#drug development

Cancer-crushing Corals

From fluorescent jellyfish proteins to drug-inspiring cone snail toxins, marine animals are a biomedical treasure trove. Soft corals and their relatives, collectively known as octocorals, possess a vast library of particularly promising compounds, diterpenes, currently under investigation as potential drugs. Yet, with little understanding of how they are produced, synthesising them in the laboratory has proved difficult, hindering progress. In a recent breakthrough, researchers identified a cluster of genes involved in the synthesis of eleutherobin, a coral diterpene with potent anti-cancer activity, in the genome of the soft coral Erythropodium caribaeorum (pictured). Unlike in many marine animals, eleutherobin is not produced by a bacterial symbiont, a microbial partner living within the coral, but by the coral itself, and similar genes exist in other octocoral genomes, suggesting that diterpene production is an ancient adaptation. Elucidating this genetic pathway provides key tools for making coral diterpenes, boosting their potential for drug development.

Written by Emmanuelle Briolet

Image by Naturalis Biodiversity Center

Research by Paul D. Scesa, Zhenjian Lin & Eric W. Schmidt, Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA

Image originally published with a Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) license

Research published in Nature Chemical Biology, May 2022

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This is huge. As of 8/30/2023, the Federal Department of Health and Human Services wants the DEA to reclassify from schedule 1 (no medical use, completely verboten) to schedule 3 (widely accepted medical use, some abuse potential, similar to Tylenol 3).

It won’t just allow doctors to prescribe it and reduce the penalties for having it if you’re not “supposed to”; it’ll also make it much easier for researchers to do studies with it, giving us health data that is currently lacking. For example, we don’t know much about how THC and CBD affect the liver or liver enzyme levels except in end stage liver disease patients, and what data we do have is decades old and of poor to middling quality.

The expansion of research a Schedule 3 reclassification would allow could pave the way for a safe, non-addictive pain medication based on cannabinoids that works primarily on the CB2 receptors and either doesn’t pass the blood-brain barrier or does cross it but doesn’t cause euphoria or sedation in most patients. In other words, the holy grail of pain medicine. Currently, the only painkiller that utilizes the endocannabinoid system is acetaminophen (Tylenol), which is a weak reuptake inhibitor of anandamide but primarily works via the prostaglandin system, and which is also highly hepatotoxic and somewhat nephrotoxic, and which probably wouldn’t be approved except as prescription fever and pain management, the latter primarily as an adjuvant to opiates, if it were a new drug being reviewed by the FDA today.

In drug development, drug forming research, including pharmacodynamics, pharmacokinetics, and early safety evaluation of drugs, is required to determine whether the active compound has the potential to be developed into a pill. The drug-forming properties of drugs are also an essential part of the drug-forming evaluation, and salt formation is one of the effective means to improve the physicochemical properties of drug molecules and enhance drug-forming properties.

Many drugs are salts of organic acids or bases. The salt formation can make some oily organic acids or organic bases solid, which is conducive to preparing concrete dosage forms. Moreover, the salt formation of drugs increases the water solubility, which is conducive to preparing some aqueous dosage forms, such as water injection and oral liquid. The salt formation process is often a purification process, which removes the impurities mixed in the drug that cannot become salt, etc. So what are the benefits of salt formation in drug development studies?

1,Salt formation of drugs can change the solubility of drugs and improve drug-forming properties

The solubility of drugs affects their pharmacokinetic properties, chemical stability, and the choice of dosage form, which is an essential element in evaluating drug-forming properties. A salt formation can change the solubility of drugs and improve the water solubility of drugs through salt formation, which is the primary method to develop intravenous injections of drugs, such as the poor water solubility of diuretic etanercept, which is mainly available in tablet form.

Still, its sodium salt has better water solubility and can be used to prepare intravenous injections. The free base of the antipsychotic haloperidol is also marketed mainly as a tablet due to its low solubility. At the same time, its lactate can be used to prepare injectable solutions with improved solubility.

Sometimes it is necessary to prepare extended-release dosage forms by reducing the solubility of the drug. In this case, it is required to form a salt of the drug with an acid or base of higher relative molecular mass and hydrophobicity. For example, the commercially available dosage forms of antidepressant trazodone hydrochloride are tablets, oral solutions, etc. The study of trazodone in salt found that its p-toluenesulfonate and dihydroxynaphthalate are much less soluble in water than sulfate, and hydrochloride p-toluenesulfonate is more suitable for the preparation of slow-release oral formulation.

2,Salt formation can improve drug stability

Formulation evaluation also needs to rely more on data generated from pre-prescription research work, such as extreme pH, high temperature, freeze-thaw, light, forced oxidation, and other forced degradation experiments to understand the stability of drugs. Medicilon offers a full suite of chemical drug development services integrated from start to finish. We provide a one-stop service through pre-prescription studies, drug analysis, drug stability studies, formulation development, and complete CMC services.

The stability of the drug is directly related to its dosage form and the selection of production and packaging conditions, and it even affects the effect of the final preparation. Some researchers chose the insoluble phenazopyridine (PAP) as a model drug and improved the solubility and stability of phenazopyridine through drug co-crystals and salts.

The marketed product of phenazopyridine is phenazopyridine hydrochloride. Still, the peak plasma concentration in rats is only 10-20 ng after 200 mg dose administration, and it is for these reasons that the clinical application of PAP is limited. Therefore, the investigators prepared one eutectic formed by phenazopyridine with phthalimide (1) and two salts with 4-hydroxyphenyl acetic acid (2) and saccharin (3) by solution method and spiked grinding method, respectively, and their structures obtained by X-ray single crystal diffraction showed the presence of hydrogen bonding between phenazopyridine and all three eutectic ligands, collectively called hydrogen bonding complexes [1].

X-ray powder diffraction, DSC, and IR characterized it. The powder solubility of the three hydrogen-bonded complexes was measured, and the hygroscopicity of the solid powders was examined at 85% and 98% relative humidity for 1, 3, 5, 7, 10, 14, 21, and 28 days. The experimental results showed that the melting points of the three hydrogen-bonded complexes were all between phenazopyridine and eutectic ligands; the powder solubility of 1-3 was 10, 7.5, and 2 times that of PAP, respectively; the hygroscopicity was much lower than that of PAP and its hydrochloride under the conditions of 85% and 98% relative humidity. According to the above results, it is clear that 1-3 has a good prospect for improving the bioavailability and stability of phenazopyridine.

3,Salt formation can change drug compliance

Drug formulation should be safe, effective, stable, and easy for patients to accept, i.e., good compliance. An essential indicator of compliance with oral formulations is the acceptability of taste, which is particularly important when the drug is administered in liquid, chewable, or effervescent dosage forms. For example, the prerequisite for oral drugs to produce a taste response must first be dissolved in the mouth or taken in solution. Therefore, one of the ways to reduce the bitterness of orally administered drugs is to make them into poorly soluble salts and to make their saturated concentration below the threshold for producing taste sensation.

4,Into salt, can extend the patent protection of the drug or circumvent its patent protection

In the R&D process of new drugs, once an active compound is discovered, it is generally applied for a patent on its chemical structure to ensure the novelty of the patent. After the drug is marketed, the developer will further develop its derivatives, such as making salts or changing the crystal form and dosage form, and file subsequent patent applications to obtain the longest possible patent protection period. Nowadays, most new drugs marketed internationally use this type of patent protection.

In addition, drug salting can reduce adverse effects. In developing salt-forming drugs, the key is to select the acid or base with which the drug is salted. The selection of the acid or base should consider its pKa value and safety, as well as the route of administration and dosage form after salting. In conclusion, drug-forming studies and drug-forming evaluations can be conducted to determine the drug-forming properties of drugs better and improve the efficiency of new drug development.

Original Air Date: March 29th, 2020

Updates: Remdesivir, an anti-viral Dr. Fauci mentions in the video as a potential treatment, is looking very promising, as early trials indicate that patients who received it have a statistically significant shorter recovery time compared to the placebo group. It still needs to be subjected to more trials to further determine safety and efficacy, but Dr. Fauci and his team are optimistic and we all could use some good news! Here is an article from yesterday (May 8th, 2020) from the NIH which describes this further testing, and clinical trials for anti-inflammatory drug baricitinib.