Naltrexone injectable sustained release formulation

A technology of sustained-release preparations and injections, applied in the field of injection-type sustained-release pharmaceutical preparations, which can solve problems such as complex manufacturing processes, difficult drug delivery procedures, and fluctuations in release curves

Active Publication Date: 2021-08-06
ALAR PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these formulations still have disadvantages such as complex manufacturing process, difficult drug delivery procedures, low drug loading and fluctuating release profiles

Method used

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  • Naltrexone injectable sustained release formulation
  • Naltrexone injectable sustained release formulation
  • Naltrexone injectable sustained release formulation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of naltrexone derivative

[0044] Naltrexone derivatives were synthesized using conventional methods as described below. Naltrexone hydrochloride was mixed with dichloromethane in a three-neck round bottom flask to form a suspension, which was then placed in an ice bath to cool. Then triethylamine was slowly added into the three-neck round bottom flask under stirring, and then the acid chloride with 1 to 20 carbons was added. Esterification was carried out under nitrogen at ambient temperature, and the reaction mixture was neutralized with saturated aqueous sodium bicarbonate. The organic layer was washed with brine, then dried over sodium sulfate, then concentrated under reduced pressure. The crude naltrexone derivative of 3-acylnaltrexone was purified by silica gel column chromatography.

Embodiment 2

[0045] Embodiment 2: Preparation of injection-type sustained-release pharmaceutical preparation

[0046] Add 15wt% to 70wt% of the naltrexone derivative to a glass vial and dissolve in one or a combination of two or more biocompatible organic solvents, such as N-methyl-2-pyrrolidone (NMP) , ethyl acetate, ethanol (EtOH), butanol, 2-butanol, isopropanol (IPA), isobutanol, glycerin, benzyl benzoate (BnBzO), dimethylsulfoxide (DMSO), propylene glycol ( PG), dimethyl glycol, N,N-dimethylacetamide (DMAc), and benzyl alcohol.

[0047] Alternatively, 15% to 70% by weight of a naltrexone derivative and a biocompatible polymer material of poly(D,L-lactide) and poly(D,L-lactide / glycolide) Add it into a glass vial at a molar ratio of 75:25 or 50:50, and then dissolve in one or a combination of two or more biocompatible organic solvents, such as N-methyl-2-pyrrolidone, ethyl acetate, Ethanol, Butanol, 2-Butanol, Isopropanol, Isobutanol, Glycerin, Benzyl Benzoate, Dimethyl Sulfoxide, Pro...

Embodiment 3

[0052] Embodiment 3: In vitro dissolution test of injectable sustained-release pharmaceutical preparation

[0053] The in vitro dissolution profiles of formulations NL003, NL005, NL006, NL007, NL008 and NL010 prepared in Example 2 were evaluated respectively. Formulations NL005, NL006, NL007 and NL008 were each mixed in a single tube with a dissolution medium which was phosphate buffered saline containing 0.1% sodium lauryl sulfate and 0.02% sodium azide, and formulations NL003 and NL010 were each mixed in a single tube with dissolution media in phosphate buffered saline containing 0.2% sodium lauryl sulfate and 0.02% sodium azide. Each test tube was shaken at 60 rpm in a 37°C water bath. 1 mL samples were withdrawn from each tube at specific time points and applied to HPLC for naltrexone derivative and naltrexone free base analysis. Refill each tube with 1 mL of fresh dissolution medium. The dissolution rate profiles for formulations NL005, NL006, NL007 and NL008 are shown...

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Abstract

Provided is an injectable sustained release pharmaceutical formulation, including 3-acyl-naltrexone or a pharmaceutically acceptable salt thereof, a biocompatible organic solvent, and optionally a biocompatible polymeric material. Also provided is a method for treating opioid use disorder or alcoholism, including administering the injectable sustained release pharmaceutical formulation to a subject in need thereof. The pharmaceutical formulation provides a sustained release profile after one single injection, and the plasma levels of naltrexone in minipigs could provide a sustained release for 2 months.

Description

technical field [0001] The present disclosure relates to injectable sustained release pharmaceutical formulations, particularly injectable sustained release pharmaceutical formulations comprising naltrexone derivatives. The present disclosure also relates to the treatment of opioid use disorder (OUD) or alcohol use disorder (AUD), also known as A method for alcohol addiction (alcoholism). Background technique [0002] Naltrexone is 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one, a derivative of thebaine, belonging to opiate alkaloids family. The structure of naltrexone is shown in the following formula I, and its molecular weight is 341.40. [0003] [0004] As a competitive antagonist with high affinity for μ receptors, naltrexone has a strong potential to compete with other full agonists (such as morphine or heroin, etc.). Naltrexone is twice as antagonistic as naloxone and is indicated for the treatment of opioid and alcohol addiction in various do...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): A61K9/10A61K31/44A61P25/30A61P25/36
CPCA61P25/30A61P25/36A61K31/485A61P25/32A61K9/0019A61K47/10A61K47/14A61K47/18A61K47/20A61K47/22A61K47/34A61K9/08A61K9/0024A61K47/32
Inventor林东和文永顺刘映廷吴致榕
OwnerALAR PHARMA INC