Abuse-resistant long-acting release opioid prodrugs

A pharmaceutical and compound technology applied in the field of anti-abuse long-acting release opioid prodrugs, which can solve the problems of limited success of formulation technology

Inactive Publication Date: 2021-10-22
SUZHOU RUNXINDATAI PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Formulation technology has had limited success in developing abuse-deterrent opioid products

Method used

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  • Abuse-resistant long-acting release opioid prodrugs
  • Abuse-resistant long-acting release opioid prodrugs
  • Abuse-resistant long-acting release opioid prodrugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Embodiment 1—synthesis of levorphanolate prodrug

[0108]

[0109] Exemplary Procedure for Preparation of Levorphanol Palmitate (n=14). Fatty acid (palmitic acid) and sulfonyl chloride (>10 molar equivalents) were added to a dry round bottom flask. The mixture was refluxed at 85° C. for 2 hours in an oil bath. The liquid sulfonyl chloride was removed under vacuum using a rotary evaporator and further using an oil pump. anhydrous CH 2 Cl 2 Add to the mixture. The added solvent was then removed under vacuum using a rotary evaporator and further using an oil pump. Will add and remove anhydrous CH 2 CH 2 The procedure was repeated three times to ensure that residual sulfonyl chloride was removed. The obtained pale yellow crystals were used in the next reaction without further purification.

[0110] Levorphanol tartrate salt (1.0 molar equiv) and triethylamine (4.0 molar equiv) were dissolved in anhydrous CH in a round bottom flask 2 Cl 2 middle. Place the flask...

Embodiment 2

[0117] Embodiment 2—Synthesis of morphine ester prodrug

[0118]

[0119] According to the method described in Example 1, using morphine chloride salt instead of compound 5-8, morphine monoesters with n being 12, 14, 16 and 20 were prepared respectively. Morphine diesters can also be prepared by a similar method, except that 2 equivalents or more of the acid chloride are used. Other monoesters can be prepared similarly, although protection / deprotection methods can be used to increase reaction yields.

Embodiment 3

[0120] Example 3 - Stability Study Under Tampering Conditions

[0121] Prodrugs were subjected to common tampering conditions including 1.0 M baking soda (pH = 8.3), vinegar (5% acetic acid, pH = 2.5) and vodka (40% alcohol) at 80 °C, and chlorine gas at 25 °C and hydrogen peroxide. The final incubation mixture contained 10 [mu]M test compound in a final volume of 0.5 mL of tamper medium. The prodrug is added to start the incubation. At 0 min, 30 min, and 60 min, 0.05 mL aliquots were removed from the incubation mixture, quenched with 0.15 mL methanol, and placed on ice. Aliquots were removed for analysis. Concentrations of prodrug and parent drug were analyzed by LC-MS / MS to compare prodrug stability.

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Abstract

There are provided, prodrugs of opioid such as levorphanol or morphine, having enhanced physical and chemical stability to resist tampering and to make long- acting release formulations, and pharmaceutically accepted salts and solvates thereof. There are also provided methods of using the disclosed compounds as abuse deterrent products.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 793,684, filed January 17, 2019, the contents of which are incorporated herein by reference in their entirety. technical field [0003] In various embodiments, the present invention relates generally to abuse-deterrent products for use in combating the abuse of prescription opioids. For example, in some embodiments, the invention relates to the preparation and use of abuse-resistant extended-release opioid products. Background technique [0004] Prescription opioids, including morphine and levorphanol, are widely used, for example, to treat pain. Prescription opioid misuse is an "epidemic" in the United States with heavy social and economic costs. Despite the heavy social and economic costs of prescription opioid misuse, opioids are critical to improving care and treatment outcomes for the 100 million adults in the United States living with chron...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/485A61P25/04A61P25/36
CPCA61P25/36A61P25/04A61K31/485A61K47/14C07D215/14C07D491/08
Inventor 欧阳晖
Owner SUZHOU RUNXINDATAI PHARMA LTD
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