WO2022025176A1 - Liquid medicine composition - Google Patents
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- WO2022025176A1 WO2022025176A1 PCT/JP2021/028088 JP2021028088W WO2022025176A1 WO 2022025176 A1 WO2022025176 A1 WO 2022025176A1 JP 2021028088 W JP2021028088 W JP 2021028088W WO 2022025176 A1 WO2022025176 A1 WO 2022025176A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Definitions
- the present inventors have obtained a liquid composition in which the bitterness of oxycodone, which is an active ingredient, is appropriately masked by adding at least three kinds of predetermined additives. I found that I could get it. Then, in order to suppress the formation of related substances of the active ingredient, it is effective to adjust the pH of the liquid preparation composition to a predetermined range, whereby the bitterness is masked and the formation of related substances is suppressed.
- the present invention has been completed by finding that a liquid composition having a guaranteed stability can be obtained.
- the total content of sodium benzoate and ethyl paraoxybenzoate is 0.005 to 0.5% by weight, preferably 0.008 to 0.1% by weight, more preferably 0, based on 100% by weight of the liquid composition. It can be 0.01 to 0.08% by weight, more preferably 0.02 to 0.06% by weight.
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Abstract
The present invention addresses the problem of providing an orally administered liquid medicine that is made easy to take by masking the bitter taste of oxycodone, which is an active ingredient thereof, and that is also highly stable. The present invention provides a liquid medicine composition containing oxycodone as an active ingredient, the liquid medicine composition being highly stable, a bitter taste being masked by an additive in the liquid medicine composition, and the formation of analogues being suppressed by adjusting the pH of the liquid medicine composition to within a prescribed range.
Description
本発明は、オキシコドン、その薬学的に許容される塩、又はそれらの水和物（以下、これらを総括して「オキシコドン」ということがある。）を有効成分として含有する経口用の液剤組成物に関する。より詳しくは、本発明は、オキシコドンの苦味がマスキングされた経口用の液剤組成物に関する。
The present invention is an oral liquid preparation composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof (hereinafter, these may be collectively referred to as "oxycodone") as an active ingredient. Regarding. More specifically, the present invention relates to an oral liquid composition in which the bitterness of oxycodone is masked.
苦味の強い有効成分を含有する経口製剤は、錠剤などの固形製剤ですら口中で苦味が出ることで忌避される。そのような有効成分を経口用の液剤で開発すれば、飲みやすさの点で患者に大きなメリットがある反面、苦味が固形製剤の場合以上に強く感じられるデメリットがあるため、何らかの手段で苦味をマスキングする方法を見つけ出さないと製品開発は難しいという課題がある。そのため、錠剤として既に開発されている苦味の強い有効成分について、あえて液剤を開発しようという機運は高くないというのが実情であった。
Oral formulations containing active ingredients with a strong bitter taste are repelled by the appearance of bitterness in the mouth even with solid formulations such as tablets. If such an active ingredient is developed as an oral liquid, it has a great advantage for patients in terms of ease of drinking, but it has a disadvantage that the bitterness is felt stronger than that of a solid preparation. There is a problem that product development is difficult unless a masking method is found. Therefore, the fact is that there is not much momentum to dare to develop a liquid agent for the active ingredient with a strong bitter taste that has already been developed as a tablet.
例えば、文献１には、強い苦味を有する苦味成分を含有する経口投与用液剤において、苦味成分に糖アルコール、酸味料及びグルタミン酸塩の３種類の成分を組み合わせることにより、苦味が抑制され、かつ経口投与後も口腔内に不快な味が残らない液剤となることが記載されている。しかし、文献１の苦味成分はオキシコドンではない。また、その苦味マスキング技術は、追って説明する本発明における３種類又はそれ以上の甘味剤等の添加剤を用いる苦味マスキング技術とは全く異なるものである。
For example, in Document 1, in a liquid for oral administration containing a bitterness component having a strong bitterness, the bitterness is suppressed and oral by combining the bitterness component with three types of components, sugar alcohol, acidulant and glutamate. It is described that the liquid agent does not leave an unpleasant taste in the oral cavity even after administration. However, the bitterness component of Document 1 is not oxycodone. Further, the bitterness masking technique is completely different from the bitterness masking technique using three or more kinds of additives such as sweeteners in the present invention, which will be described later.
一方、本発明の過程においては、オキシコドンの苦味を甘味剤等の添加剤を用いてマスキングした液剤組成物を製剤化しようとすると、当該液剤組成物のｐＨが低くなり、オキシコドンと糖アルコールとの反応等によるオキシコドンの含量低下と類縁物質の生成という問題が生じた。この製剤の安定性が担保できないという問題を解決しようと液剤組成物のｐＨを高くすると、今度は苦味マスキング効果が得られなくなるという問題が生じ、二律背反の課題があることが判明した。
On the other hand, in the process of the present invention, when an attempt is made to formulate a liquid composition in which the bitterness of oxycodone is masked with an additive such as a sweetener, the pH of the liquid composition becomes low, and oxycodone and sugar alcohol are added. Problems such as a decrease in the content of oxycodone due to a reaction and the formation of related substances have arisen. When the pH of the liquid composition was increased in order to solve the problem that the stability of this pharmaceutical product could not be guaranteed, there was a problem that the bitterness masking effect could not be obtained, and it was found that there was an antinomy problem.
類縁物質の生成を抑える技術としては、例えば、文献２には、アミノステロイド系筋弛緩薬を含有する注射剤用医薬組成物の製造方法において、アミノステロイド系筋弛緩薬を水性溶媒に添加する前に、ｐＨ調整剤を水性溶媒に予め添加することにより、当該医薬組成物の製造に際しての類縁物質の生成を抑制できることが開示されている。しかしながら、この文献２の注射用組成物の有効成分はオキシコドンではない。そして、当該方法が、有効成分がオキシコドンである液剤に適用できるかどうか、適用できるとした場合、ｐＨを具体的にどのような範囲に調整するかについては何ら記載されていない。
As a technique for suppressing the production of related substances, for example, in Document 2, in a method for producing a pharmaceutical composition for an injection containing an aminosteroid-based muscle relaxant, before adding the aminosteroid-based muscle relaxant to an aqueous solvent. Further, it is disclosed that the production of related substances in the production of the pharmaceutical composition can be suppressed by adding the pH adjuster to the aqueous solvent in advance. However, the active ingredient of the injectable composition of this document 2 is not oxycodone. Further, there is no description as to whether or not the method can be applied to a liquid preparation in which the active ingredient is oxycodone, and if applicable, to what extent the pH is specifically adjusted.
本発明は、有効成分であるオキシコドンの苦味がマスキングされた経口用の液剤組成物を提供することを課題とする。さらには、本発明は、有効成分の類縁物質生成が抑制された液剤組成物を提供することを課題とする。
An object of the present invention is to provide an oral liquid composition in which the bitterness of oxycodone, which is an active ingredient, is masked. Furthermore, it is an object of the present invention to provide a liquid composition in which the production of related substances of an active ingredient is suppressed.
本発明者らは、上記課題を解決するために鋭意研究を行った結果、少なくとも３種類の所定の添加剤を加えることにより、有効成分であるオキシコドンの苦味が適切にマスキングされた液剤組成物を得られることを見出した。そして、有効成分の類縁物質生成を抑制するためには、該液剤組成物のｐＨを所定の範囲に調整することが有効であり、これにより、苦味がマスキングされると共に、類縁物質の生成が抑えられ、安定性が担保された液剤組成物が得られることを見出し、本発明を完成した。
As a result of diligent research to solve the above problems, the present inventors have obtained a liquid composition in which the bitterness of oxycodone, which is an active ingredient, is appropriately masked by adding at least three kinds of predetermined additives. I found that I could get it. Then, in order to suppress the formation of related substances of the active ingredient, it is effective to adjust the pH of the liquid preparation composition to a predetermined range, whereby the bitterness is masked and the formation of related substances is suppressed. The present invention has been completed by finding that a liquid composition having a guaranteed stability can be obtained.
即ち本発明は、下記（１）～（２８）に関するものであるが、これらに限定されるものではく、実質的に同一の手段で同一の目的を達成するものは本発明に含まれる。
（１）オキシコドン、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する液剤組成物であって、該有効成分の苦味がマスキングされていることを特徴とする液剤組成物。
（２）オキシコドン、その薬学的に許容される塩、又はそれらの水和物が、液剤組成物１００重量％に対して、０．０１～１重量％含有されている上記（１）に記載の液剤組成物。
（３）添加剤として、アセスルファムカリウム、キシリトール、Ｄ-ソルビトール、又はＬ-グルタミン酸の中から選ばれる少なくとも３種が含有されている上記（１）又は（２）に記載の液剤組成物。
（４）アセスルファムカリウムが、液剤組成物１００重量％に対して、０．０１～０．１重量％含有されている上記（３）に記載の液剤組成物。
（５）キシリトールが、液剤組成物１００重量％に対して、０．５～１５重量％含有されている上記（３）又は（４）に記載の液剤組成物。
（６）Ｄ-ソルビトールが、液剤組成物１００重量％に対して、１～２０重量％含有されている上記（３）～（５）のいずれかに記載の液剤組成物。
（７）Ｌ-グルタミン酸が、液剤組成物１００重量％に対して、０．０１～１重量％含有されている上記（３）～（６）のいずれかに記載の液剤組成物。
（８）アセスルファムカリウム、キシリトール、Ｄ-ソルビトール、又はＬ-グルタミン酸から選ばれる少なくとも３種が、液剤組成物１００重量％に対して、０．１～４０重量％含有されている上記（３）～（７）のいずれかに記載の液剤組成物。
（９）添加剤として、さらにクエン酸水和物及び／又はクエン酸ナトリウム水和物が含有されている上記（３）～（８）のいずれかに記載の液剤組成物。
（１０）クエン酸水和物又はクエン酸ナトリウム水和物が、液剤組成物１００重量％に対して、０．０１～１重量％含有されている上記（９）に記載の液剤組成物。
（１１）添加剤として、さらに安息香酸ナトリウム及び／又はパラオキシ安息香酸エチルが含有されている上記（３）～（１０）のいずれかに記載の液剤組成物。
（１２）安息香酸ナトリウムが、液剤組成物１００重量％に対して、０．００５～０．５重量％含有されている上記（１１）に記載の液剤組成物。
（１３）パラオキシ安息香酸エチルが、液剤組成物１００重量％に対して、０．０００５～０．０５重量％含有されている上記（１１）又は（１２）に記載の組成物。
（１４）添加剤として、さらに塩化ナトリウムが含有されている上記（３）～（１３）のいずれかに記載の液剤組成物。
（１５）塩化ナトリウムが、液剤組成物１００重量％に対して、０．００５～１重量％含有されている上記（１４）に記載の液剤組成物。
（１６）添加剤として、さらにプロピレングリコールが含有されている上記（３）～（１５）のいずれかに記載の液剤組成物。
（１７）プロピレングリコールが、液剤組成物１００重量％に対して、０．００５～１重量％含有されている上記（１６）に記載の液剤組成物。
（１８）ｐＨが３．３～４．８である上記（１）～（１７）のいずれかに記載の液剤組成物。
（１９）前記有効成分からの経時的な類縁物質の生成が、日本国厚生労働省が定める医薬品の安定性試験を実施した場合、許容される規準以下に抑制された（１）～（１８）のいずれかに記載の液剤組成物。
（２０）日本国厚生労働省が定める医薬品の定性試験を実施した場合における前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.２％以下である（１９）に記載の液剤組成物。
（２１）日本国厚生労働省が定める医薬品の安定性試験を実施した場合における前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.１５％以下である（１９）に記載の液剤組成物。
（２２）日本国厚生労働省が定める医薬品の安定性試験を実施した場合における前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.１％以下である（１９）に記載の液剤組成物。
（２３）日本国厚生労働省が定める医薬品の安定性試験を実施した場合における前記有効成分の量に対する類縁物質の総量の割合が０.６％以下である上記（１９）～（２２）のいずれかに記載の液剤組成物。
（２４）オキシコドン、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する液剤組成物のｐＨを３．３～４．８に調整することで、該液剤組成物中の類縁物質の生成を抑制することを特徴とする、該液剤組成物の安定化方法。
（２５）前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.２％以下である上記（２４）に記載の安定化方法。
（２６）前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.１５％以下である上記（２４）に記載の安定化方法。
（２７）前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.１％以下である上記（２４）に記載の安定化方法。
（２８）前記有効成分の量に対する類縁物質の総量の割合が、０.６％以下である上記（２４）～（２７）のいずれかに記載の安定化方法。 That is, the present invention relates to the following (1) to (28), but is not limited thereto, and includes those that achieve the same object by substantially the same means.
(1) A liquid preparation composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, wherein the bitterness of the active ingredient is masked. thing.
(2) The above-mentioned (1), wherein oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is contained in an amount of 0.01 to 1% by weight based on 100% by weight of the liquid composition. Liquid composition.
(3) The liquid composition according to (1) or (2) above, which contains at least three selected from acesulfame potassium, xylitol, D-sorbitol, and L-glutamic acid as additives.
(4) The liquid preparation composition according to (3) above, wherein acesulfame potassium is contained in an amount of 0.01 to 0.1% by weight based on 100% by weight of the liquid preparation composition.
(5) The liquid preparation composition according to (3) or (4) above, wherein xylitol is contained in an amount of 0.5 to 15% by weight based on 100% by weight of the liquid preparation composition.
(6) The liquid preparation composition according to any one of (3) to (5) above, wherein D-sorbitol is contained in an amount of 1 to 20% by weight based on 100% by weight of the liquid preparation composition.
(7) The liquid preparation composition according to any one of (3) to (6) above, wherein L-glutamic acid is contained in an amount of 0.01 to 1% by weight based on 100% by weight of the liquid preparation composition.
(8) At least 3 kinds selected from acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid are contained in an amount of 0.1 to 40% by weight based on 100% by weight of the liquid composition (3) to the above. The liquid composition according to any one of (7).
(9) The liquid composition according to any one of (3) to (8) above, which further contains citric acid hydrate and / or sodium citrate hydrate as an additive.
(10) The liquid preparation composition according to (9) above, which contains 0.01 to 1% by weight of citric acid hydrate or sodium citrate hydrate with respect to 100% by weight of the liquid preparation composition.
(11) The liquid composition according to any one of (3) to (10) above, which further contains sodium benzoate and / or ethyl paraoxybenzoate as an additive.
(12) The liquid preparation composition according to (11) above, wherein sodium benzoate is contained in an amount of 0.005 to 0.5% by weight based on 100% by weight of the liquid preparation composition.
(13) The composition according to (11) or (12) above, wherein ethyl paraoxybenzoate is contained in an amount of 0.0005 to 0.05% by weight based on 100% by weight of the liquid preparation composition.
(14) The liquid composition according to any one of (3) to (13) above, which further contains sodium chloride as an additive.
(15) The liquid preparation composition according to (14) above, wherein sodium chloride is contained in an amount of 0.005 to 1% by weight based on 100% by weight of the liquid preparation composition.
(16) The liquid composition according to any one of (3) to (15) above, which further contains propylene glycol as an additive.
(17) The liquid preparation composition according to (16) above, wherein propylene glycol is contained in an amount of 0.005 to 1% by weight based on 100% by weight of the liquid preparation composition.
(18) The liquid composition according to any one of (1) to (17) above, wherein the pH is 3.3 to 4.8.
(19) The production of related substances from the active ingredient over time was suppressed to below the permissible standard when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan was carried out. The liquid composition according to any one.
(20) The liquid composition according to (19), wherein the ratio of the amount of each related substance to the amount of the active ingredient when the qualitative test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.2% or less, respectively. thing.
(21) The liquid preparation according to (19), wherein the ratio of the amount of each related substance to the amount of the active ingredient when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.15% or less, respectively. Composition.
(22) The liquid preparation according to (19), wherein the ratio of the amount of each related substance to the amount of the active ingredient when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.1% or less, respectively. Composition.
(23) Any of the above (19) to (22) in which the ratio of the total amount of related substances to the amount of the active ingredient when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.6% or less. The liquid composition according to.
(24) In the liquid preparation composition, the pH of the liquid preparation composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient is adjusted to 3.3 to 4.8. A method for stabilizing a liquid preparation composition, which comprises suppressing the formation of a related substance of the above.
(25) The stabilizing method according to (24) above, wherein the ratio of the amount of each related substance to the amount of the active ingredient is 0.2% or less, respectively.
(26) The stabilizing method according to (24) above, wherein the ratio of the amount of each related substance to the amount of the active ingredient is 0.15% or less, respectively.
(27) The stabilizing method according to (24) above, wherein the ratio of the amount of each related substance to the amount of the active ingredient is 0.1% or less, respectively.
(28) The stabilizing method according to any one of (24) to (27) above, wherein the ratio of the total amount of related substances to the amount of the active ingredient is 0.6% or less.
（１）オキシコドン、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する液剤組成物であって、該有効成分の苦味がマスキングされていることを特徴とする液剤組成物。
（２）オキシコドン、その薬学的に許容される塩、又はそれらの水和物が、液剤組成物１００重量％に対して、０．０１～１重量％含有されている上記（１）に記載の液剤組成物。
（３）添加剤として、アセスルファムカリウム、キシリトール、Ｄ-ソルビトール、又はＬ-グルタミン酸の中から選ばれる少なくとも３種が含有されている上記（１）又は（２）に記載の液剤組成物。
（４）アセスルファムカリウムが、液剤組成物１００重量％に対して、０．０１～０．１重量％含有されている上記（３）に記載の液剤組成物。
（５）キシリトールが、液剤組成物１００重量％に対して、０．５～１５重量％含有されている上記（３）又は（４）に記載の液剤組成物。
（６）Ｄ-ソルビトールが、液剤組成物１００重量％に対して、１～２０重量％含有されている上記（３）～（５）のいずれかに記載の液剤組成物。
（７）Ｌ-グルタミン酸が、液剤組成物１００重量％に対して、０．０１～１重量％含有されている上記（３）～（６）のいずれかに記載の液剤組成物。
（８）アセスルファムカリウム、キシリトール、Ｄ-ソルビトール、又はＬ-グルタミン酸から選ばれる少なくとも３種が、液剤組成物１００重量％に対して、０．１～４０重量％含有されている上記（３）～（７）のいずれかに記載の液剤組成物。
（９）添加剤として、さらにクエン酸水和物及び／又はクエン酸ナトリウム水和物が含有されている上記（３）～（８）のいずれかに記載の液剤組成物。
（１０）クエン酸水和物又はクエン酸ナトリウム水和物が、液剤組成物１００重量％に対して、０．０１～１重量％含有されている上記（９）に記載の液剤組成物。
（１１）添加剤として、さらに安息香酸ナトリウム及び／又はパラオキシ安息香酸エチルが含有されている上記（３）～（１０）のいずれかに記載の液剤組成物。
（１２）安息香酸ナトリウムが、液剤組成物１００重量％に対して、０．００５～０．５重量％含有されている上記（１１）に記載の液剤組成物。
（１３）パラオキシ安息香酸エチルが、液剤組成物１００重量％に対して、０．０００５～０．０５重量％含有されている上記（１１）又は（１２）に記載の組成物。
（１４）添加剤として、さらに塩化ナトリウムが含有されている上記（３）～（１３）のいずれかに記載の液剤組成物。
（１５）塩化ナトリウムが、液剤組成物１００重量％に対して、０．００５～１重量％含有されている上記（１４）に記載の液剤組成物。
（１６）添加剤として、さらにプロピレングリコールが含有されている上記（３）～（１５）のいずれかに記載の液剤組成物。
（１７）プロピレングリコールが、液剤組成物１００重量％に対して、０．００５～１重量％含有されている上記（１６）に記載の液剤組成物。
（１８）ｐＨが３．３～４．８である上記（１）～（１７）のいずれかに記載の液剤組成物。
（１９）前記有効成分からの経時的な類縁物質の生成が、日本国厚生労働省が定める医薬品の安定性試験を実施した場合、許容される規準以下に抑制された（１）～（１８）のいずれかに記載の液剤組成物。
（２０）日本国厚生労働省が定める医薬品の定性試験を実施した場合における前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.２％以下である（１９）に記載の液剤組成物。
（２１）日本国厚生労働省が定める医薬品の安定性試験を実施した場合における前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.１５％以下である（１９）に記載の液剤組成物。
（２２）日本国厚生労働省が定める医薬品の安定性試験を実施した場合における前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.１％以下である（１９）に記載の液剤組成物。
（２３）日本国厚生労働省が定める医薬品の安定性試験を実施した場合における前記有効成分の量に対する類縁物質の総量の割合が０.６％以下である上記（１９）～（２２）のいずれかに記載の液剤組成物。
（２４）オキシコドン、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する液剤組成物のｐＨを３．３～４．８に調整することで、該液剤組成物中の類縁物質の生成を抑制することを特徴とする、該液剤組成物の安定化方法。
（２５）前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.２％以下である上記（２４）に記載の安定化方法。
（２６）前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.１５％以下である上記（２４）に記載の安定化方法。
（２７）前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.１％以下である上記（２４）に記載の安定化方法。
（２８）前記有効成分の量に対する類縁物質の総量の割合が、０.６％以下である上記（２４）～（２７）のいずれかに記載の安定化方法。 That is, the present invention relates to the following (1) to (28), but is not limited thereto, and includes those that achieve the same object by substantially the same means.
(1) A liquid preparation composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, wherein the bitterness of the active ingredient is masked. thing.
(2) The above-mentioned (1), wherein oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is contained in an amount of 0.01 to 1% by weight based on 100% by weight of the liquid composition. Liquid composition.
(3) The liquid composition according to (1) or (2) above, which contains at least three selected from acesulfame potassium, xylitol, D-sorbitol, and L-glutamic acid as additives.
(4) The liquid preparation composition according to (3) above, wherein acesulfame potassium is contained in an amount of 0.01 to 0.1% by weight based on 100% by weight of the liquid preparation composition.
(5) The liquid preparation composition according to (3) or (4) above, wherein xylitol is contained in an amount of 0.5 to 15% by weight based on 100% by weight of the liquid preparation composition.
(6) The liquid preparation composition according to any one of (3) to (5) above, wherein D-sorbitol is contained in an amount of 1 to 20% by weight based on 100% by weight of the liquid preparation composition.
(7) The liquid preparation composition according to any one of (3) to (6) above, wherein L-glutamic acid is contained in an amount of 0.01 to 1% by weight based on 100% by weight of the liquid preparation composition.
(8) At least 3 kinds selected from acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid are contained in an amount of 0.1 to 40% by weight based on 100% by weight of the liquid composition (3) to the above. The liquid composition according to any one of (7).
(9) The liquid composition according to any one of (3) to (8) above, which further contains citric acid hydrate and / or sodium citrate hydrate as an additive.
(10) The liquid preparation composition according to (9) above, which contains 0.01 to 1% by weight of citric acid hydrate or sodium citrate hydrate with respect to 100% by weight of the liquid preparation composition.
(11) The liquid composition according to any one of (3) to (10) above, which further contains sodium benzoate and / or ethyl paraoxybenzoate as an additive.
(12) The liquid preparation composition according to (11) above, wherein sodium benzoate is contained in an amount of 0.005 to 0.5% by weight based on 100% by weight of the liquid preparation composition.
(13) The composition according to (11) or (12) above, wherein ethyl paraoxybenzoate is contained in an amount of 0.0005 to 0.05% by weight based on 100% by weight of the liquid preparation composition.
(14) The liquid composition according to any one of (3) to (13) above, which further contains sodium chloride as an additive.
(15) The liquid preparation composition according to (14) above, wherein sodium chloride is contained in an amount of 0.005 to 1% by weight based on 100% by weight of the liquid preparation composition.
(16) The liquid composition according to any one of (3) to (15) above, which further contains propylene glycol as an additive.
(17) The liquid preparation composition according to (16) above, wherein propylene glycol is contained in an amount of 0.005 to 1% by weight based on 100% by weight of the liquid preparation composition.
(18) The liquid composition according to any one of (1) to (17) above, wherein the pH is 3.3 to 4.8.
(19) The production of related substances from the active ingredient over time was suppressed to below the permissible standard when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan was carried out. The liquid composition according to any one.
(20) The liquid composition according to (19), wherein the ratio of the amount of each related substance to the amount of the active ingredient when the qualitative test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.2% or less, respectively. thing.
(21) The liquid preparation according to (19), wherein the ratio of the amount of each related substance to the amount of the active ingredient when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.15% or less, respectively. Composition.
(22) The liquid preparation according to (19), wherein the ratio of the amount of each related substance to the amount of the active ingredient when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.1% or less, respectively. Composition.
(23) Any of the above (19) to (22) in which the ratio of the total amount of related substances to the amount of the active ingredient when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.6% or less. The liquid composition according to.
(24) In the liquid preparation composition, the pH of the liquid preparation composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient is adjusted to 3.3 to 4.8. A method for stabilizing a liquid preparation composition, which comprises suppressing the formation of a related substance of the above.
(25) The stabilizing method according to (24) above, wherein the ratio of the amount of each related substance to the amount of the active ingredient is 0.2% or less, respectively.
(26) The stabilizing method according to (24) above, wherein the ratio of the amount of each related substance to the amount of the active ingredient is 0.15% or less, respectively.
(27) The stabilizing method according to (24) above, wherein the ratio of the amount of each related substance to the amount of the active ingredient is 0.1% or less, respectively.
(28) The stabilizing method according to any one of (24) to (27) above, wherein the ratio of the total amount of related substances to the amount of the active ingredient is 0.6% or less.
本発明液剤組成物は、がん疼痛を有する患者にとって有効成分であるオキシコドンの苦味が低減された服用しやすい経口用液剤であり、非常に有用性が高い。また、経時的な類縁物質の生成が抑制され、安定性が高いことから、年単位の品質担保が求められる医薬としての条件も十分満たすものである。
The liquid preparation composition of the present invention is an easy-to-take oral liquid preparation in which the bitterness of oxycodone, which is an active ingredient, is reduced for patients with cancer pain, and is extremely useful. In addition, since the production of related substances over time is suppressed and the stability is high, the conditions as a medicine for which quality assurance on an annual basis is required are sufficiently satisfied.
本発明は、オキシコドン、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する液剤組成物であって、該有効成分の苦味がマスキングされているものである。そのマスキングは、アセスルファムカリウム、キシリトール、Ｄ-ソルビトール、又はＬ-グルタミン酸の中から選ばれる少なくとも３種の添加剤を含有することによりなされる。また、本発明液剤組成物は、そのｐＨを３．３～４．８に調整することにより、類縁物質の生成が抑えられた安定性の高いものとすることができる。
The present invention is a liquid composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, and the bitterness of the active ingredient is masked. The masking is done by containing at least three additives selected from acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid. Further, by adjusting the pH of the liquid preparation composition of the present invention to 3.3 to 4.8, the formation of related substances can be suppressed and the composition can be made highly stable.
本発明液剤組成物は有効成分としてオキシコドン、その薬学的に許容される塩、又はそれらの水和物を含有する。オキシコドンは、１９９６年のＷＨＯ方式がん疼痛治療法においては、３段階中の３段階目で用いられる強オピオイドの一種であり、薬物として医療上の有用性を有している。オキシコドンは、フリー体のほか、薬学的に許容される塩であれば特に制限なく使用でき、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩、フッ化水素酸塩、臭化水素酸塩等の無機酸塩や、酢酸、酒石酸塩、乳酸塩、クエン酸塩、フマル酸塩、マレイン酸塩、コハク酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、ナフタレンスルホン酸塩、カンファースルホン酸塩等の有機酸塩、アルギネート、アスパラギネート、グルタメートなどのアミノ酸塩、ナトリウム塩、カリウム塩、セシウム塩などの金属塩等を挙げることができる。特に好ましいのは、がん疼痛鎮痛薬として市販され広く臨床的に用いられているオキシコドン塩酸塩である。また、オキシコドンの立体異性体や水和物、溶媒和物も本発明液剤組成物の有効成分とされ得るものに包含される。
The liquid preparation composition of the present invention contains oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. Oxycodone is a kind of strong opioid used in the third stage of the three stages in the 1996 WHO method for treating cancer pain, and has medical usefulness as a drug. Oxycodon can be used without particular limitation as long as it is a free form or a pharmaceutically acceptable salt. Inorganic acid salt, acetic acid, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, Examples thereof include organic acid salts such as camphorsulfonate, amino acid salts such as alginate, aspartate and glutamate, and metal salts such as sodium salt, potassium salt and cesium salt. Particularly preferred are oxycodone hydrochloride, which is commercially available and widely used clinically as a cancer pain analgesic. In addition, stereoisomers of oxycodone, hydrates, and solvates are also included in those that can be used as the active ingredient of the liquid preparation composition of the present invention.
本発明液剤組成物中のオキシコドン、その薬学的に許容される塩、又はそれらの水和物の含有量は、特に制限されるものではなく、適宜選択できる。例えば、オキシコドン塩酸塩又はオキシコドン塩酸塩水和物の場合は、本液剤組成物１００重量％に対して０．０１～１重量％、好ましくは０．０３～０．８重量％、より好ましくは０．０５～０．６重量％とすることができる。
The content of oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof in the liquid preparation composition of the present invention is not particularly limited and can be appropriately selected. For example, in the case of oxycodone hydrochloride or oxycodone hydrochloride hydrate, 0.01 to 1% by weight, preferably 0.03 to 0.8% by weight, more preferably 0. It can be 05 to 0.6% by weight.
本発明液剤組成物の特徴は、有効成分であるオキシコドン、その薬学的に許容される塩、又はそれらの水和物の苦味がマスキングされていることである。そのためには、アセスルファムカリウム、キシリトール、Ｄ-ソルビトール、又はＬ-グルタミン酸の中から選ばれる少なくとも３種の添加剤を添加することが一法である。さらに、本発明液剤組成物には、クエン酸水和物、クエン酸ナトリウム水和物等のｐＨ調整剤といった添加剤が組み合わせて含有されていてもよい。これにより、本発明液剤組成物は、苦味が低減される上に安定性が担保されるという長所を兼ね備えることができる。以下に本発明液剤組成物に加えられる添加剤とその含有量について詳述するが、本発明はこれらに限定されるものではない。
The characteristic of the liquid preparation composition of the present invention is that the bitter taste of oxycodone, which is an active ingredient, a pharmaceutically acceptable salt thereof, or a hydrate thereof is masked. One method is to add at least three additives selected from acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid. Further, the liquid composition of the present invention may contain a combination of additives such as a pH adjuster such as citric acid hydrate and sodium citrate hydrate. Thereby, the liquid preparation composition of the present invention can have the advantages that the bitterness is reduced and the stability is ensured. The additives added to the liquid composition of the present invention and their contents will be described in detail below, but the present invention is not limited thereto.
本発明液剤組成物の添加剤として使用され得る甘味剤としては、精製白糖、アスパルテーム、サッカリンＮａ水和物、Ｄ-マンニトール、Ｄ-ソルビトール、デキストリン、エリスリトール、スクラロース、キシリトール、粉末還元麦芽糖水アメ、タウマチン、アセスルファムカリウム、又はこれらの組合せ等が挙げられる。これらのうち、アセスルファムカリウム、キシリトール及びＤ-ソルビトールの組合せが好ましい。アセスルファムカリウムの含有量は、液剤組成物１００重量％に対して、０．０１～０．１重量％、好ましくは０．０３～０．０９重量％、より好ましくは０．０４～０．０８重量％、さらに好ましくは０．０５～０．０７重量％とすることができる。キシリトールの含有量は、液剤組成物１００重量％に対して、０．５～１５重量％、好ましくは１～１０重量％、より好ましくは２～８重量％、さらに好ましくは３～６重量％とすることができる。Ｄ-ソルビトールの含有量は、液剤組成物１００重量％に対して、１～２０重量％、好ましくは２～１５重量％、より好ましくは４～１２重量％、さらに好ましくは６～１０重量％とすることができる。これら甘味剤に加え、矯味剤であるＬ-グルタミン酸を添加してもよく、Ｌ-グルタミン酸の含有量は、液剤組成物１００重量％に対して、０．０１～１重量％、好ましくは０．０３～０．３重量％、より好ましくは０．０５～０．２重量％、さらに好ましくは０．０７～０．１５重量％とすることができる。アセスルファムカリウム、キシリトール、Ｄ-ソルビトール、又はＬ-グルタミン酸の中から選ばれる３種の添加剤の合計含有量は、液剤組成物１００重量％に対して、０．１～４０重量％、好ましくは０．５～３０重量％、より好ましくは１～２５重量％、さらに好ましくは１～２０重量％とすることができる。
Sweeteners that can be used as additives in the liquid composition of the present invention include purified sucrose, aspartame, saccharin Na hydrate, D-mannitol, D-sorbitol, dextrin, erythritol, sucralose, xylitol, powdered reduced maltose water candy, Examples thereof include taumatin, acesulfame potassium, or a combination thereof. Of these, a combination of acesulfame potassium, xylitol and D-sorbitol is preferred. The content of acesulfame potassium is 0.01 to 0.1% by weight, preferably 0.03 to 0.09% by weight, more preferably 0.04 to 0.08% by weight, based on 100% by weight of the liquid composition. %, More preferably 0.05 to 0.07% by weight. The content of xylitol is 0.5 to 15% by weight, preferably 1 to 10% by weight, more preferably 2 to 8% by weight, still more preferably 3 to 6% by weight, based on 100% by weight of the liquid composition. can do. The content of D-sorbitol is 1 to 20% by weight, preferably 2 to 15% by weight, more preferably 4 to 12% by weight, still more preferably 6 to 10% by weight, based on 100% by weight of the liquid composition. can do. In addition to these sweeteners, L-glutamic acid as a flavoring agent may be added, and the content of L-glutamic acid is 0.01 to 1% by weight, preferably 0% by weight, based on 100% by weight of the liquid composition. It can be 03 to 0.3% by weight, more preferably 0.05 to 0.2% by weight, still more preferably 0.07 to 0.15% by weight. The total content of the three additives selected from acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid is 0.1-40% by weight, preferably 0, based on 100% by weight of the liquid composition. It can be .5 to 30% by weight, more preferably 1 to 25% by weight, still more preferably 1 to 20% by weight.
本発明液剤組成物の添加剤として使用され得る保存剤としては、安息香酸、安息香酸ナトリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、ソルビン酸、ソルビン酸カリウム、エリソルビン酸、デヒドロ酢酸ナトリウム、エデト酸ナトリウム、アスコルビン酸、アスコルビン酸ナトリウム、パルミチン酸アスコルビル、プロピオン酸、プロピオン酸ナトリウム、没食子酸プロピル、トコフェロール又はこれらの組合せ等が挙げられるが、好ましい例としては、安息香酸ナトリウム及び／又はパラオキシ安息香酸エチルを挙げることができる。安息香酸ナトリウムの含有量は、液剤組成物１００重量％に対して、０．００５～０．５重量％、好ましくは０．００８～０．１重量％、より好ましくは０．０１～０．０８重量％、さらに好ましくは０．０２～０．０６重量％とすることができる。パラオキシ安息香酸エチルの含有量は、液剤組成物１００重量％に対して、０．０００５～０．０５重量％、好ましくは０．０００８～０．０１重量％、より好ましくは０．００１～０．００５重量％、さらに好ましくは０．００１５～０．００５重量％とすることができる。安息香酸ナトリウム及びパラオキシ安息香酸エチルの合計含有量は、液剤組成物１００重量％に対して、０．００５～０．５重量％、好ましくは０．００８～０．１重量％、より好ましくは０．０１～０．０８重量％、さらに好ましくは０．０２～０．０６重量％とすることができる。
Preservatives that can be used as additives in the liquid composition of the present invention include benzoic acid, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, sorbic acid, potassium sorbate, erythorbic acid, dehydro. Examples thereof include sodium acetate, sodium edetate, ascorbic acid, sodium ascorbic acid, ascorbic palmitate, propionic acid, sodium propionate, propyl gallate, tocopherol or a combination thereof, with preferred examples being sodium benzoate and /. Alternatively, ethyl paraoxybenzoate can be mentioned. The content of sodium benzoate is 0.005 to 0.5% by weight, preferably 0.008 to 0.1% by weight, more preferably 0.01 to 0.08, based on 100% by weight of the liquid composition. It can be% by weight, more preferably 0.02 to 0.06% by weight. The content of ethyl paraoxybenzoate is 0.0005 to 0.05% by weight, preferably 0.0008 to 0.01% by weight, more preferably 0.001 to 0% by weight, based on 100% by weight of the liquid composition. It can be 005% by weight, more preferably 0.0015 to 0.005% by weight. The total content of sodium benzoate and ethyl paraoxybenzoate is 0.005 to 0.5% by weight, preferably 0.008 to 0.1% by weight, more preferably 0, based on 100% by weight of the liquid composition. It can be 0.01 to 0.08% by weight, more preferably 0.02 to 0.06% by weight.
本発明液剤組成物の添加物として使用され得る矯味剤としては、ＤＬ-リンゴ酸、塩化ナトリウム、クエン酸、クエン酸水和物、クエン酸ナトリウム水和物、グリチルリチン酸、グリチルリチン酸ジカリウム、グリチルリチン酸モノアンモニウム、Ｌ-グルタミン酸、Ｌ-グルタミン酸ナトリウム、グリシン、又はこれらの組合せ等が挙げられるが、好ましい例としては、塩化ナトリウムを挙げることができる。塩化ナトリウムの含有量は、液剤組成物１００重量％に対して、０．００５～１重量％、好ましくは０．０１～０．５重量％、より好ましくは０．０３～０．３重量％、さらに好ましくは０．０５～０．２重量％とすることができる。
Examples of the flavoring agent that can be used as an additive of the liquid preparation composition of the present invention include DL-apple acid, sodium chloride, citric acid, citric acid hydrate, sodium citrate hydrate, glycyrrhizinic acid, dipotassium glycyrrhizinate, and glycyrrhizinic acid. Examples thereof include monoammonium, L-glutamic acid, sodium L-glutamate, glycine, or a combination thereof, and preferred examples include sodium chloride. The content of sodium chloride is 0.005 to 1% by weight, preferably 0.01 to 0.5% by weight, more preferably 0.03 to 0.3% by weight, based on 100% by weight of the liquid composition. More preferably, it can be 0.05 to 0.2% by weight.
本発明液剤組成物の添加物として使用され得るｐＨ調整剤としては、希塩酸、リン酸、リン酸水素ナトリウム水和物、酢酸、酢酸ナトリウム水和物、乳酸、酒石酸、リンゴ酸、クエン酸水和物、クエン酸ナトリウム水和物、又はこれらの組合せ等が挙げられるが、好ましい例としては、酒石酸、リンゴ酸、クエン酸水和物、クエン酸ナトリウム水和物が挙げられ、さらに好ましい例としては、クエン酸水和物及び／又はクエン酸ナトリウム水和物を挙げることができる。クエン酸水和物又はクエン酸ナトリウム水和物の含有量は、各々、液剤組成物１００重量％に対して、０．０１～１重量％、好ましくは０．０５～０．８重量％、より好ましくは０．１～０．６重量％、さらに好ましくは０．２～０．４重量％とすることができる。なお、クエン酸水和物又はクエン酸ナトリウム水和物は矯味剤としての作用も併せ有するため、本発明液剤組成物においては、両方の用途に用いられている。
Examples of the pH adjuster that can be used as an additive in the liquid composition of the present invention include dilute hydrochloric acid, phosphoric acid, sodium hydrogen phosphate hydrate, acetic acid, sodium acetate hydrate, lactic acid, tartrate acid, malic acid, and citric acid hydration. A substance, sodium citrate hydrate, or a combination thereof and the like can be mentioned, and preferred examples include tartrate acid, citric acid, citric acid hydrate, and sodium citrate hydrate, and more preferable examples thereof. , 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, based on 100% by weight of the liquid composition, respectively. It can be preferably 0.1 to 0.6% by weight, more preferably 0.2 to 0.4% by weight. Since citric acid hydrate or sodium citrate hydrate also acts as a flavoring agent, it is used for both purposes in the liquid preparation composition of the present invention.
本発明液剤組成物の添加物として使用され得る溶解補助剤としては、マクロゴール、グリセリン、ポビドン、シクロデキストリン、プロピレングリコール、又はこれらの組合せ等が使用できるが、好ましい例としては、プロピレングリコールを挙げることができる。プロピレングリコールの含有量は、液剤組成物１００重量％に対して、０．００５～１重量％、好ましくは０．０１～０．５重量％、より好ましくは０．０３～０．３重量％、さらに好ましくは０．０５～０．２重量％とすることができる。
As the solubilizing agent that can be used as an additive of the liquid preparation composition of the present invention, macrogol, glycerin, povidone, cyclodextrin, propylene glycol, or a combination thereof and the like can be used, and propylene glycol is a preferable example. be able to. The content of propylene glycol is 0.005 to 1% by weight, preferably 0.01 to 0.5% by weight, more preferably 0.03 to 0.3% by weight, based on 100% by weight of the liquid composition. More preferably, it can be 0.05 to 0.2% by weight.
本発明液剤組成物のｐＨは、添加剤の種類や含有量により調整され得るものであるが、好ましくは３．３～４．８、より好ましくは３．５～４．５、さらに好ましくは３．８～４．２とすることができる。当該範囲のｐＨに調整することにより、本発明液剤組成物の苦味マスキング及び安定性を担保することができる。
The pH of the liquid preparation composition of the present invention can be adjusted depending on the type and content of the additive, but is preferably 3.3 to 4.8, more preferably 3.5 to 4.5, and even more preferably 3. It can be 8.8 to 4.2. By adjusting the pH to the above range, the bitterness masking and stability of the liquid preparation composition of the present invention can be ensured.
本発明液剤組成物は、上記の他に、発明の効果に支障のない限り、一般的に医薬製剤の製造に用いられる種々の添加剤を含んでいてもよい。このような添加剤として、例えば、上記に例示した以外の、安定化剤、界面活性剤、可溶化剤、粘調化剤、懸濁化剤、香料、着色剤等が挙げられ、目的に応じて適宜選択して添加することができる。
In addition to the above, the liquid composition of the present invention may contain various additives generally used for producing pharmaceutical preparations, as long as the effects of the invention are not hindered. Examples of such additives include stabilizers, surfactants, solubilizers, thickening agents, suspending agents, fragrances, colorants and the like other than those exemplified above, depending on the intended purpose. Can be appropriately selected and added.
次に実施例を挙げて本発明を具体的に説明するが、本発明はこれに何ら限定されるものではない。
Next, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
実施例１
本発明液剤組成物の処方の一例として、表１に示した。下記製造方法に従って表１に示す組成から成るオキシコドン塩酸塩水和物を含有する液剤組成物を製造した。 Example 1
Table 1 shows an example of the formulation of the liquid preparation composition of the present invention. A liquid composition containing oxycodone hydrochloride hydrate having the composition shown in Table 1 was produced according to the following production method.
本発明液剤組成物の処方の一例として、表１に示した。下記製造方法に従って表１に示す組成から成るオキシコドン塩酸塩水和物を含有する液剤組成物を製造した。 Example 1
Table 1 shows an example of the formulation of the liquid preparation composition of the present invention. A liquid composition containing oxycodone hydrochloride hydrate having the composition shown in Table 1 was produced according to the following production method.
上記表１に基づいて、処方４の本発明液剤組成物の製造方法の一例を下記に示す。
第１７改正日本薬局方、経口液剤の項に従い、加温した精製水にクエン酸水和物１５．５０ｍｇ、クエン酸ナトリウム水和物１２．２９２ｍｇ、アセスルファムカリウム３．２５ｍｇ、塩化ナトリウム５．００ｍｇ、安息香酸ナトリウム２．００ｍｇ、パラオキシ安息香酸エチル０．１５ｍｇ、プロピレングリコール５．００ｍｇ、キシリトール２５０．００ｍｇ及びＤ-ソルビトール液（７０％溶液）６２１．５０ｍｇを順次添加溶解し、室温まで冷却した。
無水物として２０ｍｇに相当する量のオキシコドン塩酸塩水和物２３．０７ｍｇを添加し、室温で攪拌しながら完全に溶解した。精製水を加えて全量５．２５ｇ（５ｍＬ相当）とした。必要に応じ、ｐＨ調整剤を添加して、所定のｐＨに調整した。 Based on Table 1 above, an example of the method for producing the liquid composition of the present invention of Formulation 4 is shown below.
According to the 17th Amendment of the Japanese Pharmacy, Oral Solution, 15.50 mg of citric acid hydrate, 12.292 mg of sodium citrate hydrate, 3.25 mg of acesurfam potassium, 5.00 mg of sodium chloride, in warm purified water. Sodium citrate 2.00 mg, ethyl paraoxybenzoate 0.15 mg, propylene glycol 5.00 mg, xylitol 250.00 mg and D-sorbitol solution (70% solution) 621.50 mg were sequentially added and dissolved, and cooled to room temperature.
23.07 mg of oxycodone hydrochloride hydrate was added as an anhydride in an amount corresponding to 20 mg, and the mixture was completely dissolved with stirring at room temperature. Purified water was added to make a total amount of 5.25 g (equivalent to 5 mL). If necessary, a pH adjuster was added to adjust the pH to a predetermined pH.
第１７改正日本薬局方、経口液剤の項に従い、加温した精製水にクエン酸水和物１５．５０ｍｇ、クエン酸ナトリウム水和物１２．２９２ｍｇ、アセスルファムカリウム３．２５ｍｇ、塩化ナトリウム５．００ｍｇ、安息香酸ナトリウム２．００ｍｇ、パラオキシ安息香酸エチル０．１５ｍｇ、プロピレングリコール５．００ｍｇ、キシリトール２５０．００ｍｇ及びＤ-ソルビトール液（７０％溶液）６２１．５０ｍｇを順次添加溶解し、室温まで冷却した。
無水物として２０ｍｇに相当する量のオキシコドン塩酸塩水和物２３．０７ｍｇを添加し、室温で攪拌しながら完全に溶解した。精製水を加えて全量５．２５ｇ（５ｍＬ相当）とした。必要に応じ、ｐＨ調整剤を添加して、所定のｐＨに調整した。 Based on Table 1 above, an example of the method for producing the liquid composition of the present invention of Formulation 4 is shown below.
According to the 17th Amendment of the Japanese Pharmacy, Oral Solution, 15.50 mg of citric acid hydrate, 12.292 mg of sodium citrate hydrate, 3.25 mg of acesurfam potassium, 5.00 mg of sodium chloride, in warm purified water. Sodium citrate 2.00 mg, ethyl paraoxybenzoate 0.15 mg, propylene glycol 5.00 mg, xylitol 250.00 mg and D-sorbitol solution (70% solution) 621.50 mg were sequentially added and dissolved, and cooled to room temperature.
23.07 mg of oxycodone hydrochloride hydrate was added as an anhydride in an amount corresponding to 20 mg, and the mixture was completely dissolved with stirring at room temperature. Purified water was added to make a total amount of 5.25 g (equivalent to 5 mL). If necessary, a pH adjuster was added to adjust the pH to a predetermined pH.
なお、オキシコドン塩酸塩は麻薬であるためその使用が制限されており、当該成分を含む製剤において味覚官能試験を容易に実施することができない。そのため、試験例（１）及び（２）で用いる処方Ａ～Ｆについては、同等の苦味を呈する量のデキストロメトルファン臭化水素酸塩水和物又はキニーネ硫酸塩二水和物をオキシコドン塩酸塩水和物に置き換えて、実施例１と同様に製剤を製造し、下記試験例（１）及び（２）における味覚官能試験を行った。
Since oxycodone hydrochloride is a narcotic, its use is restricted, and it is not possible to easily carry out a taste sensory test on a preparation containing the component. Therefore, for the formulations A to F used in Test Examples (1) and (2), dextromethorphan hydrobromide hydrate or quinine sulfate dihydrate is hydrated with oxycodone hydrochloride in an amount exhibiting the same bitterness. The preparation was produced in the same manner as in Example 1 by replacing it with a product, and the taste sensory test in the following test examples (1) and (2) was performed.
試験例（１）：味覚官能試験
ランダムに選んだ男女２１名をパネラーとして味覚官能試験を実施した。表２に示す処方Ａ、Ｂ及びＣの液剤組成物について、「施用時」と「後味」に分けて、表３の評価基準に従って「苦味」、「甘み」及び「酸味」の評価を行った。なお、「施用時」とは「口に含んだ時」を意味する。試験手順は、（１）あらかじめ試験検体ごとに水（２０～３０ｍＬ）で３回うがいする。（２）規定量（５ｍＬ）の試験検体を約５秒間（１０秒以内）口に含み、味を評価し、直ちに吐き出す。（３）再度水（２０～３０ｍＬ）で３回うがいを行う。（４）後味を評価する。（５）最後に、３種類の中から薬の味として好ましい液剤を選定した。なお、デキストロメトルファン臭化水素酸水和物２ｍｇの苦味はオキシコドン塩酸塩水和物２３．０７ｍｇ（無水物として２０ｍｇ）の苦味に相当することを事前の味覚センサーを用いた試験及び味覚官能試験で推定した。表４に評価結果の一例を示す。 Test Example (1): Taste sensory test A taste sensory test was conducted using 21 randomly selected men and women as panelists. The liquid composition of Formulations A, B and C shown in Table 2 was divided into "at the time of application" and "aftertaste", and "bitter taste", "sweetness" and "sour taste" were evaluated according to the evaluation criteria of Table 3. .. In addition, "at the time of application" means "when it is put in the mouth". The test procedure is as follows: (1) Gargle with water (20 to 30 mL) 3 times in advance for each test sample. (2) Put a specified amount (5 mL) of the test sample in the mouth for about 5 seconds (within 10 seconds), evaluate the taste, and immediately exhale. (3) Gargle again with water (20-30 mL) three times. (4) Evaluate the aftertaste. (5) Finally, a liquid agent preferable for the taste of the medicine was selected from the three types. The bitterness of dextromethorphan hydrobromic acid hydrate 2 mg corresponds to the bitterness of oxycodone hydrochloride hydrate 23.07 mg (20 mg as anhydrate) in a preliminary test using a taste sensor and a taste sensory test. Estimated. Table 4 shows an example of the evaluation results.
ランダムに選んだ男女２１名をパネラーとして味覚官能試験を実施した。表２に示す処方Ａ、Ｂ及びＣの液剤組成物について、「施用時」と「後味」に分けて、表３の評価基準に従って「苦味」、「甘み」及び「酸味」の評価を行った。なお、「施用時」とは「口に含んだ時」を意味する。試験手順は、（１）あらかじめ試験検体ごとに水（２０～３０ｍＬ）で３回うがいする。（２）規定量（５ｍＬ）の試験検体を約５秒間（１０秒以内）口に含み、味を評価し、直ちに吐き出す。（３）再度水（２０～３０ｍＬ）で３回うがいを行う。（４）後味を評価する。（５）最後に、３種類の中から薬の味として好ましい液剤を選定した。なお、デキストロメトルファン臭化水素酸水和物２ｍｇの苦味はオキシコドン塩酸塩水和物２３．０７ｍｇ（無水物として２０ｍｇ）の苦味に相当することを事前の味覚センサーを用いた試験及び味覚官能試験で推定した。表４に評価結果の一例を示す。 Test Example (1): Taste sensory test A taste sensory test was conducted using 21 randomly selected men and women as panelists. The liquid composition of Formulations A, B and C shown in Table 2 was divided into "at the time of application" and "aftertaste", and "bitter taste", "sweetness" and "sour taste" were evaluated according to the evaluation criteria of Table 3. .. In addition, "at the time of application" means "when it is put in the mouth". The test procedure is as follows: (1) Gargle with water (20 to 30 mL) 3 times in advance for each test sample. (2) Put a specified amount (5 mL) of the test sample in the mouth for about 5 seconds (within 10 seconds), evaluate the taste, and immediately exhale. (3) Gargle again with water (20-30 mL) three times. (4) Evaluate the aftertaste. (5) Finally, a liquid agent preferable for the taste of the medicine was selected from the three types. The bitterness of dextromethorphan hydrobromic acid hydrate 2 mg corresponds to the bitterness of oxycodone hydrochloride hydrate 23.07 mg (20 mg as anhydrate) in a preliminary test using a taste sensor and a taste sensory test. Estimated. Table 4 shows an example of the evaluation results.
表４から明らかなように、本発明組成物（処方Ａ及びＢ）は味覚官能試験において、苦味マスキングがされた好ましい液剤であることが示された。
As is clear from Table 4, the compositions of the present invention (formulations A and B) were shown to be preferable liquids with bitterness masking in the taste sensory test.
試験例（２）：味覚官能試験
ランダムに選んだ男女２１名をパネラーとして味覚官能試験を実施した。表５に示す処方Ｄ、Ｅ及びＦの液剤組成物について、試験例（１）の試験手順及び評価基準と同様に行った。なお、キニーネ硫酸塩二水和物０．７５ｍｇの苦味はオキシコドン塩酸塩水和物２３．０７ｍｇ（無水物として２０ｍｇ）の苦味に相当することを事前の味覚センサーを用いた試験及び味覚官能試験で推定した。表６に評価結果の一例を示す。 Test Example (2): Taste Sensation Test A taste sensory test was conducted using 21 randomly selected men and women as panelists. The liquid composition of Formulations D, E and F shown in Table 5 was subjected to the same test procedure and evaluation criteria as in Test Example (1). It is estimated by a test using a taste sensor and a taste sensory test in advance that the bitterness of 0.75 mg of quinine sulfate dihydrate corresponds to the bitterness of 23.07 mg of oxycodone hydrochloride hydrate (20 mg as anhydrate). did. Table 6 shows an example of the evaluation results.
ランダムに選んだ男女２１名をパネラーとして味覚官能試験を実施した。表５に示す処方Ｄ、Ｅ及びＦの液剤組成物について、試験例（１）の試験手順及び評価基準と同様に行った。なお、キニーネ硫酸塩二水和物０．７５ｍｇの苦味はオキシコドン塩酸塩水和物２３．０７ｍｇ（無水物として２０ｍｇ）の苦味に相当することを事前の味覚センサーを用いた試験及び味覚官能試験で推定した。表６に評価結果の一例を示す。 Test Example (2): Taste Sensation Test A taste sensory test was conducted using 21 randomly selected men and women as panelists. The liquid composition of Formulations D, E and F shown in Table 5 was subjected to the same test procedure and evaluation criteria as in Test Example (1). It is estimated by a test using a taste sensor and a taste sensory test in advance that the bitterness of 0.75 mg of quinine sulfate dihydrate corresponds to the bitterness of 23.07 mg of oxycodone hydrochloride hydrate (20 mg as anhydrate). did. Table 6 shows an example of the evaluation results.
表６から明らかなように、本発明組成物（処方Ｅ及びＦ）は、味覚官能試験において、苦味マスキングされた好ましい液剤であることが示された。
As is clear from Table 6, the compositions of the present invention (formulations E and F) were shown to be preferred liquids with bitterness masking in the taste sensory test.
本発明組成物はわが国（日本国）においては医薬品として開発されたものであるが、厚生労働省が定める医薬品の保存安定性については、他のオキシコドン即放製剤と同等レベルの許容される規準をクリアする必要がある。そのため、本発明組成物の保存安定性に係る各種の試験を行ったので、その結果を以下に示す。
試験例（３）：安定性評価試験
表７に示す処方Ｇ、Ｈ及びＩの液剤組成物（オキシコドン塩酸塩濃度４．０ｍｇ／ｍＬ）を実施例１と同様に製造した。各処方の液剤組成物について、８０℃保存、６日間（２５℃保存、５．５年に相当）の条件で安定性評価試験を行った。評価項目として、オキシコドン塩酸塩水和物の含量、ｐＨ、類縁物質の総数及び類縁物質の総量について、下記試験方法により測定した。 Although the composition of the present invention was developed as a pharmaceutical product in Japan (Japan), the storage stability of the pharmaceutical product specified by the Ministry of Health, Labor and Welfare clears the permissible standards at the same level as other oxycodone immediate release preparations. There is a need to. Therefore, various tests relating to the storage stability of the composition of the present invention have been conducted, and the results are shown below.
Test Example (3): Stability evaluation test The liquid composition of Formulations G, H and I shown in Table 7 (oxycodone hydrochloride concentration 4.0 mg / mL) was produced in the same manner as in Example 1. The liquid composition of each formulation was subjected to a stability evaluation test under the conditions of storage at 80 ° C. and storage at 25 ° C. (corresponding to 5.5 years). As evaluation items, the content, pH, total number of related substances and total amount of related substances were measured by the following test method.
試験例（３）：安定性評価試験
表７に示す処方Ｇ、Ｈ及びＩの液剤組成物（オキシコドン塩酸塩濃度４．０ｍｇ／ｍＬ）を実施例１と同様に製造した。各処方の液剤組成物について、８０℃保存、６日間（２５℃保存、５．５年に相当）の条件で安定性評価試験を行った。評価項目として、オキシコドン塩酸塩水和物の含量、ｐＨ、類縁物質の総数及び類縁物質の総量について、下記試験方法により測定した。 Although the composition of the present invention was developed as a pharmaceutical product in Japan (Japan), the storage stability of the pharmaceutical product specified by the Ministry of Health, Labor and Welfare clears the permissible standards at the same level as other oxycodone immediate release preparations. There is a need to. Therefore, various tests relating to the storage stability of the composition of the present invention have been conducted, and the results are shown below.
Test Example (3): Stability evaluation test The liquid composition of Formulations G, H and I shown in Table 7 (oxycodone hydrochloride concentration 4.0 mg / mL) was produced in the same manner as in Example 1. The liquid composition of each formulation was subjected to a stability evaluation test under the conditions of storage at 80 ° C. and storage at 25 ° C. (corresponding to 5.5 years). As evaluation items, the content, pH, total number of related substances and total amount of related substances were measured by the following test method.
〔オキシコドン塩酸塩含量の測定方法〕
高速液体クロマトグラフィー（内部標準法、アイソクラティック条件）により測定した。オキシコドン塩酸塩含量については、各処方の液剤組成物中の開始時のオキシコドン塩酸塩に対する安定性試験後のオキシコドン塩酸塩の割合（％）で示した。 [Measurement method of oxycodone hydrochloride content]
Measured by high performance liquid chromatography (internal standard method, isocratic conditions). The oxycodone hydrochloride content is shown as the percentage of oxycodone hydrochloride after the stability test to the starting oxycodone hydrochloride in the liquid composition of each formulation.
高速液体クロマトグラフィー（内部標準法、アイソクラティック条件）により測定した。オキシコドン塩酸塩含量については、各処方の液剤組成物中の開始時のオキシコドン塩酸塩に対する安定性試験後のオキシコドン塩酸塩の割合（％）で示した。 [Measurement method of oxycodone hydrochloride content]
Measured by high performance liquid chromatography (internal standard method, isocratic conditions). The oxycodone hydrochloride content is shown as the percentage of oxycodone hydrochloride after the stability test to the starting oxycodone hydrochloride in the liquid composition of each formulation.
〔類縁物質の総量及び類縁物質の個数の測定方法〕
類縁物質の量は高速液体クロマトグラフィー（絶対検量線法、グラジエント条件）により測定した。各類縁物質の量は試料溶液のクロマトグラムのピーク面積を標準溶液のオキシコドンのピーク面積と比較して算出した。なお、標準溶液は試料溶液を1２５倍に希釈したものを用いた。類縁物質総量は、液剤組成物中のオキシコドン塩酸塩の量に対する各類縁物質の量の割合（％）で示した各類縁物質の量の和を算出し、液剤組成物中のオキシコドン塩酸塩の量に対する全類縁物質の量の割合（％）として示した。なお、後述する試験例（４）～（７）において算出する各類縁物質の含量も、同様に、液剤組成物中のオキシコドン塩酸塩の量に対する各類縁物質の量の割合（％）として示した。さらに、各試料溶液のクロマトグラムにおいて検出された類縁物質のピークの数を計測して、類縁物質総数とした。 [Measuring method of total amount of related substances and number of related substances]
The amount of related substances was measured by high performance liquid chromatography (absolute calibration curve method, gradient condition). The amount of each related substance was calculated by comparing the peak area of the chromatogram of the sample solution with the peak area of oxycodone of the standard solution. The standard solution used was a sample solution diluted 125-fold. The total amount of related substances is calculated by calculating the sum of the amounts of each related substance as the ratio (%) of the amount of each related substance to the amount of oxycodon hydrochloride in the liquid preparation composition, and the amount of oxycodon hydrochloride in the liquid preparation composition. It is shown as the ratio (%) of the amount of all related substances to. The content of each related substance calculated in Test Examples (4) to (7) described later is also shown as the ratio (%) of the amount of each related substance to the amount of oxycodone hydrochloride in the liquid preparation composition. .. Furthermore, the number of peaks of related substances detected in the chromatogram of each sample solution was measured and used as the total number of related substances.
類縁物質の量は高速液体クロマトグラフィー（絶対検量線法、グラジエント条件）により測定した。各類縁物質の量は試料溶液のクロマトグラムのピーク面積を標準溶液のオキシコドンのピーク面積と比較して算出した。なお、標準溶液は試料溶液を1２５倍に希釈したものを用いた。類縁物質総量は、液剤組成物中のオキシコドン塩酸塩の量に対する各類縁物質の量の割合（％）で示した各類縁物質の量の和を算出し、液剤組成物中のオキシコドン塩酸塩の量に対する全類縁物質の量の割合（％）として示した。なお、後述する試験例（４）～（７）において算出する各類縁物質の含量も、同様に、液剤組成物中のオキシコドン塩酸塩の量に対する各類縁物質の量の割合（％）として示した。さらに、各試料溶液のクロマトグラムにおいて検出された類縁物質のピークの数を計測して、類縁物質総数とした。 [Measuring method of total amount of related substances and number of related substances]
The amount of related substances was measured by high performance liquid chromatography (absolute calibration curve method, gradient condition). The amount of each related substance was calculated by comparing the peak area of the chromatogram of the sample solution with the peak area of oxycodone of the standard solution. The standard solution used was a sample solution diluted 125-fold. The total amount of related substances is calculated by calculating the sum of the amounts of each related substance as the ratio (%) of the amount of each related substance to the amount of oxycodon hydrochloride in the liquid preparation composition, and the amount of oxycodon hydrochloride in the liquid preparation composition. It is shown as the ratio (%) of the amount of all related substances to. The content of each related substance calculated in Test Examples (4) to (7) described later is also shown as the ratio (%) of the amount of each related substance to the amount of oxycodone hydrochloride in the liquid preparation composition. .. Furthermore, the number of peaks of related substances detected in the chromatogram of each sample solution was measured and used as the total number of related substances.
結果の一例として、表９にオキシコドン塩酸塩水和物の含量及びｐＨを示し、表１０に類縁物質総数及び類縁物質総量を示す。
As an example of the results, Table 9 shows the content and pH of oxycodone hydrochloride hydrate, and Table 10 shows the total number of related substances and the total amount of related substances.
表８及び９から明らかなように、本発明液剤組成物（処方Ｈ及びＩ）は、安定性評価試験においてｐＨが安定しており、オキシコドン塩酸塩水和物の含量低下と、類縁物質総数及び類縁物質総量の増加、の両方が抑えられていることが示された。
As is clear from Tables 8 and 9, the liquid composition of the present invention (formulations H and I) has a stable pH in the stability evaluation test, the content of oxycodone hydrochloride hydrate decreases, and the total number of related substances and related substances are related. It was shown that both the increase in the total amount of material was suppressed.
試験例（４）：苛酷試験
表１に示した処方１、処方２、処方３及び処方４の液剤組成物について、６０℃、２ヶ月（６０℃保存１ヶ月は２５℃保存４．２年に相当）の条件で苛酷試験を行い、各類縁物質含量及び類縁物質総量を試験例（３）と同様に測定した。結果の一例を表１０に示す。表１０において、各類縁物質含量の欄の１つのカラムに複数の数値が記載されているのは、別種類の複数の類縁物質が検出されたことを示し、例えば、１つのカラムに３個の類縁物質含量の記載がある場合は、３種類の類縁物質が検出されたことを示す。後述する表１１及び１２においても同様である。 Test Example (4): Severe Tests The liquid composition of Formulation 1, Formulation 2, Formulation 3 and Formulation 4 shown in Table 1 was stored at 60 ° C. for 2 months (1 month storage at 60 ° C. was stored at 25 ° C. for 4.2 years). A harsh test was carried out under the conditions of (equivalent), and the content of each related substance and the total amount of related substances were measured in the same manner as in Test Example (3). An example of the results is shown in Table 10. In Table 10, a plurality of numerical values listed in one column of each related substance content column indicates that a plurality of related substances of different types were detected, for example, three in one column. When there is a description of the related substance content, it indicates that three kinds of related substances have been detected. The same applies to Tables 11 and 12 described later.
表１に示した処方１、処方２、処方３及び処方４の液剤組成物について、６０℃、２ヶ月（６０℃保存１ヶ月は２５℃保存４．２年に相当）の条件で苛酷試験を行い、各類縁物質含量及び類縁物質総量を試験例（３）と同様に測定した。結果の一例を表１０に示す。表１０において、各類縁物質含量の欄の１つのカラムに複数の数値が記載されているのは、別種類の複数の類縁物質が検出されたことを示し、例えば、１つのカラムに３個の類縁物質含量の記載がある場合は、３種類の類縁物質が検出されたことを示す。後述する表１１及び１２においても同様である。 Test Example (4): Severe Tests The liquid composition of Formulation 1, Formulation 2, Formulation 3 and Formulation 4 shown in Table 1 was stored at 60 ° C. for 2 months (1 month storage at 60 ° C. was stored at 25 ° C. for 4.2 years). A harsh test was carried out under the conditions of (equivalent), and the content of each related substance and the total amount of related substances were measured in the same manner as in Test Example (3). An example of the results is shown in Table 10. In Table 10, a plurality of numerical values listed in one column of each related substance content column indicates that a plurality of related substances of different types were detected, for example, three in one column. When there is a description of the related substance content, it indicates that three kinds of related substances have been detected. The same applies to Tables 11 and 12 described later.
表１０から明らかなように、処方１、処方２、処方３及び処方４の液剤組成物は、上記苛酷試験において、類縁物質の生成が抑えられ、その結果、類縁物質の数、各類縁物質含量及び類縁物質総量のいずれもが抑えられていることが示された。
As is clear from Table 10, the liquid composition of Formulation 1, Formulation 2, Formulation 3 and Formulation 4 suppressed the production of related substances in the above-mentioned severe test, and as a result, the number of related substances and the content of each related substance. It was shown that both the total amount of related substances and the total amount of related substances were suppressed.
試験例（５）：加速試験
表１に示した処方１、処方２、処方３及び処方４の液剤組成物について、４０℃、７５％ＲＨ、１０ヶ月の加速試験を行い、各類縁物質含量及び類縁物質総量を試験例（３）と同様に測定した。結果の一例を表１１に示す。 Test Example (5): Accelerated test The liquid composition of Formulation 1, Formulation 2, Formulation 3 and Formulation 4 shown in Table 1 was subjected to an accelerated test at 40 ° C., 75% RH, and 10 months, and each related substance content and The total amount of related substances was measured in the same manner as in Test Example (3). An example of the results is shown in Table 11.
表１に示した処方１、処方２、処方３及び処方４の液剤組成物について、４０℃、７５％ＲＨ、１０ヶ月の加速試験を行い、各類縁物質含量及び類縁物質総量を試験例（３）と同様に測定した。結果の一例を表１１に示す。 Test Example (5): Accelerated test The liquid composition of Formulation 1, Formulation 2, Formulation 3 and Formulation 4 shown in Table 1 was subjected to an accelerated test at 40 ° C., 75% RH, and 10 months, and each related substance content and The total amount of related substances was measured in the same manner as in Test Example (3). An example of the results is shown in Table 11.
表１１から明らかなように、処方１、処方２、処方３及び処方４の液剤組成物は、上記加速試験において、類縁物質の生成が抑えられ、その結果、類縁物質の数、各類縁物質含量及び類縁物質総量のいずれもが抑えられていることが示された。
As is clear from Table 11, the liquid composition of Formulation 1, Formulation 2, Formulation 3 and Formulation 4 suppressed the production of related substances in the above accelerated test, and as a result, the number of related substances and the content of each related substance. It was shown that both the total amount of related substances and the total amount of related substances were suppressed.
試験例（６）：長期保存試験
表１に示した処方１、処方２、処方３及び処方４の液剤組成物について、２５℃、６０％ＲＨ、３６ヶ月の条件で長期保存試験を行い、各類縁物質含量及び類縁物質総量を試験例（３）と同様に測定した。結果の一例を表１２に示す。 Test Example (6): Long-term storage test The liquid composition of Formulation 1, Formulation 2, Formulation 3 and Formulation 4 shown in Table 1 was subjected to a long-term storage test under the conditions of 25 ° C., 60% RH and 36 months, and each of them was subjected to a long-term storage test. The content of related substances and the total amount of related substances were measured in the same manner as in Test Example (3). An example of the results is shown in Table 12.
表１に示した処方１、処方２、処方３及び処方４の液剤組成物について、２５℃、６０％ＲＨ、３６ヶ月の条件で長期保存試験を行い、各類縁物質含量及び類縁物質総量を試験例（３）と同様に測定した。結果の一例を表１２に示す。 Test Example (6): Long-term storage test The liquid composition of Formulation 1, Formulation 2, Formulation 3 and Formulation 4 shown in Table 1 was subjected to a long-term storage test under the conditions of 25 ° C., 60% RH and 36 months, and each of them was subjected to a long-term storage test. The content of related substances and the total amount of related substances were measured in the same manner as in Test Example (3). An example of the results is shown in Table 12.
表１２から明らかなように、処方１、処方２、処方３及び処方４の液剤組成物は、上記長期保存試験において、類縁物質の生成が抑えられ、その結果、類縁物質の数、各類縁物質含量及び類縁物質総量のいずれもが抑えられていることが示された。
As is clear from Table 12, the liquid composition of Formulation 1, Formulation 2, Formulation 3 and Formulation 4 suppresses the production of related substances in the above-mentioned long-term storage test, and as a result, the number of related substances and each related substance are suppressed. It was shown that both the content and the total amount of related substances were suppressed.
試験例（７）：安定性評価試験
表１３に示す処方５～１６の液剤組成物（オキシコドン塩酸塩濃度４．０ｍｇ／ｍＬ）を実施例１と同様に製造した。各処方の液剤組成物について、８０℃保存、６日間（２５℃保存、５．５年に相当）の条件で安定性評価試験を行い、類縁物質総数及び類縁物質の総量を試験例（３）と同様に測定した。結果の一例を表１４に示す。 Test Example (7): Stability evaluation test The liquid composition of Formulations 5 to 16 shown in Table 13 (oxycodone hydrochloride concentration 4.0 mg / mL) was produced in the same manner as in Example 1. A stability evaluation test was conducted on the liquid composition of each formulation under the conditions of storage at 80 ° C. for 6 days (equivalent to storage at 25 ° C. for 5.5 years), and the total number of related substances and the total amount of related substances were determined in Test Example (3). It was measured in the same manner as. An example of the results is shown in Table 14.
表１３に示す処方５～１６の液剤組成物（オキシコドン塩酸塩濃度４．０ｍｇ／ｍＬ）を実施例１と同様に製造した。各処方の液剤組成物について、８０℃保存、６日間（２５℃保存、５．５年に相当）の条件で安定性評価試験を行い、類縁物質総数及び類縁物質の総量を試験例（３）と同様に測定した。結果の一例を表１４に示す。 Test Example (7): Stability evaluation test The liquid composition of Formulations 5 to 16 shown in Table 13 (oxycodone hydrochloride concentration 4.0 mg / mL) was produced in the same manner as in Example 1. A stability evaluation test was conducted on the liquid composition of each formulation under the conditions of storage at 80 ° C. for 6 days (equivalent to storage at 25 ° C. for 5.5 years), and the total number of related substances and the total amount of related substances were determined in Test Example (3). It was measured in the same manner as. An example of the results is shown in Table 14.
表１４から明らかなように、上記安定性評価試験において、液剤組成物の所定範囲内のｐＨの上昇に依存して、類縁物質の生成が抑えられ、その結果、類縁物質の数、各類縁物質含量及び類縁物質総量のいずれもが抑えられていることが示された。
As is clear from Table 14, in the above stability evaluation test, the formation of related substances was suppressed depending on the increase in pH within the predetermined range of the liquid preparation composition, and as a result, the number of related substances and each related substance were suppressed. It was shown that both the content and the total amount of related substances were suppressed.
試験例（８）：味認識装置による苦味マスキングの評価
味認識装置（ＴＳ－５０００Ｚ、株式会社インテリジェントセンサーテクノロジー社製）の味覚センサーを用いて、ＣＰＡ（Ｃｈａｎｇｅ ｏｆ ｍｅｍｂｒａｎｅ Ｐｏｔｅｎｔｉａｌ ｃａｕｓｅｄ ｂｙ Ａｄｓｏｒｐｔｉｏｎ）測定法により苦味マスキング効果に対するｐＨの影響について評価した。
味覚センサーは、呈味物質と静電相互作用や疎水性相互作用することにより生じた脂質膜の膜電位の変化をセンサー出力として検知する。味覚センサーを用いた苦味の測定方法の一例は以下の通りである。最初に、味覚センサーを基準液と呼ばれる溶液に浸して、膜電位Ｖｒを得る。次に、被験液を味覚センサーに浸して、膜電位Ｖｓを得る。ここで得られる膜電位変化（Ｖｓ－Ｖｒ）は１番目のセンサー出力「相対値」と呼ばれ、酸味や塩味などの先味に相当する。その後、味覚センサーを基準液で共洗いした後、再度、基準液に味覚センサーを浸して、膜電位Ｖｒ’を得る。ここで得られる膜電位変化（Ｖｒ’－Ｖｒ）は２番目のセンサー出力「ＣＰＡ値」と呼ばれ、苦味や渋味などの後味に相当する。 Test Example (8): Evaluation of Bitter Taste Masking by Taste Recognition Device Using the taste sensor of the taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.), CPA (Change of measurement Potential caused by Addition). ) The effect of pH on the bitter taste masking effect was evaluated by the measurement method.
The taste sensor detects a change in the membrane potential of the lipid membrane caused by electrostatic interaction or hydrophobic interaction with the taste substance as a sensor output. An example of a method for measuring bitterness using a taste sensor is as follows. First, the taste sensor is immersed in a solution called a reference solution to obtain a membrane potential Vr. Next, the test solution is immersed in the taste sensor to obtain the membrane potential Vs. The membrane potential change (Vs-Vr) obtained here is called the first sensor output "relative value" and corresponds to the pre-taste such as acidity and saltiness. Then, after co-washing the taste sensor with the reference liquid, the taste sensor is immersed in the reference liquid again to obtain the membrane potential Vr'. The membrane potential change (Vr'-Vr) obtained here is called the second sensor output "CPA value" and corresponds to the aftertaste such as bitterness and astringency.
味認識装置（ＴＳ－５０００Ｚ、株式会社インテリジェントセンサーテクノロジー社製）の味覚センサーを用いて、ＣＰＡ（Ｃｈａｎｇｅ ｏｆ ｍｅｍｂｒａｎｅ Ｐｏｔｅｎｔｉａｌ ｃａｕｓｅｄ ｂｙ Ａｄｓｏｒｐｔｉｏｎ）測定法により苦味マスキング効果に対するｐＨの影響について評価した。
味覚センサーは、呈味物質と静電相互作用や疎水性相互作用することにより生じた脂質膜の膜電位の変化をセンサー出力として検知する。味覚センサーを用いた苦味の測定方法の一例は以下の通りである。最初に、味覚センサーを基準液と呼ばれる溶液に浸して、膜電位Ｖｒを得る。次に、被験液を味覚センサーに浸して、膜電位Ｖｓを得る。ここで得られる膜電位変化（Ｖｓ－Ｖｒ）は１番目のセンサー出力「相対値」と呼ばれ、酸味や塩味などの先味に相当する。その後、味覚センサーを基準液で共洗いした後、再度、基準液に味覚センサーを浸して、膜電位Ｖｒ’を得る。ここで得られる膜電位変化（Ｖｒ’－Ｖｒ）は２番目のセンサー出力「ＣＰＡ値」と呼ばれ、苦味や渋味などの後味に相当する。 Test Example (8): Evaluation of Bitter Taste Masking by Taste Recognition Device Using the taste sensor of the taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.), CPA (Change of measurement Potential caused by Addition). ) The effect of pH on the bitter taste masking effect was evaluated by the measurement method.
The taste sensor detects a change in the membrane potential of the lipid membrane caused by electrostatic interaction or hydrophobic interaction with the taste substance as a sensor output. An example of a method for measuring bitterness using a taste sensor is as follows. First, the taste sensor is immersed in a solution called a reference solution to obtain a membrane potential Vr. Next, the test solution is immersed in the taste sensor to obtain the membrane potential Vs. The membrane potential change (Vs-Vr) obtained here is called the first sensor output "relative value" and corresponds to the pre-taste such as acidity and saltiness. Then, after co-washing the taste sensor with the reference liquid, the taste sensor is immersed in the reference liquid again to obtain the membrane potential Vr'. The membrane potential change (Vr'-Vr) obtained here is called the second sensor output "CPA value" and corresponds to the aftertaste such as bitterness and astringency.
しかし、オキシコドン塩酸塩のＣＰＡ値は測定が困難であるため、ＣＰＡ値の測定が可能である苦味標準物質（キニーネ硫酸塩）を用いて、オキシコドン塩酸塩を含有する液剤組成物のＣＰＡ値を推定した。すなわち、まず、オキシコドン塩酸塩及びキニーネ硫酸塩の相対値を測定し、両者の相対値から、同等の苦みを呈すると推定される両者の濃度を決定した。その結果より、所望の濃度のオキシコドン塩酸塩と同等の苦味を呈すると推定される濃度のキニーネ硫酸塩を含有する処方について、ＣＰＡ値を測定して苦味の推定値を算出した。
However, since it is difficult to measure the CPA value of oxycodone hydrochloride, the CPA value of the liquid composition containing oxycodone hydrochloride is estimated using a bitter taste standard substance (quinine sulfate) that can measure the CPA value. did. That is, first, the relative values of oxycodone hydrochloride and quinine sulfate were measured, and the concentrations of both presumed to exhibit the same bitterness were determined from the relative values of both. From the results, the CPA value was measured and the estimated bitterness was calculated for the formulation containing the quinine sulfate at the concentration estimated to exhibit the same bitterness as the desired concentration of oxycodone hydrochloride.
（１）オキシコドン塩酸塩及びキニーネ硫酸塩の相対値の測定
味認識装置（ＴＳ－５０００Ｚ、株式会社インテリジェントセンサーテクノロジー社製）の苦味センサー（ＢＴ０センサー）を用いて、オキシコドン塩酸塩及びキニーネ硫酸塩の相対値（ｍＶ）を測定した。両者の相対値の結果から、表１５に示すとおり、１．０ｍｇ／ｍＬ、２．０ｍｇ／ｍＬ及び４．０ｍｇ／ｍＬのオキシコドン塩酸塩と同等の苦味を呈するキニーネ硫酸塩二水和物の濃度は、各々、０．０３７ｍｇ／ｍＬ、０．０５８ｍｇ／ｍＬ及び０．０９４ｍｇ／ｍＬであることが確認された。 (1) Measurement of relative values of oxycodon hydrochloride and quinine sulfate Using the bitterness sensor (BT0 sensor) of the taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.), oxycodon hydrochloride and quinine sulfate The relative value (mV) was measured. From the results of the relative values of the two, as shown in Table 15, the concentrations of quinine sulfate dihydrate having a bitter taste equivalent to that of oxycodone hydrochloride of 1.0 mg / mL, 2.0 mg / mL and 4.0 mg / mL. Were confirmed to be 0.037 mg / mL, 0.058 mg / mL and 0.094 mg / mL, respectively.
味認識装置（ＴＳ－５０００Ｚ、株式会社インテリジェントセンサーテクノロジー社製）の苦味センサー（ＢＴ０センサー）を用いて、オキシコドン塩酸塩及びキニーネ硫酸塩の相対値（ｍＶ）を測定した。両者の相対値の結果から、表１５に示すとおり、１．０ｍｇ／ｍＬ、２．０ｍｇ／ｍＬ及び４．０ｍｇ／ｍＬのオキシコドン塩酸塩と同等の苦味を呈するキニーネ硫酸塩二水和物の濃度は、各々、０．０３７ｍｇ／ｍＬ、０．０５８ｍｇ／ｍＬ及び０．０９４ｍｇ／ｍＬであることが確認された。 (1) Measurement of relative values of oxycodon hydrochloride and quinine sulfate Using the bitterness sensor (BT0 sensor) of the taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.), oxycodon hydrochloride and quinine sulfate The relative value (mV) was measured. From the results of the relative values of the two, as shown in Table 15, the concentrations of quinine sulfate dihydrate having a bitter taste equivalent to that of oxycodone hydrochloride of 1.0 mg / mL, 2.0 mg / mL and 4.0 mg / mL. Were confirmed to be 0.037 mg / mL, 0.058 mg / mL and 0.094 mg / mL, respectively.
（２）各処方のＣＰＡ値の測定
上記（１）の結果より、４．０ｍｇ／ｍＬのオキシコドン塩酸塩と同等の苦味を呈するとされたキニーネ硫酸塩二水和物０．０９４ｍｇ／ｍＬを含有する表１６の処方Ｘ～Ｚについて、味認識装置（ＴＳ－５０００Ｚ、株式会社インテリジェントセンサーテクノロジー社製）の苦味センサー（ＢＴ０センサー）を用いて、それぞれの液剤組成物のＣＰＡ値（ｍＶ）を測定し、苦味の推定値（ＣＰＡ値×０．３）を算出した。結果の一例を表１７に示す。 (2) Measurement of CPA value of each formulation Contains 0.094 mg / mL of quinine sulfate dihydrate, which is said to exhibit a bitter taste equivalent to 4.0 mg / mL of oxycodone hydrochloride based on the results of (1) above. For the formulations X to Z in Table 16, the CPA value (mV) of each liquid preparation composition was measured using the bitterness sensor (BT0 sensor) of the taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.). Then, the estimated value of bitterness (CPA value × 0.3) was calculated. An example of the results is shown in Table 17.
上記（１）の結果より、４．０ｍｇ／ｍＬのオキシコドン塩酸塩と同等の苦味を呈するとされたキニーネ硫酸塩二水和物０．０９４ｍｇ／ｍＬを含有する表１６の処方Ｘ～Ｚについて、味認識装置（ＴＳ－５０００Ｚ、株式会社インテリジェントセンサーテクノロジー社製）の苦味センサー（ＢＴ０センサー）を用いて、それぞれの液剤組成物のＣＰＡ値（ｍＶ）を測定し、苦味の推定値（ＣＰＡ値×０．３）を算出した。結果の一例を表１７に示す。 (2) Measurement of CPA value of each formulation Contains 0.094 mg / mL of quinine sulfate dihydrate, which is said to exhibit a bitter taste equivalent to 4.0 mg / mL of oxycodone hydrochloride based on the results of (1) above. For the formulations X to Z in Table 16, the CPA value (mV) of each liquid preparation composition was measured using the bitterness sensor (BT0 sensor) of the taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.). Then, the estimated value of bitterness (CPA value × 0.3) was calculated. An example of the results is shown in Table 17.
表１７から明らかなように、上記苦味センサーでのマスキング評価試験において、液剤組成物のｐＨの低下に依存して、苦味のマスキング効果が高まることが示された。なお、本苦味センサーでのマスキング評価試験の結果については、別途実施した官能試験の結果との相関性が確認された。
As is clear from Table 17, in the masking evaluation test using the bitterness sensor, it was shown that the bitterness masking effect was enhanced depending on the decrease in pH of the liquid preparation composition. The results of the masking evaluation test with this bitterness sensor were confirmed to correlate with the results of the sensory test conducted separately.
上述したとおり、オキシコドン、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する本発明液剤組成物は、添加剤として、アセスルファムカリウム、キシリトール、Ｄ-ソルビトール、又はＬ-グルタミン酸の中から選ばれる少なくとも３種の添加剤を含有させることにより苦味が適切にマスキングされる。また、本発明液剤組成物のｐＨを３．３～４．８の範囲に調整にすることにより、類縁物質の生成が抑えられ、安定性が担保される。このような本発明液剤組成物は、各種がん患者の疼痛治療剤として、有用性が高いものである。
As described above, the liquid composition of the present invention containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient can be used as an additive in acesulfame potassium, xylitol, D-sorbitol, or L-. The bitterness is appropriately masked by containing at least three additives selected from glutamic acid. Further, by adjusting the pH of the liquid preparation composition of the present invention to the range of 3.3 to 4.8, the formation of related substances is suppressed and the stability is ensured. Such a liquid composition of the present invention is highly useful as a pain remedy for various cancer patients.
Claims (13)
- オキシコドン、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する液剤組成物であって、該有効成分の苦味がマスキングされていることを特徴とする液剤組成物。 A liquid composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, wherein the bitterness of the active ingredient is masked.
- 添加剤として、アセスルファムカリウム、キシリトール、Ｄ-ソルビトール、又はＬ-グルタミン酸の中から選ばれる少なくとも３種が含有されている請求項１に記載の液剤組成物。 The liquid composition according to claim 1, which contains at least three kinds selected from acesulfame potassium, xylitol, D-sorbitol, and L-glutamic acid as additives.
- 添加剤として、さらにクエン酸水和物及び／又はクエン酸ナトリウム水和物が含有されている請求項２に記載の液剤組成物。 The liquid composition according to claim 2, further containing citric acid hydrate and / or sodium citrate hydrate as an additive.
- 添加剤として、さらに安息香酸ナトリウム及び／又はパラオキシ安息香酸エチルが含有されている請求項２又は３に記載の液剤組成物。 The liquid composition according to claim 2 or 3, further containing sodium benzoate and / or ethyl paraoxybenzoate as an additive.
- 添加剤として、さらに塩化ナトリウムが含有されている請求項２～４のいずれか一項に記載の液剤組成物。 The liquid composition according to any one of claims 2 to 4, further containing sodium chloride as an additive.
- 添加剤として、さらにプロピレングリコールが含有されている請求項２～５のいずれか一項に記載の液剤組成物。 The liquid composition according to any one of claims 2 to 5, further containing propylene glycol as an additive.
- ｐＨが３．３～４．８である請求項１～６のいずれか一項に記載の液剤組成物。 The liquid composition according to any one of claims 1 to 6, which has a pH of 3.3 to 4.8.
- 前記有効成分からの経時的な類縁物質の生成が、日本国厚生労働省が定める医薬品の安定性試験を実施した場合、許容される規準以下に抑制された請求項１～７のいずれか一項に記載の液剤組成物。 According to any one of claims 1 to 7, the production of related substances from the active ingredient over time is suppressed to be below the permissible standard when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out. The liquid composition according to the above.
- 日本国厚生労働省が定める医薬品の安定性試験を実施した場合における前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.２％以下である請求項８に記載の液剤組成物。 The liquid composition according to claim 8, wherein the ratio of the amount of each related substance to the amount of the active ingredient when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.2% or less, respectively.
- 日本国厚生労働省が定める医薬品の安定性試験を実施した場合における前記有効成分の量に対する類縁物質の総量の割合が０.６％以下である請求項８又は９に記載の液剤組成物。 The liquid composition according to claim 8 or 9, wherein the ratio of the total amount of related substances to the amount of the active ingredient when the stability test of the drug specified by the Ministry of Health, Labor and Welfare of Japan is carried out is 0.6% or less.
- オキシコドン、その薬学的に許容される塩、又はそれらの水和物を有効成分として含有する液剤組成物のｐＨを３．３～４．８に調整することで、該液剤組成物中の類縁物質の生成を抑制することを特徴とする、該液剤組成物の安定化方法。 By adjusting the pH of a liquid preparation composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient to 3.3 to 4.8, an analog substance in the liquid preparation composition. A method for stabilizing a liquid preparation composition, which comprises suppressing the formation of a liquid preparation.
- 前記有効成分の量に対する個々の類縁物質の量の割合が、それぞれ０.２％以下である請求項１１に記載の安定化方法。 The stabilization method according to claim 11, wherein the ratio of the amount of each related substance to the amount of the active ingredient is 0.2% or less, respectively.
- 前記有効成分の量に対する類縁物質の総量の割合が、０.６％以下である請求項１１又は１２に記載の安定化方法。 The stabilization method according to claim 11 or 12, wherein the ratio of the total amount of related substances to the amount of the active ingredient is 0.6% or less.
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| CN202180059438.5A CN116133643A (en) | 2020-07-30 | 2021-07-29 | Liquid composition |
| JP2022539558A JPWO2022025176A1 (en) | 2020-07-30 | 2021-07-29 | |
| KR1020227042258A KR20230044359A (en) | 2020-07-30 | 2021-07-29 | liquid composition |
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| JP (1) | JPWO2022025176A1 (en) |
| KR (1) | KR20230044359A (en) |
| CN (1) | CN116133643A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000204036A (en) * | 1998-11-11 | 2000-07-25 | Dainippon Pharmaceut Co Ltd | Glutamic salt-containing liquid preparation |
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| JP2016121073A (en) | 2014-12-24 | 2016-07-07 | ニプロ株式会社 | Method for producing pharmaceutical composition for an injection |
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- 2021-07-29 CN CN202180059438.5A patent/CN116133643A/en not_active Withdrawn
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| JP2000204036A (en) * | 1998-11-11 | 2000-07-25 | Dainippon Pharmaceut Co Ltd | Glutamic salt-containing liquid preparation |
Non-Patent Citations (8)
| Title |
|---|
| "Oxycodone Hydrochloride Oral Solution", REVISION BULLETIN, 1 February 2015 (2015-02-01), XP055905380, Retrieved from the Internet <URL:https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/oxycodone_hcl_os.pdf> * |
| "Oxycodone Injection 10mg, Oxycodone Injection 50mg", DAIICHI SANKYO' PACKAGE INSERT, February 2020 (2020-02-01) * |
| AUROLIFE PHARMA, LLC: "OXYCODONE HYDROCHLORIDE ORAL SOLUTION - oxycodone hydrochloride oral solution", December 2019 (2019-12-01) * |
| LANNETT COMPANY, INC.: "OXYCODONE HYDROCHLORIDE - oxycodone hydrochloride solution", January 2015 (2015-01-01) * |
| LOYD, V. ALLEN, JR., PHD: "Oxycodone Hydrochloride 1 mg/mL Oral Liquid", US PHARMACIST, vol. 36, no. 10, 19 October 2011 (2011-10-19), pages 37 - 38, Retrieved from the Internet <URL:https://www.uspharmacist.com/article/oxycodone-hydrochloride-1-mgml-oral-liquid> * |
| NARABAYASHI, MASARU: "Oxycodone, a medicine for immediate-release in cancer pain", 11 January 2007 (2007-01-11), Retrieved from the Internet <URL:http://medical.radionikkei.jp/suzuken/final/070111html/index.html> [retrieved on 20210906] * |
| NIPPON-ZOKI: "Oxycodone Oral Solution 2.5mg, Oxycodone Oral Solution 5mg, Oxycodone Oral Solution 10mg, Oxycodone Oral Solution 20mg", PACKAGE INSERT * |
| TURNBULL, KATHY ET AL.: "Stability of Oxycodone Hydrochloride for Injection in Dextrose and Saline Solutions", CAN. J. HOSP. PHARM, vol. 55, September 2002 (2002-09-01), pages 272 - 277, XP055905394 * |
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| JPWO2022025176A1 (en) | 2022-02-03 |
| KR20230044359A (en) | 2023-04-04 |
| CN116133643A (en) | 2023-05-16 |
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