preparation film. This is because the titanium oxide compound is used for laser printing such as lot numbers. The crystal form of the titanium oxide can be selected from a rutile type, anatase type or amorphous type, and the particle size is preferably in the form of fine particles from the viewpoint of dispersibility. The compounding amount of the titanium oxide is, for example, usually 0.0001 to 0.5 wt%, preferably 0.01 to 0.1 wt%, preferably 0.02 to 0.0. It is 08 wt%.

  Although it does not restrict | limit especially as a kind of formulation of this invention, Preferably, it is a coated tablet, a hard capsule, a soft capsule, or a seamless capsule. The reason why these preparations are preferable is that the light resistance function can be best exhibited by the presence of the pigment according to the present invention having a light resistance function in the tablet coating part or capsule film part of these preparations.

  In the embodiment of the present invention, the surface portion of the preparation is subjected to crosslinking treatment or coating treatment. The cross-linking treatment of the film is suitable for the treatment of a film containing protein. For example, cross-linking by a chemical reaction using a conventionally known cross-linking agent or cross-linking by an enzymatic reaction can be employed.

  The form of the preparation according to the present invention is a coated tablet, a hard capsule, a soft capsule, or a seamless capsule.

  In the case of a capsule preparation, the base for forming a capsule film includes a mixture of protein and water-soluble polyhydric alcohol, a mixture of protein and water-soluble polyhydric alcohol and polysaccharide, or a polysaccharide and water-soluble polyhydric alcohol. And a mixture with a monohydric alcohol. Examples of the protein include gelatin and collagen. Examples of water-soluble polyhydric alcohols include sorbitol, mannitol, glycerin, propylene glycol, polyethylene glycol, glucose, fructose, galactose, arabinose, mannose, rhamnose, maltose, raffinose, sucrose, erythritol, maltitol, trehalose, lactose, xylose, etc. Can be mentioned. Polysaccharides include agar, gellan gum, xanthan gum, locust bean gum, pectin, psyllium seed gum, guar gum, far selelain, arabinogalactan, arabinoxylan, alginate, carrageenan, gum arabic, dextrin, modified dextrin, starch, modified starch, pullulan And carboxymethyl cellulose salt. When using an alginate, gellan gum, pectin, or carrageenan, an alkali metal salt, an alkaline earth metal salt, an ammonium salt, or the like may be added as appropriate.

  In the present invention, in particular, seamless capsules containing 4,5-epoxymorphinan derivatives are preferably used because they can reduce the amount of antioxidants and are useful for single-packed preparations of plural kinds of pharmaceuticals. . The production of the seamless capsule can be prepared, for example, by a dropping method using a triple nozzle described in Patent Document 2.

  In the capsule preparation according to the present invention, the surface portion of the capsule is cross-linked, and the solubility of the portion in water decreases. In order to control the degree of crosslinking, for example, it is possible to reduce the degree of crosslinking by shortening the reaction time with the crosslinking agent or by adding dextrin or starch to the film component. Conversely, the degree of crosslinking can be increased by increasing the reaction time with the cross-linking agent, or by using only the protein as the film component or increasing the protein content of the film component. It is also possible to adjust the degree of crosslinking by adjusting the pH and temperature of the crosslinking agent.

  It is also preferable to contain a light-shielding agent in the seamless capsule. In that case, a seamless capsule can be prepared by adding a light-shielding agent to at least one of the above-mentioned film and the content liquid, or when performing a coating treatment, it can be contained in the coating film. Examples of the light-shielding agent include titanium oxide, zinc oxide, iron sesquioxide, silicon dioxide, calcium carbonate, talc, and mica, but titanium oxide is preferable. The filling liquid enclosed in the seamless capsule is not particularly limited, and examples thereof include lipophilic or hydrophilic liquids, suspensions of these liquids and insoluble powders, or mixed liquids of these liquids. . These filling liquids can contain, for example, various lipophilic or hydrophilic active ingredients such as various vitamins, minerals, fragrances and extracts contained in normal functional foods and functional beverages. Examples of the hydrophilic liquid material include water (including purified water, ion-exchanged water, etc.), water-soluble alcohol, polyhydric alcohol (glycerin, mannitol, sorbitol, etc.), and mixtures thereof. Examples of lipophilic liquids include glycerin fatty acid esters, sucrose fatty acid esters (for example, sucrose acetate isobutyrate (SAIB)), medium chain fatty acid triglycerides (MCT), lauric acid, palmitic acid, stearic acid, myristic acid, oleic acid , Behenic acid, vegetable oils and fats (such as coconut oil, sunflower oil, safflower oil, sesame oil, rapeseed oil, grape seed oil, and mixtures thereof) and mixtures thereof.

  The average particle diameter of the seamless capsule is usually 0.3 to 10 mm, and in order to obtain the high effect of the present invention, it is preferably 0.5 to 8 mm.

  The preparation according to the present invention thus obtained can be stored for a long period of one year or longer while maintaining the activity of the 4,5-epoxymorphinan derivative at room temperature and under a fluorescent lamp due to the effect of the dye and tocopherol. It is.

  As in the case of the seamless capsule, the soft capsule preparation according to the present invention contains a polyethylene glycol solution containing 4,5-epoxymorphinan derivative, tocopherol as an antioxidant, citric acid as a synergist, etc. Liquid) and a structure surrounding the film with a film sheet. This content liquid can be prepared in the same manner as the seamless capsule. As the material of the film sheet, the same material as the material of the film of the seamless capsule can be adopted. In the preparation of soft capsules, this material is formed into a sheet according to a conventional method, and is prepared according to a general method for producing soft capsules using the above-described content liquid. For example, it can be prepared by the method described in Patent Document 3, and a soft capsule is prepared by a rotary die using a coating sheet and a content liquid.

  Furthermore, as in the case of seamless capsules, when a light capsule is prepared by adding a light resistance improver such as a dye or titanium oxide in at least one of the above-mentioned film sheet and the content liquid, or when performing a coating treatment, It can be contained in the coating film. Tocopherol as an oxidative stabilizer is usually blended with the 4,5-epoxymorphinan derivative in the content liquid as in the case of seamless capsules.

  The long diameter of the soft capsule is usually 3 to 16 mm, and the short diameter is usually 2 to 10 mm. In particular, in order to obtain the high effect of the present invention, the long diameter is 5 to 7 mm and the short diameter is 2 to 3 mm. preferable.

  The soft capsules thus obtained can be stored for a long period of one year or longer while maintaining the activity of the 4,5-epoxymorphinan derivative at room temperature and under a fluorescent lamp.

  The hard capsule preparation according to the present invention comprises a polyethylene glycol solution containing a 4,5-epoxymorphinan derivative, tocopherol as an antioxidant, citric acid as a synergist, etc. in the body part of a capsule body obtained by molding in advance. It is manufactured by filling it as a content liquid (core liquid) and covering it with a cap of a capsule body. As the base material of the capsule body, gelatin, collagen, methyl cellulose, cellulose acetate, cellulose acetate propionate, polyvinyl alcohol, polyvinyl alcohol-acryl methyl ester, and the like are used, and gelatin is preferable. When the content liquid is contained, sealing is usually performed after the body portion is sealed with a cap so that the content liquid does not leak.

  As in the case of the seamless capsule, it is preferable to control the disintegration rate of the capsule film with respect to water by performing at least one of a crosslinking treatment of the capsule body and a coating treatment of the capsule.

  The hard capsules thus obtained can be stored for a long period of one year or longer while maintaining the activity of the 4,5-epoxymorphinan derivative at room temperature and under a fluorescent lamp.

  In the case of the coated tablet according to the present invention, the tablet body is a 4,5-epoxymorphinan derivative, tocopherol as an antioxidant, citric acid as a synergist or the like dissolved or dispersed in a small amount of polyethylene glycol and used in the field. The tablet can be manufactured using a general manufacturing method. As additive for tablets, excipients such as silicic anhydride, synthetic aluminum silicate, lactose, corn starch and crystalline cellulose; binders such as gum arabic, gelatin, polyvinyl pyrrolidone and hydroxypropyl cellulose; magnesium stearate, talc , Lubricants such as silicic acid anhydride; disintegrants such as corn starch and carboxymethylcellulose calcium can be used.

  For example, a thin cylindrical shaped product is obtained by an extrusion granulation method which is one of wet methods, and this is cut into an appropriate length to obtain granules. Next, the same coating treatment as that for the seamless capsule is performed. For the covering part (coating part), the same substrate as in the case of the seamless capsule can be used, and as in the case of the seamless capsule, a light fastness improving agent such as a dye or titanium oxide can be contained in the covering part.

  The tablet has a diameter of usually 3 to 8 mm and a thickness of 1 to 10 mm. In particular, in order to obtain the high effect of the present invention, the diameter is preferably 3 to 4 mm and the thickness is preferably 1 to 3 mm.

  The coated tablet thus obtained can be stored for a long period of one year or longer in the activity of the 4,5-epoxymorphinan derivative at room temperature and under fluorescent light.

  The behavior of the 4,5-epoxymorphinan derivative by the above preparation can be chemically evaluated. For example, chemical evaluation can be performed by high performance liquid chromatography.

  The present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples. In Examples and Comparative Examples, “wt%” is based on mass.

The 4,5-epoxymorphinan derivative used as the active agent (API) was a commercial product or a synthetic product as shown below:
17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamide] morphinan hydrochloride (hereinafter; “NAL-F”) Commercially available), and 17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (phenyl) acrylamide] morphinan hydrochloride In some cases, NAL-P was synthesized from naltrexone according to a conventional method, specifically, benzyl N-methylamine (BzNMeH) and sodium cyanoborohydride (NaBH ₃ CN) were reacted with naltrexone. After that, debenzylation was performed, and (2E) -N-[(5α, 6β) -17- (cyclopropylmethyl)- 3,14-dihydroxy-4,5-epoxymorphinan-6-yl] -N-methylamine (may be abbreviated as “Nal-prec”), and cinnamoyl chloride was added to Nal-prec in the presence of triethylamine. By reacting, a Nal-P basic substance was obtained, which was reacted with hydrochloric acid to obtain NAL-P.

  Tocopherol used as antioxidant, dibutylhydroxytoluene, dye used as light fastness improver (red 102, red 3, red 2, red 40, blue 1, red 106, yellow 5, copper chlorophyllin sodium ), Succinylated gelatin, glycerin, polyethylene glycol 400, sucrose fatty acid ester, medium chain fatty acid triglyceride, and the like used as capsule materials were commercially available products.

[Example 1-1] Production of colored gelatin film liquid 6.993 g of concentrated glycerin and 0.035 g of a dye were added to 65 g of purified water and dissolved by stirring (in the case of containing titanium oxide, 0. 035 g is added). Further, 27.972 g of succinated gelatin was added and dissolved by stirring at 60 ° C. to prepare each colored gelatin film solution having a solid content of 35 (w / w)%.

[Example 1-2] Manufacture of gelatin film An inner surface corona-treated PET (polyethylene terephthalate) film was laid on a glass plate kept at 60 ° C. so that the inner surface was up, and pasted so as not to bend. It was. A Baker type applicator YBA-7 type (manufactured by Yoshimi Seiki) preliminarily warmed to 60 ° C. was placed on the end of the PET film, and the scale of the applicator was adjusted to “350 μm”. An appropriate amount of the colored gelatin film solution was dropped in the vicinity of the applicator on the PET film, and the applicator was slowly slid to spread the colored gelatin film solution on the PET film. The spread solution for colored gelatin film was completely dried to produce each colored gelatin film. The obtained colored gelatin film is cut into an appropriate size together with the PET film, the colored gelatin film is peeled off from the PET film, and the film thickness is measured and confirmed using “Digimatic MicroMeter MDC-25MJ” (manufactured by Mitsutoyo). A colored gelatin film having a thickness of 120 μm (adopted range film thickness: 116 to 124 μm) was obtained.

[Example 1-3] Production of NAL-F solution (1) Under a nitrogen environment, 0.75 g of tocopherol was added to 98.64 g of Macrogol 400 and mixed by stirring to produce a tocopherol-containing base solution.
(2) Under a nitrogen environment, 0.00625 g of NAL-F and 0.6 g of anhydrous citric acid were added to 2.0 g of purified water and dissolved by stirring to produce a NAL-F-containing aqueous solution.
(3) In a nitrogen environment, a NAL-F hydrochloride aqueous solution is put into a tocopherol-containing base solution and dissolved by stirring to produce a NAL-F solution prepared to have a NAL-F concentration of 0.0061274 (w / w)%. did.

に従って、ＮＡＬ−Ｆの濃度を決定した。
（９）光照射直前のＮＡＬ−Ｆ濃度を１００とした光照射後のＮＡＬ−Ｆ濃度をＮＡＬ−Ｆ「定量比（％）」又はＮＡＬ−Ｆ「残存率（％）」として表示した。 [Example 1-4] Production of light irradiation test specimen, light irradiation test and analysis method (1) 1.2 mL of NAL-F solution was placed in a 1.5 mL colorless transparent glass bottle under air and sealed. A dispensing sample was prepared.
(2) Two colored gelatin films were superposed and heat-pressed on 3 sides at 180 ° C. for 1 second using a heat sealer to produce a colored gelatin film bag.
(3) The sample to be dispensed was packed in a bag of colored gelatin film, and one open side was thermocompression bonded at 180 ° C. for 1 second using a heat sealer to produce a sample for light irradiation test.
(4) The specimen for light irradiation test was placed in a light stability tester LT-120 (D3CJ) (manufactured by Nagano Kagaku Kikai Seisakusho Co., Ltd.) and continuously irradiated with 2500 lx white light and taken out for a predetermined time.
(5) About 0.1 g of NAL-F solution (corresponding to about 7 μg of NAL-F) is accurately measured from the dispensed sample in the atmosphere in a centrifuge tube, and about 2 mL of phosphate buffer solution (trisodium phosphate 12 water) 2 g of a Japanese product (Na ₃ PO ₄ · 12H ₂ O) and 3 g of disodium hydrogen phosphate (Na ₂ HPO ₄ ) dissolved in 50 mL of water were added and dissolved. To this solution, add exactly 2 mL of the internal standard solution (0.04 mol / L 2-[(2-cyclopropylphenoxy) methyl] -2-imidazoline / HCl aqueous solution), add about 15 mL of diethyl ether, and shake vigorously for 30 minutes. mixed. After centrifugation, about 7 mL of the upper layer was taken in another test tube, and about 1 mL of 1.46 mmol / L phosphoric acid aqueous solution was added to this solution and shaken vigorously for 10 minutes. After centrifugation, the aqueous layer was filtered through a membrane filter having a pore size of 0.45 μm to obtain a sample solution.
(6) Separately, a NAL-F standard product (about 7 μg) was treated in the same manner as above to obtain a standard solution.
(7) 50 μL of the sample solution and standard solution were analyzed by liquid chromatography under the following conditions:
Analysis conditions HPLC: Shimadzu prominence-i LC-2030C
Detector: Ultraviolet absorption detector (λ280nm) (Shimadzu SPD-M30A)
Column: ODS (Inertsil ODS-3 manufactured by GL Sciences)
Column temperature: 40 ° C
Mobile phase: 1 g of 1-octane sodium sulfonate, 14.6 mmol / L phosphoric acid 600 mL, acetonitrile 300 mL and methanol 100 mL mixed flow rate: 1 mL / min
(8) by determining the ratio _{Q T} and _{Q S} of the peak area of NAL-F to the peak area calculations within a standard substance NAL-F concentration,

The concentration of NAL-F was determined according to
(9) The NAL-F concentration after light irradiation with the NAL-F concentration immediately before light irradiation as 100 was displayed as NAL-F “quantitative ratio (%)” or NAL-F “residual rate (%)”.

[Experimental Example 1] Effect of dye on stability of NAL-F (under nitrogen environment; no tocopherol added)
A comparison was made of the effects of the types of dyes (Red No. 3, Red No. 102 dye and Blue No. 1 dye) on the stability of NAL-F in a nitrogen environment (tocopherol was not added). Each of these dyes is contained in the sheet in an amount of 0.1 wt%, and the core liquid contains NAL-F. Table 1 shows the composition of the nuclear fluid and the film, and the experimental conditions.

Samples at 14 hours and 42 hours after the start of light irradiation were analyzed immediately before the start of light irradiation, and the NAL-F residual rate was analyzed. The obtained results are shown in Table 2 and FIG.

  From Table 2 and FIG. 1, in the tocopherol-free system, the NAL-F residual rate was 95.2% in the nuclear solution completely light-shielded after 42 hours of light irradiation. The residual ratio of F is 71.8%, but the residual ratio is 80.7% with the addition of Red No. 3, the residual ratio is 79.7% with the addition of Red No. 102, and the residual ratio with the addition of Blue No. 1 The rate was 81.4%, and it was confirmed that NAL-F was stabilized by shading, and a stabilizing effect was also observed by adding a dye to the film. There was no difference in stability due to differences.

[Experimental Example 2] Effect of dye and tocopherol on the stability of NAL-F (under atmospheric environment)
The effect of the dye (red No. 102) on the stability of NAL-F in the atmospheric environment, the effect of the antioxidant tocopherol, and the combined effect of applying the present invention were investigated. The pigment is contained in the capsule film, and tocopherol is contained in the nuclear fluid together with NAL-F. Table 3 shows the composition of the nuclear fluid and the film, and the experimental conditions.

表４及び図２の結果から、４２時間光照射後でのＮＡＬ−Ｆ残存率を見ると、色素無し、トコフェロール無しでの残存率：７２．２％に対して、皮膜に色素を添加することで効果が見られ（残存率：８０．２％）、核液にトコフェロールを添加することでも効果が見られ（残存率：８８．３％）、本発明を適用する色素とトコフェロールの併用系（実施例２）で最も大きな効果が表れた（残存率：９６．７％）。 Samples at 14 hours and 42 hours after the start of light irradiation were analyzed immediately before the start of light irradiation, and the NAL-F residual rate was analyzed. The obtained results are shown in Table 4 and FIG.

From the results of Table 4 and FIG. 2, when looking at the NAL-F residual rate after 42 hours of light irradiation, the pigment was added to the film against the residual rate without pigment and without tocopherol: 72.2%. (Residual rate: 80.2%), and the effect can also be seen by adding tocopherol to the nuclear fluid (residual rate: 88.3%), and the combined use of the dye and tocopherol to which the present invention is applied ( The greatest effect was exhibited in Example 2) (residual rate: 96.7%).

[Experimental Example 3] Effect of pigment and tocopherol on the stability of NAL-F (under atmospheric environment)
The effects of red No. 106 dye, yellow No. 5 dye, red No. 2, red No. 40 and red No. 3 dye in the film on the stability of NAL-F hydrochloride in the atmospheric environment were compared. The content of the pigment is 0.4 wt% in the solid content of the film. The pigment is contained in the film, and tocopherol is contained in the nuclear fluid together with NAL-F. Table 5 shows the composition of the nuclear fluid and the film, and the experimental conditions.

Samples at 14 hours and 42 hours after the start of light irradiation were analyzed immediately before the start of light irradiation, and the NAL-F residual rate was analyzed. The obtained results are shown in Table 6 and FIG.

  From the results shown in Table 6 and FIG. 3, after the light irradiation for 14 hours, the NAL-F residual ratio in the dye-free system was 94.3%. Residual rate: 96.6%, remaining rate: 96.1% when Yellow No. 5 is added, remaining rate: 94.5% when Red No. 2 is added, remaining rate: 94.0% when Red No. 40 is added, The result was a residual ratio of 93.5% with the addition of Red No. 3, and among them, the combination effect of tocopherol was remarkably observed in Red No. 106 and Yellow No. 5.

[Experimental Example 4] Effects of dye, tocopherol and titanium oxide on stability of NAL-F (under atmospheric environment)
The combined effect of Blue No. 1 and Red No. 102 pigment in the film on the stability of NAL-F in the atmospheric environment to which the present invention is applied and the effect of using copper chlorophyllin sodium were investigated. Titanium oxide is contained in the coating in an amount of 0.2 wt% of the solid content, and in addition, the above-mentioned pigments are contained. The nuclear fluid contains 0.74 wt% of the antioxidant tocopherol together with NAL-F. Table 7 shows the composition of the nuclear fluid and the film, and the experimental conditions.

Samples of 4 hours and 17 hours after the start of light irradiation were analyzed immediately before the start of light irradiation, and the NAL-F residual rate was analyzed. The obtained results are shown in Table 8 and FIG.

  From the results shown in Table 8 and FIG. 4, in the film, the remaining ratio of NAL-F after irradiation with light for 17 hours is 95% or more of the initial concentration even in the case of Red No. 102 alone or in combination with Blue No. 1 and Red No. 102 dye. Is maintained. Among the dyes, the red No. 102 dye tends to contribute more to the stabilization effect than the blue No. 1 dye. The dye-free system (containing tocopherol and the shielding agent titanium oxide) is less stable than the dye combination system.

[Experimental Example 5]
Effect of pigment and tocopherol on the stability of NAL-F in seamless capsules (tocopherol combined use; under atmospheric environment)
Using a concentric triple nozzle, the liquid III consisting of the composition of the outer coating layer from the outermost nozzle, the liquid I consisting of the composition shown in the core layer from the innermost nozzle, and the intermediate layer from the intermediate nozzle II having the composition shown in FIG. 3 is discharged to form a three-layer droplet, and the coating solution is cured by bringing the three-layer droplet into contact with a rapeseed oil curing liquid, thereby forming the structure of the core layer-protective layer-coating layer. A three-layer seamless capsule having the same structure was prepared. Table 9 shows the composition of each layer and the experimental conditions.

The obtained seamless capsule was placed in a light stability tester LT-120 (D3CJ) (manufactured by Nagano Kagaku Kikai Seisakusho Co., Ltd.) and continuously irradiated with 2500 lx white light and taken out at a predetermined time. Samples of 3.5 hours and 17.5 hours immediately after the start of light irradiation and 3.5 hours after the start of light irradiation were analyzed to analyze the NAL-F residual rate. The obtained results are shown in Table 10 and FIG.

  From the results of Table 10 and FIG. 5, the combined use of the pigment (red No. 102) and tocopherol in the seamless capsule to which the present invention is applied, compared to the NAL-F residual rate (84.3%) of the system to which only tocopherol is added. A high residual rate of NAL-F (92.8%) was observed.

[Example 18] Manufacture of soft capsule formulation The same procedure as in Example 1-1 except that the concentrated gelatin solution was changed to 38.961 g, 0.195 g of pigment, and 155.844 g of succinylated gelatin. A colored gelatin film was produced according to the film production method of Example 1-2. The NAL-F solution of Example 1-3 was used as the soft capsule content liquid, and the gelatin film was sent between a pair of rotating cylindrical molds. The capsules were prepared by spraying onto the capsules. In this way, a soft capsule having a major axis of 4 mm and a minor axis of 3 mm was obtained.

[ Reference Example 1 ] Production of soft capsule formulation The procedure of Example 1-1 was carried out except that the concentrated gelatin solution was changed to 38.961 g of concentrated glycerol, 0.195 g of pigment, and 155.844 g of succinylated gelatin. A colored gelatin film was produced according to the film production method of Example 1-2. The NAL-F solution of Example 1-3 was used as the soft capsule content liquid, and the gelatin film was sent between a pair of rotating cylindrical molds. The capsules were prepared by spraying onto the capsules. In this way, a soft capsule having a major axis of 4 mm and a minor axis of 3 mm was obtained.

[ Reference Example 2 ] Production of coated tablet 10 mg of a 4,5-epoxymorphinan derivative NAL-P, 1200 mg of tocopherol, 960 mg of anhydrous citric acid, 250 g of lactose, 45 g of corn starch and 20 g of carboxymethylcellulose calcium were placed in a rolling granulator. The mixture was preheated and sprayed with 34 g of an aqueous solution containing 1.7 g of hydroxypropylcellulose to obtain a NAL-P-containing granulated powder. To this, 100 g of carboxymethylcellulose calcium and 40 g of talc were added and mixed, and the mixed powder was tableted with a tableting machine to obtain a bare tablet. 40 g of shellac and 40 g of hydroxypropylmethylcellulose were dissolved in 800 g of methanol, and a solution obtained by dissolving 0.2 g of red No. 102 dye in 10 g of water was mixed with the resulting solution to obtain a coating solution. The coating solution was sprayed onto the bare tablets to obtain tablets with a coating thickness of 0.3 mm.

The combination formulation according to the present invention increases the storage stability of the oral pruritus ameliorating drug 4,5-epoxymorphinan derivative (particularly NAL-F) in hemodialysis patients and chronic liver disease patients. It leads to improvement of therapeutic effect.

Claims (4)

As component (a), chemical formula (V):

17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamide] morphinan hydrochloride represented by:
(B) As a component, polyethylene glycol;
As component (c), chemical formula (VI):

Red No. 102 represented by the formula (IX):

At least one naphthol-based azo dye selected from yellow No. 5 represented by formula (XIII):

At least one dye selected from Red No. 106 xanthene dye represented by :
(D) A coated preparation containing tocopherol as a component. The coated preparation according to claim 1, wherein the preparation is a coated tablet, a hard capsule, a soft capsule or a seamless capsule. The coated preparation according to claim 1 or 2, wherein the component (c) is in a coating portion . Furthermore, the coating formulation as described in any one of Claims 1-3 which has a titanium oxide in a coating | coated part .

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