JPH1072352A - Infection solution of prednisolone sodium methyl succinate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an injection preparation having increased immediate usability on emergency rescue and life saving by separately storing a solvent for dissolving medicinal components and a medicinally effective component composition until they are mixed for application. SOLUTION: A solvent for dissolving prednisolone sodium methyl succinate containing a lower alcohol and water and a prednisolone sodium methyl succinate composition containing hygroscopic saccharides are separately contained. In the solvent for dissolving prednisolone sodium methyl succinate, the concentration of a lower alcohol is 2-70v/v%, while glycerol or sorbitol is used as a hygroscopic saccharide and its amount is 1-50w/w% based on prednisolone sodium methyl succinate as an active ingredient. Thus, redissolution of the pharmaceutically effective component composition powder is increased, the volume of the solvent for dissolving the composition powder is decreased and the powder can be readily dissolved with a small agitation space. They can be separately contained in pre-filled syringes of on-site dissolution type from two vial preparations whereby the time needed for the administration is shortened.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an injection of methylprednisolone sodium succinate with improved immediate use in emergency rescue, and is used in the field of pharmaceuticals.

[0002]

2. Description of the Related Art Commercially available methylprednisolone sodium succinate preparations are composed of two vials of a lyophilized composition containing a main ingredient and dissolved at the time of use, and a solution vial for re-dissolving the same. The drug is administered for various conditions, but is often administered particularly for the purpose of restoring emergency patients with shock symptoms. In such a case, a high dose is required, and usually, once, methylprednisolone sodium succinate (the active ingredient) 53-2.
652 mg (40 to 200 as methylprednisolone
0 mg). However, re-dissolution of the lyophilized composition is not rapid, and foaming occurs when shaken to promote dissolution, making it difficult to visually confirm dissolution, and reducing the amount of liquid that can be inhaled into the syringe. Rapid administration was difficult. In addition, the greater the amount of the dissolving solution, the better the re-dissolvability, but the operation of sucking and discharging the dissolving solution with a medical worker's syringe increases the working time, resulting in a significant reduction in the time required from dissolution to administration. I can't. Examples of glycerin which is added to an injection prepared by dissolving it at the time of use include humantrope (Lilly's recombinant human growth hormone), BCG vaccine (Or
ganon) and protein preparations such as Eminase (Roberts enzyme preparation). However, stabilization with polyols, especially glycerin, for proteins is well known (Biochemistry vol. 204).
667-4676 1981, Protein nucleic acid enzyme Vo
l. 30 No. 10 1115-1126 198
5) As can be seen, these preparations are added for the purpose of stabilizing proteins.

[0003]

In the preparation for emergency rescue in the event of a shock, it is required to administer the correct amount as soon as possible. Therefore, it is composed of two conventional freeze-dried vials and a solution vial. Dissolving solution and composition to be dissolved are separated and stored in a container combining two or more containers or one container, and they are integrated by a simple operation at the time of use, and uniform foaming in a short time than the preparation It is desired that the preparation be an injection solution free of the contaminants. As a container for such a preparation, a solution-integrated vial, a prefilled syringe, a two-chamber bag preparation having a communicating means, and the like are commercially available. The volume of the liquid-integrated vial or prefilled syringe that seals the liquid or powder is usually smaller than the conventional two-due formulation due to size restrictions and so on. A formulation that exhibits good dissolution performance is needed. In the case of the medicinal component, there is no readily soluble, ready-to-use prefilled syringe suitable for emergency administration, and thus its development is strongly desired.

[0004]

As a result of various studies, the present inventors have found means for solving the above-mentioned problems, and have completed the present invention. That is, the present invention relates to the following (1) to (9). (1) A solution for a medicinal component composition, comprising a lower alcohol and water. (2) Lower alcohol concentration in the solution is 2-70V
/ V%, the solution of (1) above. (3) The solution of (1) above, wherein the lower alcohol is ethanol. (4) The solution according to the above (3), which contains sodium chloride. (5) The medicinal component composition comprising a hygroscopic saccharide. (6) The composition according to the above (5), wherein the hygroscopic saccharide is glycerin, sorbitol, xylitol, propylene glycol or polyethylene glycol. (7) The hygroscopic saccharide is 1 to 50 W / W with respect to the medicinal component.
% Of the composition of the above (5). (8) A preparation in which the solution of the above (1) and the medicinal component are separately housed. (9) A preparation in which the solution of (1) and the composition of (5) are separately stored. (10) A preparation in which a solution of the following (A) and the medicinal component composition of the following (B) are separately stored at a ratio of (C). (A) Ethanol 10-50V / V%, water 90-50V
/ V% and a dissolution solution containing 0 to 5 W / V% of other additives. (B) The ratio of the hygroscopic saccharide selected from the group consisting of the medicinal ingredient and glycerin, sorbitol, xylitol, propylene glycol or polyethylene glycol is 0 to 50 W / W%, preferably 1 to 5 relative to the medicinal ingredient.
0 W / W% of said medicinal composition. (C) A ratio of the solution of the above (A) to the medicinal component of the above (B) by equal weight or more. (11) The above-mentioned (8), (9), or (9), wherein the separately stored preparation is a preparation separately stored in two or more independent containers or a container in which two or more containers are combined or one container. The preparation according to 10).

[0005]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

The lower alcohol to be added to the solution of the present invention includes, for example, lower alcohols having 1 to 3 carbon atoms such as methanol, ethanol, propanol, isopropanol, and glycerin, and ethanol is particularly suitable.
The concentration of the alcohol in the solution may be any concentration that substantially promotes the dissolution of the medicinal component. For example, the concentration may be about 2 V / V%, usually 6 V / V% or more, preferably 10 V / V. % Or more, more preferably 14 V / V% or more. Also, if the concentration is too high, the solubility of the medicinal component tends to decrease.
0 V / V% is good, usually 60 V / V% or less,
It is preferably 50 V / V% or less, more preferably 4 V / V% or less.
0 V / V% or less.

When the lower alcohol is ethanol, it shows hemolysis to blood depending on the ethanol concentration, but the addition of sodium chloride avoids the hemolysis (Journa).
lof Pharmaceutical Science
es Vol. 63 1974), so that it is preferable in some cases to coexist sodium chloride in the solution. When sodium chloride is allowed to coexist, the concentration thereof is usually 0.5 W / V% or more, more preferably 0.7 W / V% or more, based on the whole solution. Usually 5 W / V% or less, preferably 1.
5 W / V% or less.

The solution of the present invention can be obtained by mixing a lower alcohol with water for injection by a conventional method.

The medicinal component composition to be dissolved in the dissolving solution of the present invention may be a medicinal component methylprednisolone sodium succinate alone or a mixture of the medicinal component and a pharmacologically acceptable additive. May be. The composition is usually preferably a lyophilized composition, but is not necessarily limited thereto. When the medicinal component composition contains a hygroscopic saccharide, it tends to have a favorable effect on the solubility. Therefore, it is preferable that the hygroscopic saccharide be present together with the medicinal component.

As a coexisting hygroscopic saccharide, when left in an environment of 25 ° C. and a relative humidity of 75% for 7 days, the increase in water content is 3 W / W% or more, preferably 10 W / W%, based on the weight of the original substance. The above, more preferably 30 W / W% or more is usually used. Such a hygroscopic substance may be any of an inorganic substance and an organic substance as long as it can be dissolved in a dissolving solution without adversely affecting the medicinal component, and may be a single substance or a combination of two or more. Good. Examples of the hygroscopic saccharide include glycerin, sorbitol, xylitol, propylene glycol, polyethylene glycol and the like. Glycerin is particularly suitable in terms of effects and physical properties.

The amount of the hygroscopic saccharide to be added to the medicinal component composition may not be included, but when it is included, it is usually at least 1 W / W%, preferably at least 3 W / W%, more preferably at least 3 W / W%, based on the medicinal component. It is preferably at least 6 W / W%, and the upper limit should not be too much, usually 50 W / W% or less, preferably 30 W / W% or less, more preferably 15 W / W%.
Or less, and 10 W / W% or less is optimal.

The medicinal component composition may further contain a substance exhibiting a buffering action upon re-dissolution, such as phosphoric acid or phosphate, and the amount of these substances to be added is not particularly limited as long as the substance exhibits a buffering effect. However, it is usually at least 2 W / W%, more preferably at least 7 W / W%, based on the medicinal component. If the amount is too large, it cannot be said that the effect is improved.
0 W / W% or less, more preferably 30 W / W% or less, and most usually 20 W / W% or less.

The preferred weight ratio of the medicinal component composition is, for example, the following composition when the hygroscopic saccharide is included and the medicinal component is taken as 100 parts. The medicinal component 100 parts Hygroscopic sugar 1-50 parts, preferably 3-30 parts Buffer component 2-50 parts, preferably 7-30 parts The medicinal component composition contains the medicinal component and additives that are optionally added. Although it can be obtained by compounding, it is usually preferable to dissolve these in water for injection and freeze-dry.

The lower alcohol-containing solution and the hygroscopic substance-containing medicinal component composition according to the present invention have improved resolubility even when used alone, but can be further improved by using both in combination. When both are used in combination, conventional products require a shaking space equal to or about three times the amount of the dissolving solution, but can be sufficiently quickly dissolved even in a shaking space less than the dissolving solution amount. . Depending on the case, the amount of the solution may be less than half to about one-half of the amount of the solution, and the foam may be dissolved and foaming may be reduced. In addition,
The shaking space in the above refers to the volume of the space in the container when the entire amount of the solution is poured into the container filled with the medicinal component composition for dissolution before use.

When both are used in combination, the dissolution rate can be accelerated as the ratio of the dissolving solution to the medicinal ingredient increases, but usually the dissolving solution is equal to or more than the weight of the medicinal ingredient, preferably It is sufficient if it is 7 times or more,
The upper limit is determined by the size of the container and the like.

According to the present invention, since the resolubility is good even when the shaking space is very small as described above, the solution-integrated vial with a very small shaking space and a small amount of the solution is used. And prefilled syringes became possible.

In the present invention, the separated and stored preparation may be any preparation as long as the solution and the medicinal ingredient composition are separated and stored so as not to be mixed until they are mixed at the time of use. The storage container may be in any form, material, or the like, but preferably does not substantially adversely affect the preparation. For example, there may be mentioned two or more independent containers, a container in which two or more containers are combined, or a preparation separately stored in one container. That is, in the present invention, the solution and the medicinal component composition may be stored in separate containers such as vials, or may be separately stored in one container such as a syringe or a bag. 2
The solution and the medicinal component composition may be stored in each container of a syringe produced by combining the two containers, or two bags may be connected and integrated.
The solution and the medicinal component composition may be stored in each bag of a container having communication means between the two bags. Regardless of the type of container used, the solution is clinically applied by injecting a solution into the medicinal component composition and dissolving it at the time of use.

A pre-filled syringe preparation for use or a two-bag preparation having a communicating means is not only easy and quick to re-dissolve, but also can be administered as it is, so that there is an opportunity for bacterial contamination during preparation. And has the merit of being able to administer the correct amount, and is optimal as the preparation of the present invention.

[0019]

EXAMPLES The present invention will be described in more detail with reference to Comparative Examples and Examples, which do not limit the present invention.

Comparative Example 1 Methylprednisolone sodium succinate 132.6
g, anhydrous sodium dihydrogen phosphate 1.28 g, and anhydrous sodium monohydrogen phosphate 13.92 g were dissolved in water for injection to make a total volume of 1 liter. Vial (Internal volume about 25.5m
l) was aseptically filled with 5 ml, lyophilized and sealed. Another vial was aseptically filled with 8 ml of water for injection and sealed. Table 1 shows the formulation of Comparative Example 1.

[0021]

[Table 1]

Comparative Example 2 5 ml of a pharmaceutical preparation of the medicinal ingredient composition to be used after dissolving in Comparative Example 1 was aseptically placed in another vial (internal volume: about 8.7 ml) having a smaller volume than Comparative Example 1. Filled and sealed after lyophilization. Another vial was aseptically filled with 5 ml of water for injection and sealed.

COMPARATIVE EXAMPLE 3 5 ml of the prepared drug solution of the medicinal component composition used in Comparative Example 1 was dissolved in a pre-filled syringe before use in a sterile manner.
After filling and freeze-drying, an inner stopper was provided, and the inner stopper was further aseptically filled with 5 ml of water for injection as a dissolving solution and sealed.

Example 1 Methylprednisolone sodium succinate 132.6
g, anhydrous sodium dihydrogen phosphate 1.28 g, anhydrous sodium monohydrogen phosphate 13.92 g were dissolved in water for injection,
The total volume was 1 liter. Vial (capacity about 8.7m
l) was aseptically filled with 5 ml, lyophilized and sealed. On the other hand, the preparation of the dissolving solution was 200 ml of absolute ethanol
Was prepared by adding 800 ml of water for injection (referred to as anhydrous ethanol solution), and 5 ml of the solution was aseptically filled in another vial and sealed. Table 2 shows Example 1 which is a preferable formulation of the present formulation.

[0025]

[Table 2]

Example 2 A drug solution of the medicinal ingredient composition used after dissolving at the time of use in Example 1 was aseptically injected into a pre-filled syringe of 5 m length in a dissolving type prefilled syringe.
After filling and freeze-drying, an inner stopper was provided, and 5 ml of the solution of Example 1 was aseptically filled on the inner stopper and sealed.

Example 3 Methylprednisolone sodium succinate 132.6
g, anhydrous sodium dihydrogen phosphate 1.28 g, anhydrous sodium monohydrogen phosphate 13.92 g, concentrated glycerin 10.
0 g was dissolved in water for injection to make the total volume 1 liter. The vial (about 8.7 ml in volume) was aseptically filled with 5 ml and lyophilized and sealed. Another vial was aseptically filled with 5 ml of water for injection and sealed. Table 3 shows Example 3 which is a preferable formulation of the present formulation.

[0028]

[Table 3]

Example 4 5 ml of the drug solution of the medicinal ingredient composition used after dissolving in Example 3 was aseptically poured into a pre-filled syringe for dissolving in use.
It was filled, lyophilized and sealed (middle stopper). Further, 5 ml of water for injection was aseptically filled on the inner stopper and sealed.

Example 5 Methylprednisolone sodium succinate 132.6
g, anhydrous sodium dihydrogen phosphate 1.28 g, anhydrous sodium monohydrogen phosphate 13.92 g, concentrated glycerin 10.
0 g was dissolved in water for injection to make the total volume 1 liter. The vial (about 8.7 ml in volume) was aseptically filled with 5 ml and lyophilized and sealed. On the other hand, a solution was prepared by adding 800 ml of physiological saline to 200 ml of anhydrous ethanol (referred to as anhydrous ethanol physiological saline), and 5 ml of the solution was aseptically filled in another vial and sealed. Table 4 shows Example 5 which is a preferable formulation of the present formulation.

[0031]

[Table 4]

Example 6 5 ml of a drug solution of the medicinal composition used in Example 5 which was dissolved and used at the time of use was aseptically added to a pre-filled syringe dissolved at the time of use.
After filling and freeze-drying, an inner stopper was provided. Further, 5 ml of the solution of Example 5 was aseptically filled on the inner stopper and sealed.

Example 7 5 ml of a medicinal solution of the medicinal composition used in Example 5 dissolved and used before use was aseptically filled in a glass tube having a bypass whose one end was closed by a front stopper,
After freeze-drying, it was sealed with a middle stopper. Further, 5 ml of the solution of Example 5 was aseptically filled in a glass tube having one end sealed with a middle stopper and having a plastic connector at the same end, and sealed with an end stopper. When these two containers are connected by a connector, the preparation of the present invention is obtained.

Example 8 A vial of aseptically filled 5 ml of the medicinal solution of the medicinal ingredient composition to be dissolved and used at the time of use in Example 5 was aseptically filled, freeze-dried and sealed. The vial was aseptically filled with 5 ml of the solution of Example 5 and sealed. When these two containers are connected by a connector or an injection needle or the like to form an integrated container that can be communicated at the time of use, the preparation of the present invention can be obtained.

Test Method and Test Results The time of re-dissolution of the medicinal composition was measured for the samples of Comparative Examples 1 to 3 and Examples 1 to 6. Measurement method is Turc
o et al. (Hosp. Pharm., 11, p48).
2, 1976). That is, after adding the lysing solution to the samples of Comparative Examples and Examples, the amplitude of 40 cm, 2
It was shaken by hand at a speed of reciprocation / second, and the time until the completion of complete dissolution was defined as the re-dissolution time.

[0036]

[Table 5]

[0037]

As a result of various studies on methylprednisolone sodium succinate and a dissolving solution which are dissolved at the time of use,
The re-dissolvability of the powder of the medicinal ingredient composition to be dissolved and used at the time of use with a dissolution solution was improved. The amount of the lysis solution was reduced, and re-dissolution was facilitated even in a small shaking space. According to the present invention, it has become possible for the first time to separate and store a high dose of the pharmaceutically active ingredient from a two-vial preparation into a pre-filled syringe for dissolution at the time of use, thereby shortening the time required for administration.
The solubility is further improved in the solution-integrated vial preparation, and the injection according to the present invention is extremely useful because it can be rapidly administered to a target patient at the time of emergency.

Claims (11)

[Claims] 1. A dissolution solution for methylprednisolone sodium succinate composition, comprising a lower alcohol and water. 2. The lower alcohol concentration in the solution is 2 to 2.
The lysing solution according to claim 1, which is 70 V / V%. 3. The solution according to claim 1, wherein the lower alcohol is ethanol. 4. The solution according to claim 3, further comprising sodium chloride. 5. A composition comprising a hygroscopic saccharide.
A composition of methylprednisolone sodium succinate (hereinafter simply referred to as the pharmaceutically active ingredient). 6. The hygroscopic sugar is glycerin, sorbitol,
The composition according to claim 5, which is xylitol, propylene glycol or polyethylene glycol. 7. The method according to claim 1, wherein the hygroscopic saccharide is contained in an amount of 1 to 50 with respect to the active ingredient.
6. The composition of claim 5, wherein the composition is W / W%. 8. A preparation wherein the solution of claim 1 and said medicinal component are separately housed. 9. The solution according to claim 1 and the composition according to claim 5,
Formulations stored separately. 10. A preparation wherein the solution of the following (1) and the medicinal composition of the following (2) are separately stored in the ratio of (3). (1) Ethanol 10-50V / V%, water 90-50V
/ V% and a dissolution solution containing 0 to 5 W / V% of other additives. (2) The medicinal component composition wherein the proportion of the hygroscopic saccharide is 0 to 50 W / W% based on the medicinal component and the glycerin, sorbitol, xylitol, propylene glycol or polyethylene glycol. . (3) A ratio of the solution of the above (1) to the medicinal component of the above (2) in an amount equal to or more than the weight of the active ingredient. 11. The separated and stored preparations each have independent 2
The preparation according to claim 8, 9 or 10, which is a preparation separately stored in the above-mentioned container, a container obtained by combining two or more containers, or one container.