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Stable medicinal compositions containing 4,5-epoxymorphinane derivatives

a technology of epoxymorphinane and stable composition, which is applied in the direction of drug compositions, aerosol delivery, inorganic non-active ingredients, etc., can solve the problems of undetermined stabilization method, 4,5-epoxymorphinan derivatives are chemically unstable to heat, light and oxygen, and the stability of compositions has not been determined. , to achieve the effect of stabilizing external preparations and achieving greater stability

Inactive Publication Date: 2001-06-21
TORAY IND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0030] In the present invention, sulfites, nitrites, ascorbic acids, thiol derivatives, hydroxyquinoline sulfate, or the like is used as a water soluble antioxidant. Phenolic compounds, fat soluble vitamins, ascorbic acid esters, fat soluble vitamins, nordihydroguaiaretic acid, mercaptobenzimidazole, or the like is used as a fat soluble antioxidant. EDTA, salts thereof, citric acid, salts thereof, lecithin, or the like is used as a synergist. The above-mentioned synergist shows a weak antioxidant effect by itself. However, the effect can be increased in combination with other antioxidants.

Problems solved by technology

However, the drug has severe adverse reactions such as being addictive and causing respiratory depression and constipation, which induces clinical problems.
Furthermore, the 4,5-epoxy-morphinan derivative does not show cross-tolerance with morphine or the like, and does not show an affinity for the .sigma. receptor.
However, the 4,5-epoxy-morphinan derivatives are chemically unstable to heat, light, and oxygen.
However, with respect to a 4,5-epoxy-morphinan derivative, a stabilized composition and a method of stabilization therefore has not been determined heretofore.

Method used

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  • Stable medicinal compositions containing 4,5-epoxymorphinane derivatives
  • Stable medicinal compositions containing 4,5-epoxymorphinane derivatives
  • Stable medicinal compositions containing 4,5-epoxymorphinane derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

(Prescription Example 1)

Injection

[0053]

4TABLE 3 Drug Isotonizing Additive Example 2 Dosage Form Content Agent Rate Comparative Injection 10 .mu.g / mL Sodium chloride 0.90% Example Test 1 Injection 10 .mu.g / mL Glucose 5.00% Test 2 Injection 10 .mu.g / mL Xylitol 5.00% Test 3 Injection 10 .mu.g / mL Mannitol 5.00% Test 4 Injection 10 .mu.g / mL D-sorbitol 5.00%

[0054] Stability test: After the aqueous solutions of Tests 1 to 4, and Comparative Example were subjected to nitrogen bubbling, they were sealed in ampoules. Then, after storage at a temperature of 80.degree. C. for seven days, the residual rates of Compound 1 were measured using a HPLC method (an UV method). Thus, stability after accelerated storage was estimated.

5TABLE 4 Isotonizing Storage Residual Example 2 Agent Additive Rate Conditions Rate (%) Comparative Sodium 0.90% Seal / 80.degree. C. / 7d 66.6 Example chloride Test 1 Glucose 5.00% Seal / 80.degree. C. / 7d 90.3 Test 2 Xylitol 5.00% Seal / 80.degree. C. / 7d 97.9 Test 3 Mannitol 5.00% ...

example 2

(Prescription Example 2)

Injection

[0057]

7TABLE 5 Additive Example 3 Dosage Form Drug Content Antioxidant Rate Comparative Injection 10 .mu.g / mL None Example Test 1 Injection 10 .mu.g / mL Sodium 0.10% thiosulfate Test 2 Injection 10 .mu.g / mL Sodium 0.50% thiosulfate Test 3 Injection 10 .mu.g / mL Sodium 1.00% thiosulfate

[0058] Stability test: The aqueous solutions of Tests 1 to 3, and that of Comparative Example were sealed in ampoules. Then, after sterilization by heating at a temperature of 120.degree. C. for 60 minutes, the purities of Compound 1 in the samples were measured using a HPLC method (an UV method). Thus, pharmaceutical stability after sterilization was estimated.

8TABLE 6 Additive Purity Example 3 Antioxidant Rate Storage Conditions (%) Comparative None Seal / 120.degree. C. / 60 min 98.95 Example Test 1 Sodium 0.10% Seal / 120.degree. C. / 60 min 99.57 thiosulfate Test 2 Sodium 0.50% Seal / 120.degree. C. / 60 min 99.44 thiosulfate Test 3 Sodium 1.00% Seal / 120.degree. C. / 60 min 99.53 ...

example 3

(Prescription Example 3)

Granule

[0061]

9 Compound 1 100 mg Sodium thiosulfate 0 to 1 g Avicel PH-101 31 g Lactose Balance volume Total 100 g

[0062]

10TABLE 7 Dosage Additive Example 4 Form Drug Content Antioxidant Rate Comparative Granule 100 .mu.g / 100 mg None Example Test 1 Granule 100 .mu.g / 100 mg EDTA 0.10% Test 2 Granule 100 .mu.g / 100 mg Citric acid 0.10% Test 3 Granule 100 .mu.g / 100 mg Propyl gallate 0.10% Test 4 Granule 100 .mu.g / 100 mg Butyl 0.10% Hydroxyanisole Test 5 Granule 100 .mu.g / 100 mg Tocopherol 0.10% Test 6 Granule 100 .mu.g / 100 mg Sodium 0.10% thiosulfate Test 7 Granule 100 .mu.g / 100 mg Sodium 0.20% thiosulfate Test 8 Granule 100 .mu.g / 100 mg Sodium 0.50% thiosulfate Test 9 Granule 100 .mu.g / 100 mg Sodium 1.00% thiosulfate

[0063] Stability test: Immediately after manufacturing the granules of Tests 1 to 9 and that of Comparative Example, the purities of Compound 1 were measured using a HPLC method (an UV method). Thus, pharmaceutical stability was estimated.

11TABLE 8 Ad...

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Abstract

A stable pharmaceutical composition includes a 4,5-epoxy-morphinan derivative, and includes at least one of the group consisting of a water soluble antioxidant, a fat soluble antioxidant, a synergist, a sugar, and a surfactant.

Description

[0001] The present invention relates to a stable pharmaceutical composition including 4,5-epoxy-morphinan derivative or pharmacologically acceptable acid-addition salts thereof. More particularly, the present invention relates to a stable pharmaceutical composition including 4,5-epoxy-morphinan derivative which includes 4,5-epoxy-morphinan derivative as an effective component and includes a water soluble antioxidant, a fat soluble antioxidant, a synergist, a sugar, or a surfactant, and also relates to a method for stabilizing the pharmaceutical composition.[0002] Morphine has a significant analgesic effect and is indicated for conditions such as postoperative pain and cancer pain. However, the drug has severe adverse reactions such as being addictive and causing respiratory depression and constipation, which induces clinical problems. Therefore, morphine is an analgesic which demands meticulous care.[0003] Recently, it has become clear that opiate receptors may be classified into th...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K9/06C07D489/08A61K9/08A61K9/16A61K9/20A61K9/48A61K31/485A61K47/00A61K47/02A61K47/04A61K47/06A61K47/10A61K47/12A61K47/14A61K47/16A61K47/18A61K47/20A61K47/22A61K47/26A61K47/34A61P25/04A61P43/00
CPCA61K9/0014A61K31/485A61K47/02A61K47/10A61K47/14A61K47/183A61K47/20A61K47/22A61K47/26A61P25/04A61P43/00
Inventor HANAMURA, NOBUYUKIHORIUCHI, YASUHIDEYOSHII, RYOJIAOKI, TAKAOHARA, MICHIO
Owner TORAY IND INC
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