ORALLY DELIVERABLE FORMULATION TO PREVENT ALL CAUSE MORTALITY AND CARDIOVASCULAR EVENTS

The present disclosure describes materials and methods for providing the health benefits associated with chili peppers and cannabis to subjects in need thereof. For example, an oral formulation including at least one tissue from a fruit of the Capsicum genus, an extract therefrom, or a combination thereof, at least one cannabinoid, and a pharmaceutically acceptable excipient is provided. The oral formulation can be an oral spray, compressed tablet, or a candy-style lozenge.

FIELD OF THE INVENTION

The invention relates generally to combination products that include cannabis or extracts therefrom with chili peppers or extracts therefrom.

BACKGROUND OF THE INVENTION

Diets rich in chili peppers (fruit ofCapsicumplants) have been shown to offer material health benefits. In particular, a diet rich with chili peppers has been associated with a reduction in all-cause mortality and cardiovascular events (Spence, J Am Coll Cardiol. 2019 December, 74 (25) 3150-3152; Bonaccio et al., J Am Coll Cardiol. 2019 December, 74 (25) 3139-3149). The health advantages associated with chili peppers are frequently ascribed to the high content of capsaicin, which is far more abundant in chili than in sweet non-spicy peppers. Cannabis and extracts therefrom have also been shown to confer meaningful health benefits. Thus, there is a need in the art of nutritional supplements and pharmacotherapy to develop new products using both chili peppers and cannabis for easy administration of these protective and beneficial compounds.

SUMMARY

The present disclosure describes materials and methods for providing the health benefits associated with chili peppers and cannabis to subjects in need thereof.

In a first aspect, the present disclosure provides an oral formulation including at least one at least one tissue from a fruit of a species ofCapsicum, an extract therefrom, or a combination thereof; at least one cannabinoid; and a pharmaceutically acceptable excipient. The tissue can be dried and ground. The oral formulation can include about 10 mg to 1000 mg tissue or about 100 mg to 500 mg tissue. The oral formulation can include a quantity of tissue sufficient to achieve a predetermined amount of polyphenol, flavonoid, or capsaicin in the formulation. The tissue and extract can lack or substantially lack capsaicin. The tissue is selected from a cultivar of theCapsicumspecies with a Scoville heat unit (SHU) value of less than 50,000. The oral formulation can be an oral spray. The oral formulation can be a compressed tablet. The oral formulation can be a candy-style lozenge. The oral formulation can further contain at least one sugar alcohol. The oral formulation can further contain a hydrocolloid selected from the group consisting of gelatin, gum acacia, carob gum, carrageenan, ghatti gum, guar gum, karaya gum, pectin, tragacanth gum, locust bean gum, xanthan gum and combinations thereof. The pharmaceutically acceptable excipient can be selected from the group consisting of emulsifiers, surfactants, colorants, flavorants, taste modifiers, buffering agents, pH adjusting agents, stabilizers, sweeteners and combinations thereof. The at least one cannabinoid can be a water-soluble powder including a cannabinoid oil, isomalt, a hydrocolloid, and an emulsifier. The hydrocolloid can be gum acacia (AKA gum Arabic) and the emulsifier can be quillaja extract.

In a second aspect, the present disclosure provides a method for improving health of a subject in need thereof comprising administering to the subject an oral formulation comprising: at least one tissue from a fruit of a species ofCapsicum, an extract therefrom, or a combination thereof; at least one cannabinoid; and a pharmaceutically acceptable excipient. The oral formulation can be administered at least once a week for four weeks. The oral formulation can be administered at least three times a week.

In a third aspect, the present disclosure provides a method for reducing the probability of a cardiac event in a patient in need thereof comprising administering to the patient an oral formulation comprising: at least one tissue from a fruit of a species ofCapsicum, an extract therefrom, or a combination thereof; at least one cannabinoid; and a pharmaceutically acceptable excipient.

DETAILED DESCRIPTION

These and other systems, methods, objects, features, and advantages of the present disclosure will be apparent to those skilled in the art from the following detailed description of the embodiments and drawings.

All documents mentioned herein are hereby incorporated in their entirety by reference. References to items in the singular should be understood to include items in the plural, and vice versa, unless explicitly stated otherwise or clear from the text. Grammatical conjunctions are intended to express any and all disjunctive and conjunctive combinations of conjoined clauses, sentences, words, and the like, unless otherwise stated or clear from context.

As used herein, “all-cause mortality” refers to the lowering effect of the intervention on the risk of death occurring in a population, regardless of the cause, as compared to estimates for all-cause mortality adjusted for one or more of age, sex, educational level, occupational class, smoking, leisure-time physical activity, cardiovascular disease, cancer, drugs for diabetes, lipid-lowering drugs, medication for hypertension, diet and energy intake (kcal/day).

The term “candy-style lozenge” as used herein refers to a solid preparation that is intended to dissolve or disintegrate slowly in the mouth, keeping the active ingredients in contact with the oral cavity for an extended period of time. A candy-style lozenge can be made by compression or molding, include one or more of flavorings, colorings, and sweeteners. A candy-style lozenge can be hard, soft or chewable, and include forms such as lozenges include lollipops and gummies.

The term “cardiac event” as used herein refers to any severe or acute cardiovascular condition, including, but not limited to cardiac arrest, myocardial infarction, coronary artery disease, ECG evidence of past myocardial infarction or newly recognized left bundle branch block, angina, coronary artery bypass grafting, chest pain without significant coronary artery disease, obstructive coronary stenosis, coronary artery spasm, myocardial bridge, coronary angioplasty and exertion-induced cardiac events.

The term “tissue” as used herein refers to one or more plant tissues or organs which are obtained from a whole plant or plant parts, preferably a cannabis orcapsicumplant. Plant parts include vegetative structures (for example, leaves, stems), roots, floral organs/structures, seed (including embryo, endosperm, and seed coat), plant tissue (for example, vascular tissue, ground tissue, and the like) and cells. The plant part can be fresh or dried (e.g., powdered).

The term “extract” as used herein with respect toCapsicumfruit refers to water, organic solvent (e.g., hexane), and oil extracts of ripe or unripe fruit or powders thereof. The extracted composition can be spray dried to provide aCapsicumfruit extract as a powder. The extract includes at least one of the endogenous phytocompounds present in the source tissue, such as capsaicin, dihydrocapsaicin, nordihydrocapsaicin, omocapsaicins I and II, octyl-, nonyl-, and decylvanillamide, capsanthin, kryptxanthin, zeaxanthin, capsorubin, lutein; α-, β-, and neo-o-carotene, β-carotene epoxide, ascorbic acid, provitamins A, B1, B2, C, E, and PP, nicotinic acid amide, tocopherols, cynaroside, quercetin, apiin, luteolin-7-monoglucoside, capsicoside, citric and malonic acid, 2-methoxy-3-isobutylpyrazine, citrozanthin, violaxanthin, and capsorubin.

In addition to the naturally occurring cannabinoids, a virtually unlimited number of synthetic cannabinoids, with cannabinomimetic properties, exist and are subject to additional creation and or modification. Some of the known synthetic cannabinoids include, but are not limited to: rimonabant, JWH-018, JWH-073, CP-55940; dimethylheptyran; HU-210; HU-331, SR144528, WIN 55,212-2, JWH-133, Levonantradol (Nantrodolum), AM-2201, etc.

In some embodiments the cannabinoids and/or combinations thereof may be processed to improve hydrophilicity using any methods known to those having skill in the art, including but not limited to the creation of emulsions, micro emulsions, nanoemulsions, encapsulation, complexation with solubility enhancers such as, for example, with a cyclodextrin, including but not limited to beta cyclodextrins, sulfobutylether beta cyclodextrins and the like; and complexation with sugar alcohols such as, for example erythritol, isomalt and the like.

Various cannabinoids, used alone or in combination have shown a variety of significant biological effects including but not limited to pain relief, anti-cancer, anti-inflammatory, anti-emetic, anti-convulsant, and many others, including recreational effects.

The formulations described herein can be delivered to a patient/subject, in need of any one of these biological effects using any form suitable for cannabinoid delivery via a desired route of administration. Examples of suitable forms include but are not limited to the products listed in TABLE 2.

There are five major species of cultivatedCapsicum, C. annuum, C. chinense, C. baccatum, C. frutescens, C. pubescens, and within those species are several “taxonomic varieties”. Because of the ability of many of species to cross and generate inter-specific hybrids, albeit with low success, there are also what is referred to as “complexes” within the genusCapsicumof closely related and sexually compatible species. This includes theCapsicum annuumcomplex, which includes three closely related species,C. annuum, C. frutescens, andC. chinense. The Major species and their taxonomic varieties include:Capsicum annuum, which includes bell peppers, sweet/Italian peppers, serrano, cayenne, paprika and jalapeños;Capsicum baccatum, which includes the South American varieties, such as aji amarillo, aji limon and criolla sella;Capsicum chinense, which includes all of the Habaneros, Scotch Bonnets, Trinidad Scorpions, the Bhut Jolokia and the Carolina Reaper;Capsicum frutescens, which includes the Tabascos and many of the peppers grown in India; sometimes not distinguished as a species separate fromC. annuum; andCapsicum pubescens, which includes the Rocoto and Manzano pepper, and are distinctive plants in having violet flowers, black seeds and hairy dark green leaves and grows as a large, multi-stemmed vine up to 5 meters long.

The species and varieties include many economically important cultivars with different shapes, colors, and flavors that are grown for different purposes, such as spices, vegetables, and herbal medicines. See TABLE 3 for a non-limiting list of cultivars identified by their common names. Some confusion has resulted from the legal term “plant variety”, which is used interchangeably with “cultivar” (not with “taxonomic variety”). The terminology around a cultivar also includes terms such as heirloom, open-pollinated, self-pollinating, and hybrid.

Heirloom varieties are typically those that have been selected and grown historically with seed saved every year, and are still maintained today in similar fashion, such as the blocky-type California Wonder. Open-pollinated varieties are those that are maintained without strict barriers to prevent outcrossing and then seed is collected at and stored from each harvest such as the lamuyo-type Marconi Yellow. While open-pollinated varieties are typically true-to-type, there may be occasional outcrossing to otherCapsicumvarieties that may introduce some heterogeneity.

Hybrid varieties take advantage of a phenomenon called heterosis or hybrid vigor, which occurs in pepper. To generate a hybrid variety, two self-pollinated varieties are intentionally crossed, and all seed from this cross are collected. The new hybrid variety typically is more vigorous than either of the two parents contributing to traits such as higher yield. Hybrid seed if saved will not produce a homogeneous set of plants the next generation, meaning that the two parents will need to be crossed again to generate more hybrid seed. This method is used to produce hybridCapsicumcultivars such as the blocky-types Double-Up and Orange Blaze. Much of the commercial pepper production uses hybrid varieties for their improved traits.

Fruit of various species ofCapsicumcontain many classes of phytochemicals with important and/or interesting pharmacological activity. These include but are not limited to polyphenols, flavonoids, carotenoids, ascorbic acid, free radical scavengers, and capsaicinoids. In some embodiments of the present disclosure, the selection of the species ofCapsicumto include in the formulation is based on the polyphenol, flavonoid, carotenoid, antioxidant/free radical scavenger, and capsaicinoid content of the tissue.

Compounds known as capsaicinoids cause the spicy flavor (pungency) of chili pepper fruit. There is a linear correlation between concentration of capsaicinoids and Scoville scale (SHU). Capsaicinoid content of a chili pepper may vary during ripening. The primary capsaicinoid in chili pepper is capsaicin, followed by dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin and homocapsaicin. Capsaicin and dihydrocapsaicin account for approximately 90% of capsaicinoids in chili pepper fruit, are the two most potent capsaicinoids and their molecules differ only in the saturation of the acyl group. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a crystalline, lipophilic, colorless and odorless alkaloid with the molecular formula C18H27NO3. Its molecular weight is 305.40 g/mol, and it is fat-, alcohol- and oil-soluble. Capsaicin displays cis/trans isomerism because the double bond prevents internal rotation. Capsaicin is always found as the trans isomer because in the cis form, the —CH(CH3)2and the longer chain on the other side of the double bond will be close together, causing them to repel each other slightly; this steric hindrance does not exist in the trans isomer.

Capsaicin can bond to transient receptor potential vanilloid 1 (TRPV1), previously known as the vanilloid receptor, which is mainly expressed in the sensory neurons. This receptor is a non-selective, ligand-operated cationic channel located primarily in the small fibers of nociceptive neurons. TRPV1 is also broadly distributed in tissues of the brain, bladder, kidneys, intestines, keratinocytes of epidermis, glial cells, liver, and polymorphonuclear granulocytes, mast cells, and macrophages. It couples with a non-specific cation channel permeable to sodium and calcium ions, and is located in the plasma membrane and the endoplasmic reticulum where regulates intracellular calcium levels. This channel can be regulated and activated by endogenous substance as endovanilloids and diverse exogenous stimuli including chemical agonists as capsaicin, olvanil and resiniferatoxin, ligands highly lipophilic that share structural similarity to several endogenous fatty acids identified as TRPV1 agonists. Some compounds are being used as antagonists for TRPV1, including capsazepine, iodo-resiniferatoxin, ruthenium red, A-425619, SB-366791, AMG9810, and SB-705498. The TRPV1 contains a heat-sensitive subunit responsible for the burning sensation caused by capsaicin. Bonding of capsaicin to TRPV1 increases intracellular calcium, triggering release of neuropeptides such as substance P and the calcium gene-related peptide. Contact between capsaicin and sensory neurons produces pain, inflammation and a localized heat sensation. When applied locally to skin, it promotes an analgesic response due to desensitizing of the sensory neurons caused by substance P depletion. This mechanism has served as a base for studies of the structure-activity relationship which are aimed at development of new synthetic ligands for the TRPV1. Capsaicin's effects in the nervous system are not exclusively analgesic. A number of studies include results showing that it participates in release of somatostatine, CGRP and endotheline.

D. Other Active Ingredients

In some embodiments, the formulation includes one or more added essential oils selected from Sweet Orange (Citrus sinensisspp), Peppermint (Mentha piperitaspp), Lemon (Citrus limonspp), Lavender (Lavendula angustifoliaspp) andVanilla(Vanilla planifoliaspp). In some embodiments, the cannabis oil extract includes Vitamin E and one or more essential oils selected from Sweet Orange (Citrus sinensisspp), Peppermint (Mentha piperitaspp), Lemon (Citrus limonspp), Lavender (Lavendula angustifoliaspp) andVanilla(Vanilla planifoliaspp).

In one or more embodiments of the present disclosure the formulation comprising a cannabinoid and a tissue of theCapsicumfruit or an extract therefrom is an oral formulation for transmucosal delivery via the buccal route, labial route, gingival route or sublingual route or to be swallowed. Exemplary oral formulations include buccal gel, film, gum, chewable tablet or lozenge, orally disintegrating tablet, hard lozenge or lollipop, and liquids (e.g., solution or suspension). The oral formulations are prepared by mixing the active ingredients with one or more inactive ingredients, such as pharmaceutically acceptable excipients. In some cases, the one or more pharmaceutically acceptable excipients can be selected from sugar alcohols such as sorbitol, xylitol, maltitol, mannitol, isomalt, erythritol and combinations thereof, hydrocolloids, such as gelatin, gum acacia, carob gum, carrageenan, ghatti gum, guar gum, karaya gum, pectin, tragacanth gum, locust bean gum, xanthan gum and combinations thereof, and emulsifiers, surfactants, colorants, flavorants, taste modifiers, buffering agents, pH adjusting agents, stabilizers, and sweeteners.

In some embodiments the oral solution is packaged in order to facilitate the delivery of single doses, such as, for example, with a medicine dropper or in a spray/spritz-style package.

In some embodiments the oral formulation is a compressed tablet comprising chili pepper or a suitable extract therefrom along with at least one cannabinoid with a quantity of total cannabinoid of about 0.01 mg to 500 mg, along with at least one excipient to facilitate tablet compression. The content of chili pepper, or extract thereof can be varied based on the polyphenol, flavonoid, carotenoid, antioxidant/free radical scavenger, or capsaicinoid content of the tissue.

In some embodiments the oral formulation is a candy-style lozenge comprising chili pepper or suitable extract therefrom, along with at least one cannabinoid with a quantity of total cannabinoid of about 0.01 mg to 500 mg along with appropriate lozenge ingredients. The content of chili pepper, or extract thereof can be varied based on the polyphenol, flavonoid, carotenoid, antioxidant/free radical scavenger, or capsaicinoid content of the tissue. For example, in some cases, the amount of chili pepper or extract therefrom, varies based on capsaicin content to minimize unwanted pungency/heat.

In some embodiments the oral formulation is chewable. In some embodiments the oral formulation is a time released formulation. In some embodiments the oral formulation has been formulated to delay release of one or more of the active ingredients until the formulation has reached the stomach, small intestine, or large intestine respectively.

In some embodiments the active ingredients have been further formulated to facilitate parenteral delivery.

In some embodiments the formulations of the present invention are made by combining a formulated sugar alcohol intermediate to provide the at least one cannabinoid to the final formulation. The sugar alcohol formulated intermediate may be prepared by the procedure of the following Examples, which illustrate an embodiment of the present disclosure and should not be construed as to narrow its scope.

EXAMPLES

Sugar Alcohol Intermediate

Calculate quantities of the one or more cannabinoid containing oils to add in order to achieve a desired potency/concentration and/or cannabinoid ratio. Heat oil, or oils, to workable fluidity (e.g., 50-60° C.).

For cannabinoid mixtures, add each cannabinoid containing oil into a clean appropriately sized vessel until reaching quantity setpoints determined by formulation calculations (±1 g desired mass). Seal vessel and heat, mixing well until homogeneous. Measure density of CO Formulate by pulling 1 mL in a pipette, taring the scale, and emptying pipette back into vessel as (average of pulls in triplicate). Confirm the concentration/ratio by quantitating the cannabinoids of interest in the CO Formulate via HPLC or other suitable analytical technique. Adjust formulation as needed to achieve target cannabinoids amount and/or ratio and verify adjusted formulation by HPLC or other suitable analytical technique.

ii. Prepare a Solvent Formulate:

Calculate quantities of CO Formulate and solvent (ethanol) needed. Heat CO Formulate to workable fluidity (50-60° C.). Slowly adding each component in an appropriately sized vessel until reaching setpoints determined by formulation calculations (1 g desired mass). Typical ratio is 1:1, i.e., 1 part CO Formulate to 1 part 200 proof ethanol, or similar solvent or mixture thereof. The Ethanol Formulated is sonicated in a bath sonicator.

In some cases, the Ethanol Formulate is homogenized with a probe sonicator. A taller, thinner vessel is preferred over a shorter, wider one for sonication. Sanitize probe by wiping with 200 proof ethanol before sonicating. Run sonicator per manufacturer's recommendations according to substrate volume, viscosity, composition, etc. Place vessel containing Ethanol Formulate in ice bath to keep solution cool during sonication. (e.g., dry ice and ethanol or water when available, or mixture of ice, water, and rock salt). Set temperature probe and sonicator probe in vessel. The tip of the sonicator probe should be about ⅓ from top of Ethanol Formulate. Ensure the sonicator probe never touches any glass or metal.

During the sonication process, the vessel is watched to verify it does not move or touch sonication probe. If temperature exceeds setpoint, the program should automatically pause. When this happens, wait for solution to reach below 30° C. and restart program. When finished, remove vessel from sonicator. Clean sonicator and temperature probes. Dispose of ice bath. The homogenized Ethanol Formulate is filtered (e.g., a 200 nm filter).

Melt sugar or sugar alcohol. While isomalt is exemplified, other sugars or sugar alcohols can also be used. It takes about 55 minutes to melt 800 g isomalt in one 9″×13″ Pyrex baking dish. Larger quantities of isomalt can take several hours to melt completely. Using figures from Formulation calculations to provide a specific dose of cannabinoid (e.g., 10 mg/per dosage unit) measure isomalt into each Pyrex baking dish until total amount is achieved. Heat isomalt in oven until it becomes a uniform, clear liquid. Remove from oven immediately to avoid discoloration and off flavors (a burnt flavor).

While isomalt is heating, prepare mixing equipment and additional components (Quillaja extract (emulsifier) and gum Arabic (hydrocolloid)). A mixing container (such as a silicone pot or stainless pot) is cleaned and sanitized. When added to the isomalt, the quillaja extract will cause foaming. A suitably sized container will be at least 3 or 4 times the volume of the isomalt. Pre-measure quillaja extract per Formulation calculations in small beaker. Pre-measure gum Arabic in small beaker. When the isomalt is a clear, hot liquid, remove from oven and empty into silicone pot. While stirring, pour quillaja extract and half of the gum Arabic into isomalt. Keep stirring until foaming subsides and mixture is uniform in color.

Per Formulation calculations, add pre-determined amount of Ethanol Formulate. One method is to tare scale with vessel containing Ethanol Formulate. Pour Ethanol Formulate until scale shows the desired quantity has been removed. It is better to over-pour than to under-pour as the concentration can be reduced in the Final Formulation as needed. Ethanol will start evaporating once it hits hot isomalt, thereby removing the ethanol. This step should be done in a fume hood whenever possible. Keep stirring until color is uniform.

While hot, pour the molten mixture of isomalt, quillaja extract, gum Arabic, and cannabis oil mixture out onto suitable surface and spread, while hot, as thin of a layer as possible. Allow to cool to room temperature to solidify. The cooling process can be accelerated by cooling on and/or under dry ice.

iv. Prepare the Sugar Alcohol Intermediate

Once the isomalt formulate is completely cooled (no longer tacky and at room temperature) it can be broken into smaller pieces, aka “shards”. The hardness can be tested with a clean utensil—if the isomalt formulate does not allow deformation with a pointed utensil, it is ready to be broken. Cover the isomalt formulate to prevent isomalt shards from flying during the breaking process. Use hammer or hands or other suitable tools to break the solid sheet of isomalt formulate into small pieces.

Add the isomalt formulate shards to a collection vessel. Get a final weight of isomalt formulate added. Add remaining gum Arabic as a lubricant for size reduction. Total gum Arabic content is 1-2% of the mass of the isomalt formulate. Mix as well as possible to ensure the maximum amount of isomalt formulate is coated with gum Arabic powder. Record the amount of gum Arabic added. Mill Isomalt Formulate Shards into a powder of desired particle size using a mill or other appropriate equipment. The bulk powder was subjected to mechanical separation and filtering to provide a powder having a particle size of no greater than 600 microns.

Exemplary Dosage Forms Containing the Sugar Alcohol Intermediate and Chili Pepper or Extract

The resulting water-soluble cannabinoid powder can be combined with at least one tissue from fruit of aCapsicumspecies (e.g., sweet or hot chili pepper) or extract therefrom and suitable tabletting excipients using conventional amounts, equipment, and methods for direct compression of a specific dosage of cannabinoid. Alternatively, the soluble cannabinoid powder can be combined with at least one extract or powder from a fruit of aCapsicumspecies, as active ingredients of a solution or suspension (e.g., an oral spray) with one or more inert ingredients, selected from the group consisting of organic solvents, emulsifiers, flavor modifiers, and antifoam agents, in oil or water. The solution or suspension can be dispensed from an atomizer or nebulizer, or other means for producing droplets of liquid.

In some embodiments of an oral formulation, the dosage form includes about 10 mg to 1000 mg per dose of the tissue, powder, or extract of theCapsicumspecies, such as about 100 mg to 500 mg per dose.

All formulations described are to be made in accordance with methods known to those having skill in the art and utilizing standard excipients, diluents, and processes.

While the present disclosure includes many embodiments shown and described in detail, various modifications and improvements thereon will become readily apparent to those skilled in the art. Accordingly, the spirit and scope of the present invention is not to be limited by the foregoing examples, but is to be understood in the broadest sense allowable by law.

With respect to the above, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangement of the components listed or the steps set forth in the description or illustrated in the drawings. The various apparatus and methods of the disclosed invention are capable of other embodiments, and of being practiced and carried out in various ways that would be readily known to those skilled in the art, given the present disclosure. Further, the terms and phrases used herein are for descriptive purposes and should not be construed as in any way limiting.

As such, those skilled in the art will appreciate that the conception upon which this disclosure is based may be utilized as a basis for designing other inventions with similar properties. It is important therefore that the embodiments, objects, and claims herein, be regarded as including such equivalent construction and methodology insofar as they do not depart from the spirit and scope of the present invention.