JP6102120B2 - Pharmaceutical preparation and method for producing the same - Google Patents

Description

  The present invention relates to a pharmaceutical preparation and a method for producing the same, and more particularly to a pharmaceutical preparation containing sivelestat and a method for producing the same.

  Cibelestat sodium tetrahydrate (common name: Cibelestat, IUPAC name: N- {2- [4- (2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl} sodium acetate tetrahydrate) is preferred. Known as a neutrophil elastase inhibitor.

  A commercially available sivelestat formulation (Non-patent Document 1) contains a pH adjuster for the purpose of increasing the solubility of sivelestat. Furthermore, in order to increase the solubility of cibelestat and provide a higher concentration solution and a high-content formulation using the solution, trisodium phosphate and its hydrate, sodium hydroxide and potassium hydroxide are selected. A sivelestat formulation obtained by lyophilizing a solution containing at least one pH adjusting agent is known (Patent Document 1).

  However, it is known that such preparations do not have sufficient stability of sivelestat and are decomposed in a relatively short period of time after the preparation is obtained to produce a sivelestat-related substance.

  Furthermore, in an actual preparation site, depending on the production lot of sivelestat used, precipitation of sivelestat may occur over time after the preparation of the solution. Although it is possible to produce a freeze-dried preparation as described above as it is using a sivelestat having such properties, it may be due to the influence of the precipitate, or when a sivelestat having the above properties is used. It may be difficult to dissolve in water for injection. It is sufficient to freeze-dry immediately after preparing the above solution. However, in the preparation site, it is often difficult to produce a desired preparation smoothly in consideration of the time required for such precipitation. .

Japanese Patent No. 3956544

Attached document for "Eraspol (registered trademark) 100 for injection"

  The present invention has an object to solve the above-mentioned problems, and an object of the present invention is to provide a pharmaceutical preparation of sivelestat that can be stably dissolved in water for injection and a method for producing the same, regardless of the production lot of sivelestat. It is to provide.

  The present invention includes a lyophilizate of a solution containing sivelestat, disodium hydrogen phosphate, and an anti-precipitating agent, wherein the anti-precipitating agent is selected from the group consisting of sodium carbonate or aqueous ammonia. It is a pharmaceutical preparation that is a seed.

  In one embodiment, the anti-precipitating agent is sodium carbonate and the sodium carbonate is contained in the solution in a proportion of 0.01 w / v% to 1 w / v%.

  In one embodiment, the anti-precipitation agent is aqueous ammonia, and the aqueous ammonia is contained at a rate of 0.01 w / v% to 0.1 w / v% with respect to the solution.

  In one embodiment, the disodium hydrogen phosphate is contained in a ratio of 0.25 w / v% to 2 w / v% with respect to the solution.

  In one embodiment, the pharmaceutical formulation of the present invention is used as an injection.

  The present invention also includes a method for producing a pharmaceutical preparation, comprising the steps of preparing a solution comprising sivelestat, disodium hydrogen phosphate and an anti-precipitation agent; and lyophilizing the solution. In the method, the precipitating agent is at least one selected from the group consisting of sodium carbonate or aqueous ammonia.

  In one embodiment, the anti-precipitating agent is sodium carbonate and the sodium carbonate is contained in the solution in a proportion of 0.01 w / v% to 1 w / v%.

  In one embodiment, the anti-precipitation agent is aqueous ammonia, and the aqueous ammonia is contained at a rate of 0.01 w / v% to 0.1 w / v% with respect to the solution.

  In one embodiment, the disodium hydrogen phosphate is contained in a ratio of 0.25 w / v% to 2 w / v% with respect to the solution.

  In one embodiment, the pharmaceutical formulation is used as an injection.

  ADVANTAGE OF THE INVENTION According to this invention, generation | occurrence | production of the undesired precipitation at the time of melt | dissolving in generation | occurrence | production of the undesired precipitation in the middle of manufacture of a formulation which arises from the difference in the manufacturing lot of the sivelestat to be used, or injection water etc. can be prevented. Furthermore, the pharmaceutical preparation of the present invention can suppress the production of sibelestat-related substances when used as an injection.

  Hereinafter, the present invention will be described in detail.

  The pharmaceutical composition of the present invention contains sivelestat, disodium hydrogen phosphate, and an anti-precipitation agent.

  Cibelestat constituting the present invention is cibelestat sodium tetrahydrate (N- {2- [4- (2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl} sodium acetate tetrahydrate). . The cibelestat is also called cibelestat sodium hydrate.

  Human neutrophil elastase, a proteolytic enzyme, is known to be released from neutrophils accumulated in the lung, decompose lung connective tissue, increase pulmonary vascular permeability, and induce acute lung injury. ing. Furthermore, it promotes the production of neutrophil migration factor and amplifies the inflammatory response, and is attracting attention as an important obstacle factor in acute lung injury associated with systemic inflammatory response syndrome. The cibelestat can function as an inhibitor against such neutrophil elastase.

  In the present invention, the term “disodium hydrogen phosphate” includes disodium hydrogen phosphate itself and hydrates thereof, and functions as a pH adjusting agent in the preparation of the present invention. The disodium hydrogen phosphate preferable in the present invention is disodium hydrogen phosphate hydrate, and examples thereof include disodium hydrogen phosphate dodecahydrate.

  In the present invention, examples of the anti-precipitating agent include sodium carbonate, aqueous ammonia, or a combination thereof. Here, usable ammonia water is, for example, an ammonia aqueous solution of 9.5 w / v% to 10.5 w / v%, preferably an aqueous ammonia solution of 9.5 w / v% to 10.5 w / v%. It is a part of medicine (Japanese Pharmacopoeia ammonia water). In the present invention, it is preferable to use sodium carbonate as an anti-precipitating agent from the viewpoint of easy handling.

  As described above, at the site of conventional preparation production, Siberestat may precipitate during the period from preparation of a solution as described later to lyophilization due to the difference in production lots. Furthermore, once this precipitation occurs, it is known that insoluble matter remains even if the obtained lyophilized product is dissolved in a solvent such as an injection solution. This is thought to be due to the fact that some material remaining in the production stage of Sibelestat becomes the nucleus, causing such precipitation and generation of unwanted substances.

  In the present invention, by using the anti-precipitating agent together, such a problem caused by the difference in production lots can be solved.

  In the present invention, first, a solution containing the above-mentioned sivelestat, disodium hydrogen phosphate and an anti-precipitation agent is prepared. Specifically, the solution is prepared by dissolving sivelestat, disodium hydrogen phosphate and an anti-precipitation agent in a suitable solvent.

  Examples of this solvent include, but are not limited to, water (for example, distilled water, purified water, pure water, ion exchange water) and a lower alcohol aqueous solution (for example, an ethanol aqueous solution) containing these waters. The alcohol concentration of the lower alcohol aqueous solution is not particularly limited. In the present invention, it is preferable to use water for the reasons that the stability of the cibelestat at the time of production can be further maintained and the workability such as subsequent freeze-drying is improved. That is, in this invention, it is preferable that the solution containing the said sivelestat, disodium hydrogen phosphate, and an anti-precipitating agent is an aqueous solution containing the said sivelestat, disodium hydrogen phosphate, and an anti-precipitating agent.

  The content of cibelestat in the solution, that is, the concentration of the preparation of cibelestat in the solution is not necessarily limited, but is preferably 1 w / v% to 8 w / v%, more preferably 1.5 w / v with respect to the solution. v% to 2.5 w / v%.

  The content of disodium hydrogen phosphate in the solution, that is, the preparation concentration of disodium hydrogen phosphate in the solution is not necessarily limited, but is preferably 0.25 w / v% to 2 w / v% with respect to the solution, More preferably, it is 0.5 w / v% to 1 w / v%. If the concentration of disodium hydrogen phosphate in this solution is less than 0.25 w / v%, the cibelestat may not dissolve. If the concentration of disodium hydrogen phosphate in this solution exceeds 2 w / v%, the decomposition of cyberestat in the pharmaceutical preparation is rather accelerated, and there is a risk of producing a related substance of cyberestat through the decomposition. There is also a risk of increasing production costs.

  The content of the anti-precipitating agent in the solution, that is, the preparation concentration of the anti-precipitating agent in the solution is not necessarily limited, but in the case of sodium carbonate with respect to the solution, preferably 0.01 w / v% to 1 w / v% More preferably, it is 0.01 w / v% to 0.1 w / v%. In the case of ammonia water, it is preferably 0.01 w / v% to 0.1 w / v%, more preferably 0.01 w / v%. -0.03 w / v%. If the concentration of sodium carbonate or aqueous ammonia as an anti-precipitating agent in this solution is less than 0.01 w / v%, sivelestat may not dissolve. When the concentration of sodium carbonate or aqueous ammonia as an anti-precipitating agent in this solution exceeds 1 w / v% or 0.1 w / v%, the degradation of sivelestat in the pharmaceutical preparation is rather accelerated, and There is a risk of producing similar substances.

  In the present invention, this solution may contain other components in addition to the above-mentioned sivelestat, disodium hydrogen phosphate and an anti-precipitation agent.

  Examples of other components include other pH adjusting agents, excipients, stabilizers, soothing agents, preservatives and the like.

  Examples of other pH adjusters include trisodium phosphate and its hydrates, sodium hydroxide and potassium hydroxide. Such other pH adjusting agents are appropriately used by those skilled in the art within a range that does not affect the action of the disodium hydrogen phosphate.

  Examples of excipients include mannitol, lactose, glucose, maltose, xylitol, sorbitol, and sodium chloride. It is preferable to use mannitol because it is excellent in moldability of the preparation itself in lyophilization described later. The amount of such excipient used in the pharmaceutical preparation of the present invention or the above solution can also be appropriately set by those skilled in the art.

  The pharmaceutical preparation of the present invention contains a lyophilizate of a solution containing this cyberestat, disodium hydrogen phosphate and an anti-precipitation agent. The lyophilized product of the solution can be obtained by lyophilization using means known to those skilled in the art after preparing the solution. This lyophilization is preferably performed in a sterile environment.

  The pharmaceutical preparation of the present invention may contain any additive in addition to the lyophilized product. Examples of such additives include excipients, stabilizers, soothing agents, preservatives and the like. For example, examples of the excipient include the same excipients that the solution may contain. From the viewpoint of excellent moldability of the preparation itself, it is preferable to use mannitol.

  The pharmaceutical preparation of the present invention is preferably prepared in a sterilized or aseptic state, finally or as necessary, when the additives are contained. As a preparation method in such a sterilized or aseptic state, a method known in the art may be employed.

  In this way, the pharmaceutical preparation of the present invention can be obtained.

  The dosage form of the pharmaceutical preparation of the present invention is, for example, an injection for parenteral administration. This injection includes both the lyophilized product of the above solution itself or a solution after being dissolved in a solvent described later.

  Since the pharmaceutical preparation of the present invention is also a freeze-drying agent, it can be easily dissolved in a solvent (for example, an infusion solution) at the time of use, and has excellent handleability. Examples of the solvent used for such dissolution include physiological saline, 5% glucose aqueous solution, and the like.

  The dose of the pharmaceutical preparation of the present invention varies depending on the age, weight, symptoms, administration method, etc. of the user, and thus cannot be generally limited. For example, the daily dose per adult (Sivelestat 4 .8 kg / kg) is diluted with 250 mL to 500 mL of solvent and administered intravenously over 24 hours (0.2 mg / kg per hour). The administration period is set within 14 days, for example.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by these Examples.

(Preparation Example 1)
A plurality of lots of sivelestat sodium hydrate having different production lots were prepared, and it was determined as follows whether or not the sivelestat sodium hydrate caused precipitation after the solution was prepared.

  First, disodium hydrogen phosphate.12 hydrate (20 g) was dissolved in distilled water (100 mL). Next, this solution of disodium hydrogenphosphate.12 hydrate (3.75 mL) was placed in a transparent glass container and added to distilled water (80 mL). Tat sodium hydrate (2 g) was added and dissolved. Further, mannitol (4 g) was dissolved in this solution. By making the total amount of the obtained solution to be 100 mL with distilled water, a solution for the cyberestat lyophilized preparation was prepared.

  The solution for the cyberestat lyophilized preparation prepared above was allowed to stand overnight at room temperature, and then, whether or not a precipitate was formed on the bottom of the container was visually observed. By this visual observation, it was classified into a lot group (A group) of sivelestats in which a precipitate was formed on the bottom surface and a lot group (group B) of cybelestats in which no precipitate was formed.

Example 1
Disodium hydrogen phosphate.12 hydrate (20 g) was dissolved in distilled water (100 mL). On the other hand, sodium carbonate (5 g) was dissolved in distilled water (100 mL). A solution prepared by adding a disodium hydrogen phosphate dodecahydrate solution (3.75 mL) and a sodium carbonate solution (4 mL) to distilled water (80 mL) was further classified into Group A in Preparation Example 1 above. Sivelestat sodium hydrate (2 g) consisting of the prepared production lot was dissolved. Further, mannitol (4 g) was dissolved in this solution. By making the total amount of the obtained solution to be 100 mL with distilled water, a solution for the cyberestat lyophilized preparation was prepared.

  A part of this solution was separated and freeze-dried by means well known to those skilled in the art to obtain a pharmaceutical preparation comprising a freeze-dried product.

(Example 2)
Instead of sivelestat sodium hydrate consisting of the production lot classified in Group A in Preparation Example 1 above, sivelestat sodium hydrate (2 g) consisting of the production lot classified in Group B in Preparation Example 1 above was used. Except that it was used, a solution for a cyberestat lyophilized formulation was obtained in the same manner as in Example 1.

  A part of this solution was separated and freeze-dried by means well known to those skilled in the art to obtain a pharmaceutical preparation comprising a freeze-dried product.

(Example 3)
A solution for a cyberestat lyophilized formulation was prepared in the same manner as in Example 1 except that sodium carbonate was changed to aqueous ammonia in Example 1. In addition, since ammonia water is an aqueous solution, the operation | work which adjusts a solution becomes unnecessary. Specifically, it was prepared as follows.

  Disodium hydrogen phosphate.12 hydrate (20 g) was dissolved in distilled water (100 mL). A solution prepared by adding this disodium hydrogenphosphate dodecahydrate solution (3.75 mL) and aqueous ammonia (Japanese Pharmacopoeia: 4 mL) to distilled water (80 mL) was further added to the above preparation example 1 as A Cibelestat sodium hydrate (2 g) consisting of production lots classified into groups was dissolved. Further, mannitol (4 g) was dissolved in this solution. By making the total amount of the obtained solution to be 100 mL with distilled water, a solution for the cyberestat lyophilized preparation was prepared.

  A part of this solution was separated and freeze-dried by means well known to those skilled in the art to obtain a pharmaceutical preparation comprising a freeze-dried product.

(Comparative Example 1)
Except that sodium carbonate (5 g) was not used, the same procedure as in Example 1 was performed (that is, using sivelestat sodium hydrate (2 g) consisting of the production lot classified as Group A in Preparation Example 1 above). To prepare a solution for a cyberestat lyophilized formulation.

(Comparative Example 2)
Instead of sivelestat sodium hydrate consisting of the production lot classified in Group A in Preparation Example 1 above, sivelestat sodium hydrate (2 g) consisting of the production lot classified in Group B in Preparation Example 1 above was used. A solution for a cyberestat lyophilized formulation was obtained in the same manner as in Example 1 except that sodium carbonate (5 g) was not used.

(Test Example 1)
Regarding the solution for the cyberestat lyophilized preparation prepared and separated in Examples 1 to 3 and Comparative Examples 1 and 2, the properties of the solution immediately after the preparation and after the lapse of 1 day (standing at room temperature) Visual observation was performed from the glass container appearance. The results are shown in Table 1.

  As shown in Table 1, in the case of a pharmaceutical preparation obtained using a cibelestat consisting of a production lot classified into Group B (that is, a cibelestat consisting of a production lot that did not cause precipitation in the solution in Preparation Example 1) Regardless of the addition of sodium carbonate as an anti-precipitation agent, no precipitation of crystals was observed on the bottom of the container even after 1 day after preparation (Example 2 and Comparative Example 2). On the other hand, regarding a pharmaceutical preparation obtained using a cibelestat consisting of a production lot classified into Group A (that is, a cibelestat consisting of a production lot that caused precipitation in a solution in Preparation Example 1), as an anti-precipitation agent In the case of adding sodium carbonate (Example 1) and in the case of adding aqueous ammonia (Example 3), crystals were deposited on the bottom of the container even after 1 day from the preparation of the solution for the freeze-dried preparation of Siberestat. Was not recognized.

(Test Example 2)
Each of the pharmaceutical preparations obtained in Examples 1 to 3 and Comparative Examples 1 and 2 (100 mg as sivelestat sodium) was added to water for injection (10 mL), stirred well and allowed to stand for a while to dissolve the preparation. The degree was visually observed. The results are shown in Table 2.

  As shown in Table 2, all of the pharmaceutical preparations of Examples 1 to 3 containing sodium carbonate or aqueous ammonia as an anti-precipitation agent were dissolved in water for injection. In addition, the pharmaceutical preparation of Comparative Example 2 using Sibelestat consisting of a production lot classified into Group B without any precipitation in Preparation Example 1 was also completely dissolved in water for injection. On the other hand, in the pharmaceutical preparation of Comparative Example 1 that produced precipitation in Preparation Example 1, used Siberestat consisting of a production lot classified as Group A, and did not contain an anti-precipitating agent, it was one for water for injection. The portion did not dissolve and remained as an insoluble material. From this, it can be seen that the pharmaceutical preparation of the present invention can be stably dissolved in a solvent such as water for injection even in the case of using Siberesta, which conventionally causes precipitation due to differences in production lots. .

  According to the present invention, by combining the above-mentioned anti-precipitating agent with disodium hydrogen phosphate or a hydrate thereof, precipitation can be achieved in a solution prepared before obtaining a freeze-dried preparation for any lot of Siberestat production. It is possible to provide a sivelestat formulation that does not occur and is stably dissolved in water for injection. The pharmaceutical preparation of the present invention is useful, for example, as a preparation that has high stability of sivelestat and contributes to the improvement of acute lung injury associated with systemic inflammatory response syndrome.

Claims (6)

Includes a Shiberesutatto, and disodium hydrogen phosphate, containing lyophilisate of a solution containing an anti-precipitating agent, the anti precipitants charcoal acid sodium,
The disodium hydrogen phosphate content is 0.25 w / v% to 2 w / v% of the solution;
The content of said sodium carbonate is Ru 1 w / v% der from 0.01 w / v% relative to the solution, the pharmaceutical formulation. The pharmaceutical preparation according to claim 1, wherein the content of the cibelestat is 1 w / v% to 8 w / v% with respect to the solution. The pharmaceutical preparation according to claim 1 or 2 , which is used as an injection. A method for producing a pharmaceutical formulation comprising:
Preparing a solution comprising sivelestat, disodium hydrogen phosphate and an anti-precipitation agent; and lyophilizing the solution;
Including
Antibody precipitant comprises carbonated sodium,
The disodium hydrogen phosphate content is 0.25 w / v% to 2 w / v% of the solution;
The content of said sodium carbonate is Ru 1 w / v% der from 0.01 w / v% relative to the solution method. The method according to claim 4, wherein the content of the cibelestat is 1 w / v% to 8 w / v% with respect to the solution. The method according to claim 4 or 5 , wherein the pharmaceutical preparation is used as an injection.