JPH078800B2 - Aqueous suspension composition of macrolide antibiotics - Google Patents

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition, and more particularly to an aqueous suspension composition of a macrolide antibiotic.

(Prior art and problems) Macrolide antibiotics have a mid-range antibacterial spectrum and are commonly used as useful antibiotics because they are absorbed orally and have low toxicity, and are often used especially for children. Has been done.

When used for children, antibiotics of this kind are usually formulated as dry syrups or syrups, but syrups have a better palatability. When the amorphous solid powder of macrolide antibiotics is used for formulation as a syrup by a conventional method, that is, the amorphous solid bulk powder is added to and dispersed in an aqueous solution containing sucrose as a sweetener. If it becomes an aqueous suspension,
This suspension had fluidity at the initial stage of preparation, but had a problem in that it changed into a gel state with time and lost fluidity. This gelation occurs earlier at higher storage temperatures.

(Means and Actions for Solving the Problems) The inventors of the present invention have, as a result of intensive studies to solve the above problems, surprisingly found that the amorphous solid bulk powder of the macrolide antibiotic is water-soluble. Macrolide in which cellulosic polymer and sucrose are combined and blended, and sucrose is blended in a proportion of 20 to 40% by weight with respect to 2% by weight of amorphous solid bulk powder of macrolide antibiotics. The present invention was completed by finding that an aqueous suspension composition of antibiotics is stable even after long-term storage and does not gel.

Examples of the water-soluble cellulose-based polymer used when preparing the water suspension composition according to the present invention include hydroxypropylmethyl cellulose and hydroxypropyl cellulose. The amount ratio of the macrolide antibiotic, the water-soluble cellulose polymer, and the sucrose in the water suspension composition according to the present invention varies depending on the kind of the selected antibiotic or polymer, but generally, Amorphous solid bulk powder of macrolide antibiotics 2% by weight
On the other hand, it is preferable that the water-soluble cellulose-based polymer is 0.7-1.5% by weight and the sucrose is 20-40% by weight.

When the water suspension composition according to the present invention is formulated into a syrup, a usual additive such as a fragrance, a coloring agent, a preservative, a stabilizer, a suspending agent and a thickening agent is added. can do.

(Manufacturing Example, etc.) Next, the present invention will be described more specifically with reference to Manufacturing Examples and Comparative Examples.

Production Example 1 and Comparative Example 1 10 g of 10-acetyl-3 ″ -acetylmidecamycin (trade name: myokamycin) was dissolved in 100 ml of a dioxane solution containing 1 g of ethyl cellulose. The solution was -40 ° C.
After freezing at 10 ° C., the solvent was removed by sublimation under reduced pressure of 100 mmHg or less to obtain a completely amorphous solid of 10-acetyl-3 ″ -acetylmidecamycin.

2 g of this amorphous solid was collected, and 100 ml of an aqueous solution containing 0.5 g of hydroxypropylmethyl cellulose and 30 g of sucrose.
An aqueous suspension composition was obtained by adding the ingredients to the mixture and mixing them to sufficiently disperse them.

When this water suspension composition was stored under the temperature conditions of 25 ° C. and 40 ° C. for 1 year and then examined, it was found that a stable water suspension state was still maintained.

On the other hand, the above amorphous solid was dispersed in mere water containing no hydroxypropylmethylcellulose and sucrose in the same manner as above to prepare a water suspension composition (control composition). When this control composition was stored under a temperature condition of 25 ° C,
After 24 hours, it was in a gel state.

Preparation Example 2 and Comparative Example 2 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of dioxane solution. This solution was frozen at −40 ° C., and then the solvent was removed by sublimation under reduced pressure of 100 mmHg or less. To give a completely amorphous solid of 10-acetyl-3 "-acetylmidecamycin.

2 g of this amorphous solid was collected, and 0.5 g of hydroxypropyl methylcellulose, 15 g of sucrose and 0.05 of the acrylic acid polymer.
An aqueous suspension composition was obtained by adding to 100 ml of an aqueous solution containing 5 g, mixing and thoroughly dispersing.

When this water suspension composition was stored under the temperature conditions of 25 ° C. and 40 ° C. for 1 year and then examined, it was found that a stable water suspension state was still maintained.

On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in mere water containing no hydroxypropylmethylcellulose, sucrose and acrylic acid polymer in the same manner as above. When this control composition was stored under the temperature condition of 25 ° C., it exhibited a gel state after 24 hours.

Preparation Example 3 and Comparative Example 3 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dichloromethane solution containing 1 g of ethyl cellulose. This solution was spray-dried by a conventional method to obtain 10-acetyl-3 ″ -acetyl. A completely amorphous solid of midecamycin was obtained.

2 g of this amorphous solid was collected and 100 ml of an aqueous solution containing 1.0 g of hydroxypropylmethyl cellulose and 40 g of sucrose.
An aqueous suspension composition was obtained by adding the ingredients to the mixture and mixing them to sufficiently disperse them.

When this water suspension composition was stored under the temperature conditions of 25 ° C. and 40 ° C. for 1 year and then examined, it was found that a stable water suspension state was still maintained.

On the other hand, the above amorphous solid was dispersed in mere water containing no hydroxypropylmethylcellulose and sucrose in the same manner as above to prepare a water suspension composition (control composition). When this control composition was stored under a temperature condition of 25 ° C,
After 24 hours, it was in a gel state.

Production Example 4 and Comparative Example 4 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dichloromethane solution containing 1 g of ethyl cellulose. This solution was spray-dried by a conventional method to obtain 10-acetyl-3 ″ -acetyl. A completely amorphous solid of midecamycin was obtained.

2 g of this amorphous solid was collected and 100 ml of an aqueous solution containing 1.0 g of hydroxypropylmethyl cellulose and 35 g of sucrose.
An aqueous suspension composition was obtained by adding the ingredients to the mixture and mixing them to sufficiently disperse them.

When this water suspension composition was stored under the temperature conditions of 25 ° C. and 40 ° C. for 1 year and then examined, it was found that a stable water suspension state was still maintained.

On the other hand, the above amorphous solid was dispersed in mere water containing no hydroxypropylmethylcellulose and sucrose in the same manner as above to prepare a water suspension composition (control composition). When this control composition was stored under a temperature condition of 25 ° C,
After 24 hours, it was in a gel state.

Preparation Example 5 and Comparative Example 5 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dichloromethane solution containing 1 g of ethyl cellulose. This solution was spray-dried by a conventional method to obtain 10-acetyl-3 ″ -acetyl. A completely amorphous solid of midecamycin was obtained.

1 g of this amorphous solid was collected and added to 50 ml of an aqueous solution containing 0.7 g of hydroxypropylmethylcellulose, 10 g of sucrose and 0.5 g of gum arabic, mixed and sufficiently dispersed to obtain a water suspension composition. .

When this water suspension composition was stored under the temperature conditions of 25 ° C. and 40 ° C. for 1 year and then examined, it was found that a stable water suspension state was still maintained.

On the other hand, the above amorphous solid was dispersed in an aqueous solution containing gum arabic but not containing hydroxypropylmethylcellulose and sucrose in the same manner as above to prepare a water suspension composition (control composition). When this control composition was stored under the temperature condition of 25 ° C., it exhibited a gel state after 24 hours.

Production Example 6 and Comparative Example 6 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dichloromethane solution containing 1 g of ethyl cellulose. This solution was spray-dried by a conventional method to obtain 10-acetyl-3 ″ -acetyl. A completely amorphous solid of midecamycin was obtained.

1 g of this amorphous solid was collected and added to 50 ml of an aqueous solution containing 1.5 g of hydroxypropylmethylcellulose, 30 g of sucrose and 0.5 g of benzoic acid, mixed and sufficiently dispersed to obtain a water suspension composition. .

When this water suspension composition was stored under the temperature conditions of 25 ° C. and 40 ° C. for 1 year and then examined, it was found that a stable water suspension state was still maintained.

On the other hand, the above amorphous solid was dispersed in an aqueous solution containing benzoic acid and not containing hydroxypropylmethylcellulose and sucrose in the same manner as above to prepare a water suspension composition (control composition). When this control composition was stored under the temperature condition of 25 ° C., it exhibited a gel state after 24 hours.

Preparation Example 7 and Comparative Example 7 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dichloromethane solution. This solution was spray-dried by a conventional method to obtain 10-acetyl-3 ″ -acetylmidecamycin. A completely amorphous solid was obtained.

2 g of this amorphous solid was collected, and 1.0 g of hydroxypropylmethyl cellulose, 30 g of sucrose and 0.0
An aqueous suspension composition was obtained by adding to 100 ml of an aqueous solution containing 5 g, mixing and thoroughly dispersing.

When this water suspension composition was stored under the temperature conditions of 25 ° C. and 40 ° C. for 1 year and then examined, it was found that a stable water suspension state was still maintained.

On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in mere water containing no hydroxypropylmethylcellulose, sucrose and acrylic acid polymer in the same manner as above. When this control composition was stored under the temperature condition of 25 ° C., it exhibited a gel state after 24 hours.

Preparation Example 8 and Comparative Example 8 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dioxane solution containing 1 g of ethyl cellulose. The solution was frozen at −40 ° C. and then under reduced pressure of 100 mmHg or less. After removing the solvent by sublimation, 10-acetyl-3 ″-
A completely amorphous solid of acetylmidecamycin was obtained.

2 g of this amorphous solid was collected, and 100 ml of an aqueous solution containing 0.5 g of hydroxypropylmethyl cellulose and 25 g of sucrose.
An aqueous suspension composition was obtained by adding the ingredients to the mixture and mixing them to sufficiently disperse them.

On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in an aqueous solution containing hydroxypropylmethylcellulose and not containing sucrose in the same manner as above.

When these water suspension compositions were each stored under a temperature condition of 50 ° C. and examined over time, the control composition exhibited a gel state in 3 days, whereas the water suspension composition according to the present invention A stable water suspension state was maintained even after 2 weeks had passed.

Preparation Example 9 and Comparative Example 9 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dioxane solution containing 1 g of ethyl cellulose. The solution was frozen at −40 ° C. and then under reduced pressure of 100 mmHg or less. The solvent was removed by sublimation to obtain a completely amorphous solid of 10-acetyl-3 "-acetylmidecamycin.

2 g of this amorphous solid was collected, added to 100 ml of an aqueous solution containing 0.5 g of hydroxypropylcellulose and 35 g of sucrose, mixed and sufficiently dispersed to obtain a water suspension composition.

On the other hand, the above amorphous solid was dispersed in an aqueous solution containing hydroxypropyl cellulose but not sucrose in the same manner as above to prepare a water suspension composition (control composition).

When these water suspension compositions were respectively stored under a temperature condition of 50 ° C. and examined over time, the control composition exhibited a gel state in 3 days, whereas the water suspension composition of the present invention showed a gel state. A stable water suspension state was maintained even after 2 weeks had passed.

Preparation Example 10 and Comparative Example 10 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dioxane solution containing 1 g of ethyl cellulose. The solution was frozen at −40 ° C. and then under reduced pressure of 100 mmHg or less. The solvent was removed by sublimation to obtain a completely amorphous solid of 10-acetyl-3 "-acetylmidecamycin.

2 g of this amorphous solid was collected, added to 100 ml of an aqueous solution containing 1.5 g of hydroxypropyl cellulose and 40 g of sucrose, mixed and sufficiently dispersed to obtain a water suspension composition.

On the other hand, the above amorphous solid was dispersed in an aqueous solution containing sucrose but not hydroxypropylcellulose in the same manner as above to prepare a water suspension composition (control composition).

When these water suspension compositions were respectively stored under a temperature condition of 50 ° C. and examined over time, the control composition exhibited a gel state in 24 hours, whereas the water suspension composition according to the present invention A stable water suspension state was maintained even after 2 weeks had passed.

Production Example 11 and Comparative Example 11 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dioxane solution containing 1 g of ethyl cellulose. The solution was frozen at −40 ° C. and then under reduced pressure of 100 mmHg or less. The solvent was removed by sublimation to obtain a completely amorphous solid of 10-acetyl-3 "-acetylmidecamycin.

2 g of this amorphous solid was collected and 100 ml of an aqueous solution containing 1.0 g of hydroxypropylmethyl cellulose and 20 g of sucrose.
An aqueous suspension composition was obtained by adding the ingredients to the mixture and mixing them to sufficiently disperse them.

On the other hand, the above amorphous solid was dispersed in an aqueous solution containing sucrose and not containing hydroxypropylmethylcellulose in the same manner as above to prepare a water suspension composition (control composition).

When these water suspension compositions were respectively stored under a temperature condition of 50 ° C. and examined over time, the control composition exhibited a gel state in 24 hours, whereas the water suspension composition according to the present invention A stable water suspension state was maintained even after 2 weeks had passed.

Preparation Example 12 and Comparative Example 12 10 g of 10-acetyl-3 ″ -acetylmidecamycin was dissolved in 100 ml of a dioxane solution containing 1 g of ethyl cellulose. The solution was frozen at −40 ° C. and then under reduced pressure of 100 mmHg or less. The solvent was removed by sublimation to obtain a completely amorphous solid of 10-acetyl-3 "-acetylmidecamycin.

2 g of this amorphous solid was collected and 100 ml of an aqueous solution containing 0.5 g of hydroxypropyl cellulose, 20 g of sucrose, 0.5 g of sodium carboxymethyl cellulose, 0.5 g of sodium benzoate, 30 g of citrate buffer and 0.01 g of edible yellow No. 5
An aqueous suspension composition was obtained by adding the ingredients to the mixture and mixing them to sufficiently disperse them.

On the other hand, containing no hydroxypropyl cellulose,
The above amorphous solid was dispersed in an aqueous solution containing the above other components in the same manner as above to prepare a water suspension composition (control composition).

When these water suspension compositions were respectively stored under a temperature condition of 50 ° C. and examined over time, the control composition exhibited a gel state in 24 hours, whereas the water suspension composition according to the present invention A stable water suspension state was maintained even after 2 weeks had passed.

Production Example 13 and Comparative Example 13 5 g of midecamycin (trade name: medemycin) was dissolved in 100 ml of a dichloromethane solution. This solution was spray dried by a conventional method to obtain a completely amorphous solid of midecamycin.

1 g of this amorphous solid was collected and 100 ml of an aqueous solution containing 1.0 g of hydroxypropylmethylcellulose and 30 g of sucrose.
An aqueous suspension composition was obtained by adding the ingredients to the mixture and mixing them to sufficiently disperse them.

On the other hand, the above amorphous solid was dispersed in mere water containing no hydroxypropylmethylcellulose and sucrose in the same manner as above to prepare a water suspension composition (control composition).

When these water suspension compositions were respectively stored under a temperature condition of 40 ° C. and examined over time, the control composition exhibited a gel state in one week, whereas the water suspension composition according to the present invention showed a gel state. The stable water suspension state was maintained even after storage for 1 year.

(Effect of the Invention) When a macrolide antibiotic is formulated as a syrup, an aqueous suspension composition obtained by dispersing the amorphous solid bulk powder in a sucrose-containing aqueous solution is prepared according to a conventional method. Although it loses fluidity by gelling, gelling can be prevented or significantly delayed by coexisting a water-soluble cellulose-based polymer by the method of the present invention.

Therefore, the present invention enables the production of a stable macrolide antibiotic-containing syrup, and facilitates its storage management.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shinjiro Murata 580, Horikawa-cho, Sachi-ku, Kawasaki-shi, Kanagawa Meiji Confectionery Co., Ltd., Pharmaceutical Development Laboratory (56) Reference JP-A-56-542 (JP, A) JP Sho 53-145906 (JP, A)

Claims (1)

[Claims] 1. A non-crystalline solid bulk powder of a macrolide antibiotic, wherein a water-soluble cellulose polymer and sucrose are combined and blended, and the sucrose is an amorphous solid bulk powder of the macrolide antibiotic. A water suspension composition of a macrolide antibiotic compounded in a proportion of 20 to 40% by weight with respect to 2% by weight.