CN116133643A - liquid composition - Google Patents

Abstract

The purpose of the present invention is to provide an oral liquid agent which is easy to take and has high stability by masking the bitter taste of oxycodone which is an active ingredient. The present invention provides a liquid composition containing oxycodone as an active ingredient, which is highly stable, wherein the liquid composition is capable of masking bitterness by an additive and suppressing the formation of an analogue by adjusting the pH to a predetermined range.

Description

liquid composition

technical field

The present invention relates to a liquid composition for oral use, which contains oxycodone (oxycodone), its pharmaceutically acceptable salt, or their hydrates (hereinafter sometimes they are collectively referred to as "oxycodone") as Active ingredients. More specifically, the present invention relates to an oral liquid composition in which the bitter taste of oxycodone is masked.

Background technique

Oral preparations containing active ingredients with a strong bitter taste are rejected even if they are solid preparations such as tablets, because they release a bitter taste in the mouth. If this active ingredient is developed in the form of an oral liquid preparation, it is a great advantage for patients from the viewpoint of ease of drinking. The disadvantage of bitterness, if there is no way to cover the bitterness by some means, there will be a problem of difficulty in product development. Therefore, regarding active ingredients with a strong bitter taste that have already been developed into tablets, the chances of actually developing a liquid formulation are not high.

For example, in Document 1, it is described that in a liquid preparation for oral administration containing a bitter component having a strong bitter taste, by combining the three components of the bitter component, sugar alcohol, sour agent, and glutamate, an effective A liquid preparation that suppresses bitterness and does not leave an unpleasant taste in the oral cavity after oral administration. However, the bitter component of Document 1 is not oxycodone. In addition, its bitterness masking technique is completely different from the bitterness masking technique using additives such as three or more sweeteners in the present invention described later.

On the other hand, in the process of the present invention, if a liquid composition in which the bitterness of oxycodone is masked with an additive such as a sweetener is formulated, "the pH of the liquid composition becomes low and the oxycodone The reduction of oxycodone content and the formation of analogues caused by the reaction of codone with sugar alcohols, etc. If the pH of the liquid composition is raised to solve the problem that the stability of the formulation cannot be guaranteed, the problem of not being able to obtain the bitterness masking effect occurs this time, and it is judged to be an antinomy problem.

As for the technique of suppressing the generation of analogues, for example, in Document 2, it is disclosed that in the production method of a pharmaceutical composition for injection containing an aminosteroid muscle relaxant, by adding an aminosteroid muscle relaxant to an aqueous Adding the pH adjuster to the aqueous solvent before the solvent can suppress the generation of analogues during the manufacture of the pharmaceutical composition. However, the active ingredient of the injection composition of this document 2 is not oxycodone. In addition, there is no description as to whether this method can be applied to a liquid preparation whose active ingredient is oxycodone, and if applicable, to what range the pH should be specifically adjusted.

prior art literature

patent documents

Patent Document 1: Japanese Patent Laid-Open No. 2000-204036

Patent Document 2: Japanese Patent Laid-Open No. 2016-121073

Contents of the invention

The problem to be solved by the invention

An object of the present invention is to provide an oral liquid composition in which the bitter taste of oxycodone, which is an active ingredient, is masked. Furthermore, an object of the present invention is to provide a liquid composition in which the generation of analogues of active ingredients is suppressed.

solutions to problems

As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention have found that by adding at least three predetermined additives, a liquid composition that appropriately masks the bitter taste of oxycodone, which is an active ingredient, can be obtained. Furthermore, it has been found that it is effective to adjust the pH of the liquid composition to a predetermined range in order to suppress the generation of analogues of active ingredients, thereby obtaining a product in which the bitterness is masked, the generation of analogues is suppressed, and the stability is ensured. A liquid composition, thus completing the present invention.

That is, the present invention relates to the following (1) to (28), but is not limited thereto, and those that achieve the same object by substantially the same means are also included in the present invention.

(1) A liquid composition comprising oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, wherein the bitter taste of the active ingredient is masked .

(2) The liquid composition according to (1) above, which contains 0.01 to 1% by weight of oxycodone, a pharmaceutically acceptable salt thereof, or these, based on 100% by weight of the liquid composition. of hydrates.

(3) The liquid composition according to (1) or (2) above, which contains acesulfame potassium (acesulfamepotassium), xylitol, D-sorbitol, or L-glutamic acid At least 3 as additives.

(4) The liquid composition according to (3) above, which contains 0.01 to 0.1% by weight of acesulfame potassium based on 100% by weight of the liquid composition.

(5) The liquid composition as described in said (3) or (4) which contains 0.5-15 weight% of xylitol with respect to 100 weight% of liquid compositions.

(6) The liquid composition according to any one of (3) to (5) above, which contains 1 to 20% by weight of D-sorbitol based on 100% by weight of the liquid composition.

(7) The liquid composition according to any one of (3) to (6) above, which contains 0.01 to 1% by weight of L-glutamic acid based on 100% by weight of the liquid composition.

(8) The liquid composition according to any one of (3) to (7) above, wherein 0.1 to 40% by weight of acesulfame potassium is contained relative to 100% by weight of the liquid composition. , xylitol, D-sorbitol, or at least 3 kinds of L-glutamic acid.

(9) The liquid composition according to any one of (3) to (8) above, further comprising citric acid hydrate and/or sodium citrate hydrate as an additive.

(10) The liquid composition according to (9) above, which contains 0.01 to 1% by weight of citric acid hydrate or sodium citrate hydrate based on 100% by weight of the liquid composition.

(11) The liquid composition according to any one of (3) to (10) above, further comprising sodium benzoate and/or ethyl p-hydroxybenzoate as additives.

(12) The liquid composition according to (11) above, which contains 0.005 to 0.5% by weight of sodium benzoate based on 100% by weight of the liquid composition.

(13) The composition according to the above (11) or (12), which contains 0.0005 to 0.05% by weight of ethyl p-hydroxybenzoate relative to 100% by weight of the liquid composition.

(14) The liquid composition according to any one of (3) to (13) above, further comprising sodium chloride as an additive.

(15) The liquid composition according to (14) above, which contains 0.005 to 1% by weight of sodium chloride relative to 100% by weight of the liquid composition.

(16) The liquid composition according to any one of (3) to (15) above, further comprising propylene glycol as an additive.

(17) The liquid composition according to (16) above, which contains 0.005 to 1% by weight of propylene glycol relative to 100% by weight of the liquid composition.

(18) The liquid composition according to any one of (1) to (17) above, which has a pH of 3.3 to 4.8.

(19) The liquid composition according to any one of (1) to (18), which is produced from the active ingredient over time when the stability test of pharmaceuticals prescribed by the Ministry of Health, Labor and Welfare of Japan is carried out. Analogues are suppressed below acceptable standards.

(20) The liquid composition according to (19), wherein the ratio of the amount of each analog to the amount of the active ingredient is 0.2% when the stability test of pharmaceuticals established by the Ministry of Health, Labor and Welfare of Japan is carried out. the following.

(21) The liquid composition according to (19), wherein the ratio of the amount of each analog to the amount of the active ingredient is 0.15% when the stability test of pharmaceuticals established by the Ministry of Health, Labor and Welfare of Japan is carried out. the following.

(22) The liquid composition according to (19), wherein the ratio of the amount of each analog to the amount of the active ingredient is 0.1% when the stability test of pharmaceuticals established by the Ministry of Health, Labor and Welfare of Japan is carried out. the following.

(23) The liquid composition according to any one of the above (19) to (22), wherein the total amount of the analogue is effective relative to the aforementioned amount when the stability test of pharmaceuticals established by the Ministry of Health, Labor and Welfare of Japan is carried out. The ratio of the amounts of components is 0.6% or less.

(24) A method for stabilizing a liquid composition comprising adjusting the pH of the liquid composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. Adjusting to 3.3 to 4.8 suppresses the generation of analogues in the liquid composition.

(25) The stabilization method according to (24) above, wherein the ratio of the amount of each analog to the amount of the active ingredient is 0.2% or less.

(26) The stabilization method according to (24) above, wherein the ratio of the amount of each analog to the amount of the active ingredient is 0.15% or less.

(27) The stabilization method according to (24) above, wherein the ratio of the amount of each analog to the amount of the active ingredient is 0.1% or less.

(28) The stabilization method according to any one of (24) to (27) above, wherein the ratio of the total amount of analogs to the amount of the active ingredient is 0.6% or less.

The effect of the invention

The liquid composition of the present invention is an oral liquid preparation in which the bitterness of oxycodone, which is an active ingredient, is reduced for patients suffering from cancer pain, and is easy to take, and has very high usefulness. In addition, since the production of analogues over time is suppressed, the stability is high, and therefore, the conditions for pharmaceuticals requiring annual quality assurance are also fully met.

Detailed ways

The present invention is a liquid composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, and the bitter taste of the active ingredient is masked. The masking is carried out by containing at least three kinds of additives selected from acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid. In addition, the liquid composition of the present invention can be a highly stable liquid composition with suppressed generation of analogues by adjusting the pH thereof to 3.3 to 4.8.

The liquid composition of the present invention contains oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. Oxycodone is one of the strong opioids used in the third of the three phases of the 1996 WHO System Cancer Pain Treatment Act, and is medically useful as a drug. Oxycodone can be used without particular limitation as long as it is a pharmaceutically acceptable salt in addition to the free form, for example, hydrochloride, sulfate, nitrate, phosphate, hydrofluoride, hydrogen Inorganic acid salts such as bromate; acetic acid, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, Organic acid salts such as naphthalenesulfonate and camphorsulfonate; amino acid salts such as alginate, aspartate, and glutamate; metal salts such as sodium, potassium, and cesium salts, etc. Particularly preferred is oxycodone hydrochloride, which is commercially available and widely clinically used as an analgesic for cancer pain. In addition, stereoisomers, hydrates, and solvates of oxycodone are also included in components that can be active ingredients of the liquid composition of the present invention.

The content of oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof in the liquid composition of the present invention is not particularly limited, and may be appropriately selected. For example, in the case of oxycodone hydrochloride or oxycodone hydrochloride hydrate, it can be 0.01 to 1% by weight, preferably 0.03 to 0.8% by weight, more preferably 0.03 to 0.8% by weight, relative to 100% by weight of this liquid composition. Preferably it is 0.05 to 0.6% by weight.

The liquid composition of the present invention is characterized in that the bitter taste of oxycodone, its pharmaceutically acceptable salt, or their hydrates is masked as an active ingredient. For this purpose, adding at least three additives selected from acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid is one of the methods. Furthermore, additives such as pH adjusters such as citric acid hydrate and sodium citrate hydrate may be combined in the liquid composition of the present invention. Therefore, the liquid composition of the present invention not only reduces bitterness, but also has the advantage of ensuring stability. Hereinafter, the additives added to the liquid composition of the present invention and their contents will be described in detail, but the present invention is not limited by them.

Examples of sweeteners that can be used as additives for the liquid composition of the present invention include refined sucrose, aspartame, saccharin sodium hydrate, D-mannitol, D-sorbitol, and dextrin , erythritol, sucralose, xylitol, powdered reduced maltose syrup, thaumatin, acesulfame potassium, or combinations thereof. Among them, a combination of acesulfame potassium, xylitol, and D-sorbitol is preferable. The content of acesulfame potassium may be 0.01 to 0.1% by weight, preferably 0.03 to 0.09% by weight, more preferably 0.04 to 0.08% by weight, and even more preferably 0.05 to 0.07% by weight relative to 100% by weight of the liquid composition. %. The content of xylitol may be 0.5 to 15% by weight, preferably 1 to 10% by weight, more preferably 2 to 8% by weight, and still more preferably 3 to 6% by weight, based on 100% by weight of the liquid composition. . The content of D-sorbitol may be 1 to 20% by weight, preferably 2 to 15% by weight, more preferably 4 to 12% by weight, and even more preferably 6 to 10% by weight relative to 100% by weight of the liquid composition. weight%. In addition to these sweeteners, L-glutamic acid, which is a flavoring agent, can also be added. The content of L-glutamic acid can be set to 0.01 to 1% by weight relative to 100% by weight of the liquid composition, preferably It is 0.03 to 0.3 weight%, More preferably, it is 0.05 to 0.2 weight%, More preferably, it is 0.07 to 0.15 weight%. The total content of three additives selected from acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid can be set to 0.1 to 40% by weight relative to 100% by weight of the liquid composition , preferably 0.5 to 30% by weight, more preferably 1 to 25% by weight, even more preferably 1 to 20% by weight.

Preservatives that can be used as additives for the liquid composition of the present invention include benzoic acid, sodium benzoate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid, Potassium sorbate, erythorbic acid, sodium dehydroacetate, edetate sodium, ascorbic acid, sodium ascorbate, ascorbyl palmitate, propionic acid, sodium propionate, propyl gallate , tocopherol, or combinations thereof, and preferred examples include sodium benzoate and/or ethyl p-hydroxybenzoate. The content of sodium benzoate may be 0.005 to 0.5% by weight, preferably 0.008 to 0.1% by weight, more preferably 0.01 to 0.08% by weight, and even more preferably 0.02 to 0.06% by weight relative to 100% by weight of the liquid composition. The content of ethyl p-hydroxybenzoate may be 0.0005 to 0.05% by weight, preferably 0.0008 to 0.01% by weight, more preferably 0.001 to 0.005% by weight, and even more preferably 0.0015 to 0.0015% by weight relative to 100% by weight of the liquid composition. 0.005% by weight. The total content of sodium benzoate and ethyl p-hydroxybenzoate can be set to 0.005 to 0.5% by weight, preferably 0.008 to 0.1% by weight, more preferably 0.01 to 0.08% by weight, with respect to 100% by weight of the liquid composition. Preferably it is 0.02 to 0.06% by weight.

In terms of flavoring agents that can be used as additives for the liquid composition of the present invention, DL-malic acid, sodium chloride, citric acid, citric acid hydrate, sodium citrate hydrate, glycyrrhizic acid (glycyrrhizic acid) ), dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, L-glutamic acid, L-sodium glutamate, glycine, or combinations thereof, and sodium chloride is a preferred example. The content of sodium chloride may be 0.005 to 1% by weight, preferably 0.01 to 0.5% by weight, more preferably 0.03 to 0.3% by weight, and even more preferably 0.05 to 0.2% by weight relative to 100% by weight of the liquid composition. .

Examples of pH adjusters that can be used as additives for the liquid composition of the present invention include dilute hydrochloric acid, phosphoric acid, sodium hydrogenphosphate hydrate, acetic acid, sodium acetate hydrate, lactic acid, tartaric acid, malic acid, and citric acid hydrate. substances, sodium citrate hydrate, or combinations thereof, etc., and for preferred examples, tartaric acid, malic acid, citric acid hydrate, sodium citrate hydrate, and for further preferred examples, citric acid hydrate and/or sodium citrate hydrate. The content of citric acid hydrate or sodium citrate hydrate is 0.01 to 1% by weight, preferably 0.05 to 0.8% by weight, more preferably 0.1 to 0.6% by weight, based on 100% by weight of the liquid composition. More preferably, it is 0.2 to 0.4 weight%. In addition, since citric acid hydrate or sodium citrate hydrate also functions as a flavoring agent, it can be used for both purposes in the liquid composition of this invention.

In terms of co-solvents that can be used as additives for the liquid composition of the present invention, polyethylene glycol (Macrogol), glycerin, povidone (Povidone), cyclodextrin, propylene glycol, or combinations thereof, etc. can be used, On the other hand, as a preferable example, propylene glycol is mentioned. The content of propylene glycol may be 0.005 to 1% by weight, preferably 0.01 to 0.5% by weight, more preferably 0.03 to 0.3% by weight, and even more preferably 0.05 to 0.2% by weight based on 100% by weight of the liquid composition.

The pH of the liquid composition of the present invention can be adjusted by the kind and content of additives, but is preferably 3.3 to 4.8, more preferably 3.5 to 4.5, and still more preferably 3.8 to 4.2. The bitterness masking and stability of the liquid composition of this invention can be ensured by adjusting pH in this range.

In addition to the above, the liquid composition of the present invention may contain various additives used in the production of general pharmaceutical preparations as long as the effects of the invention are not inhibited. Such additives include, for example, stabilizers, surfactants, solubilizers, thickeners, suspending agents, fragrances, colorants, etc. in addition to the above-mentioned examples, and can be appropriately selected and added depending on the purpose.

Example

Next, examples are given to describe the present invention in detail, but the present invention is not limited thereto.

Example 1

An example of the formulation of the liquid composition of this invention is shown in Table 1. A liquid composition containing oxycodone hydrochloride hydrate having the composition shown in Table 1 was produced according to the following production method.

[Table 1]

Ingredients and Quantity (mg) Recipe 1 Recipe 2 Recipe 3 Recipe 4 Oxycodone Hydrochloride Hydrate 2.88 5.77 11.54 23.07 Citric Acid Hydrate 7.75 7.75 15.50 15.50 Sodium Citrate Hydrate 6.146 6.146 12.292 12.292 D-Sorbitol Liquid (70%) 310.75 310.75 621.50 621.50 Xylitol 125.00 125.00 250.00 250.00 Acesulfame Potassium 1.625 1.625 3.25 3.25 Sodium chloride 2.50 2.50 5.00 5.00 sodium benzoate 1.00 1.00 2.00 2.00 Ethyl p-hydroxybenzoate 0.075 0.075 0.15 0.15 Propylene Glycol 2.50 2.50 5.00 5.00 purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total 2.5mL 2.5mL 5mL 5mL pH 4.0 4.0 4.0 4.0

An example of the method for producing the liquid composition of the present invention according to Formulation 4 is shown below based on Table 1 above.

In accordance with the 17th revision of the Japanese Pharmacopoeia, oral liquid preparations, add citric acid hydrate 15.50mg, sodium citrate hydrate 12.292mg, acesulfame potassium 3.25mg, chloride Sodium 5.00mg, sodium benzoate 2.00mg, ethyl p-hydroxybenzoate 0.15mg, propylene glycol 5.00mg, xylitol 250.00mg and D-sorbitol liquid (70% solution) 621.50mg were dissolved and cooled to room temperature.

23.07 mg of oxycodone hydrochloride hydrate was added in an amount corresponding to 20 mg of the anhydrate, and was completely dissolved while stirring at room temperature. Purified water was added to adjust the total amount to 5.25 g (corresponding to 5 mL). If necessary, a pH adjuster is added to adjust to a predetermined pH.

It should be noted that since oxycodone hydrochloride is an anesthetic, its use is limited, and it is difficult to implement a taste sensory test in preparations containing this component. Therefore, regarding formulations A to F used in Test Examples (1) and (2), oxycodone hydrochloride hydrate was replaced with dextromethorphan hydrobromide hydrate or quinine in an amount that exhibited the same bitter taste. Sulfate dihydrate, and manufacture preparation with the same method as Example 1, carry out the taste sensory test in following test example (1) and (2).

Test example (1): Taste sensory test

A taste sensory test was implemented with 21 randomly selected men and women as reviewers. The liquid compositions of formulations A, B, and C shown in Table 2 were divided into "during application" and "aftertaste", and were evaluated according to the evaluation criteria in Table 3 for "bitterness", "sweetness" and "sourness". evaluation of. In addition, "when administered" means "when contained in the mouth". Test procedure: (1) Each test specimen was rinsed with water (20 to 30 mL) 3 times in advance. (2) A predetermined amount (5 mL) of the test sample is held in the mouth for about 5 seconds (within 10 seconds), the taste is evaluated, and the test sample is immediately spit out. (3) Gargle with water (20 to 30 mL) three times again. (4) Evaluate the aftertaste. (5) Finally, from among the three kinds, a preferred liquid preparation is selected in terms of the taste of the medicine. It should be noted that the bitterness of 2 mg of dexamephen hydrobromide hydrate is estimated to be equivalent to 23.07 mg of oxycodone hydrochloride hydrate (calculated as anhydrous) through previous tests using taste sensors and taste sensory tests. 20mg) of bitterness. An example of the evaluation results is shown in Table 4.

[Table 2]

Ingredients and Quantity (mg) Formula C Formula A Formula B Dexamephene Hydrobromide Hydrate 2.00 2.00 2.00 Citric Acid Hydrate 6.00 14.50 15.50 Sodium Citrate Hydrate - 13.50 12.00 L-glutamic acid 5.00 5.00 - D-Sorbitol Liquid (70%) 621.50 - 621.50 xylitol 500.00 500.00 250.00 Acesulfame Potassium 2.00 3.30 3.25 Sodium chloride 5.00 5.00 5.00 sodium benzoate 2.00 2.00 2.00 Ethyl p-hydroxybenzoate 0.15 0.15 0.15 Propylene Glycol 5.00 5.00 5.00 Dilute hydrochloric acid Appropriate amount - - purified water Appropriate amount Appropriate amount Appropriate amount Total 5mL 5mL 5mL pH 3.0 4.0 4.0

[table 3]

[Table 4]

It is evident from Table 4 that the compositions of the present invention (Formulations A and B) are preferred liquid formulations with masked bitterness in the sensory taste test.

Test example (2): Taste sensory test

A taste sensory test was implemented with 21 randomly selected men and women as reviewers. About the liquid composition of formulation D, E, and F shown in Table 5, it carried out in the same manner as the test procedure and evaluation standard of the test example (1). It should be noted that the bitterness of 0.75 mg of quinine sulfate dihydrate is estimated to be equivalent to 23.07 mg of oxycodone hydrochloride hydrate (calculated as anhydrous, 20mg) of bitterness. An example of the evaluation results is shown in Table 6.

[table 5]

Ingredients and Quantity (mg) Formula D Formula E Recipe F Quinine Sulfate Dihydrate 0.75 0.75 0.75 Citric Acid Hydrate 6.00 14.50 15.50 Sodium Citrate Hydrate - 13.50 12.00 L-glutamic acid 5.00 5.00 - D-Sorbitol Liquid (70%) 621.50 - 621.50 Xylitol 500.00 500.00 250.00 Acesulfame Potassium 2.00 3.30 3.25 Sodium chloride 5.00 5.00 5.00 sodium benzoate 2.00 2.00 2.00 Ethyl p-hydroxybenzoate 0.15 0.15 0.15 Propylene Glycol 5.00 5.00 5.00 Dilute hydrochloric acid Appropriate amount - - purified water Appropriate amount Appropriate amount Appropriate amount Total 5mL 5mL 5mL pH 3.0 4.0 4.0

[Table 6]

It is evident from Table 6 that the compositions of the present invention (Formulations E and F) are the preferred liquid formulations with masked bitterness in the taste sensory test.

The composition of the present invention is developed as a medicine in Japan. According to the storage stability of the medicine formulated by the Japanese Ministry of Health, Labor and Welfare, it must meet the same level of tolerance as other oxycodone immediate-release preparations. Therefore, various tests on the storage stability of the composition of the present invention were conducted, and the results thereof are shown below.

Test example (3): Stability evaluation test

The liquid compositions of formulations G, H and I shown in Table 7 (oxycodone hydrochloride concentration 4.0 mg/mL) were produced in the same manner as in Example 1. A stability evaluation test was performed on the liquid composition of each formulation under the condition of storing at 80° C. for 6 days (corresponding to 5.5 years at 25° C.). Regarding the evaluation items, the content of oxycodone hydrochloride hydrate, pH, the total number of analogues, and the total amount of analogues were measured by the following test methods.

[The assay method of oxycodone hydrochloride content]

Measured by high performance liquid chromatography (internal standard method, isocratic conditions). The content of oxycodone hydrochloride was represented by the ratio (%) of oxycodone hydrochloride after the stability test to the initial oxycodone hydrochloride in the liquid composition of each formulation.

[Measurement method for the total amount of analogues and the number of analogues]

The amount of analogues was determined by high performance liquid chromatography (absolute standard curve method, gradient conditions). The amount of each analog was calculated by comparing the peak area of the chromatogram of the sample solution with the peak area of oxycodone in the standard solution. In addition, the standard solution used the standard solution which diluted the sample solution by 125 times. Calculate the sum of the amount of each analog represented by the ratio (%) of the amount of each analog relative to the amount of oxycodone hydrochloride in the liquid composition, and the amount of all analogs relative to the liquid composition The ratio (%) of the amount of oxycodone hydrochloride in the drug composition represents the total amount of analogues. It should be noted that, in Test Examples (4) to (7) described later, the calculated content of each analog was similarly expressed as the amount of each analog relative to the oxycodone hydrochloride in the liquid composition. The ratio (%) of the amount expressed. Furthermore, the number of peaks of analogs detected in the chromatogram of each sample solution was counted as the total number of analogs.

[Table 7]

Ingredients and Quantity (mg) Formula G Formula H Recipe I Oxycodone Hydrochloride Hydrate 23.07 23.07 23.07 Citric Acid Hydrate 6.00 14.50 15.50 Sodium Citrate Hydrate - 13.50 12.00 L-glutamic acid 5.00 5.00 - D-Sorbitol Liquid (70%) 621.50 - 621.50 xylitol 500.00 500.00 250.00 Acesulfame Potassium 2.00 3.30 3.25 Sodium chloride 5.00 5.00 5.00 sodium benzoate 2.00 2.00 2.00 Ethyl p-hydroxybenzoate 0.15 0.15 0.15 Propylene Glycol 5.00 5.00 5.00 Dilute hydrochloric acid Appropriate amount - - purified water Appropriate amount Appropriate amount Appropriate amount Total 5mL 5mL 5mL pH 3.0 4.0 4.0

[Table 8]

...

Oxycodone hydrochloride concentration in brackets

As an example of the results, the content and pH of oxycodone hydrochloride hydrate are shown in Table 8, and the total number of analogs and the total amount of analogs are shown in Table 9.

[Table 9]

Average (n=3)

The total number of analogues and the total amount do not include the analogues contained in the original drug.

From Tables 8 and 9, it can be clearly seen that the liquid composition of the present invention (formulation H and I) shows stable pH in the stability evaluation test, the content of oxycodone hydrochloride hydrate decreases, and the total number of analogs and the total amount of analogs Increases in both are suppressed.

Test example (4): Harsh test

With regard to the liquid compositions of formulation 1, formulation 2, formulation 3, and formulation 4 shown in Table 1, a severe test was carried out at 60°C for 2 months (1 month at 60°C is equivalent to 4.2 years at 25°C). , Measure each analog content and analog total amount with the same method as test example (3). An example of the result is shown in Table 10. In Table 10, a plurality of numerical values are recorded in one field of each analogue content column, indicating that a plurality of other types of analogues can be detected. Indicates that 3 analogs can be detected. The same applies to Tables 11 and 12 described later.

[Table 10]

It can be clearly seen from Table 10 that the liquid compositions of formula 1, formula 2, formula 3 and formula 4, in the above-mentioned harsh test, the generation of analogs is suppressed, and the results show the number of analogs, the content of each analog and the content of analogs Either of the total amounts is suppressed.

Test example (5): accelerated test

With regard to the liquid compositions of formula 1, formula 2, formula 3 and formula 4 shown in Table 1, carry out 40 ℃, 75% RH, 10 months accelerated test, and measure each with the same method as test example (3). Analogue content and total amount of analogues. An example of the result is shown in Table 11.

[Table 11]

It can be clearly seen from Table 11 that for the liquid compositions of formula 1, formula 2, formula 3 and formula 4, in the above-mentioned accelerated test, the generation of analogs is inhibited, and the results show the number of analogs, the content of each analog and the content of analogs. Either of the total amounts is suppressed.

Test example (6): long-term storage test

About the liquid composition of formulation 1, formulation 2, formulation 3 and formulation 4 shown in Table 1, carry out long-term preservation test with the condition of 25 ℃, 60%RH, 36 months, and with test example (3) same The method for determining the content of each analogue and the total amount of analogues. An example of the result is shown in Table 12.

[Table 12]

From Table 12, it can be clearly seen that the liquid compositions of formula 1, formula 2, formula 3 and formula 4, in the above-mentioned long-term storage test, the generation of analogs is inhibited, and the results show that the number of analogs, the content of each analog and the content of analogs Either of the total amounts is suppressed.

Test Example (7): Stability Evaluation Test

Liquid compositions (oxycodone hydrochloride concentration: 4.0 mg/mL) of formulations 5 to 16 shown in Table 13 were produced in the same manner as in Example 1. Regarding the liquid composition of each formulation, the stability evaluation test was carried out under the condition of storing at 80°C for 6 days (equivalent to 5.5 years at 25°C), and the total number of analogues and The total amount of analogs. An example of the results is shown in Table 14.

[Table 13]

[Table 14]

It is clear from Table 14 that in the above-mentioned stability evaluation test, the production of analogs is inhibited depending on the pH increase of the liquid composition within a predetermined range. As a result, the number of analogs, the content of each analog and the total amount of analogs are shown. Either amount is suppressed.

Test Example (8): Evaluation of Bitter Taste Masking by Taste Recognition Device

Using a taste sensor of a taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.), the influence of pH on the bitterness masking effect was evaluated according to the CPA (Change of membrane potential caused by Adsorption) measurement method.

In the taste sensor, the membrane potential change of the lipid membrane due to the electrostatic interaction or hydrophobic interaction with the taste substance is examined as a sensor output. One example of a method for measuring bitterness using a taste sensor is shown below. First, the taste sensor is immersed in a solution called a reference solution to obtain the membrane potential Vr. Next, the test solution is immersed in the taste sensor to obtain the membrane potential Vs. The obtained change in membrane potential (Vs-Vr) is called the first sensor output "relative value", which corresponds to the first taste such as sour or salty. Then, after co-washing the taste sensor with the reference solution, the taste sensor was immersed in the reference solution again to obtain the membrane potential Vr'. The obtained change in membrane potential (Vr'-Vr) is called the second sensor output "CPA value", which corresponds to an aftertaste such as bitterness or astringency.

However, the CPA value of oxycodone hydrochloride is difficult to measure, so the CPA value of the liquid composition containing oxycodone hydrochloride is estimated using a bitter standard substance (quinine sulfate) that can measure the CPA value. . That is, first, the relative values of oxycodone hydrochloride and quinine sulfate are measured, and from the relative values of the two, the concentrations of the two, which are estimated to exhibit the same bitter taste, are determined. Based on the results, the CPA value was measured for the formulation containing quinine sulfate estimated to exhibit bitterness equivalent to that of oxycodone hydrochloride at the desired concentration, and the estimated value of bitterness was calculated.

(1) Determination of relative values of oxycodone hydrochloride and quinine sulfate

Relative values (mV) of oxycodone hydrochloride and quinine sulfate were measured using a bitter taste sensor (BT0 sensor) of a taste recognition device (TS-5000Z, manufactured by Smart Sensor Technology Co., Ltd.). From the results of the relative values of the two, as shown in Table 15, it was confirmed that quinine sulfate dihydrate exhibited the same bitter taste as oxycodone hydrochloride at 1.0 mg/mL, 2.0 mg/mL, and 4.0 mg/mL. The concentrations of the substances were 0.037mg/mL, 0.058mg/mL and 0.094mg/mL, respectively.

[Table 15]

(2) Determination of the CPA value of each formula

Based on the results of (1) above, for formulations X to Z in Table 16 containing 0.094 mg/mL of quinine sulfate dihydrate exhibiting a bitter taste equivalent to that of 4.0 mg/mL oxycodone hydrochloride, a taste recognition device was used (TS-5000Z, manufactured by Smart Sensor Technology Co., Ltd.) bitterness sensor (BT0 sensor), measured the CPA value (mV) of each liquid composition, and calculated the estimated value of bitterness (CPA value × 0.3). An example of the results is shown in Table 17.

[Table 16]

Ingredients and Quantity (mg) RecipeX Recipe Y Recipe Z Quinine Sulfate Dihydrate 9.4 9.4 9.4 L-glutamic acid 250 250 250 D-Sorbitol 5000 5000 5000 xylitol 10000 10000 10000 Erythritol 7500 7500 7500 sodium benzoate 40 40 40 Ethyl p-hydroxybenzoate 3 3 3 Propylene Glycol 100 100 100 Dilute hydrochloric acid Appropriate amount Appropriate amount Appropriate amount purified water Appropriate amount Appropriate amount Appropriate amount Total 100mL 100mL 100mL pH 2.5 3.0 3.5

[Table 17]

Test solution Estimated value of bitterness (mV) recipe x 2.64 Recipe Y 7.97 Recipe Z 14.00 Quinine sulfate dihydrate (0.094mg/mL) 19.33

It is clear from Table 17 that in the masking evaluation test by the above-mentioned bitter taste sensor, it was shown that the masking effect of the bitter taste was improved depending on the decrease in the pH of the liquid composition. In addition, regarding the result of the masking evaluation test by this bitter taste sensor, the correlation with the result of the sensory test by another method was confirmed.

Industrial availability

As mentioned above, the liquid composition of the present invention containing oxycodone, its pharmaceutically acceptable salt, or their hydrate as an active ingredient, by containing as an additive selected from acesulfame potassium, xylitol, D- Sorbitol, or at least three kinds of additives in L-glutamic acid can properly mask the bitterness. In addition, by adjusting the pH of the liquid composition of the present invention in the range of 3.3 to 4.8, the generation of analogues can be suppressed and stability can be ensured. Such a liquid composition of the present invention is highly useful as a pain therapeutic agent for various cancer patients.

Claims (13)

1. A liquid composition comprising oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, wherein the bitterness of the active ingredient is masked.

2. The liquid formulation composition according to claim 1, which contains at least 3 selected from the group consisting of acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid as an additive.

3. The liquid formulation composition of claim 2, further comprising citric acid hydrate and/or sodium citrate hydrate as an additive.

4. A liquid formulation composition according to claim 2 or 3, further comprising sodium benzoate and/or ethyl parahydroxybenzoate as additives.

5. The liquid formulation of any one of claims 2-4, further comprising sodium chloride as an additive.

6. The liquid formulation of any one of claims 2-5, further comprising propylene glycol as an additive.

7. The liquid formulation according to any one of claims 1 to 6, having a pH of 3.3 to 4.8.

8. The liquid formulation according to any one of claims 1 to 7, wherein an analogue produced from the active ingredient over time is suppressed to a level below an allowable standard when a stability test of a pharmaceutical product formulated in the ministry of labour of japan is carried out.

9. The liquid composition according to claim 8, wherein the ratio of the amount of each of the analogues to the amount of the active ingredient is 0.2% or less, respectively, when the stability test of the pharmaceutical product by the Ministry of the Japanese Kokai is carried out.

10. The liquid composition according to claim 8 or 9, wherein the ratio of the total amount of the analogues to the amount of the active ingredient is 0.6% or less when a stability test of a pharmaceutical product formulated in the ministry of labour of thick living in japan is performed.

11. A method for stabilizing a liquid composition, characterized in that the production of an analogue in the liquid composition is suppressed by adjusting the pH of the liquid composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient to 3.3 to 4.8.

12. The stabilization method according to claim 11, wherein the ratio of the amount of each of the analogues to the amount of the active ingredient is 0.2% or less, respectively.

13. The stabilization method according to claim 11 or 12, wherein a ratio of a total amount of analogues to an amount of the active ingredient is 0.6% or less.