WO1998001138A1

WO1998001138A1 - Methylprednisolone sodium succinate injections

Info

Publication number: WO1998001138A1
Application number: PCT/JP1997/002238
Authority: WO
Inventors: Emi Hashimoto; Michinobu Nakano
Original assignee: Nippon Kayaku Kabushiki Kaisha
Priority date: 1996-07-04
Filing date: 1997-06-27
Publication date: 1998-01-15

Abstract

Injections whereby the immediate usability of methyl-prednisolone sodium succinate in critical cases is improved. Preparations consist of the following components packed separately: (1) a solvent for a methylprednisolone sodium succinate composition characerized by containing a lower alcohol and water; and (2) a methylprednisolone sodium succinate composition characterized by containing hygroscopic saccharides.

Description

Description Methylpre-dnisolone sodium succinate Injection Technical field

The present invention relates to an injectable preparation of methylprednisolone sodium succinate with improved immediate use during emergency lifesaving, and is used in the field of pharmaceuticals.

Background art

Commercially available methylprednisolone sodium conodate manufactures two vials: a lyophilized composition vial that contains the active ingredient and is used by dissolving it at the time of use, and a lysis solution vial that redissolves it. It consists of: The drug is administered for a variety of conditions, but is often given especially to help emergency patients with shock symptoms. In such a case, a high dose is required and usually once a day, methylprednisolone sodium succinate (the active ingredient) 53 to 2652 mg (methylprednisolone) The dose is about 40 to 2000 m). However, the lyophilized composition is not rapidly re-dissolved and foams up when shaken to promote dissolution, making it difficult to visually confirm the dissolution, and The amount of fluid that could be inhaled during the period decreased, making accurate and rapid administration difficult. In addition, the higher the amount of the dissolving solution, the better the resolubility becomes, but the operation of sucking and discharging the dissolving solution by a healthcare professional in a syringe increases the working time, and consequently from dissolution to administration. The time required to do so cannot be significantly reduced. In addition, as an example in which glycerin is added to an injection to be used after dissolving at the time of use, a hyumatrope (Li11y Genetically Modified Human Beetle) is used. There are protein preparations such as growth hormone), BCG vaccine (Organon), and eminase (Roberts enzyme preparation). The stabilization of polyols against proteins, especially glycerin, is well known (Biochemistry vol. 204667-466769981, protein nucleic acid). Enzyme Vol. 30 N 0.10 11 1 15-1 12 6 19 9 8 5) As can be seen, these preparations are intended to stabilize proteins. It has been added.

Disclosure of the invention

In products used for emergency rescue in the event of a shock, it is necessary to administer the correct amount as soon as possible.Therefore, it consists of a conventional freeze-dried vial and a lysate vial. Rather than pharmaceuticals, dissolves in two or more combined containers or in a single container; separates liquid and dissolved compositions; separates and stores them in a simple operation when used; in a short time It is desirable to have a formulation that is an injection solution without uniform foaming. Containers for such preparations are commercially available such as vials with integrated solution, pre-filled syringes, or two-room bag preparations with communication means. The volume of the liquid or powder sealed part of the solution-integrated vial or pre-filled syringe is usually smaller than that of the conventional two-drug formulation due to size restrictions. However, a formulation that shows good dissolution performance even in a small dissolution place or a small volume Needed. In the case of such medicinal components, there is no readily soluble, ready-to-use formulation such as pre-filled syringe suitable for urgent administration, and therefore its development is strongly desired.

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) The solution according to (1), wherein the lower alcohol concentration in the solution is 2 to 70 VZV%.

(3) The solution of (1) above, wherein the lower alcohol is ethanol.

(3) The solution according to the above (3), characterized by containing sodium chloride.

(5) The medicinal composition comprising a hygroscopic saccharide.

(6.) Hygroscopicity. The saccharide is glycerin, sorbitan, toluene, xylitol, propylene glycol or polyethylene glycol. 5) The composition of the above.

(7) The composition according to the above (5), wherein the hygroscopic saccharide is used in an amount of 50 to 50 W / W% based on the medicinal component.

(8) A preparation in which the solution of (1) and the medicinal component are separately stored.

(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 in the ratio of (C).

(A) Dissolution solution containing 10 to 50 V / V% ethanol, 90 to 50 V V% water, and 0 to 5 W V% other additives. (B) a group consisting of the medicinal ingredient and glycerin, sorbitol, xylitol, propylene glycol, or polyethylene glycol; The medicinal component composition wherein the proportion of the hygroscopic saccharide selected from the medicinal component is 0 to 50 W / W%, preferably 1 to 50 W / W%.

(C) A ratio of the solution of (A) above to the medicinal component composition of (B) by an equivalent weight or more.

(11) The above-mentioned (8), (9) or (9), wherein the separately stored drug product is a drug product separately housed in two or more independent containers, a container obtained by combining two or more containers, or a single container. Is the preparation according to (10).

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail. .

The lower alcohol to be added to the solution of the present invention is, for example, a lower alcohol having 1 to 3 carbon atoms such as methyl alcohol, ethanol, phenol, isopanol, and glycerin. Alcohol may be mentioned, but ethanol is particularly suitable.

The concentration of the alcohol in the dissolution solution may be any concentration that substantially promotes the dissolution of the medicinal component, and may be, for example, about 2 V ZV% or 6 V ZV% or more in some cases. Better, preferably at least 10 V / V%, more preferably 14 VZV% or more. At too high a concentration, the solubility of the medicinal component tends to decrease, so it is preferably up to 70 VZV%, usually 60 VZV% or less, preferably 50 V / V. % Or less, more preferably 40 VZV% or less.

When the lower alcohol is ethanol, it shows hemolysis to the blood depending on the ethanol concentration, but the addition of sodium chloride avoids the hemolysis (Journalof Pharmamaceutical S.). In this case, it is preferable to coexist sodium chloride in the solution in some cases.

When sodium chloride is present, its concentration is usually at least 0.5 WZV%, more preferably at least 0.7 WZV%, based on the whole lysate, and is very high. However, since it has a bad effect on the living body, it is usually 5 WZV% or less, preferably 1.5 WZV% or less.

The lysate of the present invention can be obtained by mixing low-grade alcohol and alcohol with water for injection in a conventional manner.

The medicinal component composition to be dissolved in the dissolution solution of the present invention may be a single medicinal component of methyl prediblon sodium succinate, or a pharmacologically acceptable additive may be added to the medicinal component. Any of the combinations may be used. In addition, the composition is usually preferably a freeze-dried composition, but is not necessarily limited thereto. When the medicinal ingredient composition contains a hygroscopic saccharide, it tends to have a favorable effect on the solubility. It is preferable that they coexist with the components.

As a coexisting hygroscopic saccharide, when left in an environment at 25 and a relative humidity of 75% for 7 days, the increase in water content is 3 WZW% or more, preferably over the original weight of the substance. More than 10 W W%, more preferably more than 30 WZW% are usually used. Such a hygroscopic substance may be either an inorganic substance or an organic substance, as long as it can be dissolved in a lysis solution without adversely affecting the medicinal component, and even if it is a single substance. Two or more kinds may be used in combination. Examples of the hygroscopic saccharide include glycerin, sorbitol, xylitol, propylene glycol, polyethylene glycol, and the like. And the like. Glycerin is particularly suitable for its 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 WZW%, preferably at least 3 WZW%, more preferably at least 3 WZW%, based on the medicinal component. Preferably

6 WZW% or more, and the upper limit should not be too large-usually 0.50 WZW% or less, preferably 3-0 W / W% or less, more preferably i swzw ^ or less, and 10 WZW% or less is optimal.

The medicinal component composition may further contain a substance exhibiting a buffering action when redissolved, such as phosphoric acid or phosphate, and the amount of addition thereof is not particularly limited as long as the substance exhibits a buffering effect. But not more than 2 W / W% of the active ingredient, more preferably

It is more than 7 W / W%, and it cannot be said that the effect will be improved even if it is too much.In general, it is less than 50 WW%, More preferably, it is less than 30 WZW%, most usually less than 20 WZW%.

When the hygroscopic mallets are included as a preferable weight ratio of the medicinal component composition, when the medicinal component is 100 parts, for example, the following composition can be mentioned.

100 parts of said medicinal ingredient

Hygroscopic saccharide 1 to 50 parts, preferably 3 to 30 parts Buffer component 2 to 50 parts, preferably 7 to 30 parts The medicinal component composition is added to the medicinal component as needed. It can be obtained by blending such additives, but it is usually preferable to dissolve these in water for injection and freeze-dry.

Although the lower alcohol-containing solution and the hygroscopic substance-containing medicinal component composition according to the present invention have improved resolubility even if they are used alone, the combined use of both of them can be further improved. When both are used in combination, conventional products require about three times as much shaking space as the amount of lysate, whereas a shaking space less than the amount of lysate is sufficient. Dissolves quickly. Depending on the case, even less than half to a fraction of the solution volume can be dissolved well and foaming can 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 for dissolution at use.

When both are used in combination, the higher the ratio of the solution to the medicinal component, the faster the dissolution rate can be. Preferably, it should be 7 times or more, and 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 if the shaking space is very small as described above, the solution having a very small shaking space and a small amount of the solution can be obtained. Body vials and pre-filled syringes are now available.

In the present invention, the separated and stored preparation means that the solution and the medicinal component composition are separated and stored so that they are not mixed until they are mixed at the time of use. The shape and material of the storage container may be of any type, but those which do not substantially adversely affect the preparation are preferred. 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 lysis solution and the medicinal component composition may be stored in separate vials or other containers, or in one container such as a syringe or bag. It may be stored separately. In addition, the solution and the medicinal component composition may be stored in each container of a syringe prepared 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 a communicating means between two bags.

In any case, the solution is clinically applied by pouring the solution into the medicinal component composition and dissolving it at the time of use. P

Pre-dissolved syringe preparations or two-bag bag preparations with communication means are not only easy and quick to re-dissolve, but also can be administered as they are. It has the advantage that there is no chance of receiving bacterial contamination during preparation and that the correct amount can be administered.

Hereinafter, the present invention will be described in more detail with reference to Comparative Examples and Examples, but these do not limit the present invention. Comparative Example 1

Methyl prednisolone sodium succinate 13.2.6 g Sodium dihydrogen phosphate 1.28 g, sodium monohydrogen phosphate 1.3.92 g was dissolved in water for injection to make the total amount 1 liter. The vial (internal volume approx. 25.5 m 1) was aseptically filled with 5 m 1, lyophilized and sealed. Another vial was aseptically filled with 8 ml of water for injection and sealed. Table 1 shows the prescription of Comparative Example 1.

Table 1 Formulation of Comparative Example 1

Comparative Example 2 The aseptically prepared drug solution of the medicinal ingredient composition used in Comparative Example 1 was aseptically filled into another vial (internal volume: about 8.7 m1) having a volume smaller than that of Comparative Example 1 by 5 ml. After lyophilization, it was sealed. Another vial was aseptically filled with 5 ml of water for injection and sealed.

Comparative Example 3

A sterile solution of the medicinal ingredient composition to be used after dissolving at the time of use in Comparative Example 1 was aseptically filled into a pre-dissolved syringe at a volume of 5 ml, and after freeze-drying, the inner stopper was removed. Then, 5 ml of water for injection as a dissolving solution was aseptically filled on the inner stopper and sealed. Example 1

Methyl prednisolone sodium conodate 13.2.6 g sodium dihydrogen phosphate 1.28 g, sodium monohydrogen phosphate 13.92 g Was dissolved in water for injection to make the total amount 1 liter. The vial (with an internal volume of about 8.7 ml) was aseptically filled with 5 ml, lyophilized and sealed. On the other hand, the solution was prepared by adding 800 ml of water for injection to 200 ml of anhydrous ethanol (referred to as an aqueous solution of anhydrous ethanol). Al was aseptically filled and sealed. Table 2 shows Example 1, which is the preferred formulation of this formulation. Table 2 Formulation of Example 1 Ingredients Ingredients Dissolving at the time of prescription, disodium methyl citrate, sodium citrate 6G 3.0 mg Pharmaceutical active ingredient composition Sodium dihydrogen phosphate 6.4 mg Sodium monohydrogen phosphate 69.6 mg

(Volume of preparation before freeze-drying) (5 ml) Dissolution solution Anhydrous ethanol solution 5 m 1 Example 2

The preparation prepared by dissolving the active ingredient composition used in Example 1 before use was aseptically filled with 5 ml in a ffl-time-dissolving pre-filled syringe, and the inner stopper was lyophilized. Then, 5 ml of the lysis solution of Example 1 was aseptically filled on the inner stopper and sealed. Example 3

Methyl prednisolone sodium succinate 132.6 g sodium dihydrogen phosphate 1.28 g, sodium monohydrogen phosphate 13.99.2 g and concentrated glycerin (10.0 g) were dissolved in water for injection to make the total amount 1 liter. Noial (volume: about 8.7 ml) was aseptically filled with 5 ml, freeze-dried, and sealed. Another vial was aseptically filled with 5 ml of water for injection and sealed. Table 3 shows Example 3, which is the preferred formulation of this formulation.

Table 3 Composition of Example 3

Example 4 The pharmaceutical preparation of the medicinal ingredient composition to be dissolved and used at the time of use in Example 3 was aseptically filled in a pre-dissolved syringe at the time of use in an amount of 5 ml, and then lyophilized and sealed ( Middle stopper). Further, 5 ml of water for injection was aseptically filled on the inner stopper and sealed.

Example 5

132.6 g of methyl prednisolone sodium sodium phosphate 1.28 g of sodium hydrogen phosphate anhydrous, 13.99.2 g of sodium hydrogen phosphate anhydrous 10.0 g of concentrated glycerin was dissolved in water for injection to make the total amount 1 liter. Al (internal volume: about 8.7 ml) was aseptically filled with 5 ml, freeze-dried and sealed. On the other hand, the dissolving solution is 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 is added to another vial. Was filled aseptically and sealed. Table 4 shows Example 5, which is a preferred formulation of this formulation.

Table 4 Composition of Example 5

Raw material name Methylprednisolone sodium succinate dissolved at the time of use for prescription 63.0 mg Mg active ingredient group concentrated glycerin 50.0 mg Compound sodium dihydrogen phosphate anhydrous 6.4 mg

Sodium monohydrogen phosphate 69.6 mg (volume of drug preparation before freezing and drying) (5 m 1) Dissolution solution Ethanol anhydrous saline 5 m 1 Example 6

A pharmaceutical preparation of the medicinal ingredient composition to be dissolved and used before use in Example 5 was aseptically filled into a pre-dissolved pre-finolescent syringe in an amount of 5 ml, and the solution was freeze-dried, followed by centrifugation. Then, 5 ml of the lysate of Example 5 was aseptically filled on the inner stopper and sealed.

Example 7

One end of the pharmaceutical preparation of the medicinal ingredient composition used after being dissolved at the time of use was used as in Example 5. A glass tube with a no-pass sealed with-was aseptically filled with 5 ml, and after freeze-drying, sealed with a middle stopper. Further, the lysate of Example 5 was aseptically sealed in a glass tube having one end sealed with a middle stopper and having a plastic connector at the same end. 5 m 1 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 the pharmaceutical preparation of the medicinal ingredient composition to be dissolved and used at the time of use in Example 5 was aseptically filled with 5 ml, and then lyophilized and sealed. Also, 5 ml of the lysate of Example 5 was aseptically filled in a vial and sealed. The formulation of the present invention can be obtained by connecting these two containers with a connector or an injection needle to form an integrated container that can be connected when used.

Test method and test results

With respect to the samples of Comparative Examples 1 to 3 and Examples 1 to 6, the re-dissolution time of the medicinal component composition was measured. The measurement method was Turco et al. The method was performed according to the method (Hosp. Pharm., 11, P. 482, 1976). That is, for the samples of Comparative Examples and Examples, after adding the dissolving solution, shake by hand at an amplitude of 4 O cm and two reciprocations at a rate of Z seconds, and the time until complete dissolution is confirmed is the re-dissolution time. did. Table 5 shows the measurement results.

Table 5 Measurement results of reconstitution time Lyophilized lysate Solution storage time for medicinal ingredient Dry medicine m 1 part volume m I second

m 1

Comparative Formulation of Commercial Formulation 15 B No <25 5.56 0 Formulation of Commercial Formulation Comparative Formulation 255 5 vials 8.7 1550 Container Difference Comparative Example 3 5 5 Syringe 6-5 1 6 0 Anhydrous ethanol example 15 5 vials 8.7 0 7 effect example 2 5 5 syringes 6.5 9 5 cryseline embodiment 3 5 5 vials 8.7 1 2 0 Effect Example 4 5 5 Syringe 6.5 1 3 0 Improved prescription Example 5 5 5 vials 8.7 4 0 Example 6 5 5 Syringe 6.5 5 60

Industrial applicability

As a result of various studies on methyl predniblon sodium conodate and the dissolving solution that dissolve before use, the re-dissolvability of the powder of the medicinal component composition used after dissolving with the dissolving solution before use was improved. . The amount of lysate was reduced, and re-dissolution was easy even in a small shaking space. According to the present invention, it becomes possible for the first time to separate and store a high dose of the active ingredient from a two-vial formulation in a pre-dissolved pre-filled syringe. Required time. 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 the target patient at the time of emergency lifesaving.

Claims

The scope of the claims

1. Dissolver for methylprednisolone sodium succinate composition, characterized by containing a lower alcohol and water.

2. The solution according to claim 1, wherein the lower alcohol concentration in the solution is 2 to 70 VZV%.

3. The lysate according to claim 1, wherein the lower alcohol is ethanol.

4. The solution according to claim 3, wherein the solution contains sodium chloride.

5. A composition comprising methylprednisolone sodium succinate (hereinafter, simply referred to as the medicinal ingredient), comprising a hygroscopic saccharide.

6. The claim that the hygroscopic saccharide is glycerin, sorbitol, xylitol, propylene glycol or polyethylene glycol. 5 composition.

7. The composition according to claim 5, wherein the hygroscopic saccharide is 1 to 50 W / W% based on the medicinal ingredient.

8. A preparation in which the solution of claim 1 and the medicinal component are separately stored.

9. A preparation in which the solution of claim 1 and the composition of claim 5 are separately stored.

10. A preparation in which the following dissolving solution (1) and the medicinal component composition (2) are separately stored in the ratio (3). (1) A dissolving solution containing 10 to 50 VZV% of ethanol, 90 to 50 VZV% of water, and 0 to 5 W / V% of other additives.

(2) the active ingredient and selected from the group consisting of glycerin, sorbitol, xylitol, propylene glycol, and polyethylene glycol; The medicinal component composition wherein the ratio of the hygroscopic saccharide is 0 to 50 W / W% based on the medicinal component.

(3) The ratio of the solution of (1) above is equal to or more than the weight of the pharmaceutically active ingredient of (2).

11. The product according to claim 8, 9, or 10, wherein the separately packaged product is a product separately housed in two or more independent containers, a combined container of two or more containers, or a single container. Preparations.