Kappa receptor stimulant-containing pharmaceutical composition and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition containing a kappa receptor stimulant and a preparation method of the pharmaceutical composition, and belongs to the technical field of pharmaceutical preparations. The pharmaceutical composition of the present invention contains a kappa receptor agonist and an amino acid stabilizer. After being prepared, the pharmaceutical composition still stably contains effective components after being stored for a long time.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing a selective opioid kappa receptor agonist 4,5-epoxymorphinan derivative or a pharmaceutically acceptable salt thereof and a preparation method thereof. BACKGROUND

[0002] It is known that 4,5-epoxymorphinan derivatives or pharmaceutically acceptable salts thereof are compounds having a significant antipruritic effect. Nalfurafine is a selective opioid kappa receptor agonist developed by Toray Industries, Inc., and exerts an antipruritic effect through a completely different mechanism of action from existing antihistamines or antiallergics, and has a significant antipruritic effect. However, nalfurafine or a pharmaceutically acceptable salt thereof is chemically unstable to light, heat and oxygen, and a formulation with good stability needs to be developed to ensure its quality.

[0003] CN101686976A discloses a solid formulation in which the stability of nalfurafine hydrochloride is improved by containing sodium thiosulfate, a sugar or a sugar alcohol, and low-substituted hydroxypropyl cellulose as a disintegrant as a stabilizing agent. CN102196811A discloses a solid formulation in which the stability of nalfurafine hydrochloride is improved by containing sodium thiosulfate, a sugar or a sugar alcohol, and cross-linked povidone or sodium carboxymethyl starch as a disintegrant as a stabilizing agent.

[0004] However, there is no description of an amino acid stabilizer in the above patent documents, and there is no description of the effect of adding an amino acid stabilizer on the storage stability of the drug.

[0005] The results of quality research comparison show that it is difficult to maintain the sufficient stability of nalfurafine hydrochloride solid formulations using the stabilizers disclosed in the prior art (such as sodium thiosulfate antioxidants), and there are quality problems of content reduction and increase of related substances under high temperature 60℃ or high humidity 75% RH, which may affect the safety and effectiveness of clinical use.

[0006] Therefore, it has become a problem to be solved by those skilled in the art to provide a formulation of 4,5-epoxymorphinan derivatives or pharmaceutically acceptable salts thereof with higher stability. SUMMARY

[0007] To solve the above problems, the first object of the present application is to provide a stable pharmaceutical composition containing 4,5-epoxymorphinan derivatives or pharmaceutically acceptable salts thereof as an effective ingredient, especially a stable solid formulation.

[0008] As a result of intensive studies made by the present inventors in order to develop a stable preparation (e.g., solid preparation) which can withstand long-term storage and which contains as an effective ingredient a 4,5-epoxymorphinan derivative (e.g., nalfoxine) or a pharmaceutically acceptable salt thereof (e.g., nalfoxine hydrochloride), it has been found that the use of an amino acid-based stabilizer makes the 4,5-epoxymorphinan derivative (e.g., nalfoxine) or the pharmaceutically acceptable salt thereof (e.g., nalfoxine hydrochloride) more stably present in the preparation (e.g., solid preparation), thus completing the present invention.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] A pharmaceutical composition containing (1) as an effective ingredient a 4,5-epoxymorphinan derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and (2) an amino acid or a derivative thereof:

[0011]

[0012] In the general formula (I):

[0013] R 1 represents a cyclopropylmethyl group or an allyl group; R 2 represents hydrogen, a hydroxyl group, an acetyloxy group or a methoxy group; R 3 represents hydrogen, a hydroxyl group, an acetyloxy group or a methoxy group; A represents -N(R 4 )C(=O)- or -N(R 4 )C(=O)O-; R 4 represents hydrogen or a straight-chain or branched alkyl group having 1 to 5 carbon atoms; B represents a straight-chain alkylene group having 1 to 3 carbon atoms, -CH=CH- or -C≡C-; R 5 represents hydrogen, a phenyl group, a furanyl group or a thienyl group, but the hydrogen of the above-mentioned phenyl group, the above-mentioned furanyl group and the above-mentioned thienyl group is optionally replaced with one or more groups selected from the group consisting of an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkanoyloxy group having 1 to 5 carbon atoms, a hydroxyl group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, an isothiocyanato group, a trifluoromethyl group, a trifluoromethoxy group and a methylenedioxy group.

[0014] In some embodiments of the present invention, the 4,5-epoxymorphinan derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is preferably a compound represented by the following formula (II) or a hydrochloride salt thereof, i.e., 17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxymorphinan (II).

[0015] 6β-[N-methyl-trans-3-(3-furanyl)acrylamido]morphinan (hereinafter referred to as "nalfoxine") or a hydrochloride salt thereof.

[0016]

[0017] In some embodiments of the present invention, the pharmaceutical composition further contains (3) at least one of a sugar and a sugar alcohol.

[0018] In some embodiments of the present invention, the pharmaceutical composition further comprises (4) crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, or a mixture thereof.

[0019] In some embodiments of the present invention, the amino acid is selected from cysteine, lysine, arginine, histidine, cystine, methionine, asparagine, glutamine, proline, tryptophan, phenylalanine, threonine, valine, leucine, isoleucine, glycine, tyrosine, aspartic acid, or alanine.

[0020] In some embodiments of the present invention, the amino acid derivative is selected from pharmaceutically acceptable salts or pharmaceutically acceptable esters of amino acids.

[0021] In some embodiments of the present invention, the amino acid or its derivative is selected from cysteine ​​hydrochloride, lysine hydrochloride, or arginine.

[0022] In some embodiments of the present invention, the amino acid or its derivative accounts for 0.00001 to 10% by weight of the unit containing the active ingredient, preferably 0.005 to 5% by weight, and more preferably 0.005 to 1% by weight.

[0023] In some embodiments of the present invention, the sugars or sugar alcohols include at least one of starch, sucrose, lactose, mannitol, erythritol, maltitol, or xylitol.

[0024] In some embodiments of the present invention, the sugars or sugar alcohols are granulated particles prepared by extrusion granulation, wet granulation, dry granulation, spray drying, or fluidized bed granulation.

[0025] In some embodiments of the present invention, the pharmaceutical composition is a solid dosage form or a liquid dosage form.

[0026] In some embodiments of the present invention, the solid dosage form includes tablets, capsules, granules, fine granules, powders, and films.

[0027] In some embodiments of the present invention, the tablets include sublingual tablets, intraoral disintegrating tablets, and microtablets.

[0028] In some embodiments of the present invention, the pharmaceutical composition has a coating.

[0029] A second object of the present invention is to provide a method for stabilizing 4,5-epoxymorphinan derivatives or pharmaceutically acceptable salts thereof, the method comprising using an amino acid or a derivative thereof.

[0030] A third objective of the present invention is to provide a method for preparing the pharmaceutical composition, comprising the following steps: mixing the raw materials in a specified proportion.

[0031] In some embodiments of the present invention, the mixing step is performed in a mixer.

[0032] In some embodiments of the present invention, the mixer includes a V-type mixer, a three-dimensional mixer, a two-dimensional mixer, etc.

[0033] In some embodiments of the present invention, the mixing step includes direct powder pressing, dry granulation, or wet granulation.

[0034] The pharmaceutical compositions of the present invention will be described below. Unless otherwise specified, "%" means "weight %".

[0035] The active ingredient of the present invention is a 4,5-epoxymorphinan derivative or a pharmaceutically acceptable salt thereof, as shown in the following general formula (I);

[0036]

[0037] In general formula (I): R 1 Indicates cyclopropylmethyl or allyl; R 2 Indicates hydrogen, hydroxyl, acetoxy, or methoxy; R 3 A represents hydrogen, hydroxyl, acetoxy, or methoxy; A represents -N(R) 4 )C(=O)- or -N(R 4 )C(=O)O-;R 4 B represents a straight-chain or branched alkyl group with 1 to 5 carbon atoms; B represents a straight-chain alkylene group with 1 to 3 carbon atoms, -CH=CH- or -C≡C-; R 5 The group may represent hydrogen, phenyl, furanyl, or thiophene, but the hydrogen in the aforementioned phenyl, furanyl, and thiophene groups may be replaced by one or more groups selected from alkyl, alkoxy, alkanoyloxy, hydroxyl, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanate alkyl, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

[0038] The 4,5-epoxymorphinan derivative of general formula (I) or a pharmaceutically acceptable salt thereof, preferably the compound of formula (II) or its hydrochloride salt, namely 17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furanyl)acrylamido]morphinan (hereinafter referred to as "nafuraphene") or its hydrochloride salt.

[0039]

[0040] Pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate; organic carboxylic acid salts such as acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, and phthalate; and organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. Preferably, hydrochloride, hydrobromide, phosphate, tartrate, maleate, and methanesulfonate are used; most preferably, commercially available hydrochloride is used. The nafraprine of the present invention, or a pharmaceutically acceptable salt thereof, includes anhydrous, hydrated, and solvate forms.

[0041] The active ingredient of the present invention accounts for 0.00001 to 0.01% by weight of the unit weight of the active ingredient in the pharmaceutical composition, preferably 0.00005 to 0.01% by weight, and more preferably 0.00025 to 0.01% by weight.

[0042] Here, a unit containing the active ingredient refers to the unit of the formulation that is in direct contact with the active ingredient. For solid dosage forms, it refers to the unit of the solid component in direct contact with the active ingredient. For example, in film-coated tablets, it is the tablet core; in capsules, it is the filling portion that carries and disperses the drug; and in granules coated with a functional film, it is the granule core.

[0043] In this invention, the weight percentage of a unit containing the active ingredient refers to the weight percentage relative to the weight of the component unit in direct contact with the active ingredient in the formulation. For solid dosage forms, it refers to the percentage relative to the weight of the solid component unit in direct contact with the active ingredient in the solid dosage form.

[0044] The stabilizing amino acids used in this invention include cysteine, lysine, arginine, histidine, cystine, methionine, asparagine, glutamine, proline, tryptophan, phenylalanine, threonine, valine, leucine, isoleucine, glycine, tyrosine, aspartic acid, or alanine, etc.

[0045] The amino acid derivatives of this invention include pharmaceutically acceptable salts or pharmaceutically acceptable esters of amino acids. Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate; organic carboxylates such as acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, and phthalate; and organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. Preferably, hydrochloride, sulfate, hydrobromide, phosphate, tartrate, maleate, and methanesulfonate are used; most preferably, hydrochloride and sulfate are used. Pharmaceutically acceptable esters include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, sec-butyl ester, isobutyl ester, tert-butyl ester, and pentyl ester. The amino acids or their pharmaceutically acceptable salts and esters of this invention are available in anhydrous, hydrated, and solvate forms. The amino acid or its derivatives described in this invention are preferably cysteine ​​hydrochloride, lysine hydrochloride, or arginine.

[0046] The amino acid or its derivative stabilizer used in this invention can be a commercially available product. The stabilizer accounts for 0.00001–10% by weight, preferably 0.005–5% by weight, more preferably 0.005–1.0% by weight, and even more preferably 0.005–0.5% by weight, of the unit weight containing the active ingredient in the pharmaceutical composition (e.g., solid dosage form). Specifically, the stabilizer accounts for 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, and 0.10% by weight of the unit weight containing the active ingredient.

[0047] The amino acid series stabilizers of this invention can fully exert their effects when dissolved or dispersed in solution, or dispersed in semi-solid or solid substances. The amino acid series stabilizers of this invention are effective for stabilizing all dosage forms.

[0048] The pharmaceutical compositions of the present invention are not particularly limited as long as they are pharmaceutically acceptable dosage forms, and can be any possible dosage form, including liquid and solid preparations, such as syrups, powders, granules, pellets, powders, tablets, capsules, injections, freeze-dried preparations, ointments, gels, lotions, nasal drops, eye drops, aerosols, suspensions, emulsions, plasters, pills, films, and suppositories, etc.

[0049] The sugars or sugar alcohols used in this invention can be commercially available products. Examples of sugars or sugar alcohols include starch, sucrose, lactose, mannitol, erythritol, and maltitol, with mannitol being preferred. Furthermore, the granule form of the sugars or sugar alcohols can be granulated granules, powder, micro-powder, etc. When formulating the solid dosage form of this invention into tablets, granulated granules are preferred. Granulated granules can be granules prepared by known methods such as spray drying, extrusion granulation, stirred granulation, and fluidized bed granulation. Spray-dried granules are preferred, as they allow for the attainment of high tablet hardness without compressive stress. The amount of sugars or sugar alcohols added is not particularly limited, but can be 65–99% by weight of the unit weight containing the active ingredient, preferably 70–99% by weight, and more preferably 90–99% by weight.

[0050] The crospovidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose used in this invention can be commercially available products. Their addition amount can be 1-30% by weight of the unit weight containing the active ingredient.

[0051] In addition to the above-mentioned components, pharmaceutically acceptable additives such as lubricants and colorants may be added to the solid formulation of the present invention as needed. Examples of lubricants include magnesium stearate, calcium stearate, talc, stearic acid, sucrose fatty acid esters, and sodium fumarate, with magnesium stearate being preferred.

[0052] The solid dosage forms of the present invention can be prepared using the aforementioned essential components and any other components (including components that act as excipients) by known methods, for example, in the form of powders, granules, fine granules, capsules, tablets, films, etc.

[0053] To obtain a homogeneous mixture, methods of a type known to those skilled in the art can be used, such as direct powder compression, wet granulation, or dry granulation.

[0054] The apparatus for the mixing step can be a commonly used apparatus, such as a V-type mixer, a three-dimensional mixer, a two-dimensional mixer, etc.

[0055] Powders, granules, and fine granules can be prepared by wet granulation, a method comprising dissolving or suspending the active ingredient in water or a pharmaceutically acceptable solvent, and adding the solution to a sugar or sugar alcohol. Tablets can be prepared by mixing an appropriate amount of a lubricant, such as magnesium stearate, into the granulated material and then compressing it. Capsules can be prepared by filling the granulated material into, for example, gelatin capsules.

[0056] In the above preparation examples, the addition of amino acids or their derivatives can be carried out in any step. For example, amino acids or their derivatives can be dissolved or suspended together with the active ingredient in water or a pharmaceutically acceptable solvent, and then added to sugars or sugar alcohols. The addition of crospovidone, sodium carboxymethyl starch, or low-substituted hydroxypropyl cellulose can be carried out in any step. For example, crospovidone, sodium carboxymethyl starch, or low-substituted hydroxypropyl cellulose can be dissolved or suspended together with the active ingredient in water or a pharmaceutically acceptable solvent, and then added to sugars or sugar alcohols.

[0057] Wet granulation can be performed using commonly used equipment, such as fluidized bed granulators, wet granulators, and extrusion spheronizers. When water is used as the solvent for dissolving or suspending the active ingredient, fluidized bed granulators or spray dryers that can simultaneously spray and dry are preferred. When volatile solvents such as ethanol are used as the solvent for dissolving or suspending the active ingredient, fluidized bed granulators, spray dryers, and stirred granulators are preferred.

[0058] Compression molding can be performed using commonly used equipment, such as single-punch tablet presses, rotary tablet presses, etc.

[0059] There is no particular limitation on the amount of lubricant added. For example, when it is magnesium stearate, it is preferably about 0.1% to 5.0% in the pharmaceutical composition (such as solid dosage form), and more preferably about 0.5% to 3.0%.

[0060] For the solid dosage forms obtained above with 4,5-epoxymorphinan derivatives or their pharmaceutically acceptable salts as active ingredients, coating can be performed as needed to prepare coated formulations. The amount of coating agent added is not particularly limited, but preferably 0.1 to 20.0% by weight, more preferably 1 to 10% by weight, relative to the weight of the core. Examples of coating agents that can be used include hydroxypropyl methylcellulose, ethylcellulose, carboxymethyl ethyl cellulose, and polyvinyl alcohol. Iron oxide red (ferric oxide), iron oxide yellow (yellow ferric oxide), iron oxide black, and titanium dioxide can also be added as colorants and opacifiers as needed.

[0061] Commonly used equipment can be used in film coating operations. High-efficiency coating machines, such as coating pan coating devices, are preferred in the preparation of film-coated tablets. Fluidized bed granulators are preferred in the preparation of film-coated granules.

[0062] Compared with the prior art, the present invention has the following beneficial effects:

[0063] The solid dosage forms of the present invention, with 4,5-epoxymorphinan derivatives (such as nalfuraphen) or their pharmaceutically acceptable salts as the active ingredient, use amino acids or their derivatives as stabilizers. Compared with sodium thiosulfate, butylated hydroxyanisole, butylated hydroxytoluene, racemic α-tocopherol, polyethylene glycol succinate, and propyl gallate as stabilizers, this further improves the stability of 4,5-epoxymorphinan derivatives (such as nalfuraphen) or their pharmaceutically acceptable salts in solid dosage forms. The preferred amino acids are cysteine, arginine, and lysine. The preferred amino acid derivatives are cysteine ​​hydrochloride and lysine hydrochloride. The excellent stability includes stability against oxygen, heat, and light. The stabilizing amino acids or their derivatives particularly act as antioxidants.

[0064] This invention discovers that amino acid stabilizers or their derivatives have excellent stabilizing effects on solid dosage forms with 4,5-epoxymorphinan derivatives (such as nalfurazone) or their pharmaceutically acceptable salts as active ingredients. The solid dosage forms of this invention maintain stable content at high temperature (60°C) or high humidity (75% RH), with a significantly reduced increase in related substances (including single and total impurities), making them safer and more effective for clinical use.

[0065] The present invention uses 4,5-epoxymorphinan derivatives (such as nafpramine) or pharmaceutically acceptable salts thereof as active ingredients, and solid dosage forms using amino acids or their derivatives as stabilizers have excellent preservation properties and remain safe and effective over long periods of time after preparation. Detailed Implementation

[0066] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0067] Example 1 (Batch size 8000 pieces)

[0068] Weigh 120.50 parts of mannitol, disperse it by sieving through a 1.5-3.0 mm sieve, and add it to a two-dimensional mixer. Then add 1.00 parts of sodium thiosulfate, 6.50 parts of crospovidone, and 0.0025 parts of nalfurazone hydrochloride to the mixer and mix thoroughly. Finally, add 2.00 parts of magnesium stearate and mix thoroughly. Compress the resulting powder into 130 mg tablets using a tableting machine. Weigh 3 parts of a gastric-soluble film-coating premix and disperse it in purified water to prepare a coating solution with 10-15% solids content. Add the obtained tablets to a film-coating machine and spray the coating solution to produce 133.9 mg orally disintegrating coated tablets with a coating layer of 3.9 mg relative to the 130 mg tablet.

[0069] Example 2 (batch size 8000 pieces)

[0070] The sodium thiosulfate in Example 1 was replaced with cysteine ​​hydrochloride, and otherwise prepared in the same manner as in Example 1.

[0071] Example 3 (batch size 8000 pieces)

[0072] The sodium thiosulfate in Example 1 was replaced with lysine hydrochloride, and otherwise prepared in the same manner as in Example 1.

[0073] Example 4 (batch size 8000 pieces)

[0074] The sodium thiosulfate in Example 1 was replaced with arginine, and otherwise prepared in the same manner as in Example 1.

[0075] Example 5 (batch size 8000 pieces)

[0076] The sodium thiosulfate in Example 1 was replaced with BHA (butylated hydroxyanisole), and otherwise prepared in the same manner as in Example 1.

[0077] Example 6 (batch size 8000 pieces)

[0078] The sodium thiosulfate in Example 1 was replaced with BHT (butylated hydroxytoluene), and otherwise prepared in the same manner as in Example 1.

[0079] Example 7 (batch size 8000 pieces)

[0080] The sodium thiosulfate in Example 1 was replaced with tocopherol, and otherwise prepared in the same manner as in Example 1.

[0081] Example 8 (batch size 8000 pieces)

[0082] The sodium thiosulfate in Example 1 was replaced with polyethylene glycol succinate containing vitamin E, and otherwise prepared in the same manner as in Example 1.

[0083] Example 9 (batch size 8000 pieces)

[0084] The sodium thiosulfate in Example 1 was replaced with propyl gallate, and otherwise prepared in the same manner as in Example 1.

[0085] Examples 10-12 show that cysteine ​​hydrochloride, lysine hydrochloride, and arginine from the amino acid stabilizers were selected for a 200,000-unit batch scale-up study.

[0086] Example 10 (batch size 200,000 pieces)

[0087] The batch size of Example 2 was changed from 8,000 pieces to 200,000 pieces, but otherwise prepared using the same method as in Example 2.

[0088] Example 11 (Batch size 200,000 pieces)

[0089] The batch size of Example 3 was changed from 8,000 pieces to 200,000 pieces, but otherwise prepared using the same method as in Example 3.

[0090] Example 12 (batch size 200,000 pieces)

[0091] The batch size of Example 4 was changed from 8,000 pieces to 200,000 pieces, but otherwise prepared using the same method as in Example 4.

[0092] Test case

[0093] Experimental Example 1

[0094] The tablets obtained in Examples 1-9 were subjected to a comparative study on the stabilization effect at a high temperature of 60°C. The results were evaluated by the growth and changes of related substances, and the results are shown in Table 1.

[0095] Table 1. Results of stability test at 60℃

[0096]

[0097] Table 1 (continued)

[0098]

[0099] In Table 1, "-" indicates that it was not detected.

[0100] The impurities are shown in Table 2 below:

[0101] Table 2 List of impurities

[0102]

[0103] The results of a comparative study of the effects of high temperature (60℃) on the formulation samples showed that, compared with the sodium thiosulfate formulation samples, the contents of related substances (such as Z5, Z6, and total impurities) in the formulation samples containing BHA, BHT, racemic-α-tocopherol, vitamin E succinate polyethylene glycol ester, and gallic acid increased significantly after being placed at 60℃ for 30 days, while the content of nalfurazone hydrochloride decreased even more. In contrast, the content of related substances in the formulation samples containing amino acid series stabilizers such as cysteine ​​hydrochloride, lysine hydrochloride, and arginine increased more slowly and the content of nalfurazone hydrochloride was higher than that in the sodium thiosulfate formulation samples.

[0104] Experimental Example 2

[0105] The tablets obtained in Examples 10-12 were compared with a commercially available reference formulation. Stability was compared and evaluated under accelerated conditions of 40℃ / 75%RH, and the results were shown in Table 3.

[0106] Table 3. Results of stability study under accelerated conditions at 40℃ / 75%RH

[0107]

[0108] In Table 3, "-" indicates that it was not detected; the structural formulas of impurities Z5 and Z6 are as described above.

[0109] Accelerated stability studies were conducted on the scaled-up samples from Examples 10-12 together with the original formulation. The results showed that the amino acid series stabilizers "cysteine ​​hydrochloride," "lysine hydrochloride," and "arginine" effectively maintained the stability of the formulation. For nafpramine hydrochloride orally disintegrating tablets, the amino acid series stabilizers demonstrated superior stabilizing effects compared to the commercially available sodium thiosulfate. After 6 months of accelerated storage, the increase in impurity Z6 in the reference formulation was more significant.

[0110] The embodiments described above are some, but not all, embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition comprising (1) a 4,5-epoxymorphinan derivative of general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and (2) an amino acid or a derivative thereof; In general formula (I): R 1 Indicates cyclopropylmethyl or allyl; R 2 Indicates hydrogen, hydroxyl, acetoxy, or methoxy; R 3 A represents hydrogen, hydroxyl, acetoxy, or methoxy; A represents -N(R) 4 )C(=O)- or -N(R 4 )C(=O)O-;R 4 B represents a straight-chain or branched alkyl group with 1 to 5 carbon atoms; B represents a straight-chain alkylene group with 1 to 3 carbon atoms, -CH=CH- or -C≡C-; R 5 The group may represent hydrogen, phenyl, furanyl, or thiophene, but the hydrogen in the aforementioned phenyl, furanyl, and thiophene groups may be replaced by one or more groups selected from alkyl, alkoxy, alkanoyloxy, hydroxyl, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanate alkyl, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

2. The pharmaceutical composition according to claim 1, characterized in that, The 4,5-epoxymorphin derivative of general formula (I) or a pharmaceutically acceptable salt thereof, preferably nafraprine or its hydrochloride, is preferred.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition further contains (3) at least one of a sugar and a sugar alcohol, and / or (4) crospovidone, sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose or a mixture thereof.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The amino acids include cysteine, lysine, arginine, histidine, cystine, methionine, asparagine, glutamine, proline, tryptophan, phenylalanine, threonine, valine, leucine, isoleucine, glycine, tyrosine, aspartic acid, or alanine, etc. The amino acid derivatives include pharmaceutically acceptable salts or pharmaceutically acceptable esters of amino acids; and / or The amino acid or its derivatives account for 0.00001 to 10% by weight of the unit containing the active ingredient, preferably 0.005 to 5% by weight, and more preferably 0.005 to 1% by weight. Preferably, the amino acid or its derivative is selected from cysteine ​​hydrochloride, lysine hydrochloride, or arginine.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The sugars or sugar alcohols include at least one of starch, sucrose, lactose, mannitol, erythritol, maltitol, or xylitol; and / or The sugars or sugar alcohols are granulated particles prepared by extrusion granulation, wet granulation, dry granulation, spray drying, or fluidized bed granulation.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The pharmaceutical composition is a liquid or solid dosage form; Preferably, the pharmaceutical composition is a solid dosage form; More preferably, the solid dosage form includes tablets, capsules, granules, fine granules, powders, and films.

7. The pharmaceutical composition according to any one of claims 1-6, characterized in that, The pharmaceutical composition has a coating.

8. A method for stabilizing nalfuraphen or a pharmaceutically acceptable salt thereof, said method comprising using an amino acid or a derivative thereof.

9. A method for preparing the pharmaceutical composition according to any one of claims 1-7, comprising the following steps: Mix the raw materials in the specified proportions.

10. The preparation method according to claim 9, characterized in that, The mixing step is performed in a mixer; and / or The mixing step includes powder direct pressing, dry granulation, or wet granulation. Preferably, the mixer includes a V-type mixer, a three-dimensional mixer, and a two-dimensional mixer, etc.

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