FIELD OF THE INVENTION

The present invention pertains to compounds, compositions, and methods of use for chemical compounds found to inhibit the primary human nicotine metabolizing enzyme, cytochrome P450 2A6 (CYP2A6). The compositions and methods of use may reduce a frequency at which products containing nicotine are consumed, and may reduce an exposure of individuals to carcinogenic substances over time.

BACKGROUND OF THE INVENTION

Nicotine is the addictive agent in cigarettes. Tobacco users alter their smoking behavior/smoke exposure to maintain nicotine plasma concentrations within a defined range (e.g., 10 to 50 ng/mL). Nicotine elimination occurs mainly through metabolism, and factors reducing nicotine metabolism may result in fewer cigarettes smoked per day due to nicotine concentrations being maintained for longer periods. Conversely, rapid nicotine metabolism may result in elevated smoking rates and carcinogen exposure, as smokers must increase nicotine exposure to maintain plasma concentrations. Although nicotine addiction is a complex disease involving many factors, nicotine plasma concentration is a central factor.

Tobacco addiction is the leading global cause of preventable death. Aside from contributing to preventable death, tobacco addiction poses other substantial problems, such as diverting funds from other important health problems, and disproportionately impacting lower income families/individuals. Considering the adverse impact of tobacco addiction on health, the current number of treatments for decreasing tobacco use is severely deficient. Unlike many disease states for which there are many treatment options to account for variability in patient response, currently there are only three pharmacological approaches approved by the U.S. Food and Drug Administration to treat nicotine addiction. These include nicotine replacement therapy, bupropion, and varenicline. Alternative approaches (e.g. meditation, hypnosis, and others) have been used but the effectiveness of these approaches is vague or has not been studied extensively. By contrast, there are 29 drugs for depression and 33 for diabetes, for example. Thus, there is a need for compounds that can reduce the urge to smoke (or consume other nicotine-containing products), thereby reducing a potential for adverse health implications.

Cytochrome P450 2A6 (CYP2A6) is an enzyme responsible for metabolizing 70-80% of a nicotine dose. CYP2A6 displays wide genetic variability with more than 37 known polymorphisms to date. Some of these polymorphisms result in a CYP2A6 enzyme with reduced nicotine metabolizing activity. Genetic-based differences in nicotine metabolism influence smoking behavior and cigarette smoke exposure. Indeed, individuals with CYP2A6 variants that are poor metabolizers of nicotine smoke fewer cigarettes and have higher smoking cessation success rates than individuals expressing a variant of the CYP2A6 enzyme that extensively metabolizes nicotine.

It has been previously shown that trans-cinnamaldehyde (t-CA), also referred to herein as CA), comprising a low-molecular weight phenylpropanoid present in cinnamon (which contributes to cinnamon's flavor and aroma and is a major component of cinnamon oil), is a mechanism-based irreversible inhibitor (MBI) of CYP2A6. MBIs are also often referred to as time-dependent inhibitors (TDI), particularly in the drug-drug interaction literature associated with the pharmaceutical industry and related guidance from the United States Food and Drug Administration.

It is herein recognized that genetic variability (>37 polymorphisms to date, as discussed above) with regard to CYP2A6 may result in t-CA being effective in inhibiting CYP2A6 in some cases (thereby slowing a rate at which nicotine is metabolized), while not being as effective in other cases. Thus, it is herein recognized that there may be particular structural analogs of t-CA which may be more effective in certain cases, as compared to others. Furthermore, it is herein recognized that there may be structural analogs of t-CA which are more potent than t-CA, and which may thus be more effective at reducing an urge to consume nicotine-containing products.

Another cytochrome p450 enzyme CYP2A13, is localized in the lung, and shows overlapping substrate specificity with CYP2A6. Specifically, it has been previously shown that CYP2A13 can catalyze the metabolism of nicotine. CYP2A13 also catalyzes the metabolism of tobacco-specific nitrosamines, which contributes to carcinogenic processes and lung cancer. Accordingly, it is herein recognized that particular structural analogs of t-CA may in some examples inhibit CYP2A13, which may reduce a rate at which nicotine is metabolized and also reduce the activation of tobacco-specific carcinogens to metabolites that alkylate DNA.

SUMMARY

The present disclosure provides compounds, compositions, and methods of use for such compounds and compositions that may possess improved ability to inhibit/inactivate CYP2A6. The improved ability may relate to an increased inhibition potency as compared to t-CA, for example. The improved ability may relate to a particular t-CA structural analog displaying increased potency for a particular CYP2A6 genotype, in other examples. Similarly, the improved ability may relate to a particular t-CA structural analog being more effective than other t-CA structural analogs (or t-CA itself) with regard to how nicotine is metabolized in a particular individual (e.g., whether the particular individual is an ultrafast, fast, intermediate, or slow metabolizer of nicotine). In some examples, the compounds, compositions and methods of use for such compounds and compositions may additionally or alternatively possess an ability to inhibit/inactivate CYP2A13.

The compounds of the present disclosure may include α-bromocinnamaldehyde, α-chlorocinnamaldehyde, 2-nitrocinnamaldehyde, 2-trifluoromethylcinnamaldehyde, 2,6-difluorocinnamaldehyde, 2-methoxycinnamaldehyde, 3-nitrocinnamaldehyde, 4-nitrocinnamaldehyde and 2-nitro-α-methylcinnamaldehyde, 2-nitro-α-ethylcinnamaldehyde, 2-nitro-α-propylcinnamaldehyde, 2-nitro-α-isopropylcinnamaldehyde, 2-nitro-α-butylcinnamaldehyde, 2-nitro-α-amylcinnamaldehyde, 2-nitro-α-hexylcinnamaldehyde, and hydrocinnamaldehyde. The above-mentioned compounds may be time-dependent inhibitors of CYP2A6 and/or CYP2A13. In some examples, a method for treating an individual with an addiction to nicotine may comprise administering to the individual one or more of the above-mentioned chemical structures, wherein a rate at which nicotine is metabolized is reduced upon administration of the compound to the individual. In such a method, a genetic variant of CYP2A6 may in some examples be determined, wherein selection of the compound to administer may be based on the genetic variant. In some examples, selection of the compound to administer may be based on whether the individual is an ultrafast, fast, intermediate, or slow metabolizer of nicotine. The one or more compounds may be administered orally to the individual.

Another embodiment of the present disclosure may include a pharmaceutical composition for reducing a rate at which nicotine is metabolized, where the pharmaceutical composition comprises one or more of the above-mentioned compounds (α-bromocinnamaldehyde, α-chlorocinnamaldehyde, 2-nitrocinnamaldehyde, 2-trifluoromethylcinnamaldehyde, 2,6-difluorocinnamaldehyde, 2-methoxycinnamaldehyde, 3-nitrocinnamaldehyde, 4-nitrocinnamaldehyde and 2-nitro-α-methylcinnamaldehyde, 2-nitro-α-ethylcinnamaldehyde, 2-nitro-α-propylcinnamaldehyde, 2-nitro-α-isopropylcinnamaldehyde, 2-nitro-α-butylcinnamaldehyde, 2-nitro-α-amylcinnamaldehyde, 2-nitro-α-hexylcinnamaldehyde, 2-methoxycinnamaldehyde, and hydrocinnamaldehyde). For such a composition, the rate at which nicotine is metabolized may be reduced based on the pharmaceutical composition inhibiting an enzyme (e.g., CYP2A6, CYP2A13) that metabolizes nicotine. The composition may in some examples further comprise an oil. Additionally or alternatively, the composition may further comprise a surfactant. Additionally or alternatively, the composition may further comprise a co-surfactant.

Another embodiment of the present disclosure includes structural analogs of t-CA (such as the compounds discussed above), additionally designed to specifically protect t-CA (or structural analogs thereof) from being degraded. Specifically, while t-CA is well-absorbed in the intestinal tract following oral administration, clearance is rapid, as the aldehyde group of t-CA (and structural analogs thereof) may be susceptible to metabolism by a variety of pathways. Thus, in one aspect of the present invention, the rate of t-CA (or structural analogs thereof) degradation may be reduced by utilizing a ‘prodrug’ oxime-ether form of t-CA (or structural analogs thereof), which may protect the aldehyde group from degrading as the t-CA (or structural analogs thereof) travels to its therapeutic target.

In another aspect of the disclosure, the rate of degradation of t-CA (or structural analogs thereof) may be reduced by, as a first example, utilizing a first formulation that includes a co-solvent solution using tri-block co-polymers. t-CA (and structural analogs thereof) may be incorporated into such tri-block co-polymers by a solvation method. In one example, the tri-block co-polymers (e.g., polaxamers) are selected based on an enhancement in the oral bioavailability of t-CA (and structural analogs thereof). However, other tri-block co-polymers may be used without departing from the scope of this disclosure. In some examples, block co-polymers comprising PEG-PCL or PEG-PLA, may be used to obtain higher drug concentrations.

In another aspect of the disclosure, a self-emulsifying drug delivery system (SEDDS) may be utilized to formulate a second formulation that includes t-CA or structural analogs thereof. Briefly, a SEDDS may comprise physically stable mixtures of oil, surfactants, co-surfactants and solubilized drug substances (e.g. t-CA and structural analogs thereof), which may then be administered orally (in soft or hard gelatin capsules for example). The oil may be a long chain triglyceride, a medium chain triglyceride, etc., with varying degrees of saturation. The surfactants may be anionic surfactants, cationic surfactants, ampholytic surfactants, nonionic surfactants, etc. Examples of anionic surfactants of the present disclosure include potassium laurate and sodium lauryl sulphate. An example of a cationic surfactant of the present disclosure includes quaternary ammonium halide. An example of ampholytic surfactants of the present disclosure include sulfobetaines. An example of nonionic surfactants of the present disclosure include sorbitan esters (Spans) and polysorbates (Tweens). In a gastrointestinal tract environment, the SEDDS may spontaneously emulsify. In developing the SEDDS, particular surfactant/particular mixtures of surfactants may be selected to match a Hydrophile-Lipophile Balance (HLB) value for t-CA oil (or structural analogs thereof). t-CA (and structural analogs thereof) loading and stability may be assessed by monitoring size and zeta potential. t-CA (and structural analogs thereof) release may be assessed by a dialysis method under sink conditions.

In this way, an individual's dependence on nicotine may be reduced. In some examples, by relying on the compounds, compositions, formulations and methods discussed herein, an individual may be able to completely quit their use of nicotine-containing products. Dosages and selection of particular compounds may in some examples be based on how an individual metabolizes nicotine. For example, a first compound may be administered to an individual who is determined to be a fast metabolizer of nicotine, whereas a second compound may be administered to an individual who is determined to be a slow metabolizer of nicotine. For example, the first compound may have a greater potency with regard to CYP2A6 inhibition, as compared to the second compound. In other examples, a same compound may be administered to both an individual that is a fast metabolizer of nicotine and an individual that is a slow metabolizer of nicotine, but a dosage may be greater for the individual that is the fast metabolizer, as compared to the individual that is the slow metabolizer. Determining whether an individual is a fast or slow (or in other examples also ultrafast and intermediate) metabolizer of nicotine may be accomplished by methodology readily available to those of ordinary skill in the art. As examples, nicotine metabolism in an individual may be measured (e.g., by monitoring nicotine metabolites as will be elaborated in further detail below), may be determined based on a genetic profile of CYP2A6 (or in some examples CYP2A13) for the individual, or may be qualitatively determined based on an interview or questionnaire provided to the individual who desires to reduce their dependence on nicotine.

It should be understood that the summary above is provided to introduce in simplified form a selection of concepts that are further described in the detailed description. It is not meant to identify key or essential features of the claimed subject matter, the scope of which is defined uniquely by the claims that follow the detailed description. Furthermore, the claimed subject matter is not limited to implementations that solve any disadvantages noted above or in any part of this disclosure.

