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Long-acting injectable formulations and crystalline forms of buprenorphine derivatives

A crystalline, formalized technology for the treatment of opioid dependence, pain, and depression that addresses problems without significant burst effects

Active Publication Date: 2020-11-17
ALAR PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Although the above existing pharmaceutical formulations are able to provide prolonged release of buprenorphine, there is still a need to develop formulations with better properties, such as formulations free of organic solvents, to reduce the risk of local site irritation, or to have higher bioavailability bioavailability, or a pharmacokinetic profile with less fluctuations, and no significant burst effect after a single injection

Method used

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  • Long-acting injectable formulations and crystalline forms of buprenorphine derivatives
  • Long-acting injectable formulations and crystalline forms of buprenorphine derivatives
  • Long-acting injectable formulations and crystalline forms of buprenorphine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1: Synthesis of 3-acyl-buprenorphine derivatives

[0081] Described below is the method used to synthesize 3-acyl-buprenorphine derivatives. Add the suspension of buprenorphine hydrochloride and dichloromethane (DCM) to a suitable three-neck round bottom flask and place in an ice bath to cool. Then, trimethylamine (TEA) was slowly added under stirring, and acid chloride was added dropwise into the flask. After all materials were added, the ice bath was stopped. The reaction mixture was reacted at ambient temperature for 1 to 4 hours, and the reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, then dried over sodium sulfate. After condensation under reduced pressure, crude buprenorphine derivatives were obtained (Table 1).

[0082] Table 1. Synthetic conditions for various 3-acyl-buprenorphine derivatives

[0083]

Embodiment 2

[0084] Example 2: Crystallization of 3-acyl-buprenorphine derivatives

[0085] The following is the crystallization method of 3-acyl-buprenorphine derivatives. The crude 3-acyl-buprenorphine derivatives were dissolved in the solvents described in Table 2 at ambient temperature or in a heated oil or water bath. Then, the dissolved mixture was cooled in an ice bath to form a crystalline 3-acyl-buprenorphine derivative.

[0086] Table 2. Crystallization conditions for 3-acyl-buprenorphine derivatives

[0087]

[0088] The crystalline 3-acyl-buprenorphine derivative obtained above was characterized by XRD, DSC, NMR and IR.

[0089] The crystalline form of buprenorphine acetate is characterized by an X-ray diffraction pattern (Bruker, D8 DISCOVER SSS multipurpose thin-film X-ray diffractometer), with peaks at 4.70, 8.44, 9.38, 10.74, 12.42, 14.12 , 17.72, 18.40, 18.78, 20.08, 20.56, 25.04, 26.88, 28.42, 28.46 degrees 2θ ( figure 1 ), and its melting point was determined to b...

Embodiment 3

[0097] Example 3: Solubility of buprenorphine derivatives and their salt forms in dissolution media

[0098] An excess of compound (including buprenorphine free base, buprenorphine derivative or its salt form) was weighed into a glass tube containing 5 mL of dissolution medium. The medium is the same as the previous embodiment. The tube was then sealed and placed in a reciprocating shaker at 60 rpm in a 55°C water bath. The solution was filtered through a 0.45 μm nylon filter, and then the filtrate was further diluted with acetonitrile, and the content of each compound was determined by HPLC.

[0099] Table 3. Solubility of Buprenorphine Derivatives

[0100]

[0101] Table 4. Solubility of buprenorphine derivative salt forms

[0102]

[0103]

[0104] Table 3 shows that the buprenorphine derivative (crystalline form) is less soluble than its parent compound (buprenorphine free base). The crystalline form of buprenorphine decanoate is nearly 10 times less soluble t...

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Abstract

Disclosed are crystalline forms of 3-acyl-buprenorphine derivatives and sustained release injectable pharmaceutical compositions for treatment of opioid dependence, pain or depression, including an aqueous suspension of crystalline 3-acyl-buprenoprhine, or a pharmaceutically acceptable salt thereof, wherein the composition does not include an organic solvent, a polylactide polymer, a polyglycolidepolymer, or a copolymer of polylactide and polyglycolide. The disclosure also includes 3-acyl-buprenoprhine or a pharmaceutically acceptable salt thereof prepared in a controlled release matrix, including poly (lactide-co-glycolide), sucrose acetoisobutyrate, lecithin, diolein and a combination of two or more thereof.

Description

technical field [0001] The present disclosure relates to crystalline forms and formulations of buprenorphine derivatives. In particular, the present disclosure relates to injectable compositions comprising buprenorphine derivatives or metabolites or prodrugs thereof, uses thereof, and the use of such buprenorphine derivatives or metabolites or prodrugs thereof for the treatment of opioid dependence , pain and depression treatments. Background technique [0002] Buprenorphine ((5α,7α(s))-17-cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro -3-Hydroxy-6-methoxy-α-methyl-6,14-vinylidenemorphinan-7-methanol) is a derivative of thebaine and belongs to the opioid alkaloids. The structure of buprenorphine is shown in the following formula (formula I), and molecular weight is 467.64: [0003] [0004] As a partially potent μ-receptor agonist, buprenorphine has a high affinity that can compete with other full agonists (eg morphine, methadone, etc.). Buprenorphin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D489/12A61K31/485A61P1/10A61P29/00A61P25/30
CPCA61P29/00C07D489/12A61P25/30A61P1/10A61K31/485A61K9/0019A61K9/10A61K9/1647A61K47/24A61K47/26A61P25/36A61P25/24C07B2200/13A61K9/08A61K9/5031A61K47/34C07D489/04
Inventor 林东和文永顺梁芮玮
Owner ALAR PHARMA INC
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