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Myrcene-containing complex mixtures targeting trpv1

A composition and technology of cannabinoids, applied in the direction of drug combination, active ingredients of hydrocarbon compounds, active ingredients of hydroxyl compounds, etc., can solve the problems of highly irritating sensitive areas, and cannot solve problems such as visceral pain, bone pain disorder, etc.

Pending Publication Date: 2020-03-24
GBS GLOBAL BIOPHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Second, the use of high-affinity and high-specificity TRPV1 agonists, such as capsaicin, causes high levels of discomfort during the initial treatment period (period prior to desensitization)
It is for this reason that TRPV1-mediated desensitization cannot currently be used to address postherpetic pain due to the highly irritating treatment of sensitive areas such as the gastric and genital mucosa
Third, capsaicin-mediated desensitization is limited to topical use; this therapy does not address visceral pain, headaches, and certain musculoskeletal pain disorders
However, currently there are no TRPV1 agonists suitable for systemic administration and for the long-term downregulation of TRPV1 in visceral organs, so there is a need to develop such methods in a similar manner to the chronic pain methods described above

Method used

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  • Myrcene-containing complex mixtures targeting trpv1
  • Myrcene-containing complex mixtures targeting trpv1
  • Myrcene-containing complex mixtures targeting trpv1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0227] 4.10.2. Example 2: Cell culture system for testing TRPV1-mediated calcium response

[0228] HEK293 cell line was stably transfected with pcDNA6TR (Invitrogen, CA) plasmid (encoding tetracycline-sensitive TREx repressor protein) and kept at 37°C in 5% humidified CO 2 In DMEM+10% fetal bovine serum (inactivated at 55°C for 1 hour)+2mM glutamine in atmosphere. Selective pressure on TRex 293 cells was maintained by continuous culture in 10 μg / ml elastin (Sigma, St Louis, MO).

[0229] To generate TRex HEK293 cells with inducible expression of TRPV1, parental cells were electroporated with rat TRPV1 cDNA in pcDNA4TO vector and clones were selected by limiting dilution in the presence of 400 μg / ml zeocin (Invitrogen, CA) cell line. TRPV1 expression was induced with 1 μg / ml tetracycline for 16 hours at 37°C. Stable lines were screened for inducible protein expression using anti-FLAG western blot and inducible expression was confirmed. Electrophysiological measurements furt...

Embodiment 3

[0231] 4.10.3. Example 3: TRPV1-Mediated Calcium Influx in Response to Strain A Mixture, Cannabinoid Mixture or Terpene Mixture

[0232] TRPV1 -mediated calcium influx was tested in response to the strain A mixture, the cannabinoid mixture and the terpene mixture as described above. Each mixture was applied to cell culture medium to expose the cells to the final concentrations of the various components provided in Table 1 ("concentration μg / ml"). For example, cells were exposed to 5.6 μg / ml cannabidiol (CBDV), 8.75 μg / ml myrcene, etc. using the strain A mixture.

[0233] Figure 2A to Figure 2C Calcium flux data measured as Fluo-4 relative fluorescence units (Fluo-4 RFU) as a function of time (seconds) are presented. like Figure 2A to Figure 2C As shown, it was observed that in response to the application of the strain A mixture ( Figure 2A ) and terpene mixtures ( Figure 2C ) significant calcium flux, but in response to the application of cannabinoid mixture ( Figur...

Embodiment 7

[0254] 4.10.7. Example 7: Desensitization of myrcene to TRPV1

[0255] The TRPV1 agonistic effects of various concentrations of myrcene and capsaicin were compared. Specifically, the areas under the curve (AUC) of the calcium response curves of myrcene and capsaicin were calculated respectively and plotted in Figure 14Aat the corresponding concentration in . Higher concentrations of myrcene were required to induce the same calcium influx as capsaicin. For example, myrcene at about 200 nM and capsaicin at about 30 nM induce calcium influx to a similar extent when the extent of calcium influx is determined from the AUC of the calcium response curve between 20 nM and 300 nM.

[0256] The long-term effects of myrcene and capsaicin on TRPV1 were also compared. like Figure 14B As shown, both myrcene and capsaicin caused desensitization of TRPV1 after 24 hours of exposure to each compound. For example, when myrcene was first introduced into cells expressing TRPV1, myrcene indu...

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Abstract

Provided herein are pharmaceutical compositions that comprise myrcene, optionally in admixture with cannabinoids and other terpenes, typically substantially free of THC and THCA, for targeting TRPV1 receptors. Also provided are methods of using the pharmaceutical compositions to desensitize TRPV1 receptors in order to treat pain, cardiovascular diseases such as cardiac hypertrophy, overactive bladder, and chronic cough.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 62 / 509,546, filed May 22, 2017, the entire disclosure of which is hereby incorporated by reference for all purposes. [0003] 1. Background technology [0004] Channels of the transient receptor superfamily (TRP), such as TRPV1 , TRPM8 and TRPA1 , are non-selective cation channels that conduct calcium and sodium into various cell types in mammals. They are present on sensory neurons due to their molecular binding to plant secondary metabolites that are nociomimetic (such as capsaicin) and to irritating and simulating burning or cooling compounds (such as allicin , cinnamaldehyde, menthol), initially identified as playing a role in nociception. [0005] Due to their role in nociception, TRP channels have been identified as targets for the treatment of pain disorders. Both antagonism and agonism of TRP channels have been used for pain control. For exam...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K45/06A61K31/01A61K31/015A61K31/045A61K31/05A61K31/192A61K31/352A61P9/00A61P11/14A61P13/10A61P29/00A61P43/00
CPCA61K9/0014A61K45/06A61K31/015A61K31/045A61K31/05A61K31/192A61P29/02A61K9/0019A61K31/01A61K31/352A61K2300/00A61K9/006A61K9/0073A61K36/185A61K2236/51
Inventor A·斯马尔-霍华德H·特纳
Owner GBS GLOBAL BIOPHARMA INC
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