Particles containing lipid matrix core and active ingredient

Abstract

To provide a composition having a multiparticulate material capable of sufficiently incorporating a therapeutically effective amount of a fat-soluble active ingredient, having suitable efficacy and storage stability.SOLUTION: A composition containing a plurality of particles containing a core having a lipid matrix including an active ingredient dispersed therein is disclosed. The active ingredient can include a fat-soluble active ingredient. The particles can be contained in a capsule. Also provided are methods for producing a pharmaceutical composition containing a plurality of particles containing a core having a lipid matrix including an active ingredient dispersed therein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application is based on and claims priority to U.S. Provisional Patent Application No. 62 / 946,107, filed December 10, 2019, and is incorporated herein by reference. [Background technology]

[0002] Food preparations and pharmaceutical preparations may contain multiparticulate materials that are coated with specific ingredients and incorporated into dosage forms. In fact, these multiparticulates contain starter particles or pellets, also known as seeds, beads, nonpareils, microparticles, or starter cores. The cores are formed from inert materials such as sucrose or microcrystalline cellulose. These cores are used as starter materials and layered with active ingredient compounds before being incorporated into the final oral dosage form. However, it can be very difficult to incorporate certain active ingredients, such as fat-soluble ingredients, into the starter core. For example, to enable layering on the inert core, certain fat-soluble active substances must first be processed into a dry form and then micronized into fine particles. This can significantly reduce the efficacy of the finished particulate product and cause stability problems.

[0003] Thus, there is a need for multiparticulate materials that can adequately incorporate therapeutically effective amounts of lipid-soluble active ingredients with suitable potency and storage stability. Summary of the Invention

[0004] The present disclosure is generally directed to a composition containing a plurality of particles, each of which comprises a core containing a lipid matrix with an active ingredient dispersed therein. The active ingredient may be a lipid-soluble active ingredient. The particles may also comprise one or more outer layers disposed on the core. The one or more outer layers may also contain one or more active ingredients. In some embodiments, the outer layer containing one or more active ingredients may be layered on the core. The particles may be incorporated into a capsule or any other suitable oral dosage form. Also disclosed is a pharmaceutical composition containing a capsule filled with one or more particles, each of which comprises a core having a lipid matrix with a dispersed active ingredient therein and an outer layer having one or more active ingredients disposed thereon.

[0005] In some embodiments, the active ingredient is a fat-soluble component, such as one or more fat-soluble vitamins and minerals, one or more carotenoids, one or more cannabis extracts, coenzyme Q10, and combinations thereof. In certain embodiments, the fat-soluble component comprises a carotenoid, such as lutein, astaxanthin, zeaxanthin, α-carotene, β-carotene, cryptoxanthin, lycopene, and mixtures thereof.

[0006] In some embodiments, the active ingredient may comprise about 10% to about 60% by weight of the core. In some embodiments, the core may have an average diameter ranging from about 40 μm to about 3000 μm. The core may further contain one or more outer layers having one or more active ingredients therein. For example, the core may be coated with a suitable adhesive and layered with a second active ingredient. In some embodiments, the core may comprise about 5% to about 60% by weight of the finished particle. In some embodiments, the one or more finished particles may have an average diameter of about 0.5 mm to about 1.5 mm.

[0007] Further, the method includes providing one or more cores comprising a lipid matrix having a lipid-soluble active ingredient dispersed therein, and layering the one or more cores with one or more active ingredient layers to form one or more particles. and forming a pharmaceutical composition comprising:

[0008] Other features and aspects of the disclosure are discussed in more detail below. DETAILED DESCRIPTION OF THE INVENTION

[0009] It should be understood by those skilled in the art that this discussion is merely a description of exemplary embodiments and is not intended to limit the broader aspects of the present disclosure.

[0010] The present disclosure is generally directed to a composition containing a plurality of particles, each of which contains a core containing a lipid matrix with an active ingredient dispersed therein. The active ingredient may be a lipid-soluble active ingredient. The plurality of particles may also contain one or more outer layers disposed thereon. The one or more outer layers may contain one or more active ingredients. The plurality of particles may be incorporated into a capsule or any other suitable oral dosage form. Also disclosed is a pharmaceutical composition containing a capsule filled with one or more particles, each of which contains a core with a lipid matrix with an active ingredient dispersed therein. Various embodiments are disclosed herein.

[0011] The following description is exemplary in nature and is not intended to limit the scope, applicability, or configuration of the present invention in any manner. Various changes to the described embodiments may be made in the function and arrangement of elements described herein without departing from the scope of the disclosure.

[0012] As used in this application and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Additionally, the term "include" means "comprise." Methods and compositions including components of the present disclosure can include, consist of, or consist essentially of the essential elements and limitations of the embodiments described herein, as well as any additional or optional ingredients, components, or limitations useful in nutritional compositions described herein or elsewhere.

[0013] Unless otherwise indicated, all numerical values ​​expressing properties such as the amount, molecular weight, and proportion of ingredients used in this specification or claims should be understood as modified by the term "about." Thus, unless otherwise indicated, numerical parameters implicitly or explicitly indicated are approximations that may depend on the desired properties and / or limits of detection sought under standard testing conditions / methods. When directly and explicitly distinguishing an embodiment from the prior art discussed, the numerical values ​​of the embodiments are not approximations unless the word "about" is used.

[0014] As used herein, "optional" or "optionally" means that the subsequently described material, event, or circumstance may or may not be present or may occur, and the description is meant to include cases where the material, event, or circumstance is present or occurs, as well as cases where it is not. As used herein, "w / w%" and "% by weight" mean weight as a percentage of the total weight in a composition, or as compared to another component.

[0015] The term "about" is intended to mean, in the region, approximately, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by expanding the boundaries above and below the set forth numerical values. Unless otherwise indicated, the numerical parameters set forth in the following specification and attached claims should be understood to be approximations. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, the numerical parameters should be understood to be within the bounds of the reported significant digits and the approximate range of values. should be read in light of the application of normal rounding techniques.

[0016] The phrase "effective amount" refers to an amount of a compound that promotes, ameliorates, stimulates, or facilitates a response to a particular condition or disorder, or a particular symptom of a condition or disorder.

[0017] The term "supplement" refers to a product that is added to the normal diet, but can be combined with the normal food or beverage composition of a mammal. The supplement can be in any form, including, but not limited to, a solid, liquid, gel, capsule, or powder. The supplement can also be administered simultaneously with or as a component of a food composition, which can include food, beverage, pet food, snack, or treat. In one embodiment, the beverage can be an active beverage.

[0018] As used herein, the term "pour point" refers to the temperature at which any portion of a mixture becomes sufficiently fluid that the entire mixture can be atomized. Generally, a mixture is sufficiently fluid for atomization when the viscosity of the molten mixture is less than 20,000 cp, or less than 15,000 cp, or less than 10,000 cp, or less than 5000 cp, or even less than 1000 cp. Viscosity can be measured using a controlled stress rheometer, which measures viscosity as a function of temperature, and either a shear or rotational rheometer can be used. As used herein, melting point refers to the temperature that indicates the midpoint of the transition from a solid crystalline or semi-crystalline state to a liquid state. As measured by DSC, melting point is the temperature at which maximum exothermic heat flow occurs when a solid material is heated. Generally, melting point is used in reference to relatively pure single-component materials, such as some active agents or essentially single-component excipients (e.g., stearyl alcohol), while pour point is used in reference to multi-component materials or mixtures.

[0019] The term "ambient temperature" refers to a temperature of 20°C.

[0020] As used herein, the term "semi-solid" refers to a substance that is solid at ambient temperature but becomes liquid at temperatures above 30° C. or 40° C., or at body temperature.

[0021] Unless otherwise indicated, "capsule" means a container suitable for enclosing a solid or liquid, and includes the empty capsule shell and its components, such as the cap and body, which may be assembled together to form a capsule.

[0022] Unless otherwise indicated, "dosage form" refers to a solid composition comprising the active ingredient.

[0023] As used herein, the term "particle" refers to a portion or amount of material, e.g., a small portion or amount of material. For example, as provided herein, the term particle may generally refer to a composition containing a core and one or more outer layers surrounding the core. In some embodiments, the described particles may be generally spherical. As used herein, the term particle may include, or be used interchangeably with, pellets, beadlets, multiparticulates, microparticles, spheres, seeds, and the like. The term particle, as used herein, is not limited to particles formed by a particular method or process. Indeed, the particles described herein may be formed by any suitable process. Specific suitable processes include, but are not limited to, spheronization, extrusion, compression, powder layering, liquid layering, pelletization by melt and wet granulation, and combinations thereof. The particles described herein may be solid or semi-solid particles. In some embodiments, the particles described herein may include both solid and semi-solid compositions contained on or within the particle itself.

[0024] Embodiments of the disclosed compositions may include at least one active ingredient or agent. A composition may contain one or more active ingredients. As used herein, "active" or "active ingredient" refers to a drug, medicament, pharmaceutical, therapeutic, dietary supplement, or other compound that may be desired to be administered to the body. An active ingredient may be a "small molecule" generally having a molecular weight of 2000 daltons or less. An active ingredient may also be a "bioactive substance." Bioactive ingredients include proteins, antibodies, antibody fragments, peptides, oligonucleotides, vaccines, and various derivatives of such materials. In one embodiment, the active ingredient is a small molecule. In another embodiment, the active ingredient is a bioactive substance. In yet another embodiment, the active ingredient is a mixture of a small molecule and a bioactive substance. Also, as used herein, the terms "active ingredient," "first active ingredient," "second active ingredient," etc. may be used to refer to active ingredients located in different locations within the particle, such as those located within the core or within one or more outer layers. However, the terms "first" or "second" do not necessarily indicate that the first active ingredient is different from the second active ingredient. For example, in certain embodiments, the active ingredient contained in the core may be the same as the second active ingredient contained in the outer layer disposed on the core. In certain other embodiments, the active ingredient contained in the core may be different from the second active ingredient contained in the outer layer disposed on the core.

[0025] In some embodiments, the active ingredient may include a fat-soluble component, such as a fat-soluble vitamin or mineral. Examples of fat-soluble vitamins and minerals include vitamin A, vitamin D, vitamin E, vitamin K, coenzyme Q10, one or more carotenoids (beta-carotene, lutein, astaxanthin, lycopene, zeaxanthin), one or more cannabinoids, such as tetrahydrocannabinol, and combinations thereof.

[0026] In some embodiments, the active ingredient may include a carotenoid. Carotenoids, also known as tetraterpenoids, belong to a class of compounds known as phytonutrients and can be found in a wide variety of plants, algae, and bacteria. Carotenoids also have important antioxidant functions, deactivating free radicals and acting as antioxidants in the human body. Carotenoids may also provide other health benefits when ingested, including certain anti-cancer properties, and may contribute to overall eye and bone health. Carotenoids are also responsible for the bright red, yellow, and orange hues found in many fruits and vegetables.

[0027] Examples of carotenoids include lutein, astaxanthin, zeaxanthin, α-carotene, β-carotene, cryptoxanthin, lycopene, and mixtures thereof. Carotenoids include xanthophylls such as lutein and zeaxanthin, carotenes such as β-carotene, α-carotene, and ζ-carotene, and lycopene and related molecules, including 1-HO-3′,4′-didehydrolycopene, 3,1′-(HO)2-γ-carotene, 1,1′-(HO)2-3,4,3′,4′-tetradehydrolycopene, and 1,1′-(HO)2-3,4-didehydrolycopene.

[0028] Other suitable carotenoid compounds that may be used as described herein include lycopersene (7,8,11,12,15,7',8',11',12',15'-decahydro-γ,γ-carotene), phytofluene, hexahydrolycopene (15-cis-7,8,11,12,7',8'-hexahydro-γ,γ-carotene), tolulene (3',4'-didehydro-β,γ-carotene), and α - Hydrocarbons such as zeacarotene (7',8'-dihydro-ε,γ-carotene); alloxanthin, scinthiaxanthin, pectenoxanthin, cryptomonaxanthin, ((3r,3'r)-7,8,7',8'-tetradehydro-β,β-carotene-3,3'-diol), clusteraxanthin (β,-carotene-3,4,3',4'-tetrol), gazaniaxanthin ((3r)-5'-cis -β,γ-carotene-3-ol), oh-chlorobactene (1',2'-dihydro-f,γ-carotene-1'-ol), loroxanthin (β,ε-carotene-3,19,3'-triol), lycoxanthin (γ,γ-carotene-16-ol), rhodopin (1,2-dihydro-γ,γ-carotene-1-ol), rhodopinol (also known as warmingol; 13-cis-1,2-dihydro-γ,γ-carotene-1,20-diol), saproxanthin (3',4'-didehydro-1',2'-dihydro- alcohols such as β,γ-carotene-3,1′-diol) and zeaxanthin; glycosides such as osilaxanthin (2,2′-bis(β-1-rhamnopyranosyloxy)-3,4,3′,4′-tetradehydro-1,2,1′,2′-tetrahydro-γ,γ-carotene-1,1′-diol) and flexanthophyll (1′-(β-d-glucopyranosyloxy)-3′,4′-didehydro-1′,2′-dihydro-β,γ-carotene-2′-ol); Ethers such as spheroidene (1-methoxy-3,4-didehydro-1,2,7',8'-tetrahydro-γ,γ-carotene), epoxides such as diadinoxanthin (5,6-epoxy-7',8'-didehydro-5,6-dihydro-carotene-3,3-diol), luteoxanthin (5,6:5',8'-diepoxy-5,6,5',8'-tetrahydro-β,β-carotene-3,3'-diol), muta toxanthin, citroxanthin, zeaxanthin (furanoxide 5,8-epoxy-5,8-dihydro-β,β-carotene-3,3′-diol), neochrome (5′,8′-epoxy-6,7-didehydro-5,6,5′,8′-tetrahydro-β,β-carotene-3,5,3′-triol), foliachrome, trolichrome, and baucheriaxanthin (5′,6′-epoxy-6,7-didehydro-5,6,5′,6′-tetrahydro-β,β-carotene-3,5,19,3′-tetrol);Aldehydes such as rhodopinal, wammingone (13-cis-1-hydroxy-1,2-dihydro-γ,γ-carotene-20-al), and torularhodin aldehyde (3',4'-didehydro-β,γ-carotene-16'-al); acids and acid esters such as torularhodin (3',4'-didehydro-β,γ-carotene-16'-oic acid) and torularhodin methyl ester (methyl 3',4'-didehydro-β,γ-carotene-16'-oate); astaxanthin, canthaxanthin (also known as aphanisin), and chloroform. Relaxanthin (β,β-carotene-4,4′-dione), capsanthin ((3r,3′s,5′r)-3,3′-dihydroxy-β,κ-carotene-6′-one), capsorubin ((3s,5r,3′s,5′r)-3,3′-dihydroxy-κ,κ-carotene-6,6′-dione), cryptocapsin ((3′r,5′r)-3′-hydroxy-β,κ-carotene-6′-one), 2,2′-diketospirilloxanthin (1,1′-dimethoxy-3,4,3′,4′-tetradehydro-1,2,1′,2′-tetrahydro- γ,γ-carotene-2,2′-dione), flexixanthin (3,1′-dihydroxy-3′,4′-didehydro-1′,2′-dihydro-β,γ-carotene-4-one), 3-oh-canthaxanthin (also known as adonirubin; also known as phoenicoxanthin; 3-hydroxy-β,β-carotene-4,4′-dione), hydroxyspheriodenone (1′-hydroxy-1-methoxy-3,4-didehydro-1,2,1′,2′,7′,8′-hexahydro-γ,γ-carotene-2-one), okenone (1′-methoxy-1′,2′ ketones such as -dihydro-c,γ-caroten-4′-one), pectenolone (3,3′-dihydroxy-7′,8′-didehydro-β,β-caroten-4-one), pheniconone (also known as dehydroadnirubin; 3-hydroxy-2,3-didehydro-β,β-carotene-4,4′-dione), phenicopterone (β,ε-caroten-4-one), rubixanthone (3-hydroxy-β,γ-caroten-4′-one), and siphonaxanthin (3,19,3′-trihydroxy-7,8-dihydro-β,ε-caroten-8-one);Astacein (3,3′-bispalmitoyloxy-2,3,2′,3′-tetradehydro-β,β-carotene-4,4′-dione or 3,3′-dihydroxy-2,3,2′,3′-tetradehydro-β,β-carotene-4,4′-dione dipalmitate), fucoxanthin (3′-acetoxy-5,6-ethoxy; acetoxy-3,5'-dihydroxy-6',7'-didehydro-5,6,7,8,5',6'-hexahydro-β,β-caroten-8-one), isofucoxanthin (3'-acetoxy-3,5,5'-trihydroxy-6',7'-didehydro-5,8,5',6'-tetrahydro-β,β-caroten-8-one), physaliene, zeaxanthin dipalmitate ((3r,3'r)-3,3'- Esters of alcohols such as bispalmitoyloxy-β,β-carotene or (3r,3′r)-β,β-carotene-3,3′-diol dipalmitate) and siphonein (3,3′-dihydroxy-19-lauroyloxy-7,8-dihydro-β,ε-caroten-8-one or 3,19,3′-trihydroxy-7,8-dihydro-β,ε-caroten-8-one 19-laurate);β-Apo-2′-carotenal (3′,4′-didehydro-2′-apo-β-carotene-2′-al), apo-2-lycopenal, apo-6′-lycopenal (6′-apo-γ-carotene-6′-al), azafurinaldehyde (5,6-dihydroxy-5,6-dihydro-10′-apo-β-carotene-10′-al), bixin (6′-methylhydrogen 9′-cis-6,6′-diapocarotene-6,6′-dioate), ), citranaxanthin (5',6'-dihydro-5'-apo-β-carotene-6'-one or 5',6'-dihydro-5'-apo-18'-nor-β-carotene-6'-one or 6'-methyl-6'-apo-β-carotene-6'-one), crocetin (8,8'-diapo-8,8'-carotene diacid), crocetin semialdehyde (8'-oxo-8,8'-diapo-8-carotene diacid), crocin (digestive 8, 8'-diapo-8,8'-carotene dioate), hopkinciaxanthin (3-hydroxy-7,8-didehydro-7',8'-dihydro-7'-apo-b-carotene-4,8'-dione or 3-hydroxy-8'-methyl-7,8-didehydro-8'-apo-b-carotene-4,8'-dione), methyl apo-6'-lycopenoate (methyl 6'-apo-y-carotene-6'-oate), paracentrone (3,5-di apocarotenoids such as hydroxy-6,7-didehydro-5,6,7′,8′-tetrahydro-7′-apo-b-caroten-8′-one or 3,5-dihydroxy-8′-methyl-6,7-didehydro-5,6-dihydro-8′-apo-b-caroten-8′-one) and syntaxanthin (7′,8′-dihydro-7′-apo-b-caroten-8′-one or 8′-methyl-8′-apo-b-caroten-8′-one);Actinioerythrin (3,3'-bisacyloxy-2,2'-dinor-b,b-carotene-4,4'-dione), β-carotenone (5,6:5',6'-diseco-b,b-carotene-5,6,5',6'-tetrone), peridinin (3'-acetoxy-5,6-epoxy-3,5'-dihydroxy-6',7'-didehydro-5,6,5',6'-tetrahydro-12',13',20'-trinor-b,b-carotene-19,11-olide), pyroxanthininol (5,6-epoxy- oxy-3,3′-dihydroxy-7′,8′-didehydro-5,6-dihydro-12′,13′,20′-trinor-b,b-carotene-19,11-olide), semi-α-carotenone (5,6-seco-b,e-carotene-5,6-dione), semi-β-carotenone (5,6-seco-b,b-carotene-5,6-dione) or 5′,6′-seco-b,b-carotene-5′,6′-dione) and triphasiaxanthin (3-hydroxysemi-b-carotene 3′-hydroxy-5,6- nor- and seco-carotenoids such as seco-b,b-carotene-5,6-dione or 3-hydroxy-5',6'-seco-b,b-carotene-5',6'-dione; escholtzuxanthin (4',5'-didehydro-4,5'-retro-b,b-carotene-3,3'-diol), escholtzuxanthon (3'-hydroxy-4',5'-didehydro-4,5'-retro-b,b-carotene-3-one), rhodoxanthin (4',5'-didehydro-4,5'-retro-b,b-carotene-3-one), retrocarotenoids and retroapocarotenoids such as tangeraxanthin (3-hydroxy-5′-methyl-4,5′-retro-5′-apo-β-carotene-5′-one or 3-hydroxy-4,5′-retro-5′-apo-β-carotene-5′-one); and nonaprenoxanthin (2-(4-hydroxy-3-methyl-2-butenyl)-7′,8′,11′,12′-tetrahydro-e,y-carotene), decaprenoxanthin (2,2; These include high carotenoid content, such as CP450 (2-[4-hydroxy-3-(hydroxymethyl)-2-butenyl]-2'-(3-methyl-2-butenyl)-b,b-carotene), CP473 (2'-(4-hydroxy-3-methyl-2-butenyl)-2-(3-methyl-2-butenyl)-3',4'-didehydro-1',2'-dihydro-b,y-caroten-1'-ol), and bacterioruberin (2,2'-bis(3-hydroxy-3-methylbutyl)-3,4,3',4'-tetradehydro-1,2,1',2'-tetrahydro-y,y-carotene-1,1'-diol).

[0029] The carotenoid compounds for use herein can be obtained from natural sources, i.e., extracted from plants such as tomatoes, melons, or marigolds.Various methods for extracting, concentrating, and / or purifying carotenoids from plants are known in the art.For example, solvent extraction using ethanol, DMSO, ethyl acetate, hexane, acetone, soybean, or other vegetable oils, or non-vegetable oils, can be used.Carotenoid compounds can be isolated free or substantially free from other molecules found in their natural source or environment.The use of such extraction and purification methods is known to those skilled in the art.

[0030] Carotenoid compounds for use as described herein may be synthetic, i.e., produced by artificial means, for example, by chemical synthesis or fermentation. Various methods for the chemical synthesis of carotenoids are known in the art.

[0031] In some embodiments, carotenoids are obtained as oils, typically extracts from natural sources, and may contain a variety of components, those structurally and functionally similar to lutein, astaxanthin, and zeaxanthin being considered active ingredients.

[0032] In one embodiment, the carotenoids included in the composition, such as a dietary supplement, include carotenoids that are metabolized in the body to vitamin A, such as retinal, retinol, or retinoic acid. Such carotenoids can be considered vitamin A precursors. Examples of such carotenoids include β-carotene, α-carotene, γ-carotene, and β-cryptoxanthin.

[0033] In an alternative embodiment, the carotenoid included in the composition may include carotenoids with antioxidant activity, such as lutein, zeaxanthin, lycopene, crocetin, and the like.

[0034] Carotenoids may present certain stability and administration complications when formulated into oral dosage forms. For example, given the bright color of many carotenoid compounds, these compounds tend to discolor the resulting dosage form, which can be unpleasant for consumers. Furthermore, carotenoids are prone to degradation, making them difficult to use in coatings for multiparticulate dosage forms. Such degradation can result in reduced efficacy in the final dosage form. However, as provided herein, the core can contain a lipid matrix in which a fat-soluble active ingredient, such as a carotenoid, is dispersed. Thus, the carotenoid may be included in the core in an amount sufficient to address any efficacy concerns. Furthermore, because the core is coated with an additional layer, the carotenoid is protected from further degradation during storage and shipping. Additionally, given that the core can be coated, this prevents the carotenoid composition from bleeding or staining the resulting oral dosage form. Thus, formulating the core of the present disclosure with a sufficient amount of carotenoid can address potential efficacy, storage stability, and product quality issues.

[0035] In some embodiments, the active ingredient is crystalline in the composition. In other embodiments, the active ingredient is amorphous in the composition. In yet other embodiments, the active ingredient may comprise crystalline and amorphous regions in the composition. In some embodiments, the active ingredient is at least 60% crystalline by weight. In other embodiments, the active ingredient is at least 75% crystalline by weight. In other embodiments, the active ingredient is at least 90% crystalline by weight. In other embodiments, the active ingredient may be dissolved in certain excipients of the lipid matrix prior to core formation. During core formation, a portion of the crystalline active ingredient may dissolve in the molten mixture up to the solubility limit of the active ingredient in the molten mixture under processing conditions. When the molten mixture is cooled to form the multiparticulate core, the multiparticulate core comprises particles of the crystalline active ingredient encapsulated in a solid solution in the lipid matrix and the dissolved active ingredient.

[0036] In certain embodiments, the active ingredient may contain one or more cannabis extracts. As used herein, "cannabis" may refer to any variety of the cannabis plant, such as cannabis sativa or cannabis indica. More specifically, the present disclosure may refer to leaves, stems, seeds, and flowers, or any other part of the cannabis plant, as cannabis. Nevertheless, the cannabis referred to herein includes cannabis containing average or high levels of THC and / or CBD (commonly known as marijuana), hemp, which may contain low or very low levels of THC, industrial hemp, which may refer to cannabis plants containing less than 0.3% THC, or a combination thereof.

[0037] "Cannabinoids" is a group of compounds that includes endocannabinoids, phytocannabinoids, and compounds that are neither endocannabinoids nor phytocannabinoids, hereafter referred to as "synthetic cannabinoids."

[0038] "Endocannabinoids" are endogenous cannabinoids that are high-affinity ligands for CB1 and CB2 receptors.

[0039] "Phytocannabinoids" are cannabinoids that are naturally occurring and can be found in the cannabis plant. Phytocannabinoids can be present in extracts containing botanical drug substances, isolated, or synthetically reproduced.

[0040] "Synthetic cannabinoids" are compounds that can interact with cannabinoid receptors (CB1 and / or CB2) but are not found endogenously or in the cannabis plant. Examples include WIN55212 and rimonabant.

[0041] "Synthetic cannabinoids" are those produced by chemical synthesis, and the term includes modifying isolated phytocannabinoids, for example, by forming pharmaceutically acceptable salts thereof.

[0042] Active ingredients according to the present disclosure may contain one or more cannabinoids. For example, cannabinoids can be obtained from cannabis. Cannabis, or the cannabis plant, can refer to both marijuana, which is generally used for recreational purposes, and hemp, which is generally used for industrial purposes. Cannabis is a green and / or brown mixture of dried and fragmented leaves, stems, stalks, seeds, and flowers of the plant, and may refer to the leaves, stems, seeds, and flowers from the cannabis plant, including varieties such as Cannabis sativa and Cannabis indica. Hemp (particularly industrial hemp varieties) has a very similar appearance to marijuana, but unlike the cannabis plant varieties referred to as marijuana, hemp generally contains only small amounts of tetrahydrocannabinol (THC), while both hemp and marijuana can contain large amounts of cannabidiol (CBD). For example, hemp, particularly industrial hemp, may contain less than about 0.3% THC, while the cannabis varieties referred to as marijuana contain only about 0.3% THC. It can contain approximately 5% to 30% THC. Recently, over 25 states in the United States have legalized cannabis use, at least for medical purposes. Additionally, Canada has now legalized cannabis use for both medical and recreational purposes. In light of these recent developments, the commercialization of cannabis has increased exponentially.

[0043] In addition to THC, cannabis may also contain cannabidiol (CBD). CBD does not interact with pain receptors in the brain, but it does not produce the same euphoria caused by THC. However, CBD exerts pain-relieving and anti-inflammatory effects. Cannabis, and CBD in particular, does not have the same addictive effects as many opioids.

[0044] Cannabinoids that can be incorporated into the compositions of the present disclosure include endocannabinoids, phytocannabinoids, and synthetic cannabinoids. In one embodiment, for example, the one or more cannabinoids incorporated into the product include phytocannabinoids extracted from a plant such as cannabis.

[0045] In certain embodiments, the lipid matrix of the core may be formulated so that the core contains about 10% to about 60% by weight of the active ingredient. For example, in certain embodiments, the core may contain at least about 15% by weight of the active ingredient, such as at least about 20% by weight, such as at least about 25% by weight, such as at least about 30% by weight, such as at least about 35% by weight, such as at least about 40% by weight, such as at least about 45% by weight, such as at least about 50% by weight, or up to about 60% by weight.

[0046] In some embodiments, the active ingredient may include any suitable water-soluble vitamin or mineral.Suitable water-soluble vitamins and minerals may include B vitamins such as vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine), vitamin B7 (biotin), vitamin B9, vitamin B12 (cobalamin), and mixtures thereof.Other suitable water-soluble vitamins include vitamin C.

[0047] In certain embodiments, the active ingredient can be selected from choline, calcium, chloride, chromium, copper, fluoride, iodine, iron, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, sodium, sulfur, zinc, and combinations thereof.In certain embodiments, the active ingredient can include any suitable vitamin, mineral, plant extract, herbal extract, dietary supplement including synthetic dietary supplement, active pharmaceutical ingredient, powder containing suitable active ingredient, and combinations thereof.Exemplary, non-limiting active ingredients include vitamins and minerals, including but not limited to magnesium, vitamin C, B vitamins-riboflavin, pyridoxine HCl, methylcobalamin, folic acid, calcium pantothenate, iron, chromium, potassium, iodine, and other similar ingredients.

[0048] In certain embodiments, the core of one or more particles disclosed herein may contain a fat-soluble active ingredient, and the active ingredient layer may contain one or more active ingredients that can be either fat-soluble or water-soluble. In some embodiments, the core and the active ingredient layer may contain the same active ingredient, while in other embodiments, the active ingredient in the core may be the same or different from the active ingredient contained in the active ingredient layer disposed on the outer surface of the core.

[0049] One or more cores described herein may comprise a lipid matrix. US Patent Publication No. 2018 / 0125863 (incorporated herein by reference in its entirety) describes certain oral formulations containing an active ingredient incorporated into a lipid matrix. Thus, in certain embodiments, the core comprising a lipid matrix may be a lipid matrix-containing core as described in US Patent Publication No. 2001 The compositions may be formulated according to the exemplary embodiments provided in US Pat. No. 8 / 0125863.

[0050] In certain embodiments, the lipid matrix of the core may comprise a) at least one low pour point excipient, b) at least one high pour point excipient, c) at least one low pour point surfactant, and d) optionally an antioxidant.

[0051] The core disclosed herein may comprise a lipid matrix containing a low-pour excipient. For example, in certain embodiments, the lipid matrix may contain one or more low-pour excipients. Low-pour excipients generally include fatty alcohols, fatty acids, glycols and polyglycols, fatty acid esters of polyglycerol, and fatty acid esters of glycerol (glycerides) with a pour point of less than 50°C. When the low-pour excipient is a relatively pure material, its melting point is also less than 50°C. A preferred class of low-pour excipients is low-pour glycerides. A "low-pour" excipient such as a glyceride means that the melting point of the excipient, such as a glyceride, is less than 50°C. In some embodiments, the low-pour glyceride has a melting point of less than 40°C. In some embodiments, the low-pour excipient, such as a glyceride, is a mixture of compounds with a pour point of 50°C or less. In some embodiments, the low-pour excipient, such as a glyceride, has a pour point of 40°C or less. In some embodiments, the low-pour-point glyceride has a low pour point of 30°C or less. Exemplary low-pour-point glycerides include polyglycolized glycerides, such as some of the Gelucire products manufactured by Gattefosse, such as Gelucire® 43 / 01, which has a nominal melting point of 43°C. Mixtures of low-pour-point glycerides are also effective, such as Gelucire® 43 / 01 (C10-C18 triglyceride), Gelucire® 50 / 13 (stearoyl polyoxylglyceride), Gelucire® 44 / 14 (lauroyl macrogol-32 glyceride), and mixtures thereof. Other glycerides, such as fatty acid esters of glycols and polyglycols, and fatty acid esters of polyglycerol, can also be used.

[0052] The function of the low pour point excipient is to ensure that at least a substantial portion of the formulation matrix softens at the temperature of the GI tract (approximately 37°C in humans) when orally ingested by a patient in need of treatment. This allows the formulation to be broken down by digestion in the gastrointestinal (GI) tract and ultimately dispersed in the GI tract to facilitate dissolution and absorption of the active agent. In certain embodiments, the low pour point excipient provides a substantial portion of the formulation matrix that exists in a non-crystalline liquid or amorphous state when ingested and softened in the GI tract.

[0053] Exemplary low pour point fatty alcohols include myristyl alcohol (Tm 38°C), lauryl alcohol (Tm 23°C), and capric alcohol (Tm 7°C).

[0054] Exemplary low pour point fatty acids include lauric acid (Tm 44°C) and oleic acid (Tm 16°C).

[0055] In certain embodiments, the core may comprise a lipid matrix comprising a high pour point excipient. For example, in certain embodiments, the lipid matrix may contain one or more high pour point excipients. A "high pour point" excipient refers to an excipient that has a pour point of 50°C or higher. A high pour point excipient may also have a melting point above 50°C. High pour point excipients generally include fatty alcohols, fatty acids, fatty acid esters of glycols and polyglycols, fatty acid esters of polyglycerol, fatty acid esters of glycerol (glycerides), waxes, polar waxes, and other materials with a pour point above 50. A preferred class of high pour point excipients is "high pour point glycerides." High pour point glycerides are also known as glycerides. High pour point glycerides mean that the pour point or melting point of the glyceride is 50°C or higher. In some embodiments, high pour point glycerides have a melting point of 60°C or higher. In some embodiments, high melting point glycerides are mixtures of compounds that have a pour point of 50°C or higher. In some embodiments, high pour point glycerides have a pour point of 60°C or higher. In some embodiments, high pour point glycerides have a pour point of 70°C or higher.

[0056] Exemplary high pour point glycerides include glycerol behenate, glycerol dibehenate, glycerol palmitate, hydrogenated castor oil, and mixtures thereof.

[0057] High pour point glycerides are often mixtures of compounds that are formulated into products and sold under various trade names.

[0058] Exemplary high pour point, high melting point fatty alcohols include stearyl alcohol (Tm 58°C) and behenyl alcohol (Tm 71°C).

[0059] Exemplary high pour and melting point fatty acids include palmitic acid (Tm 63°C) and stearic acid (Tm > 70°C).

[0060] Exemplary waxes include paraffin wax, beeswax, candelilla wax, carnauba wax, and mixtures thereof.

[0061] The function of the high pour point excipient is to aid in the manufacturability of the core by allowing the core to solidify at a lower temperature during the melt spray congealing process to obtain solid particles. In certain embodiments, the high pour point excipient aids in the physical stability of the core formulation. In most embodiments, the high pour point excipient is not appreciably digested in the GI tract.

[0062] In some embodiments, the core or the lipid matrix of the core may contain other excipients to improve the performance and chemical stability of the formulation. In some embodiments, a dispersing agent is included in the core. Exemplary dispersing agents include lecithin, glyceryl monostearate, ethylene glycol palmitostearate, aluminum oxide, polyethylene alkyl ether, sorbitan ester, and mixtures thereof. In one embodiment, the core contains an antioxidant to maintain the chemical stability of the active agent. Exemplary antioxidants include vitamin E, tocopheryl polyethylene glycol succinate (TPGS), rosemary extract, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and mixtures and combinations thereof.

[0063] In some embodiments, flow aids are used to improve the flow characteristics of the core. Exemplary flow aids, also known as glidants, include calcium silicate, cab-o-sil, silicon dioxide, tricalcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch, talc, and other flow aids.

[0064] The cores described herein are generally solid particles or beadlets at ambient temperature and generally spherical. Generally, spherical means that most particles are essentially spherical, but the particles do not necessarily form "perfect" spheres. Such particle changes in sphericity during melt spray congealing and similar particle formation methods are known to those skilled in the art.

[0065] The cores may have an average diameter ranging from about 40 μm to about 3000 μm, such as from about 50 μm to about 2500 μm, for example, from about 80 μm to about 2000 μm, for example, from about 100 μm to about 1500 μm, for example, from about 200 μm to about 1000 μm, for example, from about 300 μm to about 800 μm. Several methods can be used to measure particle diameter, including laser diffraction, optical microscopy, and / or SEM.

[0066] Further, in one embodiment, the core may form from about 1% to about 70% by weight of the particle, e.g., from about 5% to about 60% by weight of the particle, e.g., from about 10% to about 50% by weight, e.g., from about 20% to about 40% by weight, or any range or value therebetween.

[0067] In certain embodiments, the core containing the active ingredient and lipid matrix has a pour point above 25°C, such as above 30°C, such as above 35°C, such as above 40°C.

[0068] In one embodiment, the lipid matrix comprises fatty alcohols, fatty acids, fatty acid esters of glycerol, glycols and polyglycols, fatty acid esters of polyglycerol, polyglycolized glycerides, C8-C18 triglycerides, stearoyl polyoxylglycerides, lauroyl macrogol-32 glycerides, caprylocaproyl macrogol-8 glycerides, oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, myristyl alcohol, la Ingredients: uryl alcohol, capric alcohol, glycerol behenate, glycerol dibehenate, glycerol palmitate, hydrogenated castor oil, stearyl alcohol, behenyl alcohol, palmitic acid, stearic acid, paraffin wax, beeswax, candelilla wax, carnauba wax, polyethoxylated 12-hydroxystearic acid, propylene glycol monocaprylate ester, propylene glycol dicaprate / dicaprylate ester, propylene glycol heptanoate, pro The oils and fats may contain propylene glycol monostearate, propylene glycol monooleate, propylene glycol monopalmitate, propylene glycol monomyristate, esterified alpha-tocopheryl polyethylene glycol succinate, propylene glycol monolaurate ester, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, lecithin such as sunflower lecithin, vitamin E, tocopheryl polyethylene glycol succinate (TPGS), sugar fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene copolymers, propylene glycol, triacetin, isopropyl myristate, diethylene glycol monoethyl ether, polyethylene glycol, glycerol, rosemary extract, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and mixtures and combinations thereof.

[0069] In one embodiment, the lipid matrix composition comprises greater than 50% by weight of low pour point excipients. In one embodiment, the lipid matrix composition comprises at least 2% by weight of high pour point excipients. In another embodiment, the lipid matrix composition comprises less than 30% by weight of high pour point excipients. In another embodiment, the mass ratio of low flow excipients to high flow excipients is at least 20:1. In yet another embodiment, the mass ratio of low flow excipients to high flow excipients is at least 15:1. In another embodiment, the mass ratio of low flow excipients to high flow excipients is at least 10:1. In another embodiment, the mass ratio of low flow excipients to high flow excipients is at least 4:1. In another embodiment, the mass ratio of low flow excipients to high flow excipients is at least 3:1. In another embodiment, the mass ratio of low flow excipients to high flow excipients is at least 2:1.

[0070] In some embodiments, the active ingredient is stearyl alcohol, stearic acid, The active ingredient is contained within a lipid matrix containing candelilla wax and lecithin. In certain embodiments, the lipid matrix may contain about 40% to about 60% by weight of the active ingredient, e.g., about 50% by weight of the active ingredient. In certain embodiments, the lipid matrix may contain about 15% to about 25% by weight of stearyl alcohol, e.g., about 17% by weight of stearyl alcohol. In some embodiments, the lipid matrix may contain about 10% to about 20% by weight of stearic acid, e.g., about 15% by weight of stearic acid. In some embodiments, the lipid matrix may contain about 10% to about 20% by weight of a suitable wax, e.g., about 15% by weight of a suitable wax, such as candelilla wax. In some embodiments, the lipid matrix may contain about 1% to about 3% lecithin, e.g., about 2% lecithin, such as soybean lecithin.

[0071] In certain embodiments, a lipid matrix containing the active ingredient may be formed and then formulated into one or more particles having a generally spherical shape and an average diameter in the range of about 40 μm to 3000 μm, e.g., about 100 μm to 2000 μm, e.g., about 300 μm to 1000 μm.

[0072] In one embodiment, the lipid matrix is ​​comprised of at least 10% to 50% by weight of a low pour point excipient, hi another embodiment, the lipid matrix is ​​comprised of at least 50% to 75% by weight of a low pour point excipient.

[0073] In one embodiment, the lipid matrix comprises at least 2% by weight of a high pour point excipient. In another embodiment, the lipid matrix is ​​comprised of 1% to 30% by weight of a high pour point excipient. In yet another embodiment, the lipid matrix is ​​comprised of 2% to 20% by weight of a high pour point excipient. In yet another embodiment, the lipid matrix is ​​comprised of 3% to 15% by weight of a high pour point excipient.

[0074] The lipid matrix may also include a dispersing agent. In one embodiment, the lipid matrix is ​​comprised of 0% to 20% by weight, e.g., 0.01% to 20% by weight, of a dispersing agent. In another embodiment, the lipid matrix is ​​comprised of 2% to 10% by weight of a dispersing agent.

[0075] The lipid matrix may also include an antioxidant. In one embodiment, the lipid matrix includes 0% to 20% by weight, for example, 0.01% to 20% by weight, of the antioxidant. In one embodiment, the lipid matrix includes 1% to 15% by weight of the antioxidant.

[0076] The lipid matrix may also include a flow aid. In one embodiment, the lipid matrix may include 0% to 5% by weight, for example, 0.01% to 5% by weight, of a flow aid. In another embodiment, the lipid matrix may include 0.5% to 2% by weight of a flow aid.

[0077] The core containing lipid matrix described herein can be formulated by any suitable process.In some embodiments, the core can be formulated by suitable melt-spray congealing process.Exemplary process includes " melt-spray congealing " process, such as the process described in U.S. Patent No. 7,235,260, U.S. Patent No. 7,887,844, EP1691787 and U.S. Patent No. 7,625,507.

[0078] The molten mixture is formed by mixing and heating the lipid matrix composition as described above. Such a composition may include an active ingredient, a low pour point excipient, and a high pour point excipient. A "molten mixture" refers to a mixture of the active ingredient and the lipid matrix material that is sufficiently mixed. This means that the mixture is mixed and heated to become sufficiently fluid so that it can be atomized into droplets. Generally, the mixture is melted in the sense that it will flow when subjected to one or more forces, such as pressure, shear, and centrifugal forces, such as those provided by a centrifugal or spinning disk atomizer.

[0079] Once the molten mixture is formed, it is delivered to an atomizer, which breaks the molten mixture into small droplets. Virtually any method can be used to deliver the molten mixture to the atomizer. In certain embodiments of the disclosed method, the molten mixture is delivered to the atomizer by using a pump and / or various types of pneumatic devices, such as a pressurized container or a piston pot or an extruder. In certain embodiments, the molten mixture is maintained at an elevated temperature during delivery to the atomizer to prevent it from solidifying and maintain it in a flowable state.

[0080] When using a centrifugal atomizer (also known as a rotary atomizer or spinning disk atomizer), the molten mixture is fed onto a rotating surface, where it spreads and flows outward due to centrifugal force. The rotating surface can take several forms, including a flat disk, a cup, a bunned disk, and a slotted wheel. The surface of the disk may be heated to aid in atomization of the molten mixture, or cooled to aid in solidification of the core containing the lipid matrix. Depending on the flow of the molten mixture onto the disk, the disk rotation speed, the disk diameter, the viscosity of the feed, and the surface tension and density of the feed, several mechanisms of atomization are observed with flat disk and cup centrifugal atomizers. At low flow rates, the molten mixture spreads across the entire surface of the disk, forming discrete droplets as it reaches the edge of the disk, which are then ejected from the disk.

[0081] Once the molten mixture is atomized, the droplets are typically solidified by contact with a gas at a temperature below the solidification temperature of the composition. Typically, it is desirable for the droplets to solidify in less than 60 seconds, less than 10 seconds, or even less than 1 second. In certain embodiments, solidification at ambient temperature using an ambient temperature cooling medium results in sufficiently rapid solidification of the droplets. However, since certain embodiments of the disclosed compositions are composed of at least 50% by weight of low-pour-point excipients, it is often preferable to use a cooling medium that is at least 10°C lower than ambient temperature. In some embodiments, it is preferable to use a cooling medium that is at least 20°C lower than ambient temperature.

[0082] In certain embodiments, the core disclosed herein can be subjected to additional processing to deposit one or more layers of active ingredient material on the core disclosed herein.For example, the core described herein can contain one or more outer layers disposed on the core, which contain at least one second active ingredient.Furthermore, the one or more outer layers disposed on the core can contain adhesive in addition to one or more active ingredients.For example, to provide an outer layer disposed on the core, the core can be coated with a suitable adhesive, and then further coated with an active ingredient to provide a particle having one or more outer layers containing one or more active ingredients surrounding the core.

[0083] In certain embodiments, one or more particles can be subjected to any suitable coating process for edible tablets or particles to apply active ingredients to the core or particles disclosed herein.Suitable processes can include what is commonly known as the Wurster process.The Wurster process is known in the art and can be synonymous with certain fluidized bed microencapsulation processes.A description of the Wurster process is disclosed in U.S. Patent Nos. 2,648,609 and 3,241,520.Generally, during the Wurster process, cores or particles are placed in a bed such as a fluidized bed.A fluidized bed uses differential airflow to create a circular movement of the particle material.To coat the core structure, one or more cores can be placed in a particle bed, and the cores are coated with a suitable adhesive or A different air flow can move through the bed of particle material (i.e., core) so that it is coated with a material such as an active ingredient material. Generally, this process can be continued until the desired thickness of the active ingredient layer is achieved on the core. To provide one or more active ingredient layers on the particles, the particles disclosed herein can be subjected to a suitable Wurster process. In some embodiments, the core or particles disclosed herein can be coated through any suitable fluidized bed coating process.

[0084] In some embodiments, the cores and / or particles can be coated using any known drum coating process. Generally, a drum coating process refers to a method of coating particles by placing particles in a rotating drum and applying a desired coating material to the particles while they rotate in the drum. Suitable devices for drum coating particles are known, including those described in U.S. Patent Publication No. 2015 / 0144058. In certain embodiments, the cores disclosed herein can be placed in any suitable drum coating device, and an adhesive can be applied to the cores or particles. Once sufficiently coated with the adhesive, an active ingredient can then be applied to the cores or particles in the drum to create an active ingredient layer on the cores or particles. This process of applying a suitable adhesive and an active ingredient can be repeated as many times as necessary to create the desired number of active ingredient layers on the particles. In certain embodiments, the adhesive can be applied directly to the cores or particles along with one or more active ingredients.

[0085] In certain embodiments, the cores or particles may be coated with a suitable adhesive. A suitable adhesive may include pharmaceutical-grade shellac, such as a pharmaceutical glaze, which is an alcohol-based solution that may include various types of food-grade shellac. In certain embodiments, the pharmaceutical glaze may contain about 20% to about 51% by weight of shellac in an ethyl alcohol solution. The pharmaceutical glaze may further contain additional additives, such as waxes, titanium dioxide, and combinations thereof. In certain embodiments, the pharmaceutical glaze utilized in accordance with embodiments herein has been recognized as Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration (FDA). In certain embodiments, the adhesive may include a suitable non-animal-based product, such as zein. Zein generally refers to a class of prolamin proteins found in corn that can be manufactured as adhesive coatings or binders.

[0086] Thus, in some embodiments, the outer surface of the core described herein is coated with a suitable adhesive in an amount sufficient to allow the active ingredient to bond to the outer surface of the core. Generally, the adhesive can be applied so that the outer surface of the core is sticky or tacky, but not so sticky that the core or particles clump together. Once the adhesive is applied, the active ingredient can be applied to the particles to create an active ingredient layer thereon. In some embodiments, the process of layering the particles with an adhesive layer and layering the particles with an active ingredient can be repeated as many times as desired to form particles with a desired amount of active ingredient layer. For example, the particles disclosed herein may include a core having at least one outer layer thereon containing at least one active ingredient, such as at least two outer layers, such as at least three outer layers, such as at least four outer layers, such as at least five outer layers, such as at least six outer layers, etc. In certain embodiments, each outer layer may contain one or more active ingredients. In some embodiments, one or more of the outer layers may contain the same or different active ingredient as the active ingredient contained in the core. In certain embodiments, the particle may contain one or more outer layers that do not contain an additional active ingredient. For example, the particles may contain one or more outer layers composed of a suitable coating material to seal the particle or to provide a particular release profile, such as sustained release or release at a particular pH upon ingestion. Exemplary outer coating materials include, for example, ethyl cellulose, shellac, zein, HPMC, and other similar components.

[0087] In some embodiments, one or more particles provided herein may be formulated into any suitable dosage form.For example, in certain embodiments, one or more particles provided herein may be placed in a capsule for oral delivery.Exemplary capsules include hard gelatin capsules, soft gelatin capsules, HPMC capsules, and capsules made of other materials.One or more particles may be suspended in an aqueous-based or oil-based matrix within the capsule itself.In certain embodiments in which particles are suspended in an aqueous-based or oil-based matrix, the aqueous-based or oil-based matrix may further comprise one or more active ingredients.In certain embodiments, one or more particles may be contained in a monolithic enteric capsule suitable for providing a modified release profile upon ingestion.

[0088] Capsules typically consist of a shell filled with one or more specific substances. The shell itself may be a soft or hard capsule shell. Hard capsule shells are typically manufactured using a dip-molding process, which can be divided into two alternative procedures. In the first procedure, capsules are prepared by dipping stainless steel mold pins into a solution of a polymer, optionally containing one or more gelling agents (e.g., carrageenan) and co-gelling agents (e.g., inorganic cations). The mold pins are then removed, inverted, and allowed to dry, forming a film on the surface. The dried capsule film is then removed from the mold and cut to the desired length, after which the elastic-fit cap and body are assembled together, printed, and packaged. See, for example, U.S. Patent Nos. 5,264,223, 5,756,123, and 5,756,123. In the second procedure, no gelling agent or co-gelling agent is used, and gelation of the film-forming polymer solution on the mold pin is thermally induced by immersing a preheated mold pin in the polymer solution. This second process is generally referred to as thermogelation or thermogelation dip molding. See, for example, EP 0401832, U.S. Patent Nos. 3,493,407, 4,001,211, and 3,617,588, GB 1310697, and WO 2008 / 050209. The aforementioned manufacturing process involves the use of solutions of different components required to produce a stretch-fit hard capsule shell.

[0089] Hard capsules can be filled with active ingredients, such as the particles described herein, by procedures known in the art. Typically, the active ingredient is combined with various compatible excipients to facilitate filling. The resulting fill can be dry powder, granules, particles, lipid particles, suspensions, or liquids. In addition, stable filled hard capsules offer advantages over other dosage delivery forms, such as liquids and solid tablets. Certain active ingredients may be difficult to formulate into dry granules or may otherwise be incompatible with the tableting process. Another consideration is improved patient compliance due to taste masking and ease of swallowing, i.e., capsules are preferred by consumers over tablets. For example, in some embodiments, a pharmaceutical composition is provided containing a capsule filled with one or more particles disclosed herein. In some embodiments, the one or more particles are not enterically coated for release modification or gastric protection.

[0090] In certain other embodiments, one or more particles can be orally administered as a solid, liquid, suspension, or gas. The particle composition can be administered via buccal or sublingual administration. In one embodiment, one or more particles can be administered as a capsule, tablet, caplet, pill, troche, drop, lozenge, powder, granule, syrup, tea, beverage, film, seed, paste, herb, plant, etc. In addition to being orally administered, one or more particles can also be administered using other routes, including intranasal, intravenous, intramuscular, intragastric, etc. [Example]

[0091] Example 1: Multivitamin beadlets containing fat-soluble vitamins in a lipid multiparticulate (LMP) core Beadlets are made using a pan coating process in which a starter core contains fat-soluble vitamins provided in the form of LMP particles. The LMP particles contain 7.5% vitamin E (as d-alpha tocopherol in a 20% solution), 0.5% vitamin K2 (as menaquinone 7), and 15% vitamin A (as beta-carotene in a 30% solution) by weight of the LMP. The remainder of the LMP consists of 74% candelilla wax and 3% sunflower lecithin by weight of the LMP. The LMP has a particle size of 200-500 μm and is produced using a melt-spray-congealing process at temperatures of 60-80°C to form the fat-soluble vitamin and LMP core. This LMP core is then added to a pan coater in an amount of 25 parts by weight of the beadlet components, and other vitamins and minerals are layered on top to build beadlets with a particle size of 800-1200 μm. The vitamins and minerals include magnesium (as magnesium oxide) in an amount of 57 parts by weight of the beadlet, and vitamin C in an amount of 13 parts by weight of the beadlet. The beadlets are then finished with a final coating to protect the beadlets, which is hydroxypropyl methylcellulose (HPMP) in an amount of 5 parts by weight of the beadlet.

[0092] Example 2: Oil and Water Phase Eye Health Beadlets The beadlets are made using a pan coating process. The starter core contains fat-soluble carotenoids provided in the form of LMP particles, including 22% by weight of the LMP—lutein (20% solution) and 10% by weight of the LMP—vitamin A (as β-carotene (30% solution)). The remainder of the LMP consists of 64% by weight of the LMP—candelilla wax and 4% by weight of the LMP—sunflower lecithin. The LMP has a particle size of 200-500 μm and is produced using a melt-spray-congealing process at temperatures of 60-80°C, which forms an LMP core with the fat-soluble vitamins. This LMP core is then added to a pan coater in an amount of 25 parts by weight of the beadlet components, and other eye health ingredients, such as water-soluble eye health ingredients, are layered on top of the LMP to build up into beadlets with a particle size of 800-1200 μm. These water-soluble eye health ingredients include vitamin C at 43 parts by weight of beadlet and bilberry extract at 27 parts by weight of beadlet. The beadlets are then finished with a final coating to protect the beadlets, which is hydroxypropyl methylcellulose (HPMP) at an amount of 5 parts by weight of beadlet.

[0093] These and other modifications and variations to the present disclosure may be practiced by those of ordinary skill in the art without departing from the spirit and scope of the present invention, as more particularly set forth in the appended claims. In addition, it should be understood that aspects of the various embodiments may be interchanged in whole or in part. Furthermore, those skilled in the art will appreciate that the foregoing description is by way of example only and is not intended to limit the invention as further set forth in such appended claims.

Claims

1. 1. A composition comprising:

1. A composition comprising a plurality of particles, each of said particles comprising a core having a lipid matrix with an active ingredient dispersed therein, said active ingredient comprising a lipid-soluble active ingredient, and at least one outer layer disposed on said core, said at least one outer layer comprising at least one second active ingredient layer.

2. The composition of claim 1, wherein the active ingredient comprises from about 10% to about 60% by weight of the core.

3. 10. A composition according to any one of the preceding claims, wherein the fat-soluble active ingredient is selected from the group consisting of one or more carotenoids, one or more fat-soluble vitamins or minerals, one or more cannabinoid derivatives, and combinations thereof.

4. The composition of claim 3 , wherein the fat-soluble active ingredient comprises one or more carotenoids.

5. 5. The composition of claim 4, wherein the one or more carotenoids are selected from the group consisting of lutein, astaxanthin, zeaxanthin, α-carotene, β-carotene, cryptoxanthin, lycopene, and mixtures thereof.

6. 10. A composition according to any one of the preceding claims, wherein the core is solid at ambient temperature.

7. 10. The composition of any one of the preceding claims, wherein the core has an average diameter in the range of about 40 μm to about 3000 μm.

8. 10. The composition of any one of the preceding claims, wherein the lipid matrix comprises at least one low pour point excipient and at least one high pour point excipient.

9. 10. The composition of any one of the preceding claims, wherein the outer layer comprises one or more adhesives and one or more active ingredients.

10. 10. The composition of any one of the preceding claims, wherein the second active ingredient comprises one or more fat-soluble vitamins or minerals, one or more water-soluble vitamins or minerals, and combinations thereof.

11. 10. The composition of any one of the preceding claims, wherein the core comprises from about 5% to about 60% by weight of the particle.

12. 10. The composition of any one of the preceding claims, wherein the one or more particles comprise an average diameter of from about 0.5 mm to about 1.5 mm.

13. 10. The composition of any one of the preceding claims, further comprising an outermost layer of a coating material to seal each particle.

14. 10. The composition of any one of the preceding claims, wherein the one or more particles further comprise one or more adjuvants selected from anti-adherents, binders, coating agents, colorants, disintegrants, fillers, flavoring agents, glidants, lubricants, preservatives, adsorbents, sweeteners, vehicles, vitamins, and the like.

15. 1. A pharmaceutical or dietary supplement composition comprising:

1. A pharmaceutical or nutraceutical composition comprising a capsule filled with one or more particles comprising a core and at least one outer layer disposed on the core, wherein the core comprises a lipid matrix having an active ingredient dispersed therein, the active ingredient comprising a fat-soluble active ingredient, and wherein the at least one outer layer comprises at least one second active ingredient.

16. 16. The composition of claim 15, wherein the fat-soluble active ingredient is selected from the group consisting of one or more carotenoids, one or more fat-soluble vitamins or minerals, one or more cannabinoid derivatives, and combinations thereof.

17. 17. The composition of claim 15 or 16, wherein the fat-soluble active ingredient comprises one or more carotenoids.

18. 18. The composition of claim 17, wherein the one or more carotenoids are selected from the group consisting of lutein, astaxanthin, zeaxanthin, α-carotene, β-carotene, cryptoxanthin, lycopene, and mixtures thereof.

19. 19. The composition of claim 15, 16, 17, or 18, wherein the core has an average diameter in the range of about 40 μm to about 3000 μm.

20. 20. The composition of any one of claims 15 to 19, wherein the lipid matrix comprises at least one low pour point excipient and at least one high pour point excipient.

21. The composition of any one of claims 15 to 20, wherein the at least one outer layer comprises one or more adhesives.

22. 22. The composition of any one of claims 15 to 21, wherein the second active ingredient comprises one or more fat-soluble vitamins or minerals, one or more water-soluble vitamins or minerals, and combinations thereof.

23. 23. The composition of any one of claims 15 to 22, wherein the core comprises from about 5% to about 60% by weight of the particle.

24. 24. The composition of any one of claims 15 to 23, wherein the one or more particles comprise an average diameter of from about 0.5 mm to about 1.5 mm.

25. The composition of any one of claims 15 to 24, wherein the one or more particles are suspended in an aqueous-based matrix contained within the capsule.

26. A composition according to any one of claims 15 to 24, wherein the one or more particles are suspended in an oil-based matrix contained within the capsule.

27. 27. The composition of claim 25 or 26, wherein the aqueous-based matrix or the oil-based matrix comprises one or more active ingredients.

28. 28. The composition of any one of claims 15 to 27, wherein the active ingredient comprises from about 10% to about 60% by weight of the core.

29. 1. A method of producing a pharmaceutical composition, comprising: providing one or more cores comprising a lipid matrix having an active ingredient dispersed therein; wherein the active ingredient comprises one or more lipid-soluble active ingredients; layering said one or more cores with one or more outer layers containing one or more second active ingredients to form one or more particles.

30. 30. The method of claim 29, wherein the active ingredient comprises from about 10% to about 60% by weight of the core.

31. 31. The method of claim 29 or 30, wherein the fat-soluble active ingredient is selected from the group consisting of one or more carotenoids, one or more fat-soluble vitamins or minerals, one or more cannabinoid derivatives, and combinations thereof.

32. 32. The method of claim 31, wherein the fat-soluble active ingredient comprises one or more carotenoids.

33. 33. The method of claim 32, wherein the one or more carotenoids are selected from the group consisting of lutein, astaxanthin, zeaxanthin, α-carotene, β-carotene, cryptoxanthin, lycopene, and mixtures thereof.

34. 34. The method of any one of claims 29 to 33, wherein the one or more cores have an average diameter in the range of about 40 μm to about 3000 μm.

35. 35. The method of any one of claims 29 to 34, wherein the lipid matrix comprises at least one low pour point excipient and at least one high pour point excipient.

36. The method of any one of claims 29 to 35, wherein the one or more outer layers comprise one or more adhesives.

37. 37. The method of any one of claims 29-36, wherein the one or more second active ingredients comprise one or more fat-soluble vitamins or minerals, one or more water-soluble vitamins or minerals, and combinations thereof.

38. 38. The method of any one of claims 29 to 37, wherein the one or more cores comprise from about 5% to about 60% by weight of the one or more particles.

39. 39. The method of any one of claims 29 to 38, wherein the one or more particles comprise an average diameter of from about 0.5 mm to about 1.5 mm.

40. 40. The method of any one of claims 29 to 39, further comprising filling a capsule with the one or more particles.

41. 41. The method of any one of claims 29-40, wherein layering the one or more cores with one or more outer layers comprises layering the one or more cores via a Wurster process.

42. 41. The method of any one of claims 29 to 40, wherein layering the one or more cores with one or more outer layers comprises layering the one or more cores via a fluidized bed process.

43. 41. The method of any one of claims 29-40, wherein layering the one or more cores with one or more active ingredient layers comprises layering the one or more cores via a drum coating process.

44. 41. The method of any one of claims 29 to 40, wherein layering the one or more cores with one or more active ingredient layers comprises coating the one or more cores with an adhesive, and coating the one or more cores containing the adhesive with one or more active ingredients.

45. 41. The method of any one of claims 29 to 40, wherein layering the one or more cores with one or more outer layers comprises: coating the one or more cores with an adhesive; and coating the one or more cores containing the adhesive with one or more second active ingredients to form a core having a second active ingredient layer thereon; and coating the core with the second active ingredient layer thereon with an adhesive; and coating the core with the adhesive-containing second active ingredient layer thereon with one or more third active ingredients to form a core having one or more active ingredient layers thereon.