Cannabinoid lipid premix

Abstract

The present invention relates to a powder premix for oral administration of cannabinoids, comprising a cannabinoid powder composition comprising one or more isolated cannabinoids in an amount of at least 2% by mass of the powder premix, a lipid composition comprising one or more triglycerides in an amount of at least 1.0% by mass of the powder premix, and a sweetener powder composition comprising one or more sweeteners, wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:1.

Description

Technical Field

[0001] Field of the Invention The present invention relates to the field of cannabinoids. In particular, the present invention relates to a powder premixture for oral administration of cannabinoids.

Background Art

[0002] Background of the Invention Cannabinoids are a group of chemicals found in Cannabis sativa, Cannabis indica, Cannabis ruderalis, marijuana plants and related plant species. They are known to activate cannabinoid receptors (CB1 and CB2). These chemicals are also produced endogenously in humans and other animals. Cannabinoids are cyclic molecules that exhibit unique properties, such as being lipophilic, having the ability to easily cross the blood-brain barrier, and having low toxicity.

[0003] Cannabis sativa contains over 400 chemicals as well as approximately 120 cannabinoids which are the active constituents of cannabis, such as tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV) and cannabigerol (CBG). Pharmacologically, the main psychoactive constituent of cannabis is tetrahydrocannabinol (THC), which is used in the treatment of a wide range of medical conditions, such as glaucoma, AIDS wasting, neuropathic pain, spasticity associated with multiple sclerosis, fibromyalgia, and chemotherapy-induced nausea. THC is also effective in the treatment of allergies, inflammation, infection, depression, migraine, bipolar disorder, anxiety disorders, drug dependence and drug withdrawal syndromes.

[0004] Oral administration of cannabinoids is a common route of administration. Cannabinoids are highly lipophilic, i.e., soluble in lipids and some organic solvents while being substantially insoluble or only slightly soluble in water. Cannabinoids are soluble in highly nonpolar solvents. Some of these solvents are not pharmaceutically acceptable and it is necessary to use pharmaceutically acceptable solvents at high concentrations to form a solution.

[0005] Regarding oral formulations for the delivery of cannabinoids, various solutions have been proposed in the prior art. Among these solutions, solid dosage forms, lozenges, chewing gums and pouches have been proposed. These solutions may have certain benefits regarding the oral delivery of cannabinoids, such as CBD or THC, but these solutions mainly focus on either the release from the application form or any specific component that enables effective absorption of the cannabinoid into the mucosa.

[0006] Generally, not much attention has been paid to the accurate dosing of cannabinoids and the reliability of formulating cannabinoids, such as CBD or THC, into oral formulations. As an example, homogeneous products are beneficial but are to some extent offset by the nature of cannabinoids, which are highly lipophilic and thereby may interact with the remaining components of the oral formulation.

[0007] Improved homogeneity has been desired in the prior art, but the solutions provided so far have traditionally been considered less suitable, taking into account the desire to provide, among other things, immediate-release products. The available means for providing improved homogeneity have shown drawbacks while at the same time there is a need to provide immediate release of cannabinoids.

[0008] In the formulation of solid dosage forms, there are various problems associated with obtaining a homogeneous mixture in which variations are avoided and safe and convenient delivery can be achieved. Also, there is no need to compromise the general formulation of tablets that provide convenience to the user, as is often the case when conventional delivery means are applied.

[0009] Furthermore, it is preferred that a formulation be provided that can also help to obtain improved sensory properties for oral cannabinoid delivery. Here, the important sensory properties include abrasion, texture, flavor perception, sweetness perception, and off-notes associated with cannabinoids. These properties are important from the perspective of convenience in solid dosage forms, but are also important to ensure proper delivery of cannabinoids from tablets and to avoid harmful side effects of cannabinoids.

[0010] Another problem is that cannabinoids tend to have off-notes during administration due to certain physicochemical properties of the compounds. The problem of taste masking is more severe when higher-release cannabinoids are delivered. If the off-note is the dominant sensation during administration, convenience may be affected, and more seriously, cannabinoid delivery may also be affected.

Prior Art Documents

Patent Documents

[0011]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Non-Patent Documents

[0012]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Summary of the Invention

Problems to be Solved by the Invention

[0013] Therefore, powders and formulations that solve the above-mentioned problems and issues of the prior art are needed in the prior art. In particular, powders applicable in various dosage forms, such as tablets, pouches, chewing gum agents, and troches, having a suitable uniformity in the cannabinoid content and providing suitable sensory properties are needed in the prior art. In particular, these formulations are also acceptable or improved with respect to taste masking and are desired to provide the desired release during administration.

Means for Solving the Problems

[0014] Summary of the Invention Accordingly, there is provided a powder premix for oral administration of cannabinoids, comprising a cannabinoid powder composition comprising at least 2% by mass of one or more isolated cannabinoids in an amount of the powder premix, a lipid composition comprising at least 1.0% by mass of one or more triglycerides in an amount of the powder premix, and a sweetener powder composition comprising one or more sweeteners, wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:1.

[0015] In another aspect of the invention, there is provided an oral dosage form in which this powder is incorporated, for example, partially or completely.

[0016] In yet another aspect, there is provided a method for preparing a powder premix for oral administration of cannabinoids.

[0017] One advantage of the present invention is that accurate dosing of cannabinoids and reliability in formulating cannabinoids, such as CBD or THC, into oral formulations can be provided. By way of example, homogeneous products, while beneficial, are highly lipophilic and are thus somewhat offset by the nature of the cannabinoids, which can interact with the remaining components of the oral formulation.

[0018] Traditionally, the solutions provided heretofore have been considered less suitable, taking into account the desire to provide, among other things, immediate-release products. The means already available for providing improved homogeneity have shown drawbacks while at the same time the need to provide immediate release of cannabinoids is required.

[0019] One prejudice in the prior art is that highly lipophilic cannabinoids cannot be properly formulated with other components in powder or solid dosage forms without impairing other components and interactions within the system.

[0020] Another advantage is that the formulations according to the present invention can also help to obtain improved sensory properties for oral cannabinoid delivery. Here, the important sensory properties include abrasion, texture, flavor perception, sweetness perception and off-notes associated with cannabinoids. These properties are important from a convenience perspective in solid dosage forms, but are also important to assist in the proper delivery of cannabinoids from solid dosage forms and to avoid harmful side effects of cannabinoids.

[0021] Yet another advantage is that the present invention can help to address off-notes during administration. The problem of taste masking is more severe when higher release cannabinoids are delivered by such solid dosage forms. If off-notes are the dominant sensation during administration, convenience may be affected, and more seriously, cannabinoid delivery may also be affected.

[0022] Surprising results were seen in terms of improved uniform content. Generally, the method used for the content uniformity of samples is determined when using test method 2.9.40 Uniformity of dosage units according to the European Pharmacopoeia 10.8. The acceptance value (AV) is calculated using mass variation (MV) or content uniformity (CU) depending on the dose and ratio of the active ingredient. For content uniformity, it is selected to use an appropriate analytical method, for example, standard HPLC techniques.

[0023] When attempting to obtain a highly uniform distribution, insufficient mixing may lead to non-uniform distribution, such as undesirable aggregation of particles within a particular portion of a solid dosage form. Also, even when the components are mixed very well, undesirable handling of the mixture from mixing to the tablet press may lead to segregation. For example, smaller particles typically segregate to the bottom of the container, which may lead to different particle distributions in different solid dosage forms. Especially when different components have different particle sizes, segregation may lead to different contents in different solid dosage forms.

[0024] When compared to the powder in which the lipid composition according to the present invention was not applied in a formulation containing a cannabinoid powder composition, the uniform content was inferior. This was very surprising to the inventors of the present invention and was not expected considering the prior art attempts to provide suitable solutions.

[0025] In some embodiments of the present invention, a series of at least 5 samples taken from the powder mixture being analyzed, each having the same fixed mass in the range of 0.25 to 2 g, vary with a relative standard deviation (RSD) of less than 10% with respect to the content of one or more cannabinoids.

[0026] In some embodiments of the present invention, a series of at least 5 samples taken from the powder mixture being analyzed, each having the same fixed mass in the range of 0.25 to 2 g, vary with a relative standard deviation (RSD) of less than 5% with respect to the content of one or more cannabinoids.

[0027] In some embodiments of the present invention, a series of at least 5 samples taken from the powder mixture being analyzed, each having the same fixed mass in the range of 0.25 to 2 g, vary with a relative standard deviation (RSD) of less than 2% with respect to the content of one or more cannabinoids.

[0028] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:50 to 1:2. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:50 to 1:3. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:50 to 1:4. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:50 to 1:5. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:50 to 1:6. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:50 to 1:7.

[0029] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:50 to 1:10.

[0030] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:40 to 1:10. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:40 to 1:12. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:40 to 1:15. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more sweeteners is in the range of 1:40 to 1:20.

[0031] In some embodiments of the present invention, one or more triglycerides are of plant origin. In some embodiments of the present invention, one or more triglycerides do not contain triglycerides of animal origin.

[0032] In some embodiments of the present invention, one or more triglycerides are selected from one or more C4 to C14 triglycerides. In some embodiments of the present invention, one or more triglycerides are selected from one or more C4 to C12 triglycerides. In some embodiments of the present invention, one or more triglycerides are selected from one or more C6 to C14 triglycerides. In some embodiments of the present invention, one or more triglycerides are selected from one or more C6 to C12 triglycerides. In some embodiments of the present invention, one or more triglycerides are selected from one or more C6 to C10 triglycerides. In some embodiments of the present invention, one or more triglycerides are selected from one or more C8 to C12 triglycerides. In some embodiments of the present invention, one or more triglycerides are selected from one or more C8 to C10 triglycerides.

[0033] In some embodiments of the present invention, one or more triglycerides include partially hydrogenated vegetable oil. In some embodiments of the present invention, one or more triglycerides include fully hydrogenated vegetable oil (HVO).

[0034] In some embodiments of the present invention, one or more triglycerides are selected from triglycerides that are liquid at 0 °C or higher.

[0035] In some embodiments of the present invention, one or more triglycerides are a blend of multiple triglycerides, such as a blend of corn oil and oleic acid, such as a blend of corn oil and oleic acid in a ratio of 1:3 to 3:1.

[0036] In some embodiments of the present invention, one or more triglycerides are heated to a temperature above room temperature before being added to the premix.

[0037] In some embodiments of the present invention, one or more triglycerides are heated to a temperature of 50 to 80 °C before being added to the premix. In some embodiments of the present invention, one or more triglycerides are heated to a temperature of 50 to 70 °C before being added to the premix. In some embodiments of the present invention, one or more triglycerides are heated to a temperature of 50 to 60 °C before being added to the premix. In some embodiments of the present invention, one or more triglycerides are heated to a temperature of 60 to 70 °C before being added to the premix. In some embodiments of the present invention, one or more triglycerides are heated to a temperature of 40 to 80 °C before being added to the premix. In some embodiments of the present invention, one or more triglycerides are heated to a temperature of 40 to 70 °C before being added to the premix.

[0038] In some embodiments of the present invention, one or more triglycerides are selected from triglycerides that are liquid at 20 °C or higher. In some embodiments of the present invention, one or more triglycerides are selected from triglycerides that are liquid at 25 °C or higher. In some embodiments of the present invention, one or more triglycerides are selected from triglycerides that are liquid at 30 °C or higher. In some embodiments of the present invention, one or more triglycerides are selected from triglycerides that are liquid at 40 °C or higher.

[0039] In some embodiments of the present invention, one or more triglycerides are selected from triglycerides having a melting temperature of 25 to 50 °C. In some embodiments of the present invention, one or more triglycerides are selected from triglycerides having a melting temperature of 25 to 40 °C. In some embodiments of the present invention, one or more triglycerides are selected from triglycerides having a melting temperature of 30 to 40 °C. In some embodiments of the present invention, one or more triglycerides are selected from triglycerides having a melting temperature of 30 to 50 °C.

[0040] In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 50 to 80% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 50 to 70% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 50 to 90% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 60 to 90% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 65 to 80% by mass.

[0041] In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 20 to 45% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 20 to 50% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 20 to 40% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 20 to 35% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 25 to 50% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 25 to 40% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 30 to 50% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 30 to 45% by mass. In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 20 to 30% by mass.

[0042] In some embodiments of the present invention, one or more triglycerides contain capric acid in an amount of 65 to 80% by mass and capric acid in an amount of 20 to 35% by mass.

[0043] In some embodiments of the present invention, one or more triglycerides comprise capric acid in an amount of 50 to 65% by mass and capric acid in an amount of 30 to 45% by mass.

[0044] In some embodiments of the present invention, one or more triglycerides comprise coconut oil and / or corn oil and / or oleic acid. In some embodiments of the present invention, one or more triglycerides consist essentially of coconut oil and / or corn oil and / or oleic acid. In some embodiments of the present invention, one or more triglycerides are coconut oil and / or corn oil and / or oleic acid.

[0045] In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 1.5% by mass of the powder premix.

[0046] In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 2.0% by mass of the powder premix.

[0047] In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 2.5% by mass of the powder premix.

[0048] In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 3.0% by mass of the powder premix.

[0049] In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 4.0% by mass of the powder premix.

[0050] In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 5.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 6.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 7.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 8.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 9.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 10.0% by mass of the powder premix.

[0051] In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 15.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 20.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 25.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of at least 30.0% by mass of the powder premix.

[0052] In some embodiments of the present invention, one or more triglycerides are present in an amount of from 1 to 30.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of from 1 to 25.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of from 1 to 20.0% by mass of the powder premix.

[0053] In some embodiments of the present invention, one or more triglycerides are present in an amount of 2 to 30.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of 2 to 25.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of 2 to 20.0% by mass of the powder premix.

[0054] In some embodiments of the present invention, one or more triglycerides are present in an amount of 5 to 30.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of 5 to 25.0% by mass of the powder premix. In some embodiments of the present invention, one or more triglycerides are present in an amount of 5 to 20.0% by mass of the powder premix.

[0055] In some embodiments of the present invention, one or more sweeteners are present in an amount of at least 40% by mass of the powder premix.

[0056] In some embodiments of the present invention, one or more sweeteners are present in an amount of at least 50% by mass of the powder premix.

[0057] In some embodiments of the present invention, one or more sweeteners are present in an amount of at least 60% by mass of the powder premix.

[0058] In some embodiments of the present invention, one or more sweeteners are present in an amount of at least 70% by mass of the powder premix.

[0059] In some embodiments of the present invention, one or more sweeteners are present in an amount of at least 75% by mass of the powder premix.

[0060] In some embodiments of the present invention, one or more sweeteners are present in an amount of at least 80% by mass of the powder premix. In some embodiments of the present invention, one or more sweeteners are present in an amount of at least 90% by mass of the powder premix. In some embodiments of the present invention, one or more sweeteners are present in an amount of at least 95% by mass of the powder premix.

[0061] In some embodiments of the present invention, one or more sweeteners are selected, alone or in combination, from the group consisting of saccharide-containing components such as sucrose, dextrose, maltose, saccharose, lactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, fructose, levulose, galactose, corn syrup solids, glucose syrup, and the like. These sugar sweeteners may also be included as humectants.

[0062] In some embodiments of the present invention, one or more sweeteners include dextrose. In some embodiments of the present invention, one or more sweeteners are dextrose.

[0063] In some embodiments of the present invention, one or more sweeteners include dextrin. In some embodiments of the present invention, one or more sweeteners are dextrin.

[0064] In some embodiments of the present invention, one or more sweeteners include sucrose. In some embodiments of the present invention, one or more sweeteners are sucrose.

[0065] In some embodiments of the present invention, one or more sweeteners include fructose. In some embodiments of the present invention, one or more sweeteners are fructose.

[0066] In some embodiments of the present invention, one or more sweeteners include one or more sugar alcohols.

[0067] In some embodiments of the present invention, the one or more sugar alcohols are selected from the group consisting of sorbitol, xylitol, maltitol, isomalt, mannitol, erythritol, lactitol, and combinations thereof.

[0068] In some embodiments of the present invention, the one or more sugar alcohols are selected from the group consisting of xylitol, erythritol, maltitol, mannitol, and combinations thereof.

[0069] In some embodiments of the present invention, the one or more sugar alcohols include xylitol. In some embodiments of the present invention, the one or more sugar alcohols are xylitol.

[0070] In some embodiments of the present invention, the one or more sugar alcohols include erythritol. In some embodiments of the present invention, the one or more sugar alcohols are erythritol.

[0071] In some embodiments of the present invention, the one or more sugar alcohols include mannitol. In some embodiments of the present invention, the one or more sugar alcohols are mannitol.

[0072] In some embodiments of the present invention, the one or more sugar alcohols include maltitol. In some embodiments of the present invention, the one or more sugar alcohols are maltitol.

[0073] In some embodiments of the present invention, the one or more sugar alcohols include granulated sugar alcohol particles.

[0074] In some embodiments of the present invention, the one or more sugar alcohols include non-direct (non-DC) sugar alcohol particles.

[0075] In some embodiments of the present invention, the one or more sweeteners include one or more saccharides.

[0076] In some embodiments of the present invention, the one or more sweeteners comprise at least two types of sweetener particles.

[0077] In some embodiments of the present invention, the one or more sweeteners comprise sweetener particles in which more than 50% of the particles have a particle size of less than 250 microns. In some embodiments of the present invention, the one or more sweeteners comprise sweetener particles in which more than 60% of the particles have a particle size of less than 250 microns. In some embodiments of the present invention, the one or more sweeteners comprise sweetener particles in which more than 70% of the particles have a particle size of less than 250 microns. In some embodiments of the present invention, the one or more sweeteners comprise sweetener particles in which more than 80% of the particles have a particle size of less than 250 microns.

[0078] In some embodiments of the present invention, the one or more sweeteners comprise sweetener particles in which more than 20% of the particles have a particle size greater than 500 microns. In some embodiments of the present invention, the one or more sweeteners comprise sweetener particles in which more than 30% of the particles have a particle size greater than 500 microns. In some embodiments of the present invention, the one or more sweeteners comprise sweetener particles in which more than 50% of the particles have a particle size greater than 500 microns.

[0079] In some embodiments of the present invention, the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:40 to 1:1. In some embodiments of the present invention, the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:30 to 1:1. In some embodiments of the present invention, the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:20 to 1:1.

[0080] In some embodiments of the present invention, the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:15 to 1:1.

[0081] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:10 to 1:1. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:10 to 1:2. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:8 to 1:2. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:7 to 1:2. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:6 to 1:2. In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:5 to 1:2.

[0082] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:40 to 1:5, such as 1:40 to 1:4, such as 1:40 to 1:3, such as 1:40 to 1:2, such as 1:40 to 1:1.

[0083] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:20 to 1:5, such as 1:20 to 1:4, such as 1:20 to 1:3, such as 1:20 to 1:2, such as 1:20 to 1:1.

[0084] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:10 to 1:5, such as 1:10 to 1:4, such as 1:10 to 1:3, such as 1:10 to 1:2, such as 1:10 to 1:1.

[0085] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:5 to 1:4, such as 1:5 to 1:3, such as 1:5 to 1:2.

[0086] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:4 to 4:1, such as 1:4 to 3:1, such as 1:4 to 2:1, such as 1:4 to 1:1, such as 1:4 to 1:2.

[0087] In some embodiments of the present invention, the mass ratio of one or more triglycerides to one or more isolated cannabinoids is in the range of 1:3 to 4:1, such as 1:2 to 4:1, such as 1:1 to 4:1, such as 2:1 to 4:1.

[0088] In some embodiments of the present invention, one or more isolated cannabinoids are present in an amount of at least 5% by mass of the powder premix. In some embodiments of the present invention, one or more isolated cannabinoids are present in an amount of at least 7% by mass of the powder premix.

[0089] In some embodiments of the present invention, one or more isolated cannabinoids are present in an amount of at least 10% by mass of the powder premix. In some embodiments of the present invention, one or more isolated cannabinoids are present in an amount of at least 15% by mass of the powder premix.

[0090] In some embodiments of the present invention, one or more isolated cannabinoids are present in an amount of at least 20% by mass of the powder premix. In some embodiments of the present invention, one or more isolated cannabinoids are present in an amount of at least 25% by mass of the powder premix.

[0091] In some embodiments of the present invention, one or more isolated cannabinoids are present in an amount of at least 30% by mass of the powder premix. In some embodiments of the present invention, one or more isolated cannabinoids are present in an amount of at least 35% by mass of the powder premix. In some embodiments of the present invention, one or more isolated cannabinoids are present in an amount of at least 40% by mass of the powder premix.

[0092] In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder mixture in an amount of 0.1 to 400 mg. In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder mixture in an amount of 0.1 to 300 mg. In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder mixture in an amount of 0.1 to 250 mg.

[0093] In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 1 to 200 mg. In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 1 to 150 mg. In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 1 to 100 mg.

[0094] In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 5 to 200 mg. In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 5 to 100 mg.

[0095] In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 3 to 200 mg. In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 3 to 100 mg.

[0096] In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 2 to 200 mg. In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 2 to 100 mg.

[0097] In some embodiments of the present invention, one or more isolated cannabinoids are present in the powder premix in an amount of 10 to 100 mg.

[0098] In some embodiments of the present invention, one or more isolated cannabinoids are selected from the group consisting of cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), and combinations thereof.

[0099] In some embodiments of the present invention, one or more isolated cannabinoids are selected from the group consisting of tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and combinations thereof.

[0100] In some embodiments of the present invention, one or more isolated cannabinoids include cannabigerol (CBG).

[0101] In one embodiment of the present invention, one or more cannabinoids include cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), salts and derivatives thereof.

[0102] In one embodiment of the present invention, one or more cannabinoids include tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), salts and derivatives thereof.

[0103] In one embodiment of the present invention, one or more cannabinoids include cannabigerol (CBG), salts and derivatives thereof.

[0104] In some embodiments of the present invention, the cannabinoid is selected from the group consisting of cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG), cannabinchromene (CBC), cannabinol (CBN), cannabielsoin (CBE), iso - tetrahydrocannabinol (iso - THC), cannabinocyclol (CBL), cannabinitran (CBT), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabinchromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), salts thereof, derivatives thereof, and mixtures of cannabinoids.

[0105] In one embodiment of the present invention, the one or more cannabinoids include cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), salts and derivatives thereof. In one embodiment of the present invention, the one or more cannabinoids include CBD, salts and derivatives thereof, such as analogs and homologs by way of example. In one embodiment of the present invention, the one or more cannabinoids include CBD. In one embodiment of the present invention, the one or more cannabinoids are CBD.

[0106] In one embodiment of the present invention, the one or more cannabinoids include tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), salts and derivatives thereof. In one embodiment of the present invention, the one or more cannabinoids include tetrahydrocannabinol (THC). Preferably, THC is intended to mean (-)-trans - Δ 9 -tetrahydrocannabinol, i.e., (6aR,10aR)-delta - 9 - tetrahydrocannabinol). In one embodiment of the present invention, the one or more cannabinoids are THC.

[0107] In one embodiment of the present invention, the one or more cannabinoids include at least two cannabinoids. In one embodiment of the present invention, the one or more cannabinoids include a combination of several cannabinoids, such as THC and CBD. In one embodiment of the present invention, the one or more cannabinoids are a combination of THC and CBD.

[0108] In some embodiments of the present invention, the one or more isolated cannabinoids are present at a purity of at least 90% (w / w).

[0109] In some embodiments of the present invention, the one or more isolated cannabinoids are present at a purity of at least 95% (w / w).

[0110] In some embodiments of the present invention, the one or more isolated cannabinoids are present at a purity of at least 98% (w / w).

[0111] In some embodiments of the present invention, the one or more isolated cannabinoids do not include a cannabinoid distillate.

[0112] In some embodiments of the present invention, the one or more isolated cannabinoids do not include a cannabinoid extract.

[0113] In some embodiments of the present invention, the one or more isolated cannabinoids do not include one or more isolated cannabinoids having a purity of less than 90% (w / w).

[0114] In some embodiments of the present invention, the one or more isolated cannabinoids are dissolved in one or more triglycerides before admixing with the sweetener powder composition.

[0115] In some embodiments of the present invention, the one or more isolated cannabinoids are added to the sweetener powder composition before admixing with the one or more triglycerides.

[0116] In some embodiments of the present invention, one or more triglycerides are added to the sweetener powder composition before admixing with one or more isolated cannabinoids.

[0117] In some embodiments of the present invention, additional components are added to the premix.

[0118] Generally, when it is mentioned that additional components are "added to the premix" or similar language, the intended meaning is that these components are added to the total mixture. Therefore, the premix can also be added to additional components, depending on the relevant procedures and amounts. Usually, "premix" or "pre - mixture" are expressions used interchangeably. Additional components combined with the premix are usually referred to as "powder blend" or similar language. A "powder blend" can contain additional components.

[0119] In some embodiments of the present invention, additional components selected from the group consisting of flavoring agents, dry binders, tableting aids, anti - caking agents, surfactants, emulsifiers, antioxidants, enhancers, mucoadhesive agents, absorption enhancers, high - intensity sweeteners, softeners, colorants, further active ingredients, water - soluble indigestible polysaccharides, water - insoluble polysaccharides, and any combination thereof are added to the premix or powder blend.

[0120] In some embodiments of the present invention, one or more flavoring agents are added to the premix or powder blend.

[0121] In some embodiments of the present invention, high - intensity sweeteners are added to the premix or powder blend.

[0122] In some embodiments of the present invention, the premix is a ready - to - use premix.

[0123] In some embodiments of the present invention, the premix is applied in an amount of 10 - 99.9% by mass in combination with additional components.

[0124] In some embodiments of the present invention, the premix is applied in an amount of 10 to 99.9% by mass in combination with further components, such as oral care agents.

[0125] In one embodiment of the present invention, the oral care agent comprises one or more anti-plaque agents.

[0126] The anti-plaque agent comprises a fluoride ion source. The anti-plaque agent is any substance that by itself acts to inhibit the accumulation of bacterial deposits on the surfaces of the oral cavity. Examples include xylitol and other antimicrobial agents. The inhibitory effect of xylitol on oral microorganisms may have a better effect when used in combination with the extract, because the extract also acts to incapacitate the microorganisms.

[0127] Typical examples of active ingredients that are particularly desirable in view of anti-plaque effectiveness, safety and formulation considerations are as follows: Naficillin, Oxacillin, Vancomycin, Clindamycin, Erythromycin, Trimethoprim-Sulfamethoxazole, Rifampin, Ciprofloxacin, Extended-Spectrum Penicillins, Amoxicillin, Gentamicin, Ceftriazoxone, Cefotaxime, Chloramphenicol, Clavunate, Sulbactam, Probenecid, Doxycycline, Spectinomycin, Cefixime, Penicillin G, Minocycline, Beta-Lactamase Inhibitors; Meziocillin, Piperacillin, Aztreonam, Norfloxacin, Trimethoprim, Ceftazidime, Dapsone. Halogenated Diphenyl Ethers, e.g., 2',4,4'-Trichloro-2-Hydroxydiphenyl Ether (Triclosan), 2,2'-Dihydroxy-5,5'-Dibromo-Diphenyl Ether. Halogenated Salicylanilides, e.g., 4',5-Dibromosalicylanilide, 3,4',5-Trichloro-Salicylanilide, 3,4',5-Tribromo-Salicylanilide, 2,3,3',5-Tetrachloro-Salicylanilide, 3,3,3',5-Tetrachloro-Salicylanilide, 3,5-Dibromo-3'-Trifluoromethyl-Salicylanilide, 5-n-Octanoyl-3'-Trifluoromethyl-Salicylanilide, 3,5-Dibromo-4'-Trifluoromethyl-Salicylanilide, 3,5-Dibromo-3'-Trifluoromethyl-Salicylanilide (Flurophene). Benzoic Acid Esters, e.g., Methyl-p-Hydroxybenzoate, Ethyl-p-Hydroxybenzoate, Propyl-p-Hydroxybenzoate, Butyl-p-Hydroxybenzoate. Halogenated Carb anilides, e.g., 3,4,4'-Trichlorocarbanilide, 3-Trifluoromethyl-4,4'-Dichlorocarbanilide, or 3,3,4'-Trichlorocarbanilide. Phenolic Compounds (including Phenol and its Homologs, Mono- and Poly-Alkyl and Aromatic Halo-Phenols and their Homologs), e.g., Phenol, 2-Methyl-Phenol, 3-Methyl-Phenol, 4-Methyl-Phenol, 4-Ethyl-Phenol, 2,4-Dimethyl-phenol, 2,5-dimethyl-phenol, 3,4-dimethyl-phenol, 2,6-dimethyl-phenol, 4-n-propyl-phenol, 4-n-butyl-phenol, 4-n-amyl-phenol, 4-tert-amyl-phenol, 4-n-hexyl-phenol, 4-n-heptyl-phenol, 2-methoxy-4-(2-propenyl)-phenol (eugenol), 2-isopropyl-5-methyl-phenol (thymol), mono- and poly-alkyl- as well as aralkyl-halophenols, methyl-p-chlorophenol, ethyl-p-chlorophenol (chlorphenol), n-propyl-p-chlorophenol, n-butyl-p-chlorophenol, n-amyl-p-chlorophenol, sec-amyl-p-chlorophenol, n-hexyl-p-chlorophenol, cyclohexyl-p-chlorophenol, n-heptyl-p-chlorophenol, n-octyl-p-chlorophenol, o-chlorophenol, methyl-o-chlorophenol, ethyl-o-chlorophenol, n-propyl-o-chlorophenol, n-butyl-o-chlorophenol, n-amyl-o-chlorophenol, tert-amyl-o-chlorophenol, n-hexyl-o-chlorophenol, n-heptyl-o-chlorophenol (chloropenol), p-chlorophenol, o-benzyl-p-chlorophenol, o-benzyl-m-methyl-p-chlorophenol, o-benzyl-m,m-dimethyl-p-chlorophenol, o-phenylethyl-p-chlorophenol, o-phenylethyl-m-methyl-p-chlorophenol, 3-methyl-p-chlorophenol, 3,5-dimethyl-p-chlorophenol, 6-ethyl-3-methyl-p-chlorophenol, 6-n-propyl-3-methyl-p-chlorophenol, 6-iso-propyl-3-methyl-p-chlorophenol, 2-ethyl-3,5-dimethyl-p-chlorophenol, 6-sec-butyl-3-methyl-p-chlorophenol, 2-iso-propyl-3,5-dimethyl-p-chlorophenol, 6-diethylmethyl-3-methyl-p-chlorophenol, 6-iso-propyl-2-ethyl-3-methyl-p-chlorophenol, 2-sec-amyl-3,5-Dimethyl-p-chlorophenol, 2-Diethylmethyl-3,5-dimethyl-p-chlorophenol, 6-sec-Octyl-3-methyl-p-chlorophenol, p-Bromophenol, Methyl-p-bromophenol, Ethyl-p-bromophenol, n-Propyl-p-bromophenol, n-Butyl-p-bromophenol, n-Amyl-p-bromophenol, sec-Amyl-p-bromophenol, n-Hexyl-p-bromophenol, Cyclohexyl-p-bromophenol, o-Bromophenol, tert-Amyl-o-bromophenol, n-Hexyl-o-bromophenol, n-Propyl-m,m-dimethyl-o-bromophenol, 2-Phenyl-phenol, 4-Chloro-2-methyl-phenol, 4-Chloro-3-methyl-phenol, 4-Chloro-3,5-dimethyl-phenol, 2,4-Dichloro-3,5-dimethyl-phenol, 3,4,5,6-Tetrabromo-2-methylphenol, 5-Methyl-2-pentylphenol 4-Isopropyl-3-methylphenol 5-Chloro-2-hydroxydiphenyl-methane. Resorcinol and its derivatives, for example, Resorcinol, Methyl-resorcinol, Ethyl-resorcinol, n-Propyl-resorcinol, n-Butyl-resorcinol, n-Amyl-resorcinol, n-Hexyl-resorcinol, n-Heptyl-resorcinol, n-Octyl-resorcinol, n-Nonyl-resorcinol, Phenyl-resorcinol, Benzyl-resorcinol, Phenylethyl-resorcinol, Phenylpropyl-resorcinol, p-Chlorobenzyl-resorcinol, 5-Chloro-2,4-dihydroxydiphenyl-methane, 4'-Chloro-2,4-dihydroxydiphenyl-methane, 5-Bromo-2,4-dihydroxydiphenyl-methane, 4"-Bromo-2,4-dihydroxydiphenyl-methane. Bisphenol compounds, for example, Bisphenol A, 2,2'-Methylene-bis-(4-chlorophenol), 2,2'-Methylene-bis-(3,4,6-trichlorophenol) (Hexachlorophene), 2,2'-Methylene-bis-(4-chloro-6-bromophenol), Bis-(2-hydroxy-3,5-dichlorophenyl)-sulfide, bis-(2-hydroxy-5-chlorobenzyl)-sulfide.,

[0128] Examples of polyphosphate compounds having plaque inhibitory properties are dialkali metal and tetraalkali metal pyrophosphates in hydrated or non-hydrated form and mixtures thereof. Examples of pyrophosphates are Na2H2P2O7, Na4P2O7 and K4P2O7. Other suitable polyphosphates include hydrated or non-hydrated alkali metal tripolyphosphates such as Na5P3O10 and K5P3O10.

[0129] In one embodiment of the present invention, the active ingredient comprises one or more anti-gingivitis agents.

[0130] The anti-gingivitis agent can be an anti-inflammatory agent such as a salicylic acid derivative (e.g., aspirin), a para-aminophenol derivative (e.g., acetaminophen), indole and indene acetic acid (indomethacin, sulindac and etodalac), heteroaryl acetic acid (tolmetin, diclofenac and ketorolac), arylpropionic acid derivative (ibuprofen, naproxen, ketoprofen, fenopren, oxaprozin), anthranilic acid-(mefenamic acid, meclofenamic acid), enolic acid (piroxicam, tenoxicam, phenylbutazone and oxyphenthatrazone), lactic acid bacteria (LAB), osteopontin (ONP), IG-Lyt, hexefine, Aloe Vera, chlorhexedine, myrrh, or sage.

[0131] The anti-gingivitis agent also includes a psychotherapeutic agent, such as thorazine, serentil, mellaril, millazine, tindal, permitil, prolixin, trilafon, stelazine, suprazine, taractan, navan, clozaril, haldol, halperon, loxitane, moban, orap, risperdal, alprazolam, chlordiaepoxide, clonezepam, clorezepate, diazepam, halazepam, lorazepam, oxazepam, prazeepam, buspirone, elvavil, anafranil, adapin, sinequan, tofranil, surmontil, asendin, norpramin, pertofrane, ludiomil, pamelor, vivactil, prozac, luvox, paxil, zoloft, effexor, welibutrin, serzone, desyrel, nardil, parnate, or eldepryl.

[0132] In one embodiment of the present invention, the oral care agent includes one or more dental cosmetic ingredients.

[0133] Dental cosmetic ingredients include whitening agents. These are conveniently selected from among the tooth color modifying substances that may be considered useful in the tablets according to the present invention among oral care active substances. These substances, for example those listed in CTFA Cosmetic Ingredient Handbook, 3rd Edition, Cosmetic and Fragrances Association Inc., Washington D.C. (1982), which is incorporated herein by reference, are suitable for modifying the color of teeth to satisfy consumers. Specific examples include talc, mica, magnesium carbonate, calcium carbonate, calcium pyrophosphate, sodium bicarbonate, Iceland moss, bamboo, sodium hexametaphosphate, magnesium silicate, magnesium aluminum carbonate, silica, titanium dioxide, zinc oxide, red iron oxide, brown iron oxide, yellow iron oxide, black iron oxide, ammonium ferric ferrocyanide, manganese violet, gunjo, nylon powder, polyethylene powder, methacrylate powder, polystyrene powder, silk powder, crystalline cellulose, starch, mica titania, iron oxide mica titania, bismuth oxychloride, and mixtures thereof. Typical levels are from about 0.05% to about 20% by weight of the composition, preferably from about 0.1% to about 15% by weight, most preferably from about 0.25% to about 10% by weight.

[0134] Whitening agents for use herein may also include materials that remove or bleach endogenous or exogenous staining on or in the tooth surface. Such substances are selected from the group consisting of peroxides, metal hypochlorites, perborates, percarbonates, peroxyacids, persulfates, and combinations thereof. Suitable peroxide compounds include hydrogen peroxide, urea peroxide, calcium peroxide, carbamide peroxide, and mixtures thereof. Suitable metal hypochlorites include calcium hypochlorite, barium hypochlorite, magnesium hypochlorite, lithium hypochlorite, sodium hypochlorite, and potassium hypochlorite. Additional bleaching substances may be hypochlorites, and chlorine dioxide. A preferred percarbonate is sodium percarbonate. A preferred persulfate is oxone. The content of these substances depends on the available oxygen or chlorine.

[0135] In one embodiment of the present invention, the oral care agent contains one or more abrasives.

[0136] Within the scope of the present invention, the oral tablet may contain an abrasive. Typical materials include silica gel and precipitates, alumina, phosphates, and mixtures thereof. Specific examples include dicalcium orthophosphate dihydrate, calcium pyrophosphate, bamboo, tricalcium phosphate, hydrated alumina, beta-calcium pyrophosphate, calcium carbonate, sodium polymetaphosphate, sodium hexametaphosphate, Calgen, Giltex, Quadrafos, Hagan phosphate, micromet, calcium hydrogen phosphate, calcium monohydrogen phosphate, dicalcium orthophosphate secondary calcium phosphate, calcium carbonate salts, cacti, calcichew, calcidia, citrical, aragonite, calcite, valerite, aluminum oxide, alumina, silicon dioxide, silica, silicic anhydride, and resinous abrasive materials such as particulate condensation products of urea and formaldehyde and others such as those disclosed in U.S. Patent No. 3,070,510. Mixtures of polishing agents can also be used.

[0137] The silica polishing material generally has an average particle size in the range of about 0.1 to about 30 microns, preferably in the range of about 5 to about 15 microns. The polishing agent can be precipitated silica or silica gel, such as the silica xerogel described in U.S. Patent No. 3,538,230 or U.S. Patent No. 3,862,307. Silica xeropgels commercially available under the name "Syloid" by W. R. Grace and Company, Davison Chemical Division are preferred. Precipitated silica materials, such as those commercially available by J. M. Huber Corporation under the trade name "Zeodent", especially silica having the name "Zeodent 119" are also preferred. The types of silica dental polishing agents useful in the tablets of the present invention are described in more detail by U.S. Patent No. 4,340,583. The polishing agent in the tablets according to the present invention generally exists in the range of about 6% to about 70% by weight, preferably about 10% to about 50% by weight of the tablets. In one aspect of the present invention, a solid dosage form for oral administration of cannabinoids is provided, which comprises a premix according to the present invention.

[0138] In some embodiments of the present invention, the premix is present in an amount of 10 - 100% by weight of the solid dosage form. In some embodiments of the present invention, the premix is present in an amount of about 100% by weight of the solid dosage form. In some embodiments of the present invention, the premix is present in an amount of substantially 100% by weight of the solid dosage form. In some embodiments of the present invention, the premix is present in an amount of 10 - 90% by weight of the solid dosage form.

[0139] In some embodiments of the present invention, the premix is present in an amount of 15 - 75% by weight of the solid dosage form. In some embodiments of the present invention, the premix is present in an amount of 20 - 70% by weight of the solid dosage form. In some embodiments of the present invention, the premix is present in an amount of 25 - 60% by weight of the solid dosage form. In some embodiments of the present invention, the premix is present in an amount of 30 - 50% by weight of the solid dosage form.

[0140] In some embodiments of the present invention, a series of at least 10 solid dosage forms contain an amount of one or more cannabinoids that varies with a relative standard deviation (RSD) of less than 5%.

[0141] Generally, the method used for the content uniformity of a sample is determined when using Test Method 2.9.40. Uniformity of dosage units in accordance with the European Pharmacopoeia 10.8. The acceptance value (AV) is calculated using mass variation (MV) or content uniformity (CU) according to the dose and ratio of the active ingredient. For content uniformity, an appropriate analytical method is selected.

[0142] In some embodiments of the present invention, a series of at least 10 solid dosage forms contain an amount of one or more cannabinoids that varies with a relative standard deviation (RSD) of less than 2%.

[0143] In one aspect of the present invention, there is provided a tablet for oral administration of a cannabinoid, which contains a premix according to the present invention.

[0144] In some embodiments of the present invention, the premix is present in an amount of 10 to 100% by mass of the tablet.

[0145] In some embodiments of the present invention, the premix is present in an amount of 15 to 75% by mass of the tablet.

[0146] In some embodiments of the present invention, the tablet contains one or more sugar alcohols selected from the group consisting of sorbitol, erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof, in addition to one or more sweeteners in the premix.

[0147] In some embodiments of the present invention, the tablet contains one or more sweeteners in an amount of 20 to 80% by mass of the tablet, in addition to one or more sweeteners in the premix.

[0148] In some embodiments of the present invention, a series of at least 10 tablets comprises an amount of one or more pharmaceutical active ingredients that varies with a relative standard deviation (RSD) of less than 5%.

[0149] Generally, the method used for the content uniformity of tablets is determined when using Test method 2.9.40. Uniformity of dosage units in accordance with the European Pharmacopoeia 10.8. The acceptance value (AV) is calculated using mass variation (MV) or content uniformity (CU) depending on the dose and ratio of the active ingredient. For content uniformity, an appropriate analytical method is selected.

[0150] In some embodiments of the present invention, a series of at least 10 tablets comprises an amount of one or more cannabinoids that varies with a relative standard deviation (RSD) of less than 2%.

[0151] In some embodiments of the present invention, the tablets comprise directly compressible (DC) sugar alcohol particles and non-directly compressible (non-DC) sugar alcohol particles.

[0152] In some embodiments of the present invention, the tablets have a mass ratio of the non-DC sugar alcohol particles to the DC sugar alcohol particles that is between 0.2 and 1.2.

[0153] In some embodiments of the present invention, the tablets have a mass ratio of the non-DC sugar alcohol particles to the DC sugar alcohol particles that is between 0.3 and 0.7.

[0154] In some embodiments of the present invention, the tablets comprise one or more insoluble components selected from the group consisting of silica, microcrystalline cellulose, cellulose, silicified microcrystalline cellulose, clay, talc, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, magnesium carbonate, magnesium aluminometasilicate, superporous silica, and mixtures thereof.

[0155] In some embodiments of the present invention, the tablets comprise one or more binders in an amount of 0.1 to 6% by mass of the tablets.

[0156] In some embodiments of the present invention, the tablet contains one or more binders in an amount of 0.1 to 8% by mass of the tablet, for example 0.1 to 7% by mass, for example 1 to 7% by mass, for example 2 to 7% by mass, for example 0.1 to 6% by mass, for example 1 to 6% by mass.

[0157] In some embodiments of the present invention, the tablet contains at least two modules, and the premix is contained in at least one module of the tablet.

[0158] In some embodiments of the present invention, the tablet contains additional components selected from the group consisting of flavoring agents, dry binders, tableting aids, anti-caking agents, surfactants, emulsifiers, antioxidants, enhancers, mucoadhesive agents, absorption enhancers, high-intensity sweeteners, softening agents, colorants, further active ingredients, water-soluble indigestible polysaccharides, water-insoluble polysaccharides, and any combination thereof.

[0159] In one aspect of the present invention, there is provided a chewing gum agent for oral administration of cannabinoids, which contains the premix according to the present invention.

[0160] In some embodiments of the present invention, the premix is present in an amount of 15 to 75% by mass of the chewing gum agent.

[0161] In some embodiments of the present invention, a series of at least 10 chewing gum agents contain one or more cannabinoids in an amount that varies with a relative standard deviation (RSD) of less than 5%.

[0162] Generally, the method used for the content uniformity of cannabinoids in the chewing gum agent is determined when using test method 2.9.40. Uniformity of dosage units in accordance with the European Pharmacopoeia 10.8. The acceptance value (AV) is calculated using mass variation (MV) or content uniformity (CU) depending on the dosage and ratio of the active ingredient. For content uniformity, an appropriate analytical method is selected.

[0163] In some embodiments of the present invention, a series of at least 10 chewing gum agents contain an amount of one or more cannabinoids that varies with a relative standard deviation (RSD) of less than 2%.

[0164] In some embodiments of the present invention, the chewing gum agent contains a gum base in an amount of 20 to 40% by mass of the chewing gum agent, and the chewing gum agent is designed to be chewed into a coherent residue containing water-insoluble components.

[0165] In some embodiments of the present invention, the chewing gum agent contains a gum base, and the gum base contains an elastomer selected from the group consisting of styrene-butadiene rubber (SBR), butyl rubber, polyisobutylene (PIB), and combinations thereof.

[0166] In some embodiments of the present invention, the chewing gum agent contains a gum base, and the gum base contains at least 5% by mass of an elastomer.

[0167] In some embodiments of the present invention, the chewing gum agent contains a gum base, and the gum base contains a gum base resin selected from natural resins and / or synthetic resins.

[0168] In some embodiments of the present invention, the chewing gum agent contains a gum base, and the gum base contains at least 5% by mass of the gum base resin.

[0169] In some embodiments of the present invention, the chewing gum agent contains a gum base, and the gum base contains gum base particles having an average particle size between 400 μm and 1400 μm.

[0170] In some embodiments of the present invention, in addition to one or more sweeteners in the premix, the chewing gum agent contains one or more sugar alcohols selected from the group consisting of sorbitol, erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof.

[0171] In some embodiments of the present invention, the chewing gum composition comprises one or more sweeteners in an amount of 20 to 60% by mass of the chewing gum composition in addition to the one or more sweeteners in the premix.

[0172] In some embodiments of the present invention, a series of at least 10 compressed chewing gum compositions comprise one or more cannabinoids in an amount that varies with a relative standard deviation (RSD) of less than 5%.

[0173] Generally, the method used for the content uniformity of cannabinoids in the compressed chewing gum composition is determined when using Test Method 2.9.40. Uniformity of dosage units in accordance with the European Pharmacopoeia 10.8. The acceptance value (AV) is calculated using mass variation (MV) or content uniformity (CU) depending on the dosage and ratio of the active ingredient. For content uniformity, an appropriate analytical method is selected.

[0174] In some embodiments of the present invention, a series of at least 10 compressed chewing gum compositions comprise one or more cannabinoids in an amount that varies with a relative standard deviation (RSD) of less than 2%.

[0175] In some embodiments of the present invention, the chewing gum composition comprises at least two compression modules, and the premix is included in at least one of the two compression modules.

[0176] In some embodiments of the present invention, the chewing gum composition comprises at least two compression modules, and the two modules have different compositions.

[0177] In some embodiments of the present invention, the chewing gum composition comprises at least two compression modules, and at least one of the two compression modules does not contain a gum base.

[0178] In some embodiments of the present invention, the chewing gum agent includes additional components selected from the group consisting of flavoring agents, dry binders, tableting aids, anti-caking agents, surfactants, emulsifiers, antioxidants, enhancers, mucoadhesives, absorption enhancers, high-intensity sweeteners, softeners, colorants, further active ingredients, water-soluble indigestible polysaccharides, water-insoluble polysaccharides, and any combination thereof.

[0179] In one aspect of the present invention, there is provided a lozenge for oral administration of cannabinoids, comprising a premix according to the present invention.

[0180] In some embodiments of the present invention, the premix is present in an amount of 10 to 100% by mass of the lozenge.

[0181] In some embodiments of the present invention, the premix is present in an amount of 15 to 75% by mass of the lozenge.

[0182] In some embodiments of the present invention, a series of at least 10 lozenges contain one or more cannabinoids in amounts that vary with a relative standard deviation (RSD) of less than 5%.

[0183] Generally, the method used for the content uniformity of lozenges is determined when using Test Method 2.9.40. Uniformity of dosage units according to the European Pharmacopoeia 10.8. The acceptance value (AV) is calculated using mass variation (MV) or content uniformity (CU) according to the dose and ratio of the active ingredient. For content uniformity, an appropriate analytical method is selected.

[0184] In some embodiments of the present invention, a series of at least 10 lozenges contain one or more cannabinoids in amounts that vary with a relative standard deviation (RSD) of less than 2%.

[0185] In some embodiments of the present invention, the troche comprises one or more sugar alcohols selected from the group consisting of sorbitol, erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof, in addition to one or more sweeteners in the premix.

[0186] In some embodiments of the present invention, the troche comprises one or more sweeteners in an amount of 20 to 60% by mass of the troche, in addition to one or more sweeteners in the premix.

[0187] In some embodiments of the present invention, the troche comprises one or more insoluble components selected from the group consisting of silica, microcrystalline cellulose, cellulose, silicified microcrystalline cellulose, clay, talc, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, magnesium carbonate, magnesium aluminometasilicate, superporous silica, and mixtures thereof.

[0188] In some embodiments of the present invention, the troche comprises one or more disintegrants capable of acting to disintegrate the troche within a period of 1 minute or less upon contact with oral saliva.

[0189] In some embodiments of the present invention, the troche comprises one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and combinations thereof.

[0190] In some embodiments of the present invention, the troche comprises one or more disintegrants in an amount of 0.5 to 25% by mass of the troche.

[0191] In some embodiments of the present invention, the troche comprises additional components selected from the group consisting of flavoring agents, dry binders, tableting aids, anti-caking agents, surfactants, emulsifiers, antioxidants, enhancers, mucoadhesive agents, absorption enhancers, high-intensity sweeteners, softening agents, coloring agents, further active ingredients, water-soluble indigestible polysaccharides, water-insoluble polysaccharides, and any combination thereof.

[0192] In one aspect of the present invention, there is provided a pouch for oral administration of cannabinoids, comprising a premix according to the present invention.

[0193] In some embodiments of the present invention, the premix is present in an amount of 10 to 100% by mass of the pouch.

[0194] In some embodiments of the present invention, the premix is present in an amount of 15 to 75% by mass of the pouch.

[0195] In some embodiments of the present invention, a series of at least 10 pouches contain one or more cannabinoids in amounts that vary with a relative standard deviation (RSD) of less than 5%.

[0196] Generally, the method used for the content uniformity of the pouch is determined when using Test Method 2.9.40. Uniformity of dosage units in accordance with the European Pharmacopoeia 10.8. The acceptance value (AV) is calculated using mass variation (MV) or content uniformity (CU) depending on the dosage and ratio of the active ingredient. For content uniformity, an appropriate analytical method is selected.

[0197] In some embodiments of the present invention, a series of at least 10 pouches contain one or more cannabinoids in amounts that vary with a relative standard deviation (RSD) of less than 2%.

[0198] In some embodiments of the present invention, the pouch contains one or more insoluble components selected from the group consisting of silica, clay, talc, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, magnesium carbonate, magnesium aluminometasilicate, superporous silica, and mixtures thereof.

[0199] In some embodiments of the present invention, the pouch contains one or more insoluble fibers.

[0200] In some embodiments of the present invention, the pouch contains one or more insoluble fibers selected from wheat fiber, pea fiber, rice fiber, corn fiber, rye fiber, tomato fiber, barley fiber, triticale fiber, sugar beet fiber, buckwheat fiber, potato fiber, cellulose fiber, apple fiber, cocoa fiber, bran fiber, bamboo fiber, powdered cellulose, microcrystalline cellulose, and combinations thereof.

[0201] In some embodiments of the present invention, the pouch contains one or more sugar alcohols selected from the group consisting of sorbitol, erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof, in addition to one or more sweeteners in the premix.

[0202] In some embodiments of the present invention, the pouch contains one or more sweeteners in an amount of 20 to 60% by mass of the pouch, in addition to one or more sweeteners in the premix.

[0203] In some embodiments of the present invention, the pouch contains additional components selected from the group consisting of flavoring agents, dry binders, anti-caking agents, surfactants, emulsifiers, antioxidants, enhancers, mucoadhesive agents, absorption enhancers, high-intensity sweeteners, softening agents, colorants, further active ingredients, water-soluble indigestible polysaccharides, water-insoluble polysaccharides, and any combinations thereof.

[0204] In one aspect of the present invention, i) following the step of dissolving or dispersing a cannabinoid powder composition comprising one or more isolated cannabinoids in a lipid composition comprising one or more triglycerides, ii) mixing a sweetener powder composition comprising one or more sweeteners with the mixture obtained in i) to obtain a powder premix A method for preparing a powder premix for oral administration of cannabinoids is provided, which includes a mass ratio of one or more triglycerides to one or more sweeteners in the range of 1:50 to 1:1.

[0205] In some embodiments of the present invention, one or more triglycerides are heated to a temperature above room temperature before being added to the premix.

[0206] In one aspect of the present invention, i) following the step of mixing a sweetener powder composition comprising one or more sweeteners with a cannabinoid powder composition comprising one or more isolated cannabinoids, ii) a step of mixing a lipid composition comprising one or more triglycerides with the mixture obtained in i) to obtain a powder premix A powder premix for oral administration of cannabinoids is provided, comprising a mass ratio of one or more triglycerides to one or more sweeteners in the range of 1:50 to 1:1.

[0207] In some embodiments of the present invention, one or more triglycerides are heated to a temperature above room temperature before being added to the premix.

[0208] In one aspect of the present invention, i) following the step of mixing a sweetener powder composition comprising one or more sweeteners with a lipid composition comprising one or more triglycerides, ii) a step of mixing a cannabinoid powder composition comprising one or more isolated cannabinoids with the mixture obtained in i) to obtain a powder premix A powder premix for oral administration of cannabinoids is provided, comprising a mass ratio of one or more triglycerides to one or more sweeteners in the range of 1:50 to 1:1.

[0209] In some embodiments of the present invention, one or more triglycerides are heated to a temperature above room temperature before being added to the premix.

Mode for Carrying Out the Invention

[0210] Detailed Description of the Present Invention As used in this specification and the claims, the verb "comprising" and its conjugations are used in their non-limiting sense to mean that the items following the word are included, but items not specifically recited are not excluded. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element exists, unless the context clearly requires that there be only one of the element. Thus, the indefinite article "a" or "an" typically means "at least one." In addition, as used herein in connection with the words "comprising" or "containing," the words "a" and "an" indicate "one or more." The expression "one or more" is intended to mean one, two, three, or more.

[0211] As used herein, the terms "about" or "approximately" in connection with a number generally mean a number falling within the range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of that number, unless otherwise stated or otherwise apparent from the context (except where such a number would be less than 0% or greater than 100% of a possible value).

[0212] As used herein, the terms "%" and "percent" refer to weight percent, unless otherwise stated.

[0213] The term "particle size" relates to the ability of particles to pass through or be retained by a sieve aperture of a particular size. As used herein, the term "particle size" refers to the average particle size determined according to European Pharmacopoeia 9.1, using test method 2.9.38 particle size distribution estimation by analytical sieving, unless otherwise specifically recited.

[0214] The term "particle" or similar language is intended to refer to a single discrete composition of a solid material, such as an individual element in a granule or powder, having a particular size that can vary significantly.

[0215] In the context of the present invention, the term "releasing" refers to the release of the substance from the solid dosage form. In some embodiments, the process of releasing the substance corresponds to the dissolution of the substance in saliva. The term "releasing" in the context of the present invention is intended to mean that it has been tested under "in vivo" conditions, unless otherwise stated. In the context of the present invention, when the solid dosage form is chewed, the "in vivo" conditions are intended to mean that, unless otherwise stated, the sample is chewed at a chewing frequency of 60 times per minute for a specific period in a test panel of 8 subjects. These subjects refrain from eating and drinking for at least 30 minutes before the start of any test. The subjects are healthy individuals objectively selected according to the specified requirements.

[0216] The terms "sustained release" or "extended release" are intended to mean a long-term continuous release herein. The terms "rapid release" or "quick release" or "high release" are intended to mean that a higher content is released over a given period herein.

[0217] The phrase "texture" means the characteristics of the solid dosage form and the overall qualitative measure of the mouthfeel experienced by the user during use. Thus, the term "texture" encompasses not only measurable quantities such as hardness but also more subjective parameters related to the feel experienced by the user.

[0218] The term "sustained release" or "extended release" is intended in this specification to mean a long-term continuous release. The terms "rapid release" or "quick release" or "high release" are intended in this specification to mean that a higher content is released over a given period. The term "controlled release" is intended to mean that the release of a substance from a solid dosage form is assisted by the active use of the solid dosage form in the oral cavity of a subject, thereby controlling the amount of the substance that is released by the active use.

[0219] A "self-emulsifying agent" is an agent that forms an emulsion with a minimum amount of required energy when another phase is provided. In contrast, an emulsifying agent, as opposed to a self-emulsifying agent, requires additional energy to form an emulsion.

[0220] Due to the insufficient solubility of certain active ingredients in physiological fluids, solubilizing cannabinoids upon mixing with the physiological fluids of the body to promote bioabsorption is an unmet need. To overcome low oral bioavailability, various lipid-based drug delivery systems and self-emulsifying systems have been developed. Lipid-based delivery systems, particularly self-emulsifying drug delivery systems (SEDDS), have been demonstrated to increase the solubility, dissolution, and bioavailability of many insoluble active ingredients. However, lipid-based and SEDDS delivery systems are highly limited by the amount of active ingredient loading that needs to be dissolved in the vehicle composition. The use of co-solvents allows for higher concentrations of active ingredients to be obtained, which in certain cases enables loading up to 30%.

[0221] In the formulation of solid dosage forms containing SEDDS, specific problems are thought to arise. As an example, problems can occur regarding obtaining a homogeneous mixture where variability is avoided and safe and convenient delivery can be achieved. Also, without prior attention, there is no need to compromise the general formulation of solid dosage forms that provide convenience to the user, as is often the case when a high load of active ingredient is required.

[0222] Particularly with respect to SEDDS, the formulations of the present invention offer several distinct advantages, enabling higher loading of active ingredients and, at the same time, providing improved sensory properties of the formulations in use. Other advantages also exist.

[0223] Importantly, it has been found that the presence of SEDDS or at least self-emulsifying agents acts synergistically with an increase in saliva production. The increase in saliva production has been found to partition certain active ingredients and allocate a higher load of active ingredients, for example, to mucosal surfaces, while the presence of SEDDS or at least self-emulsifying agents has been found to further increase the uptake of these active ingredients through the oral surface. Thus, the synergistic effect between the presence of SEDDS or at least self-emulsifying agents according to the present invention and the increase in saliva production was surprising to the inventors. In some embodiments, the increase in saliva production can result in a higher exposure of the active ingredient to the mucosal surface. The presence of SEDDS can function to increase the affinity of the active ingredient from this saliva for the mucosa. In particular, the potential for SEDDS to have a high load of active ingredients, in combination with the improvement in saliva production, further contributes to the synergistic effect of the solid dosage forms according to the present invention.

[0224] In the context of the present invention, SEDDS is a solid or liquid dosage form comprising an oil phase, a surfactant, and optionally a co-surfactant, characterized mainly in that the dosage form can spontaneously form an oil-in-water emulsion in the oral cavity or at room temperature (generally referring to body temperature, i.e., 37 °C). When SEDDS enters the oral cavity, it is first self-emulsified as emulsion droplets and rapidly dispersed throughout the oral cavity, thus reducing the irritation caused by the direct contact of the active ingredient with the oral mucosa and therefore serving to mask the taste of the active ingredient. In the oral cavity, the structure of the emulsion microparticles changes or is disrupted. The resulting microparticles at the micrometer or nanometer level can, for example, penetrate the oral mucosa, and the absorbed oil droplets enter the bloodstream, thereby significantly improving the bioavailability of the active ingredient.

[0225] In one embodiment of the present invention, the self-emulsifying system comprises one or more emulsifiers and one or more oil carriers.

[0226] In one embodiment of the present invention, the self-emulsifying system comprises one or more emulsifiers, one or more oil carriers and one or more solubilizers.

[0227] In one embodiment of the present invention, the self-emulsifying system comprises one or more emulsifiers, one or more oil carriers, one or more solubilizers and one or more solvents.

[0228] In one embodiment of the present invention, the self-emulsifying system comprises one or more emulsifiers and one or more solvents.

[0229] In one embodiment of the present invention, the self-emulsifying system comprises one or more emulsifiers having both emulsifying and solubilizing properties.

[0230] In one embodiment of the present invention, the self-emulsifying system comprises one or more emulsifiers acting as both emulsifiers and carriers.

[0231] In one embodiment of the present invention, the self-emulsifying system comprises one or more emulsifiers acting as both emulsifiers, carriers and solubilizers.

[0232] In one embodiment of the present invention, the self-emulsifying system comprises one or more fatty acids, one or more glycerols, one or more waxes, one or more flavonoids and one or more terpenes.

[0233] In one embodiment of the present invention, the self-emulsifying system comprises one or more emulsifiers having an HLB value greater than 6, preferably between 8 and 18.

[0234] In one embodiment of the present invention, the one or more emulsifiers are selected from the group consisting of PEG-35 castor oil, PEG-6 oleoyl glyceride, PEG-6 linoleoyl glyceride, PEG-8 caprylic / capric glyceride, sorbitan monolaurate, sorbitan monooleate, polyoxyethylene(20)sorbitan monolaurate, polyoxyethylene(60)sorbitan monostearate, polyoxyethylene(80)sorbitan monooleate, lauroylpoloxyl-32 glyceride, stearoylpoloxyl-32 glyceride, polyoxyl-32 stearate, propylene glycol monolaurate, propylene glycol dilaurate, and mixtures and combinations thereof.

[0235] In one embodiment of the present invention, the one or more emulsifiers include PEG-35 castor oil.

[0236] In one embodiment of the present invention, the oil carrier is selected from the group consisting of natural fatty acids; medium-chain triglycerides of caprylic acid (C8) and capric acid (C10); propylene glycol esters of caprylic acid (C8) and capric acid (C10); mono-, di- and triglycerides mainly of linoleic acid (C18:2) and oleic acid (C18:1); fatty acid 18:1 cis-9; natural fatty acids; mono-, di- and triglycerides of oleic acid (C18:1), and mixtures and combinations thereof.

[0237] In one embodiment of the present invention, the one or more solvents are selected from the group consisting of polyglyceryl-3 dioleate, 1,2-propanediol, polyethylene glycol 300, polyethylene glycol 400, diethylene glycol monoethyl ether, and mixtures and combinations thereof.

[0238] In one embodiment of the present invention, the oil carrier is selected from the group consisting of corn oil, Labrafac lipophile WL1349, Labrafac PG, Maisine CC, oleic acid, olive oil, Peceol, and mixtures and combinations thereof.

[0239] In one embodiment of the present invention, the one or more solvents are selected from the group consisting of polyglyceryl-3 dioleate, 1,2-propanediol, polyethylene glycol 300, polyethylene glycol 400, diethylene glycol monoethyl ether, and mixtures and combinations thereof.

[0240] In one embodiment of the present invention, the one or more solubilizers are selected from the group consisting of lauroyl polyoxyl-32 glyceride; stearoyl polyoxyl-32 glyceride; polyoxyl-32 stearate; a synthetic copolymer of ethylene oxide (80) and propylene oxide (27); a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; alpha-, beta- or gamma-cyclodextrin and derivatives thereof; legume proteins (globulin, albumin, gluten protein); and mixtures and combinations thereof.

[0241] In one embodiment of the present invention, the formulation further comprises one or more lipids in addition to the lipid composition according to the present invention.

[0242] The term "non-DC sugar alcohol particles" refers to particles of non-direct compressible (non-DC) sugar alcohol. Note that the terms "non-DC sugar alcohol particles" and "non-DC particles" are used interchangeably. In the context of the present invention, non-DC sugar alcohol particles refer to particles that have not been pre-processed, for example, by granulating with other sugar alcohols or binders, for the purpose of obtaining so-called directly compressible particles (DC). In the context of the present invention, non-DC sugar alcohol particles include particles obtained by milling without other sugar alcohols or binders following crystallization. Thus, non-DC sugar alcohol particles are considered to be particles consisting of non-DC sugar alcohol.

[0243] The term "DC sugar alcohol particles" refers to particles of directly compressible (DC) sugar alcohol. Note that the terms "DC sugar alcohol particles" and "DC particles" are used interchangeably. DC sugar alcohol particles can be obtained, for example, as particles of a sugar alcohol originally having a DC grade, such as sorbitol, or by granulating a non-DC sugar alcohol, for example, together with another sugar alcohol or a binder, for the purpose of obtaining so-called directly compressible particles (DC). Also, granulation of a non-DC sugar alcohol using water as a binder is considered to result in "DC sugar alcohol particles" in the context of the present invention.

[0244] The terms "tableted" or "tablet" or "compressed" are intended to mean that the tablet composition is pressed in a tableting apparatus and is mainly composed of particulate matter. These terms imply a method step, but in the context of the present invention, these terms are intended to mean the obtained tablet, which is obtained in the tableting of a part of the particles. Note that a tablet or tableting composition that is finally referred to as containing particles is understood to be particles pressed together in the tableting step.

[0245] The following description outlines a method for manufacturing the tablets of the present invention and further details of what can be added to the compositions of the present invention.

[0246] Typically, the tablet manufacturing process of the present invention can be carried out in a single tablet press, such as a rotary tablet press. However, in some situations, it may be beneficial to apply a separate tablet press.

[0247] Preferably, the upper punch is convex to give a concave form to the upper surface of the pressed tablet.

[0248] Of course, it should be noted that the shape of the punch can vary according to the desired tablet shape.

[0249] In some embodiments of the present invention, the tablet pressing is carried out with a force of 20 to 50 kN.

[0250] In one aspect of the present invention, "tablet" is intended to mean "fast-disintegrating tablet" ("FDT"), or similar language such as "orally disintegrating tablet" ("ODT"). Unless otherwise stated, if a tablet according to the present invention is made as one module for two or more modules, the tablet is intended to be an FDT tablet. On the other hand, if a tablet is made of two or more modules, for example two modules, such additional modules are intended to be "lozenge" modules that provide a longer disintegration time compared to the FDT modules according to the present invention. The combination of "FDT" modules and "lozenge" modules contributes to another aspect of the present invention. The "lozenge" module according to the present invention may also include elements from the "FDT" module, but generally has a different composition and provides an extended disintegration time.

[0251] The term "lozenge" is intended to encompass that the "lozenge composition" is "compressed" into the "lozenge module". In the context of the present invention, the term "lozenge module" or similar language is intended to mean that the module in use in the oral cavity is intended to be sucked or licked. The term "lozenge" is given its ordinary meaning in the technical field of lozenges. The intention is that the lozenge module should not be chewed. The intention is also that the FDT module should not be chewed. Generally, the "lozenge module" of the present invention can disintegrate in minutes as opposed to seconds for orally disintegrating tablets (ODT) or fast-disintegrating tablets (FDT) when sucked or licked. Therefore, the intention is that when a tablet is made as a combination of two modules, the "lozenge module" delivers one or more cannabinoids over a longer period than the FDT module.

[0252] The term "module" is generally intended to be composed of a composition of substances having substantially the same characteristics throughout the module. Therefore, if there are two modules, the two modules have different compositions and generally have two different characteristics throughout each module. In the context of the present invention, if there is only one module, this module is considered an FDT tablet. On the other hand, if there are two modules, the tablet is composed of a troche tablet or a troche module fused with an FDT tablet or an FDT tablet module. The term "fused" is intended to mean that the tablets are assembled together by compression force. Usually, if there are two modules, the troche module is made as the first module and the FDT module is made as the second module. The tablet can be composed of three or more modules. In certain embodiments, the troche module can be replaced with a gum base module. In the context of the present invention, the present invention provides an attractive two-stage delivery of masking even when the delivery of nicotine is "single-stage".

[0253] The term "cannabinoid composition" is intended to mean a mass of substances containing one or more cannabinoids. The cannabinoid composition may contain components other than cannabinoids. The cannabinoid composition may constitute a cannabinoid. The cannabinoid composition may constitute one type of cannabinoid. The cannabinoid composition may constitute two types of cannabinoids. The cannabinoid composition may constitute two or more types of cannabinoids.

[0254] The term "water-insoluble gum base" or "gum base" or "gum base matrix" or similar wording means mainly water-insoluble components and hydrophobic gum base components. The "gum base" may contain a gum base polymer as well as a plasticizer, wax, emulsifier, fat and / or filler.

[0255] As used herein, the term "natural resin" means a resinous compound that is either a polyterpene derived from terpenes of natural origin or a resinous compound derived from gum rosin, wood rosin or tall oil rosin.

[0256] An elastomer imparts a rubbery and elastic springy property to the gum agent, which varies depending on the chemical structure of this component and the way it can be formulated with other components. Elastomers suitable for use in the gum base and gum agent of the present invention can include natural or synthetic types. Polyvinyl acetate elastomer plasticizers are not considered elastomers according to the present invention.

[0257] The elastomer can be selected from the group consisting of styrene-butadiene copolymers, polyisobutylene, isobutylene-isoprene copolymers, polyethylene, polyurethane, or any combination thereof. Preferred elastomers are styrene-butadiene copolymers (SBR), polyisobutylene, and isobutylene-isoprene copolymers (BR).

[0258] Styrene-butadiene type elastomers, or alternatively SBR, are typically copolymers of styrene:butadiene monomers in a ratio of about 20:80 to 60:40. The ratio of these monomers affects the elasticity of the SBR as evaluated by the Mooney viscosity. As the styrene:butadiene ratio decreases, the Mooney viscosity decreases.

[0259] The structure of SBR typically consists of linear 1,3-butadiene copolymerized with phenylethylene (styrene). The average molecular weight of SBR is <600,000 g / mol.

[0260] Isobutylene-isoprene type elastomers, or alternatively butyl, have isoprene mole percent levels in the range of 0.2 to 4.0. Similar to SBR, as the isoprene:isobutylene ratio decreases, the elasticity measured by the Mooney viscosity also decreases.

[0261] The structure of butyl rubber typically consists of branched 2-methyl-1,3-butadiene (isoprene) copolymerized with branched 2-methylpropene (isobutylene). The average molecular weight of BR ranges from 150,000 g / mol to 1,000,000 g / mol.

[0262] Polyisobutylene, or the so-called PIB type elastomer, is a polymer of 2-methylpropene. Low molecular weight elastomers impart soft chewing characteristics to the gum base and, like other elastomers, also impart elastic qualities. The average molecular weight can range from about 30,000 to 120,000 g / mol, and the penetration can range from about 4 millimeters to 20 millimeters. The higher the penetration, the softer the PIB. Similar to SBR and butyl, high molecular weight elastomers impart elasticity to the gum base. The average molecular weight can range from 120,000 to 1,000,000 g / mol.

[0263] Polybutene has an average molecular weight in the range of about 5,000 g / mol to about 30,000 g / mol.

[0264] Useful natural elastomers include natural rubber such as smoked or liquid latex and guayule rubber, natural gums such as jelutong, lechi caspi, perillo, sorva, massaranduba balaata, massaranduba chocolate, nispero, rocidinha, chicle, gutta percha, gutta kataiu, niger gutta, tunu, tilte, chiku bulu, gutta hancan. Natural elastomers can also be applied in aspects of the present invention.

[0265] Elastomer plasticizers change the hardness of the gum base. When used in the base, its specificity for intermolecular chain breakage (plasticization) of the elastomer, together with its various softening points, results in various degrees of finished gum base hardness and compatibility. Polyvinyl acetate elastomer plasticizer is an example of the elastomer plasticizer of the present invention.

[0266] The natural resin can be selected from ester gums, for example, glycerol esters of partially hydrogenated rosin, glycerol esters of polymerized rosin, glycerol esters of partially dimerized rosin, glycerol esters of tall oil rosin, pentaerythritol esters of partially hydrogenated rosin, methyl esters of rosin, partially hydrogenated methyl esters of rosin, pentaerythritol esters of rosin, synthetic resins, such as terpene resins derived from alpha-pinene, beta-pinene, and / or d-limonene, and natural terpene resins.

[0267] In one embodiment of the present invention, the solid dosage form comprises a further component selected from the group consisting of a flavoring agent, a dry binder, a tableting aid, an anti-caking agent, an emulsifier, an antioxidant, a strengthening agent, a mucoadhesive, an absorption enhancer, a high-intensity sweetener, a softening agent, a coloring agent, an active ingredient, a water-soluble indigestible polysaccharide, a water-insoluble polysaccharide, or any combination thereof.

[0268] The solid dosage form according to the present invention is manufactured by applying pressure to the contents of the particles by suitable compression means. Then, the particles or powder are pressed to form a dense, cohesive tablet. The particles can include, for example, so-called primary particles or aggregated primary particles. When these are pressed, a bond is established between the particles or granules, thereby imparting a specific mechanical strength to the pressed tablet.

[0269] It should be noted that the terms introduced above: powder, primary particles, and aggregated primary particles can be somewhat misleading in that the difference between primary particles and aggregated primary particles can often be viewed differently depending on the user's background. As an example, some people may consider sorbitol, for example, to be a primary particle even though sorbitol should rather be regarded as a kind of aggregated primary particle due to the preprocessing that is typically carried out on sorbitol when it is delivered to the customer. The definition adopted in the description of the present invention is that aggregated primary particles refer to macro-particles containing more or less preprocessed primary particles.

[0270] When pressure is applied to the particles, the bulk volume decreases and the amount of air decreases. During this process, energy is consumed. As the particles approach each other more closely during the volume reduction process, bonds can be established between the particles or granules. The formation of bonds is accompanied by a decrease in the energy of the system since energy is released. The volume reduction occurs by various mechanisms, and depending on the applied pressure and the properties of the particles or granules, different types of bonds can be established between the particles or granules. The first thing that happens when the powder is pressed is that the particles are rearranged under a low consolidation pressure to form a more compact packing structure. Particles with regular shapes seem to undergo rearrangement more easily than those with irregular shapes. As the pressure increases, further rearrangement is prevented and subsequent volume reduction is obtained by plastic and elastic deformation and / or fragmentation of the tablet particles. Fragile particles are likely to undergo fragmentation, i.e., crushing into smaller units of the original particles. Plastic deformation is an irreversible process that results in a permanent change in the particle shape, whereas after elastic deformation, the particles recover their original shape. Clearly, when compressing a solid dosage form, both plastic and elastic deformation can occur.

[0271] Over the years, several studies on the types of bonds in pressed tablets have been conducted, typically in relation to pharmaceuticals, and several techniques for obtaining pressed tablets based on available powders have been provided. Such studies have focused quite a bit on what happens when volume reduction is carried out and how the final product can be optimized for a given purpose. As an example, several improvements have been made to pressed tablets, for example, by adding binders to the tablet formulation, in order to obtain sufficient strength in the final pressed tablet while maintaining acceptable properties, such as properties related to release.

[0272] For tableted chewing gum agents, conventional chewing gum agents can be manufactured by sequentially adding various chewing gum agent components to a commercially available mixer known in the art where a finished gum base already exists. After thoroughly mixing the initial components, the gum mass is discharged from the mixer and shaped into the desired form, for example, by rolling it into a sheet, cutting it into rods, extruding it into large chunks, or molding it into pellets. Generally, the components of conventional chewing gum agents can be mixed by first melting the gum base and adding it to an operating mixer. Colorants, active agents, and / or emulsifiers can also be added at this point. Softening agents, such as glycerin, can also be added at this point, along with a portion of the syrup and bulking agent / sweetener. Subsequently, a further portion of the bulking agent / sweetener can be added to the mixer. Flavoring agents are typically added along with the final portion of the bulking agent / sweetener. High-intensity sweeteners are preferably added after the final portions of the bulking agent and flavoring agent have been added. The entire mixing procedure typically takes from 30 to 40 minutes, although longer mixing times may be required. Those skilled in the art will recognize that many variations of the above procedure may be followed.

[0273] In some embodiments of the present invention, the solid dosage form does not include conventional chewing gum agents, i.e., so-called extruded chewing gum agents.

[0274] According to the present invention, the tableted solid dosage form according to the present invention may include an outer coating of about 0.1 to about 75% by mass applied over the solid dosage form center. Thus, suitable coating types include hard coatings, film coatings, and soft coatings of any composition, such as those currently used in coating tableted solid dosage forms.

[0275] One presently preferred outer coating type is a hard coating, and this term is used in its conventional meaning which includes sugar coatings and sugar-free coatings and combinations thereof. The purpose of the hard coating is to obtain a sweet and crispy layer that is pleasing to the consumer, which can further protect the solid dosage form core for various reasons. In a typical process for applying a protective sugar coating to the solid dosage form core, the solid dosage form core is continuously treated in a suitable coating facility with an aqueous solution of a crystalline sugar, such as sucrose or dextrose, which may contain other functional ingredients, such as fillers, binders, colorants, etc., depending on the stage of the coating reached. In the context of the present invention, the sugar coating may contain further functional or active compounds, by way of example flavor compounds and / or active compounds.

[0276] In a typical hard coating process described in detail below, a suspension containing crystalline sugar and / or polyol is applied onto the solid dosage form core and the water it contains is removed by evaporation by blowing air through it. This cycle has to be repeated several times, typically from 3 to 80 times, to reach the required expansion. The term "expansion" refers to an increase in the mass or thickness of the product that is considered with respect to the final mass or thickness of the coated product at the end of the coating operation compared to the start. According to the present invention, the coating layer constitutes from about 0.1 to about 75% by weight, such as from about 10 to about 60% by weight, by way of example from about 15 to about 50% by weight of the finished solid dosage form element.

[0277] In one embodiment of the present invention, the product is a pouch.

[0278] In one aspect of the present invention, the particle population used for tableting may also be present in the pouch as a powder. Therefore, this aspect of the present invention includes a particle population in a pouch as a powder or part of a powder that has not been tableted and is accompanied by other powders or powder components. Thus, the direct compressibility (DC) and non-direct compressibility (non-DC) sugar alcohol particles of the present invention can be included in the pouch according to the present invention. Additional embodiments regarding the particle population of the present invention are also applicable when included in the pouch. Note that additional components, such as water-soluble fibers or water-insoluble fibers, for example microcrystalline cellulose, may be present in the pouch.

[0279] According to an advantageous embodiment of the present invention, the pouch includes a water-permeable membrane, such as a woven or non-woven fabric.

[0280] The pouch according to the present invention includes an opening, and the characteristic opening dimension is adapted to the characteristic dimension of the particle population so as to hold the matrix composition in the pouch before use and / or hold a part of the contents in the pouch during use.

[0281] In other words, according to various embodiments, the pouch forms a membrane that allows the passage of saliva and prevents or inhibits the passage of at least a part of the contents. The membrane of the pouch can be made of any suitable material, such as a woven or non-woven fabric (e.g., cotton, fleece, etc.), a heat-sealable non-woven cellulose, or other polymeric materials, such as synthetic, semi-synthetic, or natural polymeric materials. An example of a suitable pouch material is paper made of pulp and a small amount of wet strength agent. The material suitable for use must provide a semi-permeable membrane layer that prevents the powder or composition from exiting the bag or pouch during use. The suitable material also has little effect on the release of the active ingredient from the pouch.

[0282] The powder is filled into a pouch and maintained in the pouch by sealing. An ideal pouch is chemically and physically stable, pharmaceutically acceptable, water-insoluble, easy to fill with powder and seal, and provides a semi-permeable membrane layer that prevents the powder from exiting the bag but allows saliva and components dissolved therein from the powder in the pouch or sufficiently small suspended components to pass through the pouch.

[0283] The pouch may be placed in the oral cavity by the user. Then, saliva enters the pouch, and active ingredients and other ingredients that are soluble in saliva begin to dissolve and are transported out of the pouch together with the saliva and into the oral cavity. In some embodiments of the present invention, the pouch can be chewed in a manner similar to chewing a gum. This is particularly advantageous when the particle population contains a gum base. Therefore, the pouch can be chewed into a coherent residue containing water-insoluble components.

[0284] According to an embodiment of the present invention, the flavoring agent may be selected from the group consisting of coconut, coffee, chocolate, vanilla, grapefruit, orange, lime, menthol, licorice, caramel aroma, honey aroma, peanut, walnut, cashew, hazelnut, almond, pineapple, strawberry, raspberry, tropical fruit, cherry, cinnamon, peppermint, wintergreen, spearmint, eucalyptus, and mint, fruit essences such as those derived from apple, pear, peach, strawberry, apricot, raspberry, cherry, pineapple, and plum essence. The essential oils include peppermint, spearmint, menthol, eucalyptus, clove oil, bay oil, anise, thyme, hinoki oil, myrrh, and the oils of the fruits mentioned above.

[0285] Antioxidants suitable for use include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), beta-carotene, tocopherol, acidulants such as vitamin C (ascorbic acid or the corresponding salts (ascorbates)), propyl gallate, catechin, green tea extract, and other synthetic and natural types or mixtures thereof.

[0286] High-intensity sweeteners can also be used according to a preferred embodiment of the present invention. Preferred high-intensity sweeteners include, but are not limited to, sucralose, aspartame, salts of acesulfame, alitame, neotame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcone, thaumatin, monellin, lakanka extract, advantame, stevioside, etc., either alone or in combination.

[0287] In order to provide a longer-lasting sweet and flavor perception, it may be desirable to encapsulate at least a portion of the high-intensity sweetener or otherwise control its release.

[0288] Techniques such as wet granulation, wax granulation, spray drying, spray cooling, fluidized bed coating, storage, encapsulation in yeast cells, and fiber extrusion can be used to achieve the desired release characteristics. Encapsulation of the sweetener can also be provided using another formulation component, such as a resinous compound.

[0289] The usage level of the high-intensity sweetener varies significantly and depends on factors such as the potency of the sweetener, the release rate, the desired sweetness of the product, the level and type of flavoring used, and cost considerations. Thus, the active level of the artificial sweetener can vary from about 0.001% to about 8% by weight (preferably from about 0.02% to about 8% by weight). When the carrier used for encapsulation is included, the usage level of the encapsulated high-intensity sweetener will be proportionally higher.

[0290] The present invention may include, if desired, one or more fillers / conditioning agents, such as magnesium and calcium carbonates, sodium sulfate, ground limestone, silicate compounds such as magnesium and aluminum silicates, kaolin and clay, aluminum oxide, silicon oxide, talc, titanium oxide, monocalcium, dicalcium, and tricalcium phosphates, cellulose polymers such as wood, and combinations thereof. According to one embodiment of the present invention, one preferred filler / conditioning agent is calcium carbonate.

[0291] According to the present invention, the one or more cannabinoids can be selected from various cannabinoids.

[0292] "Cannabinoid" is a group of compounds including endocannabinoids, phytocannabinoids, and those that are neither endocannabinoids nor phytocannabinoids (hereinafter referred to as "syntho-cannabinoids" in this specification).

[0293] "Endocannabinoid" is an endogenous cannabinoid, which can have high-affinity ligands for CB1 and CB2 receptors.

[0294] "Phytocannabinoid" is a cannabinoid that originates from nature and can be found in the cannabis plant. Phytocannabinoids can be present in extracts containing plant-based raw materials, isolated, or synthetically reproduced.

[0295] "Syntho-cannabinoid" is a compound that can interact with cannabinoid receptors (CB1 and / or CB2), but is not found endogenously or in the cannabis plant. Examples include WIN 55212 and rimonabant.

[0296] "Isolated phytocannabinoid" or "isolated cannabinoid" is purified to the extent that it is extracted from the cannabis plant and substantially free of additional components, such as minor amounts of secondary cannabinoids and non-cannabinoid fractions.

[0297] "Synthetic cannabinoid" is produced by chemical synthesis. This term includes modifying an isolated phytocannabinoid, for example, by forming a pharmaceutically acceptable salt thereof.

[0298] A "substantially pure" cannabinoid is defined as a cannabinoid that is present at a purity of greater than 95% (w / w). More preferably, it is greater than 96% (w / w) to 97% (w / w) to 98% (w / w) to 99% (w / w) or more.

[0299] A "highly purified" cannabinoid is defined as a cannabinoid that has been extracted from a cannabis plant and purified to such an extent that other cannabinoid and non-cannabinoid components co-extracted with the cannabinoid have been substantially removed, such that the highly purified cannabinoid is 95% (w / w) pure or greater.

[0300] "Plant material" is defined as a plant or a part of a plant (e.g., bark, wood, leaves, stems, roots, flowers, fruits, seeds, sap or a part thereof) and exudates, and includes materials corresponding to the definition of "botanical raw materials" in Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research.

[0301] In the context of this application, the terms "cannabinoid extract" or "extract of cannabinoids" are used interchangeably and include "botanical drug substances" derived from cannabis plant material. A botanical drug substance is defined in Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research, as follows: "A drug substance derived from one or more plants, algae, or macroscopic fungi. It is prepared from botanical raw materials by one or more of the following processes: pulverization, decoction, pressing, aqueous extraction, ethanol extraction, or other similar processes." A botanical drug substance does not include highly purified or chemically modified substances derived from natural sources. Thus, in the case of cannabis, the "botanical drug substance" derived from the cannabis plant does not include highly purified pharmacopeial grade cannabinoids.

[0302] The term "cannabis plant" includes wild-type Cannabis sativa and furthermore its variants, such as cannabis chemovars that naturally contain different amounts of individual cannabinoids, the subspecies indica of Cannabis sativa (including the variants var. indica and var. kafiristanica which are variants), Cannabis indica, Cannabis ruderalis and furthermore plants that are the result of genetic crossing, self-crossing or their hybrids. The term "cannabis plant material" should be correspondingly interpreted as including plant material derived from one or more cannabis plants. To avoid doubt, in this specification, "cannabis plant material" is described as including dried cannabis biomass.

[0303] Preferably, the one or more cannabinoids are selected from cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabinocyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabinotriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and tetrahydrocannabivarinic acid (THCVA). More preferably, the one or more cannabinoids are CBD or THC. This list is not exhaustive and is merely provided for reference to detail the cannabinoids identified in the present application.

[0304] To date, over 120 different phytocannabinoids have been identified and are within the scope of the present invention.

[0305] Cannabinoids can be divided into different groups as follows: phytocannabinoids; endocannabinoids; and synthetic cannabinoids.

[0306] For the purposes of the present invention, cannabinoid receptors, whether or not explicitly so named herein, are lipophilic in nature and can be activated by agonists of three major groups of ligands, which are classified as endocannabinoids (produced endogenously by mammalian cells); phytocannabinoids (e.g., cannabidiol, produced by the cannabis plant); and synthetic cannabinoids (e.g., HU-210), respectively.

[0307] Phytocannabinoids can be found either in the neutral carboxylic acid form or in the decarboxylated form, depending on the method used to extract the cannabinoid. For example, heating the carboxylic acid form is known to decarboxylate most of the carboxylic acid form.

[0308] Phytocannabinoids can also exist as either pentyl (5 carbon atoms) or propyl (3 carbon atoms) variants. For example, the phytocannabinoid THC is known to be a CB1 receptor agonist, whereas the propyl variant THCV has been discovered to be a CB1 receptor antagonist, i.e., having almost the opposite effect.

[0309] According to the present invention, examples of phytocannabinoids can be cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabinotriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and tetrahydrocannabivarinic acid (THCV A). More preferably, the one or more cannabinoids are CBD or THC.

[0310] The formulation according to the present invention can also contain at least one cannabinoid selected from those disclosed by A. Douglas Kinghorn et al., Phytocannabinoids, Volume 103, Chapter 1, pages 1 - 30.

[0311] Examples of endocannabinoids are molecules that activate cannabinoid receptors in the body. Examples include 2-arachidonoylglycerol (2AG), 2-arachidonoylglyceryl ether (2AGE), arachidonyl dopamine, and arachidonyl ethanolamide (anandamide). Endogenous molecules that share similar structural features but exhibit weak or no activity towards cannabinoid receptors have been identified and are also referred to as endocannabinoids. Examples of these endocannabinoid lipids include 2-acylglycerols, alkyl or alkenyl glyceryl ethers, acyl dopamine, and N-acylethanolamides containing alternative fatty acid or alcohol moieties, as well as other fatty acid amides containing different head groups. These include N-acylserine and many other N-acylated amino acids. Examples of cannabinoid receptor agonists are neuromodulatory and affect short-term memory, appetite, stress response, anxiety, immune function, and analgesia.

[0312] In one embodiment, the cannabinoid is palmitoylethanolamide (PEA), which is an endogenous fatty acid amide belonging to the class of nuclear factor agonists.

[0313] Synthetic cannabinoids include a variety of distinct chemical classes: cannabinoids structurally related to THC, cannabinoids not related to THC, such as (cannabimimetics), for example aminoalkyl indoles, 1,5-diarylpyrazoles, quinoline, and arylsulfonamides, and eicosanoids related to endocannabinoids. All or any of these cannabinoids can be used in the present invention.

[0314] The formulation preferably contains one or two main cannabinoids, which are preferably selected from the group consisting of cannabidiol (CBD) or cannabidivarin (CBDV), tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG), and cannabidiolic acid (CBDA) or combinations thereof. The formulation preferably contains cannabidiol and / or tetrahydrocannabinol.

[0315] Preferably, the solid dosage form of the present invention can be used for the treatment or alleviation of pain, epilepsy, cancer, nausea, inflammation, congenital disorders, neuropathy, oral infections, toothache, sleep apnea, mental disorders, gastrointestinal disorders, inflammatory bowel disease, loss of appetite, diabetes, and fibromyalgia.

[0316] In a further aspect of the present invention, the oral cannabinoid formulation is suitable for use in the treatment of conditions that require the administration of a neuroprotective or antispasmodic agent.

[0317] The oral cannabinoid formulation can be for use in the treatment of seizures.

[0318] The oral cannabinoid formulation can be for use in the treatment of Dravet syndrome, Lennox-Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile dystonia, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis complex, brain tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's disease, and autism.

[0319] The following non-limiting examples illustrate different variants of the present invention. The examples are intended to illustrate the concepts of the present invention and, therefore, the examples mentioned should not be understood as exhaustive at the present time. In particular, CBD is used as an exemplary compound, but this may also be another cannabinoid.

Examples

[0320] Example (Example 1) Premix: A mixture of hydrogenated vegetable oil (HVO) added to a mixture of isolated CBD and a sweetener Mannitol (Pearlitol 150SD) provided by Roquette in an amount of approximately 1780 g was added to a Lodige high-shear mixer and heated to a temperature of approximately 55°C. Subsequently, a cannabinoid powder composition containing CBD isolate (phytocannabinoid) from hemp plant tissue with a 99% CBD content provided by Medical Hemp (batch number MH B 18592) in an amount of approximately 140 g was sieved through a 600-micron sieve and added to the sweetener powder composition. This mixture was mixed in the mixer at a speed of approximately 80 rpm for approximately 5 minutes. After activating the chopper (approximately 600 rpm) of the Lodige mixer, HVO provided by AAK under the trade name Akocrem NT 76-33 having a melting temperature of 30 - 35°C was melted at a temperature of approximately 55°C and added to the mixture in an amount of approximately 80 g. After adding the lipid composition, the temperature inside the mixer was approximately 49°C, and the mixture was further mixed for approximately 10 minutes. After 10 minutes, the temperature of the final mixture was approximately 51°C. A total of 2 kg of mixed powder premix with a CBD content of approximately 70 mg / g was prepared.

[0321] [Table 1]

[0322] [Table 2]

[0323] [Table 3]

[0324] (Example 2) Premix: A mixture of Miglyol added to a mixture of isolated CBD and a sweetener Mannitol (Pearlitol 150SD) provided by Roquette in an amount of approximately 1780 g was added to a Lodige high-shear mixer and heated to a temperature of approximately 55°C. Subsequently, a cannabinoid powder composition containing CBD isolate (phytocannabinoid) from hemp plant tissue with a 99% CBD content provided by Medical Hemp (batch number MH B 18592) in an amount of approximately 140 g was sieved through a 600-micron sieve and added to the sweetener powder composition. This mixture was mixed in the mixer at a speed of approximately 80 rpm for approximately 5 minutes. After activating the chopper (approximately 600 rpm) of the Lodige mixer, Miglyol 812, a medium-chain triglyceride (MCT) provided by Sasol, was added to the mixture in an amount of approximately 80 g over a period of approximately 3 minutes. After adding Miglyol 812, the mixture was further mixed for approximately 10 minutes. After 10 minutes, the temperature of the final mixture was approximately 51°C. A total of 2 kg of mixed powder premix with a CBD content of approximately 70 mg / g was prepared.

[0325]

Table 4

[0326]

Table 5

[0327]

Table 6

[0328]

Table 7

[0329] (Example 3) Premix: High-load - hydrogenated vegetable oil (HVO) added to a mixture of isolated CBD and sweetener A quantity of about 1220 g of mannitol (Pearlitol 150SD) provided by Roquette was added to a Lodige high-shear mixer and heated to a temperature of about 55°C. Subsequently, a cannabinoid powder composition containing CBD isolate (phytocannabinoid) from hemp plant tissue with a 99% CBD content provided by Medical Hemp (batch number MH B 18592) in an amount of about 700 g was sieved through a 600-micron sieve and added to the sweetener powder composition. This mixture was mixed in the mixer at a speed of about 80 rpm for about 5 minutes. After activating the chopper (about 600 rpm) of the Lodige mixer, HVO provided by AAK under the trade name Akocrem NT 76-33 having a melting temperature of 30 - 35°C was melted at a temperature of about 55°C and added to the mixture in an amount of about 80 g. After adding the lipid composition, the temperature inside the mixer was about 49°C, and the mixture was further mixed for about 10 minutes. After 10 minutes, the temperature of the final mixture was about 51°C. A total of 2 kg of mixed powder premix with a CBD content of about 350 mg / g was prepared.

[0330]

Table 8

[0331]

Table 9

[0332]

Table 10

[0333] (Example 4) Premix: A mixture of hydrogenated vegetable oil (HVO) and isolated CBD added to a sweetener A quantity of about 721 g of mannitol (Pearlitol 150SD) provided by Roquette was added to a Lodige high-shear mixer and heated to a temperature of about 55°C. Then, a cannabinoid powder composition containing CBD isolate (phytocannabinoid) from hemp plant tissue with a 99% CBD content provided by Medical Hemp (batch number MH B 18592) in an amount of about 91 g was mixed with HVO provided by AAK under the trade name Akocrem NT 76-33 having a melting temperature of 30 - 35°C in an amount of about 29 g. While stirring, the CBD-HVO mixture was heated to a temperature of about 60°C to form a solution of CBD in HVO. Subsequently, a mixture of CBD and HVO corresponding to a ratio of about 75 / 25 (hereinafter referred to as 75% CBD mixture) was added to a sweetener powder composition in an amount of about 79 g. After adding the lipid composition, the mixture was mixed for about 10 minutes. A total of 800 g of mixed powder premix was prepared.

[0334]

Table 11

[0335]

Table 12

[0336]

Table 13

[0337] (Example 4A) Premix: A mixture of corn oil and oleic acid and isolated CBD added to a sweetener An amount of about 666 g of mannitol (Pearlitol 150SD) provided by Roquette was added to a Lodige high-shear mixer and heated to a temperature of about 55°C. Then, a cannabinoid powder composition containing CBD isolate (phytocannabinoid) from hemp plant tissue with a 99% CBD content provided by Medical Hemp (batch number MH B 18592) in an amount of about 151.6 g was mixed and dissolved with a combination of about 25.0 g of liquid corn oil (melting temperature below 0°C) provided by ADM and about 25.0 g of liquid oleic acid (melting temperature of about 13°C) provided by Sigma Aldrich under the trade name W281506. While stirring, the CBD-oil mixture was heated to a temperature of about 60°C to form a solution of CBD in the oil. Subsequently, a mixture of CBD and oil corresponding to a ratio of about 75 / 25 (hereinafter referred to as the 75% CBD mixture) was added to the sweetener powder composition in an amount of about 134 g. After adding the lipid composition, the mixture was mixed for about 10 minutes. A total of 800 g of mixed powder premix was prepared.

[0338]

Table 14

[0339]

Table 15

[0340] (Example 5) Premix: A mixture of Miglyol and isolated CBD added to a sweetener Mannitol (Pearlitol 150SD) provided by Roquette in an amount of about 721 g was added to a Lodige high shear mixer and heated to a temperature of about 55° C. Then, a cannabinoid powder composition comprising CBD isolate (phytocannabinoid) from cannabis plant tissue having a CBD content of 99% provided by Medical Hemp (batch number MH B 18592) in an amount of about 91 g was mixed with Miglyol 812, a medium chain triglyceride (MCT) provided by Sasol in an amount of about 29 g. While stirring, the CBD-MCT mixture was heated to a temperature of about 70° C. to form a solution of CBD in MCT. Then, a mixture of CBD and Miglyol 812 corresponding to a ratio of about 75 / 25 (hereinafter referred to as 75% CBD mixture) was added to the sweetener powder composition in an amount of about 79 g. After adding the lipid composition, the mixture was mixed for about 10 minutes. A total of 800 g of mixed powder premix was made.

[0341] [Table 16]

[0342] [Table 17]

[0343] [Table 18]

[0344] Example 6 Premix: Comparison sample - contains no triglyceride lipids Mannitol (Pearlitol 150SD) provided by Roquette was added to a Lodige high-shear mixer and heated to a temperature of approximately 55°C. Subsequently, a cannabinoid powder composition containing CBD isolate (phytocannabinoid) from hemp plant tissue with a purity of approximately 99% CBD provided by either Medical Hemp (batch number MH18592) or Valens (batch number BVA032013) was sieved through a 600-micron sieve and added to the sweetener powder composition. This mixture was mixed for approximately 10 minutes at a speed of approximately 80 rpm. No lipid composition was present.

[0345]

Table 19

[0346]

Table 20

[0347]

Table 21

[0348] (Example 7) Preparation of Tablets with Two Layers Based on the CBD-containing powder mixture of Examples 1-2, tablets were prepared in which each layer had a mass of approximately 50% of the total tablet. The total mass of the tablets was 1800 mg. The tablets were prepared using a standard tablet press (3090i, available from Fette GmbH) containing a dosing apparatus (P 3200 C, available from Fette GmbH, Germany). The punches used: 16.00 mm round punches. The rotor speed used was 11 rpm.

[0349] In Examples 1 to 2, a first layer (denoted as layer 1) containing the CBD-containing powder mixture and additional ingredients was prepared and tabletted, and then a layer containing a gum base (denoted as layer 2) was tabletted. Layer 1 having a mass of about 900 mg was compressed with a compression force of about 5 kN. Thereafter, layer 2 having a mass of about 900 mg and containing a gum base and additional ingredients was pressed onto layer 1 with a compression force of 40 kN. The tablet machine was test-run by adjusting the filling depth and compression force so that the mass and hardness of the tablets met the criteria. To avoid capping, pre-pressure can also be included.

[0350] [Table 22]

[0351] [Table 23]

[0352] [Table 24]

[0353] (Example 8) Preparation of a tablet having two layers Based on the CBD-containing powder mixture of Example 3, tablets were prepared in which each layer had a mass of about 50% of the total tablet. The total mass of the tablets was 1800 mg. The tablets were prepared using a standard tablet press (3090i, available from Fette GmbH) including a metering device (P 3200 C, available from Fette GmbH, Germany). Punches used: 16.00 mm round punches. The rotor speed used was 11 rpm.

[0354] A first layer (designated as layer 1) containing the CBD-containing powder mixture prepared in Example 3 and additional ingredients was prepared and tabletted, and then a layer containing a gum base (designated as layer 2) was tabletted. Layer 1 was compressed with a compression force of about 5 kN. Then, layer 2 containing the gum base and additional ingredients was pressed onto layer 1 with a compression force of 40 kN. The tablet machine was run in by adjusting the filling depth and compression force so that the mass and hardness of the tablets met the criteria. To avoid capping, pre-pressure can also be included.

[0355] [Table 25]

[0356] [Table 26]

[0357] (Example 9) Preparation of tablets having two layers Based on the CBD-containing powder mixtures of Examples 4-5, tablets having two layers were prepared, where one layer had a mass of about 45% of the total tablet mass and the other layer had a mass of about 55% (the layer without CBD). The total mass of the tablets was 1800 mg. The tablets were prepared using a standard tablet press (3090i, available from Fette GmbH) containing a metering device (P 3200 C, available from Fette GmbH, Germany). Punches used: 16.00 mm round punches. The rotor speed used was 11 rpm.

[0358] In Examples 1 to 2, a first layer (referred to as layer 1) containing the CBD-containing powder mixture prepared and additional components was prepared and tabletted, and then a layer containing a gum base (referred to as layer 2) was tabletted. Layer 1 was compressed with a compression force of about 5 kN. Thereafter, layer 2 containing the gum base and additional components was pressed onto layer 1 with a compression force of 40 kN. The tablet machine was test-run by adjusting the filling depth and compression force so that the mass and hardness of the tablets met the criteria. To avoid capping, pre-pressure can also be included.

[0359] [Table 27]

[0360] [Table 28]

[0361] (Example 9A) Preparation of Troches Based on the CBD-containing powder mixture of Example 4A, troches were prepared. The troches were prepared using a standard tablet press (3090i, available from Fette GmbH) containing a metering device (P 3200 C, available from Fette GmbH, Germany). Punches used: 16.00 mm round punches. The rotor speed used was 11 rpm.

[0362] Troches based on the CBD-containing powder mixture of Example 4A and additional components were prepared and tabletted with a compression force of about 35 kN. The troches had a total mass of 1800 mg. The tablet machine was test-run by adjusting the filling depth and compression force so that the mass and hardness of the troches met the criteria.

[0363] [Table 29]

[0364] (Example 9B) Preparation of Chewable Tablets Based on the CBD-containing powder mixture of Example 4A, chewable tablets were prepared. The chewable tablets were prepared using a standard tableting machine (3090i, available from Fette GmbH) including a metering device (P 3200 C, available from Fette GmbH, Germany). Punches used: 16.00 mm round punches. The rotor speed used was 11 rpm.

[0365] Chewable tablets based on the CBD-containing powder mixture of Example 4A and additional ingredients were prepared and tabletted with a compression force of approximately 30 kN. The chewable tablets had a total mass of 1800 mg. The tablet machine was run in a trial by adjusting the filling depth and compression force so that the mass and hardness of the lozenges met the criteria.

[0366] [Table 30]

[0367] (Example 9C) Preparation of Pouch Powder Based on the CBD-containing powder mixture of Example 4A, pouch powder was prepared. The total mass of the pouch powder was 1800 mg.

[0368] [Table 31]

[0369] (Example 10) Comparative Tablets with Two Layers Based on the CBD-containing powder mixture of Example 6, a tablet having two layers was prepared, where one layer had a mass of about 45% of the total tablet and the other layer had a mass of about 55% (the layer without CBD). The total mass of the tablet was 1800 mg. The tablets were prepared using a standard tableting press (3090i, available from Fette GmbH) including a dosing device (P 3200 C, available from Fette GmbH, Germany). Punches used: 16.00 mm round punches. The rotor speed used was 11 rpm.

[0370] A first layer (designated as layer 1) containing the CBD-containing powder mixture and additional components prepared in Examples 1-2 was prepared and tabletted, and then a layer containing a gum base (designated as layer 2) was tabletted. Layer 1 was compressed with a compression force of about 5 kN. Then, layer 2 containing the gum base and additional components was pressed onto layer 1 with a compression force of 40 kN. The tablet machine was run in a test mode by adjusting the filling depth and compression force so that the mass and hardness of the tablets met the criteria. Pre-pressure can also be included to avoid capping.

[0371] [Table 32]

[0372] [Table 33]

[0373] [Table 34]

[0374] (Example 11A) Test method for content uniformity in powder premixes and powder blends The content uniformity (CU), i.e., the homogeneity of the CBD active substance, in the powder pre-mixture (powder pre-mix sample) and the powder blend (powder blend) which is a mixture with additional ingredients processed into an oral dosage form, is determined in accordance with European Pharmacopoeia 10.8 using test method 2.9.40 Uniformity of dosage units.

[0375] At least 5 samples having the same fixed mass in the range of 0.25 to 2 grams each are taken from the powder mixture to be analyzed. For each sample, the content of the CBD active substance is analyzed by standard HPLC techniques. Then, the content uniformity is calculated as the relative standard deviation (RSD) of the individual results.

[0376] (Example 11B) Test method for content uniformity in solid dosage forms The content uniformity (CU), i.e., the homogeneity of the CBD active substance, in the solid dosage form is determined in accordance with European Pharmacopoeia 10.8 using test method 2.9.40 Uniformity of dosage units.

[0377] At least 10 samples are taken from the solid dosage form to be analyzed, e.g., tablets. For each sample, the content of the CBD active substance is analyzed by standard HPLC techniques. Then, the content uniformity is calculated as the relative standard deviation (RSD) of the individual results.

[0378] (Example 12) In vivo test of release in solid dosage forms The sample solid dosage form was tested in a test panel of 8 subjects. The subjects refrained from eating and drinking for at least 30 minutes before the start of any of the tests. The subjects were healthy individuals objectively selected according to the specified requirements. After specific use time intervals, for example, 0, 0.5, 1, 2, 3, 5, and 10 minutes, the content of CBD in the remaining solid dosage form residue was measured. The solid dosage form was subjected to triple measurements for each of the 8 subjects, and a total of 24 measurement values were obtained for each sample. The average of the 24 measurement values was calculated, and the percentage of released mass was calculated based on the original content of CBD in the sample. The content of CBD in the remaining solid dosage form residue (if any) was measured.

[0379] The solid dosage form was weighed, placed in the mouth, and the subjects were instructed to place and use the solid dosage form as intended. For chewing gum dosage forms, the subjects were instructed to chew the sample at a frequency of 60 chews per minute. For lozenge dosage forms, the subjects were instructed to place the sample between the tongue and the palate, then aspirate the solid dosage form and rotate it every 0.5 minutes. When the desired test time was achieved (0.5, 1, 2, 3, 5, and 10 minutes), the solid dosage form was removed and weighed directly into a measuring glass used for the analysis of CBD content. By analyzing the content of CBD in the solid dosage form at different dissolution times, an in vivo dissolution profile was obtained.

[0380] This test was conducted on tablets, chewing gum dosage forms, and lozenge dosage forms. This test was also conducted on other cannabinoids, for example, THC.

[0381] (Example 13) In vitro test of release in solid dosage form The sample solid dosage form was tested. After specific use time intervals, for example, 0, 0.5, 1, 2, 3, 5, and 10 minutes, the content of CBD in the remaining solid dosage form residue was measured. The solid dosage form was subjected to triple measurements. The average of the measurement values was calculated, and the percentage of released mass was calculated based on the original content of CBD in the sample. The content of CBD in the remaining solid dosage form residue (if any) was measured.

[0382] The solid dosage form was weighed. Next, 25 ml of phosphate buffer was added into a 50 ml graduated cylinder with a screw cap. The solid dosage form was added to the cylinder. The cylinder was horizontally fixed on a shaker. After shaking, the solid dosage form was analyzed for the content of CBD. By analyzing the content of CBD in the solid dosage form at different dissolution times, an in vitro profile was obtained.

[0383] This test was conducted on tablets, chewing gum dosage forms, and troche dosage forms. Also, this test was conducted on other cannabinoids, for example THC.

[0384] (Example 14) CBD delivered from the solid dosage form to the oral mucosa A test panel of 8 subjects used the sample as intended for 1 minute. The subjects were healthy individuals objectively selected according to the specified requirements. The test subjects refrained from eating and drinking for at least 30 minutes before the start of any test. The subjects were not allowed to swallow during the procedure. The solid dosage form was weighed, placed in the mouth, and the subjects were instructed to place and use the solid dosage form as intended. For the chewing gum dosage form, the subjects were instructed to chew the sample at a frequency of 60 chews per minute. For the troche dosage form, the subjects were instructed to place the sample between the tongue and the palate, then aspirate the solid dosage form and rotate it every 10 seconds. After 1 minute, saliva was collected from the subjects and collected in a beaker for later analysis. In the test for 2-minute release, the same procedure was followed until 2 minutes, where the last saliva sample was collected and added to the same beaker for pooled analysis. The pooled saliva sample was collected 2 minutes later, and the content of CBD in the saliva was measured. The content of CBD in the remaining residue was also measured. The residue (if any) was placed in a flask, weighed, and analyzed. The residue (if any) and saliva were subjected to three triplicate measurements for each of the 8 subjects to obtain a total of 24 measured values for each sample. Then, the average of the 24 measured values was calculated. By comparing the amount of CBD in the residue and the amount of CBD in the saliva with the amount of CBD in the solid dosage form before use, the amount of CBD delivered to the oral mucosa could be estimated.

[0385] This test was conducted on tablets, chewing gum preparations, and troche preparations. Also, this test was conducted on other cannabinoids, for example THC.

[0386] (Example 15) Sensory evaluation test settings for solid dosage forms In addition to measuring release in either in vivo or in vitro, a sensory test was conducted to clarify very important features and properties of solid dosage forms. These sensory parameters are important as an indicator of the structure of the solid dosage form composition. Structure is a basic guideline regarding how similar the solid dosage form is to the structure of a comparative solid dosage form set as a reference substance in the test series, that is, the solid dosage forms are preferably compared to each other in a test series of 5 samples. The test setup consisted of 8 subjects in 1 test panel. All subjects were healthy individuals objectively selected according to the specified requirements. The sensory analysis was carried out according to ISO 4121 - 2003 under test conditions according to ISO 8589. The results are the average of the results of 8 individuals.

[0387] The subjects gave ratings from "+" to "+++++", where "+" is insufficient and "+++++" is excellent, that is, "+++++" means that the solid dosage form was excellent compared to the reference substance, "+++" means that the solid dosage form was equivalent to the reference substance, and "+" means that the solid dosage form was deviated from being equivalent to the reference substance. "0" indicated that it was not tested.

[0388] Four different parameters were tested in the test panel:

[0389]

Table 35

[0390] "Texture" - The overall impression of a solid dosage form when placed in the mouth, regarding elements such as hardness, roughness, and smoothness.

[0391] "Wear degree" - The impression of a solid dosage form when placed in the mouth and the intended use is initiated. As an example, a very hard and viscous structure was given a very low rating, and a very brittle structure was also given a very low rating.

[0392] "Flavor" - The overall impression of a solid dosage form during the intended use regarding flavor. As an example, a very low flavor experience was given a very low rating, and an overly high flavor experience that was not equivalent to the reference substance was also given a very low rating.

[0393] "Sweetness" - The overall impression of the taste of a solid dosage form during the intended use regarding sweetness. As an example, if the sweetness rapidly decreased, a very low rating was given, and if the sweetness was too high and caused discomfort, a very low rating was also given.

[0394] "Off-note" - The overall impression of off-notes from one or more cannabinoids in the composition during the intended use. As an example, if an off-note (such as grassy, bitter, throat irritation) was experienced in the throat, a low rating was given, and if other unpleasant sensations were experienced, a low rating was also given.

[0395] (Example 16) Results regarding content uniformity in the powder premix The procedure of Example 11A was used for the above powder premix (powder premix sample), and the results are shown in the following table. The results of the content uniformity of the samples are provided as a single value obtained as the relative standard deviation (RSD) of the CBD content of multiple samples taken at the end of the premix preparation procedure.

[0396] [Table 36]

[0397] [Table 37]

[0398]

Table 38

[0399]

Table 39

[0400]

Table 40

[0401]

Table 41

[0402]

Table 42

[0403]

Table 43

[0404]

Table 44

[0405]

Table 45

[0406]

Table 46

[0407]

Table 47

[0408]

Table 48

[0409]

Table 49

[0410]

Table 50

[0411]

Table 51

[0412]

Table 52

[0413]

Table 53

[0414]

Table 54

[0415] (Example 16A) Results on content uniformity in the powder premix The procedure of Example 11A was used for the above powder premix (powder premix sample), and the results are shown in the following table. The results of the content uniformity of the samples are provided as a single value obtained as the relative standard deviation (RSD) of the CBD content of a plurality of samples collected at the end of the premix preparation procedure.

[0416]

Table 55

[0417] (Example 17) Results regarding content uniformity in powder blends and solid dosage forms The procedure of Example 11A was used for a powder blend (powder blend) which was a powder premix (powder premix sample) containing additional components outlined in the formulation of oral dosage forms. These powder blends were formed into solid dosage forms. The procedure of Example 11B was used for the solid dosage forms. The results are shown in the table below.

[0418] The results of content uniformity (CU) of the samples are provided as a single value obtained as the relative standard deviation (RSD) of the CBD content of multiple samples taken at the end of the preparation procedure. When individual samples are collected at different stages of the tableting process (e.g., start, middle, end), content uniformity is determined by analysis of pooled samples from different process stages.

[0419] [Table 56]

[0420] [Table 57]

[0421] [Table 58]

[0422] [Table 59]

[0423] (Example 17A) Results regarding content uniformity in powder blends and solid dosage forms The procedure of Example 11A was used for a powder blend (powder blend sample), which is a powder premix containing additional ingredients outlined in the formulation of an oral dosage form. These powder blends were formed into solid dosage forms. The procedure of Example 11B was used for the solid dosage forms. The results are shown in the table below.

[0424] The results of the content uniformity (CU) of the samples are provided as a single value obtained as the relative standard deviation (RSD) of the CBD content of multiple samples taken at the end of the preparation procedure. When individual samples are collected at different stages of the tableting process (e.g., start, middle, end), the content uniformity is determined by analysis of the pooled samples from different process stages.

[0425] [Table 60]

[0426] [Table 61]

[0427] [Table 62]

[0428] (Example 18) Results regarding content uniformity in additional powder premixes and powder blends The procedure of Example 11A was also performed with additional powder premixes and powder blends used in different application forms. As an example, when the powders provided in the above examples were applied in pouches, sachets, and flow packs, similar good results regarding content uniformity were seen. Some examples can be found in Examples 16A and 17A.

[0429] (Example 19) Results regarding content uniformity in additional solid dosage forms The procedure of Example 11B was also carried out with additional solid dosage forms. Similar good results were seen for tablets without a gum base, FDT tablets, chewing gum, and troches. Some examples can be found in Example 17A.

Claims

1. A powder premix for oral administration of cannabinoids, a cannabinoid powder composition comprising one or more isolated cannabinoids in an amount of at least 2% by mass of the powder premix, a lipid composition comprising one or more triglycerides in an amount of at least 1.0% by mass of the powder premix, and a sweetener powder composition comprising one or more sweeteners comprising, wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:1, a powder premix.

2. The powder premix according to claim 1, wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:

2.

3. The powder premix according to claim 1 or 2, wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:

4.

4. The powder premix according to any one of claims 1 to 3, wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:

5.

5. The powder premix according to any one of claims 1 to 4, wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:

10.

6. The powder premix according to any one of claims 1 to 5, wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:40 to 1:10, for example 1:40 to 1:15, for example 1:40 to 1:

20.

7. The powder premix according to any one of claims 1 to 6, wherein the one or more triglycerides are of plant origin.

8. The powder premix according to any one of claims 1 to 7, wherein the one or more triglycerides do not contain triglycerides of animal origin.

9. The powder premix according to any one of claims 1 to 8, wherein the one or more triglycerides are selected from one or more C4 to C14 triglycerides.

10. The powder premix according to any one of claims 1 to 9, wherein the one or more triglycerides are selected from one or more C6 to C12 triglycerides.

11. The powder premix according to any one of claims 1 to 10, wherein the one or more triglycerides are selected from one or more C8 to C12 triglycerides.

12. The powder premix according to any one of claims 1 to 11, wherein the one or more triglycerides comprise a partially hydrogenated vegetable oil.

13. The powder premix according to any one of claims 1 to 11, wherein the one or more triglycerides comprise a fully hydrogenated vegetable oil.

14. The powder premix according to any one of claims 1 to 13, wherein the one or more triglycerides are selected from triglycerides that are liquid at 0 °C or higher.

15. The powder premix according to any one of claims 1 to 14, wherein the one or more triglycerides are a blend of a plurality of triglycerides, such as a blend of corn oil and oleic acid, such as a blend of corn oil and oleic acid in a ratio of 1:3 to 3:

1.

16. The powder premix according to any one of claims 1 to 15, wherein the one or more triglycerides are heated to a temperature above room temperature before being added to the premix.

17. The powder premix according to any one of claims 1 to 16, wherein the one or more triglycerides are heated to a temperature of 50 to 80 °C before being added to the premix.

18. The powder premix according to any one of claims 1 to 17, wherein the one or more triglycerides are heated to a temperature of 60 to 70 °C before being added to the premix.

19. The powder premix according to any one of claims 1 to 18, wherein the one or more triglycerides are selected from triglycerides that are liquid at 20 °C or higher.

20. The powder premix according to any one of claims 1 to 18, wherein the one or more triglycerides are selected from triglycerides that are liquid at 25 °C or higher.

21. The powder premix according to any one of claims 1 to 20, wherein the one or more triglycerides are selected from triglycerides having a melting temperature of 25 to 50 °C.

22. The powder premix according to any one of claims 1 to 21, wherein the one or more triglycerides are selected from triglycerides having a melting temperature of 30 to 40 °C.

23. The powder premix according to any one of claims 1 to 18, wherein the one or more triglycerides contain caprylic acid in an amount of 50 to 80% by mass.

24. The powder premix according to any one of claims 1 to 19, wherein the one or more triglycerides contain capric acid in an amount of 20 to 45% by mass.

25. The powder premix according to any one of claims 1 to 23, wherein the one or more triglycerides contain coconut oil and / or corn oil and / or oleic acid.

26. The powder premix according to claim 25, wherein the one or more triglycerides consist essentially of coconut oil and / or corn oil and / or oleic acid.

27. The powder premix according to claim 25 or 26, wherein the one or more triglycerides form part of a self-emulsifying drug delivery system (SEDDS) or are a self-emulsifying drug delivery system (SEDDS).

28. The powder premix according to any one of claims 1 to 27, wherein the one or more triglycerides are present in an amount of at least 1.5% by mass of the powder premix.

29. The powder premix according to any one of claims 1 to 28, wherein the one or more triglycerides are present in an amount of at least 2.0% by mass of the powder premix.

30. The powder premix according to any one of claims 1 to 29, wherein the one or more triglycerides are present in an amount of at least 3.0% by mass of the powder premix.

31. The powder premix according to any one of claims 1 to 30, wherein the one or more triglycerides are present in an amount of at least 5.0% by mass of the powder premix.

32. The powder premix according to any one of claims 1 to 31, wherein the one or more triglycerides are present in an amount of at least 10.0% by mass of the powder premix.

33. The powder premix according to any one of claims 1 to 32, wherein the one or more triglycerides are present in an amount of at least 20.0% by mass of the powder premix.

34. The powder premix according to any one of claims 1 to 33, wherein the one or more sweeteners are present in an amount of at least 50% by mass of the powder premix.

35. The powder premix according to any one of claims 1 to 34, wherein the one or more sweeteners are present in an amount of at least 60% by mass of the powder premix.

36. The powder premix according to any one of claims 1 to 35, wherein the one or more sweeteners are present in an amount of at least 70% by mass of the powder premix.

37. The powder premix according to any one of claims 1 to 36, wherein the one or more sweeteners are present in an amount of at least 75% by mass of the powder premix.

38. The powder premix according to any one of claims 1 to 37, wherein the one or more sweeteners are present in an amount of at least 80% by mass of the powder premix.

39. The powder premix according to any one of claims 1 to 38, wherein the one or more sweeteners include one or more sugar alcohols.

40. The powder premix according to any one of claims 1 to 39, wherein the one or more sugar alcohols are selected from the group consisting of sorbitol, xylitol, maltitol, isomalt, mannitol, erythritol, lactitol, and combinations thereof.

41. The powder premix according to any one of claims 1 to 40, wherein the one or more sugar alcohols are selected from the group consisting of xylitol, erythritol, maltitol, mannitol, and combinations thereof.

42. The powder premix according to any one of claims 1 to 41, wherein the one or more sugar alcohols include xylitol.

43. The powder premix according to any one of claims 1 to 42, wherein the one or more sugar alcohols include erythritol.

44. The powder premix according to any one of claims 1 to 43, wherein the one or more sugar alcohols include mannitol.

45. The powder premix according to any one of claims 1 to 44, wherein the one or more sugar alcohols include maltitol.

46. The powder premix according to any one of claims 1 to 45, wherein the one or more sugar alcohols include granulated sugar alcohol particles.

47. The powder premix according to any one of claims 1 to 46, wherein the one or more sugar alcohols include non-direct (non-DC) sugar alcohol particles.

48. The powder premix according to any one of claims 1 to 38, wherein the one or more sweeteners comprise one or more saccharides.

49. The powder premix according to any one of claims 1 to 48, wherein the one or more sweeteners comprise at least two types of sweetener particles.

50. The powder premix according to any one of claims 1 to 49, wherein the one or more sweeteners are sweetener particles, and more than 50% of the particles have a particle size of less than 250 microns.

51. The powder premix according to any one of claims 1 to 50, wherein the one or more sweeteners are sweetener particles, and more than 20% of the particles have a particle size greater than 500 microns.

52. The powder premix according to any one of claims 1 to 51, wherein the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:40 to 1:5, for example 1:40 to 1:4, for example 1:40 to 1:3, for example 1:40 to 1:2, for example 1:40 to 1:

1.

53. The powder premix according to any one of claims 1 to 52, wherein the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:20 to 1:5, for example 1:20 to 1:4, for example 1:20 to 1:3, for example 1:20 to 1:2, for example 1:20 to 1:

1.

54. The powder premix according to any one of claims 1 to 53, wherein the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:10 to 1:5, for example 1:10 to 1:4, for example 1:10 to 1:3, for example 1:10 to 1:2, for example 1:10 to 1:

1.

55. The powder premix according to any one of claims 1 to 54, wherein the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:5 to 1:4, for example 1:5 to 1:3, for example 1:5 to 1:

2.

56. The powder premix according to any one of claims 1 to 55, wherein the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:4 to 4:1, for example 1:4 to 3:1, for example 1:4 to 2:1, for example 1:4 to 1:1, for example 1:4 to 1:

2.

57. The powder premix according to any one of claims 1 to 56, wherein the mass ratio of the one or more triglycerides to the one or more isolated cannabinoids is in the range of 1:3 to 4:1, for example 1:2 to 4:1, for example 1:1 to 4:1, for example 2:1 to 4:

1.

58. The powder premix according to any one of claims 1 to 57, wherein the one or more isolated cannabinoids are present in an amount of at least 5% by mass of the powder premix.

59. The powder premix according to any one of claims 1 to 58, wherein the one or more isolated cannabinoids are present in an amount of at least 10% by mass of the powder premix.

60. The powder premix according to any one of claims 1 to 59, wherein the one or more isolated cannabinoids are present in an amount of at least 20% by mass of the powder premix.

61. The powder premix according to any one of claims 1 to 60, wherein the one or more isolated cannabinoids are present in an amount of at least 30% by mass of the powder premix.

62. The powder premix according to any one of claims 1 to 61, wherein the one or more isolated cannabinoids are present in the powder mixture in an amount of 0.1 to 400 mg.

63. The powder premix according to any one of claims 1 to 62, wherein the one or more isolated cannabinoids are present in the powder premix in an amount of 1 to 200 mg.

64. The powder premix according to any one of claims 1 to 63, wherein the one or more isolated cannabinoids are present in the powder premix in an amount of 10 to 100 mg.

65. The powder premix according to any one of claims 1 to 64, wherein the one or more isolated cannabinoids are selected from the group consisting of cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), and combinations thereof.

66. The powder premix according to any one of claims 1 to 64, wherein the one or more isolated cannabinoids are selected from the group consisting of tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and combinations thereof.

67. The powder premix according to any one of claims 1 to 64, wherein the one or more isolated cannabinoids include cannabigerol (CBG).

68. The powder premix according to any one of claims 1 to 67, wherein the one or more isolated cannabinoids are present with a purity of at least 90% (w / w).

69. The powder premix according to any one of claims 1 to 68, wherein the one or more isolated cannabinoids are present with a purity of at least 95% (w / w).

70. The powder premix according to any one of claims 1 to 69, wherein the one or more isolated cannabinoids are present with a purity of at least 98% (w / w).

71. The powder premix according to any one of claims 1 to 70, wherein the one or more isolated cannabinoids do not contain a cannabinoid distillate.

72. The powder premix according to any one of claims 1 to 71, wherein the one or more isolated cannabinoids do not contain a cannabinoid extract.

73. The powder premix according to any one of claims 1 to 68, wherein the one or more isolated cannabinoids do not contain one or more isolated cannabinoids with a purity of less than 90% (w / w).

74. The powder premix according to any one of claims 1 to 73, wherein the one or more isolated cannabinoids are dissolved in the one or more triglycerides before mixing with the sweetener powder composition.

75. The powder premix according to any one of claims 1 to 73, wherein the one or more isolated cannabinoids are added to the sweetener powder composition before mixing with the one or more triglycerides.

76. The powder premix according to any one of claims 1 to 73, wherein the one or more triglycerides are added to the sweetener powder composition before mixing with the one or more isolated cannabinoids.

77. The powder premix according to any one of claims 1 to 76, wherein a further component is added to the premix.

78. The powder premix according to any one of claims 1 to 77, wherein a further component selected from the group consisting of flavorings, dry binders, tableting aids, anti-caking agents, surfactants, emulsifiers, antioxidants, enhancers, mucoadhesive agents, absorption enhancers, high-intensity sweeteners, softeners, colorants, further active ingredients, water-soluble indigestible polysaccharides, water-insoluble polysaccharides, and any combination thereof is added to the premix.

79. The powder premix according to any one of claims 1 to 78, wherein one or more flavoring agents are added to the premix.

80. The powder premix according to any one of claims 1 to 79, wherein a high-intensity sweetener is added to the premix.

81. The powder premix according to any one of claims 1 to 80, wherein the premix is a ready-to-use premix.

82. The powder premix according to any one of claims 1 to 80, wherein the premix is applied in an amount of 10 to 99.9% by mass in combination with a further component, for example an oral care agent.

83. A solid dosage form for oral administration of cannabinoids, comprising the premix according to any one of claims 1 to 80.

84. The solid dosage form according to claim 83, wherein the premix is present in an amount of 10 to 100% by mass of the solid dosage form.

85. The solid dosage form according to claim 83 or 84, wherein the premix is present in an amount of 15 to 75% by mass of the solid dosage form.

86. A tablet for oral administration of cannabinoids, comprising the premix according to any one of claims 1 to 80.

87. The tablet according to claim 86, wherein the premix is present in an amount of 10 to 100% by mass of the tablet.

88. The tablet according to claim 86 or 87, wherein the premix is present in an amount of 15 to 75% by mass of the tablet.

89. The tablet according to any one of claims 86 to 88, wherein the tablet comprises one or more sugar alcohols selected from the group consisting of sorbitol, erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof, in addition to the one or more sweeteners in the premix.

90. The tablet according to any one of claims 86 to 89, wherein the tablet comprises one or more sweeteners in an amount of 20 to 80% by mass of the tablet, in addition to the one or more sweeteners in the premix.

91. The tablet according to any one of claims 86 to 90, wherein the tablet comprises directly compressible (DC) sugar alcohol particles and non-directly compressible (non-DC) sugar alcohol particles.

92. The tablet according to claim 91, having a mass ratio of the non-DC sugar alcohol particles to the DC sugar alcohol particles that is between 0.2 and 1.

2.

93. The tablet according to claim 91 or 92, having a mass ratio of the non-DC sugar alcohol particles to the DC sugar alcohol particles that is between 0.3 and 0.

7.

94. The tablet according to any one of claims 86 to 93, wherein the tablet contains one or more insoluble components selected from the group consisting of silica, microcrystalline cellulose, cellulose, silicified microcrystalline cellulose, clay, talc, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, magnesium carbonate, magnesium aluminometasilicate, superporous silica, and mixtures thereof.

95. The tablet according to any one of claims 86 to 94, wherein the tablet contains one or more binders in an amount of 0.1 to 8% by mass of the tablet, such as 0.1 to 7% by mass, such as 1 to 7% by mass, such as 2 to 7% by mass, such as 0.1 to 6% by mass, such as 1 to 6% by mass.

96. The tablet according to any one of claims 86 to 95, wherein the tablet contains at least two modules, and the premix is contained in at least one module of the tablet.

97. A chewing gum for oral administration of a cannabinoid, comprising the premix according to any one of claims 1 to 80.

98. The chewing gum according to claim 97, wherein the premix is present in an amount of 15 to 75% by mass of the chewing gum.

99. The chewing gum according to claim 97 or 98, wherein the chewing gum contains a gum base in an amount of 20 to 40% by mass of the chewing gum, and the chewing gum is designed to be chewed into a coherent residue containing water-insoluble components.

100. The chewing gum according to any one of claims 97 to 99, wherein the chewing gum contains a gum base, and the gum base contains an elastomer selected from the group consisting of styrene-butadiene rubber (SBR), butyl rubber, polyisobutylene (PIB), and combinations thereof.

101. The chewing gum according to any one of claims 97 to 100, wherein the chewing gum contains a gum base, and the gum base contains at least 5% by mass of an elastomer.

102. The chewing gum agent according to any one of claims 97 to 101, wherein the chewing gum agent contains a gum base, and the gum base contains a gum base resin selected from natural resins and / or synthetic resins.

103. The chewing gum agent according to any one of claims 97 to 102, wherein the chewing gum agent contains a gum base, and the gum base contains at least 5% by mass of a gum base resin.

104. The chewing gum agent according to any one of claims 97 to 103, wherein the chewing gum agent contains a gum base, and the gum base contains gum base particles having an average particle diameter between 400 μm and 1400 μm.

105. The chewing gum agent according to any one of claims 97 to 104, wherein the chewing gum agent contains, in addition to the one or more sweeteners in the premix, one or more sugar alcohols selected from the group consisting of sorbitol, erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof.

106. The chewing gum agent according to any one of claims 97 to 105, wherein the chewing gum agent contains, in addition to the one or more sweeteners in the premix, one or more sweeteners in an amount of 20 to 60% by mass of the chewing gum agent.

107. The chewing gum agent according to any one of claims 97 to 106, wherein the chewing gum agent contains at least two compression modules, and the premix is included in at least one of the two compression modules.

108. The chewing gum agent according to any one of claims 97 to 107, wherein the chewing gum agent contains at least two compression modules, and the two modules have different compositions.

109. The chewing gum agent according to any one of claims 97 to 108, wherein the chewing gum agent contains at least two compression modules, and at least one of the two compression modules does not contain a gum base.

110. A troche for oral administration of cannabinoids, comprising the premix according to any one of claims 1 to 80.

111. The troche according to claim 110, wherein the premix is present in an amount of 10 to 100% by mass of the troche.

112. The troche according to claim 110 or 111, wherein the premix is present in an amount of 15 to 75% by mass of the troche.

113. The troche according to any one of claims 110 to 112, wherein the troche comprises, in addition to the one or more sweeteners in the premix, one or more sugar alcohols selected from the group consisting of sorbitol, erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof.

114. The troche according to any one of claims 110 to 113, wherein the troche comprises, in addition to the one or more sweeteners in the premix, one or more sweeteners in an amount of 20 to 60% by mass of the troche.

115. The troche according to any one of claims 110 to 114, wherein the troche comprises one or more insoluble components selected from the group consisting of silica, microcrystalline cellulose, cellulose, silicified microcrystalline cellulose, clay, talc, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, magnesium carbonate, magnesium aluminometasilicate, superporous silica, and mixtures thereof.

116. The troche according to any one of claims 110 to 115, wherein the troche comprises one or more disintegrants capable of causing the troche to disintegrate within a period of 1 minute or less upon contact with oral saliva.

117. The troche according to any one of claims 110 to 116, wherein the troche comprises one or more disintegrants selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, and combinations thereof.

118. The troche according to any one of claims 110 to 117, wherein the troche comprises one or more disintegrants in an amount of 0.5 to 25% by mass of the troche.

119. A pouch for oral administration of cannabinoids, comprising the premix according to any one of claims 1 to 80.

120. The pouch according to claim 119, wherein the premix is present in an amount of 10 to 100% by mass of the pouch.

121. The pouch according to claim 119 or 120, wherein the premix is present in an amount of 15 to 75% by mass of the pouch.

122. The pouch according to claim 120 or 121, wherein the pouch contains one or more insoluble components selected from the group consisting of silica, clay, talc, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, magnesium carbonate, magnesium aluminometasilicate, superporous silica, and mixtures thereof.

123. The pouch according to any one of claims 120 to 122, wherein the pouch contains one or more insoluble fibers.

124. The pouch according to any one of claims 120 to 123, wherein the pouch contains one or more insoluble fibers selected from the group consisting of wheat fiber, pea fiber, rice fiber, corn fiber, rye fiber, tomato fiber, barley fiber, lime fiber, sugar beet fiber, buckwheat fiber, potato fiber, cellulose fiber, apple fiber, cocoa fiber, cellulose fiber, bran fiber, bamboo fiber, powdered cellulose, microcrystalline cellulose, and combinations thereof.

125. The pouch according to any one of claims 120 to 124, wherein the pouch contains one or more sugar alcohols selected from the group consisting of sorbitol, erythritol, maltitol, xylitol, isomalt, lactitol, mannitol, and combinations thereof, in addition to the one or more sweeteners in the premix.

126. The pouch according to any one of claims 120 to 125, wherein the pouch contains one or more sweeteners in an amount of 20 to 60% by mass of the pouch, in addition to the one or more sweeteners in the premix.

127. i) Following the step of dissolving or dispersing a cannabinoid powder composition containing one or more isolated cannabinoids in a lipid composition containing one or more triglycerides, ii) A method for preparing a powder premix for oral administration of cannabinoids, comprising the step of mixing a sweetener powder composition containing one or more sweeteners with the mixture obtained in i) to obtain a powder premix, wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:

1.

128. The method according to claim 127, wherein the one or more triglycerides are heated to a temperature above room temperature before being added to the premix.

129. ​ The method according to claim 127 or 128, wherein the powder premix is as described in any one of claims 1 to 80.

130. i) following the step of mixing a sweetener powder composition comprising one or more sweeteners with a cannabinoid powder composition comprising one or more isolated cannabinoids, ii) the step of mixing a lipid composition comprising one or more triglycerides with the mixture obtained in i) to obtain a powder premix A method for preparing a powder premix for oral administration of cannabinoids, comprising: The method wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:

1.

131. The method according to claim 130, wherein the one or more triglycerides are heated to a temperature above room temperature before being added to the premix.

132. The method according to claim 130 or 131, wherein the powder premix is as described in any one of claims 1 to 80.

133. i) following the step of mixing a sweetener powder composition comprising one or more sweeteners with a lipid composition comprising one or more triglycerides, ii) the step of mixing a cannabinoid powder composition comprising one or more isolated cannabinoids with the mixture obtained in i) to obtain a powder premix A method for preparing a powder premix for oral administration of cannabinoids, comprising: The method wherein the mass ratio of the one or more triglycerides to the one or more sweeteners is in the range of 1:50 to 1:

1.

134. The method according to claim 133, wherein the one or more triglycerides are heated to a temperature above room temperature before being added to the premix.

135. The method according to claim 133 or 134, wherein the powder premix is as described in any one of claims 1 to 80.

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