阅读说明：本技术 一种氟比洛芬注射液与容器的组合 (Combination of flurbiprofen injection and container ) 是由 林静文 其他发明人请求不公开姓名 于 2019-04-30 设计创作，主要内容包括：本发明提供一种氟比洛芬注射液与容器的组合。其中,容器的材料为可药品包装用高分子材料,优选的容器材料包括聚丙烯、环烯烃聚合物和多层共挤膜。本发明提供的组合能够避免多种处方下氟比洛芬注射液中有效成分氟比洛芬的降解以及其他组分在灭菌或储存中含量的过度损失。(The invention provides a combination of flurbiprofen injection and a container. The material of the container is a high polymer material for medicine packaging, and the preferable material of the container comprises polypropylene, cyclic olefin polymer and a multilayer co-extrusion film. The combination provided by the invention can avoid the degradation of the effective ingredient flurbiprofen in the flurbiprofen injection under various prescriptions and the excessive loss of the content of other components in the flurbiprofen injection during sterilization or storage.)

1. The combination of the flurbiprofen injection and the container is characterized in that the material of the container is a polymer material capable of being used for medicine packaging.

2. The flurbiprofen injection in combination with a container as claimed in claim 1, wherein the container is made of polypropylene.

3. The flurbiprofen injection solution in combination with a container as claimed in claim 1, wherein the material of the container is a cyclic olefin polymer.

4. The flurbiprofen injection solution in combination with a container as claimed in claim 1, wherein the container is made of a multi-layer co-extruded film.

5. The flurbiprofen injection in combination with a container according to claim 1, wherein the flurbiprofen injection contains flurbiprofen and water for injection.

6. The flurbiprofen injection in combination with a container according to claim 5, wherein the flurbiprofen injection further comprises an amino acid, an aminopolyol, a phosphate, or a combination thereof.

7. The flurbiprofen injection in combination with a container according to claim 1, wherein the container has closure means for storing the pharmaceutical composition.

8. The flurbiprofen injection-container combination according to claim 1, wherein the flurbiprofen is selected from the group consisting of (RS) -flurbiprofen or its derivatives, R-flurbiprofen or its derivatives, S-flurbiprofen or its derivatives, and R-flurbiprofen or its derivatives in any ratio with S-flurbiprofen or its derivatives.

9. The combination of a flurbiprofen injection and a container according to claim 1, wherein the concentration of flurbiprofen in the flurbiprofen injection is 0.1 to 50mg/ml, preferably 0.25 to 10 mg/ml.

10. The flurbiprofen injection in combination with a container according to claim 1, wherein the container has a volume of 1ml to 250ml, preferably 5ml to 100 ml.

Technical Field

The invention relates to the technical field of medicines, in particular to a stable combination of flurbiprofen injection and a container.

Background

Flurbiprofen, with the chemical name of (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid, is a nonsteroidal antipyretic, anti-inflammatory and analgesic drug, has the action mechanism of inhibiting prostaglandin epoxidase and blocking the biosynthesis of prostaglandin, thereby exerting the curative effect, has stronger anti-inflammatory and analgesic abilities than aspirin and flurbiprofen, has smaller side effects and good tolerance, and is widely used for treating rheumatoid arthritis and other rheumatic diseases.

Due to the property that flurbiprofen is almost insoluble in water, no intravenous flurbiprofen preparation is on the market at present. The flurbiprofen prodrug flurbiprofen axetil is prepared into fat emulsion injection for intravenous injection and is clinically used for postoperative and cancer analgesia. Patent zl201210064288.x provides a pharmaceutical composition aqueous solution of flurbiprofen and basic amino acid.

Generally, the container that is in direct contact with the drug must be pharmaceutically acceptable. Packaging materials and containers that directly contact the pharmaceutical product are an integral part of the pharmaceutical product, along with the entire process of production, distribution and use of the pharmaceutical product. For injection, sterilization is usually required during the preparation process, the high temperature and high pressure environment during the sterilization process may cause degradation of the drug packaging material, the degraded substance may react with the components in the pharmaceutical composition, and the components in the pharmaceutical composition may be excessively adsorbed in the packaging material. In addition, the long-term storage of the drug, the change of external environment such as light and temperature, may also cause the degradation of the components in the packaging material and the adsorption of the components in the drug in the packaging material. No matter what kind of changes, the stability of the preparation is possibly reduced, and potential safety hazards are brought to clinical use.

Disclosure of Invention

The invention provides a combination of flurbiprofen injection and a container; the material of the container is a high polymer material for medicine packaging.

The material of the container is polypropylene (PP), including its homopolymer, one or more copolymers or a combination thereof.

The material of the container is a cyclic olefin polymer, including a homopolymer thereof, one or more copolymers thereof, or a combination thereof. Cyclic olefin polymers include COC and COP.

The container is made of a multi-layer co-extrusion film, namely 5 layers of co-extrusion films or 3 layers of co-extrusion films. The 5 layers of the co-extruded films are respectively ester copolymer/ethylene methacrylate polymer/polyethylene/modified ethylene-propylene polymer from outside to inside, and the 3 layers of the co-extruded films are respectively polypropylene/polypropylene from outside to inside.

The flurbiprofen injection comprises flurbiprofen and water for injection.

The flurbiprofen injection may further comprise an amino acid, an aminopolyol, a phosphate, or a combination thereof.

According to one aspect of the object of the present invention, the present invention provides a combination of a flurbiprofen injection solution and a container, which can prevent the loss of inactive ingredients in the flurbiprofen injection solution, for example, can prevent the loss of amino acids and aminopolyols in a large amount during autoclaving and 24-month storage at room temperature.

In some embodiments of the present invention, the flurbiprofen injection comprises flurbiprofen, an amino acid, and water for injection. The molar ratio of amino acid to flurbiprofen is in the range of 0.1 to 10:1, wherein 0.1 to 10 includes any number between 0.1 and 10, such as 0.1:1, 0.25:1, 0.5:1, 1:1, 2:1, 5:1, 10:1, and the like. Amino acids include, but are not limited to, arginine, lysine, histidine, or combinations thereof, which may be in the L-or D-form.

In another embodiment, the flurbiprofen injection comprises flurbiprofen, aminopolyol and water for injection. The molar ratio of aminopolyol to flurbiprofen is in the range of 0.1 to 10:1, wherein 0.1 to 10 includes any number between 0.1 and 10, such as 0.1:1, 0.25:1, 0.5:1, 1:1, 2:1, 5:1, 10:1, and the like. Wherein the aminopolyols include, but are not limited to, tromethamine, meglumine, methanolamine, monoethanolamine, diethanolamine, propanolamine, alkylenediamines, or combinations thereof; preferably tromethamine and/or meglumine.

In another embodiment, the flurbiprofen injection comprises flurbiprofen, a phosphate salt and water for injection. The molar ratio of phosphate to flurbiprofen is in the range of 0.1 to 10:1, where 0.1 to 10 includes any number between 0.1 and 10, such as 0.1:1, 0.25:1, 0.5:1, 1:1, 2:1, 5:1, 10:1, and the like. Among them, the phosphate includes, but is not limited to, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate or a combination thereof, and is preferably disodium hydrogen phosphate.

According to another aspect of the present invention, there is provided a combination of a flurbiprofen injection solution and a container, which can prevent degradation of flurbiprofen, an effective ingredient of the flurbiprofen injection solution, during autoclaving and long-term storage.

The container has a closure means for storing the pharmaceutical composition.

The flurbiprofen is selected from (RS) -flurbiprofen or derivatives thereof, R-flurbiprofen or derivatives thereof, S-flurbiprofen or derivatives thereof, or a combination of R-flurbiprofen or derivatives thereof and S-flurbiprofen or derivatives thereof in any proportion.

In the flurbiprofen injection, the concentration of flurbiprofen is 0.1-50 mg/ml, the concentration of flurbiprofen can be any concentration value (such as 0.25mg/ml, 0.375mg/ml, 0.5mg/ml, 5mg/ml, 7.5mg/ml and 10mg/ml) in the concentration range and an optional concentration range, and the preferable concentration range is 0.25-10 mg/ml.

The container has a volume in the range of 1ml to 250ml, and the volume may be any volume or an optional volume in the range, with a preferred volume in the range of 5ml to 100 ml.

The structure of the degraded impurity 2-fluorobiphenyl-4-carboxylic acid is shown as follows:

surprisingly, the combination of flurbiprofen injection and container of the present application enables to avoid the loss of inactive ingredients and to maintain the stability of the active ingredient flurbiprofen before and after autoclaving as well as during long-term storage for different formulations of flurbiprofen injection.

Detailed Description