WO2023245107A1 - Microencapsulation de cannabidiol ou de son mélange avec de la nicotine pour administration orale et topique - Google Patents
Microencapsulation de cannabidiol ou de son mélange avec de la nicotine pour administration orale et topique Download PDFInfo
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- WO2023245107A1 WO2023245107A1 PCT/US2023/068497 US2023068497W WO2023245107A1 WO 2023245107 A1 WO2023245107 A1 WO 2023245107A1 US 2023068497 W US2023068497 W US 2023068497W WO 2023245107 A1 WO2023245107 A1 WO 2023245107A1
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Classifications
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Definitions
- CBD cannabidiol
- This disclosure provides cannabidiol (CBD)-loaded microcapsules for use in treating or preventing anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, a metabolic syndrome-related disorder, eczema or psoriasis.
- CBD and nicotine cannabidiol-loaded microcapsules for use in treating or preventing nicotine dependence, or a withdrawal symptom thereof, in a subject in need thereof.
- the disclosure also provides pharmaceutical compositions and pharmaceutical formulations comprising CBD-loaded or (CBD and nicotine)-loaded microcapsules, and methods of making CBD-loaded or (CBD and nicotine)-loaded microcapsules, with or without flavors or fragrances.
- CBD cannabidiol
- EPIDIOLEX® epilepsy
- CBD also shows promise for the treatment of other diseases, disorders, and/or conditions, such as anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorders, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders.
- CBD is an oily solid at room temperature and therefore is difficult to handle and to effectively administer to subjects at a controlled dose.
- Nicotine is an addictive substance that is usually taken in through the lungs through smoking tobacco products.
- the urge to continue smoking and the well documented difficulties in quitting the habit come from nicotine dependence. Treating nicotine dependence involves reducing the impact of withdrawal symptoms and addressing the psychological urges. Breaking the smoking habit can be difficult.
- CBD helps stop smoking for a few reasons, including anxiety reduction, lower cravings and anti-inflammatory effects, as a non-additive substitute.
- the disclosure provides a microcapsule comprising: (a) an agglomeration of primary microcapsules, wherein the primary microcapsules comprise an inner core and a primary shell surrounding the inner core; and (b) an outer shell surrounding the agglomeration of primary microcapsules, wherein (i) the inner core comprises CBD and, optionally, nicotine and one or more food grade oils; (ii) the primary shell comprises one or more food grade wall materials; and (iii) the outer shell is produced by spray drying and comprises one or more food grade wall materials.
- the disclosure provides an emulsion or agglomeration comprising CBD and, optionally, nicotine, one or more food grade oils, one or more food grade wall materials, and water.
- the disclosure provides a method of making a CBD-loaded or (CBD and nicotine)-loaded microcapsule, the method comprising (i) providing an emulsion or agglomeration comprising CBD and, optionally, nicotine, one or more food grade oils, one or more food grade wall materials, water, and, optionally, one or more processing aids; and (ii) spray drying the emulsion or agglomeration to provide a powder comprising the microcapsule.
- the microcapsule comprises an outer shell.
- the disclosure provides a method of making a CBD-loaded or (CBD and nicotine)-loaded microcapsule, the method comprising (i) providing an emulsion or agglomeration comprising CBD and, optionally, nicotine, one or more food grade oils, one or more food grade wall materials, water, and, optionally, one or more processing aids; (ii) adjusting the pH, temperature, concentration, or mixing speed, or combination thereof, of the emulsion or agglomeration to form a coacervate slurry with an outer shell; and (iii) spray drying the coacervate slurry to provide a powder comprising the microcapsule.
- the disclosure provides a microcapsule comprising: (a) an emulsion or agglomeration of primary microcapsules, wherein the primary microcapsules comprise an inner core and a primary shell surrounding the inner core; and (b) an outer shell surrounding the emulsion or agglomeration of primary microcapsules, wherein (i) the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils; (ii) the primary shell comprises one or more food grade wall materials; and (iii) the outer shell comprises one or more food grade wall materials, produced by adjusting the pH, temperature, concentration, or mixing speed, or combination thereof, of the emulsion or agglomeration to form a coacervate slurry comprising an outer shell; and (c) spray drying the coacervate slurry to provide a powder comprising the microcapsule.
- the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils
- the primary shell comprises one or more food grade wall materials
- the outer shell
- the disclosure provides a microcapsule comprising an inner core and a primary shell surrounding the inner core, wherein: (i) the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils; and (ii) the primary shell comprises one or more food grade wall materials, and (iii) the outer shell is produced by spray drying.
- the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils
- the primary shell comprises one or more food grade wall materials
- the outer shell is produced by spray drying.
- the disclosure provides a microcapsule comprising: (a) an agglomeration of primary microcapsules, wherein the primary microcapsules comprise an inner core and a primary shell surrounding the inner core; and (b) an outer shell surrounding the agglomeration of primary microcapsules, wherein (i) the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils; (ii) the primary shell comprises one or more food grade wall materials; and (iii) the outer shell is produced by adjusting the pH, temperature, concentration, or mixing speed, or combination thereof, to form a coacervate comprising an outer shell and one or more food grade wall materials.
- a multicore microcapsule This is referred to herein as a multicore microcapsule.
- the term "microcapsule” as used herein refers to single-core, multicore, or a mixture of single-core and multicore microcapsules.
- the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, corn oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.
- the food grade oil comprises palm oil or coconut oil.
- the primary shell and/or outer shell may comprise a surfactant, gelatin, protein, polyphosphate, or polysaccharide, or mixtures thereof.
- suitable wall materials for the primary shell and/or outer shell include, but are not limited to, gelatin type A, gelatin type B, polyphosphate, gum arabic, alginate, chitosan, carrageenan, pectin, low-methoxyl-pectin, starch, modified starch, alpha-lactalbumin, beta-lactoglobumin, ovalbumin, polysorbiton, maltodextrin, cyclodextrin, cellulose, methyl cellulose, ethyl cellulose, hydropropylmethylcellulose, carboxymethylcellulose, milk protein, whey protein, soy protein, canola protein, albumin, chitin, polylactides, poly-lactide-co-glycolides, derivatized chitin, poly-lysine, kosher gelatin, non-kosher gelatin, Halal gelatin, and nonHalal gelatin, including combinations and mixtures thereof. Derivatives of these polymers can also be used.
- the primary and/or outer shell material can have a Bloom number of from about 0 to about 50, and in other examples, the primary and/or outer shell material can have a Bloom number of from about 51 to about 350. Still other specific examples include microcapsules comprising a primary shell and/or outer shell material having a Bloom number of about 0, about 210, about 220, or about 240. In one example, the microcapsule does not contain "low Bloom" gelatin, which is gelatin having a Bloom number less than 50.
- the outer shell can have an average diameter of from about 1 pm to about 2,000 pm, from about 10 pm to about 1,000 pm, or from about 10 pm to about 80 pm.
- the average diameter of the outer shell can be about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 pm, where any of the stated values can form an upper or lower endpoint when appropriate.
- Shell-stabilizing agent(s) may comprise, for example, lysine, leucine, isoleucine, glutamine, methionine, tyrosine, phenylalanine, tyrosine, tryptophan, or cysteine or any combination thereof.
- Amino acids can be present in the shell material at a ratio of from about 1 :5 to about 5:1, e.g., about 2: 1, in comparison to the polymer component(s).
- Further examples include microcapsules with an amino acid to polymer component ratio of about 1 :5, 1 :4, 1 :3, 1 :2, 1 : 1, 2: 1, 3: 1, 4: 1, and 5: 1, where any ratio can form an upper or lower endpoint of a range of ratios.
- Suitable proteins and peptides are compounds composed of amino acids chemically bound together.
- the amino acids are chemically bound together via amide linkages (-CONH-); however, the amino acids may be bound together by other chemical bonds known in the art.
- the amino acids can be connected by amine linkages.
- peptides and proteins linked to other molecules e.g., conjugates.
- carbohydrates e.g., glycoproteins, can be linked to the protein or peptide.
- Such derivatives, variants, and analogs of peptides and proteins are contemplated herein within the meaning of the terms protein.
- Suitable acids for making the chitosan salts for use in the methods described herein are those acids that form water-soluble salts with chitosan. It is not necessary that the acid itself be water-soluble; however, such water-soluble acids can ease handling.
- Inorganic acids, which form water-soluble chitosan salts include the halogen acids and nitric acid, but exclude sulfuric and phosphoric acids because they do not form water- soluble salts with chitosan.
- Organic acids are particularly suitable and include, but are not limited to, lactic acid, glycolic acid, glutamic acid, formic acid, acetic acid, and a mixture thereof. Either mono- or poly-functional carboxylic acids can also be used. They can be aliphatic or aromatic, so long as they form water-soluble salts with chitosan.
- maltodextrin DE18, DE 21, DE40 etc.
- modified starch N- LOK
- oligofructans cyclodextrins (alpha-, beta- and gamma-cyclodextrins)
- carboxymethylcellulose HPMC
- HPMC hydroxypropylmethylcellulose
- Ethocel ethylcellulose
- HPC hydroxypropyl cellulose
- HPC hydroxypropyl cellulose
- cellulose ether e.g., Benecel
- agar alginate, pectin, low-methoxyl-pectin, gum arabic, carrageenan, cellulose gum, dilutan gum, gellan gum, locus bean gum, welan gum, and xanthan gum.
- suitable saccharides are monosaccharides such as glucose, fructose, galactose, arabinose, ribose, ribulose, xylose, mannose, and xylulose. Still further, suitable saccharides, including residues thereof, include disaccharides or tri saccharides where the saccharide exists in the form of a pyranose or furanose (6 or 5 member rings). Non-limiting examples of di- and tri-saccharides include sucrose, lactose, cellobiose, sorbose, cellotriose, trehalose, maltose, and raffinose and the like.
- saccharides that can be used are maple syrup, honey, and com syrup, which are safe and can add flavor to the microcapsules.
- Various saccharide derivatives such as xylitol, sorbitol, isomalt, and glucosamine are also suitable for use in the disclosed microcapsules.
- the saccharides disclosed herein can be present in the shell material at a ratio to the total shell material, e.g., first and second polymer components, of from about 1 :0.2 to about 1 :5 or about 1 :0.02 to 1 :0.5 the ratio to the second polymer component (e.g., polyphosphate).
- Further examples include microcapsules with a saccharide to total polymer component ratio of about 1 :0.2, 1 :0.5, 1 : 1, 1 : 1.5, 1 :2.0, 1 :2.5, 1 :3.0, 1 :3.5, 1 :4.0, 1 :4.5, and 1 :5.0, where any ratio can form an upper or lower endpoint of a range of ratios.
- Still further examples include microcapsules with a saccharide to second polymer component ratio of about 1 :0.02, 1 :0.05, 1 :0.1, 1 :0.15, 1 :0.2, 1 :0.25, 1 :0.3, 1 :0.35, 1 :0.4, 1 :0.45, and 1 :0.5, where any ratio can form an upper or lower endpoint of a range of ratios.
- a suitable wax that can be present in the disclosed microcapsules shells is carnauba wax, which can be present in a microemulsion or agglomeration form.
- Other suitable waxes include, but are not limited to, candelilla, cersines, (synthetic) Japan wax, orange peel wax, rice bran wax, shellac, paraffin, montan, microcrystalline wax, polyethylene, and beeswax.
- the wax can be present in the shell material at a ratio to the second polymer component of from about 1 : 1 to about 1 : 10. (e.g., 1 :6).
- the primary and/or outer shell comprises one or more food grade wall materials.
- the primary and/or outer shell comprises one, two, three, four, or five food grade wall materials.
- the primary and/or outer shell comprises one food grade wall material.
- the primary and/or outer shell comprises two food grade wall materials.
- the primary and/or outer shell comprises three food grade wall materials.
- the primary and/or outer shell comprises four food grade wall materials.
- the primary and/or outer shell comprises five food grade wall materials.
- the food grade wall material comprises modified starch, gum arabic, gelatin, pectin, lecithin, casein, caseinate, whey protein isolates, pea protein isolates, soy protein isolates, egg protein, yeast protein, algae protein, hempseed protein, rice protein, barley protein, pumpkin seed protein, almond protein, canola protein, plant-based proteins, insect based proteins, xanthan gum, gellan gum, polyphosphate, alginate, agar, carrageenan, starch, oligofructans, konnyaku, alpha-lactalbumin, beta-lactoglobumin, ovalbumin, polysorbate, maltodextrin, alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, chitosan, chitin, cellulose, methyl cellulose, ethyl cellulose, hydropropylmethyl
- the inner core further comprises one or more processing aids.
- the primary shell surrounding the inner core further comprises one or more processing aids.
- the outer shell surrounding the agglomeration further comprises one or more processing aids.
- the inner core, primary shell, and/or outer shell further comprise one or more processing aids.
- the one or more processing aids comprise an antioxidant.
- the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, or tocopherols, or a mixture thereof. In another embodiment, the antioxidant is ascorbic acid.
- the inner core further comprises a flavoring agent.
- the inner core further comprises a fragrance and/or flavor oil.
- fragrance and/or flavor oils include mint family fragrances and/or flavors, e.g., peppermint; floral family fragrances and/or flavors, e.g., vanilla, rose, jasmine and lavender; fruity family fragrances and/or flavors, e.g., lemon, orange, mango, pineapple, lychee, raspberry, peach and strawberry; and woody family fragrances and/or flavors, e.g., musk oil.
- the shell surrounding the inner core and/or the outer shell surrounding the agglomerate comprises a complex coacervate of the food grade wall materials.
- the microcapsule comprises from about 1 wt % to about 50 wt % of CBD and, optionally, nicotine, e.g., from about 3 wt % to about 20 wt % of CBD and, optionally, nicotine, e.g., from about 5 wt % to about 15 wt % of CBD and, optionally, nicotine.
- the disclosure provides a pharmaceutical composition comprising a Microcapsule of the Disclosure and one or more pharmaceutically acceptable excipients.
- compositions of the Disclosure are collectively referred to as “Pharmaceutical Compositions of the Disclosure” (each individually referred to as a “Pharmaceutical Composition of the Disclosure”).
- the pharmaceutical formulation is administered to the subject as a softgel, a tablet, a capsule, a gummie, a lozenge, a chewing gum, a taffy, a film, or an edible product.
- the pharmaceutical formulations described in this section are collectively referred to as "Pharmaceutical Formulations of the Disclosure” (each individually referred to as a “Pharmaceutical Formulation of the Disclosure”).
- the emulsion or agglomeration droplet size is about 2 pm or less.
- the emulsion or agglomeration droplet is formed by a microfluidizer.
- the food grade oil used in the emulsion or agglomeration comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, corn oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.
- the food grade oil comprises palm oil or coconut oil.
- the food grade wall material comprises modified starch, gum arabic, gelatin, pectin, lecithin, casein, caseinate, whey protein isolates, pea protein isolates, soy protein isolates, egg proteins, yeast protein, algae protein, hempseed protein, rice protein, barley protein, pumpkin seed protein, almond protein, canola protein, plant-based proteins, insect based proteins, xanthan gum, gellan gum, polyphosphate, alginate, agar, carrageenan, starch, oligofructans, konnyaku, alpha-lactalbumin, beta-lactoglobumin, ovalbumin, polysorbate, maltodextrin, alpha-cyclodextrins, beta-cyclodextrins, gammacyclodextrins, chitosan, chitin, cellulose, methyl cellulose, ethyl cellulose, hydro
- the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, or tocopherols, or a mixture thereof.
- the one or more processing aids comprise a transglutaminase enzyme.
- the emulsion or agglomeration is formed using a microfluizider.
- the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, corn oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.
- the food grade oil comprises palm oil or coconut oil.
- the emulsion or agglomeration comprises one or more processing aids.
- the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, tocopherols, or a mixture thereof.
- the one or more processing aids comprise a transglutaminase enzyme.
- the Microcapsules of the Disclosure prepared by the processes disclosed herein typically have a combination of payload i.e., CBD and, optionally, nicotine, and shell wall structural strength and stability that are suitable to orally administer to a human subject.
- the payload further comprises a fragrance and/or flavor oil.
- Microcapsules of the Disclosure can be prepared, for example, by a process that comprises providing an emulsion or agglomeration comprising CBD and, optionally, nicotine, one or more food grade oils, one or more food grade wall materials, water, and, optionally, one or more processing aids; adjusting pH, temperature, concentration, mixing speed, or a combination thereof to form an aqueous mixture comprising wall material, wherein the wall material comprises one or more food grade wall materials and surrounds the CBD and, optionally, nicotine and one or more food grade oils; cooling the aqueous mixture to a temperature above the gel point of the wall material until the wall material forms agglomerations; and further cooling the aqueous mixture to form an outer shell around the agglomeration of CBD and, optionally, nicotine and one or more food grade oils.
- an aqueous mixture of CBD and, optionally, nicotine, one or more food grade oils, one or more food grade wall materials, and, optionally, one or more processing aids is formed.
- the aqueous mixture can be an emulsion or agglomeration.
- One or more processing aids can also be added to the emulsion or agglomeration and/or aqueous mixture. Such processing aids can be added before, during, and/or after the emulsion or agglomeration is provided.
- Exemplary processing aids include, but art not limited to, antioxidants, surfactants, and/or chelators.
- Autoxidation of lipids is catalyzed by metal ions, particularly iron and copper ions.
- chelating of the metal ions can help retard the oxidation and extend its "lag phase" thereby extending the shelf-life of bulk oil or encapsulated oils.
- the chelators can be added before, during and/or after the emulsion or agglomeration is provided.
- suitable chelators include, but are not limited to are disodium ethylenediamine tetraacetic acid, which is one of the most frequently used chelating agents in food processing, citric acid, phytic acid, malic acid, tartaric acid, oxalic acid, succinic acid, polyphosphoric acids etc.
- the pH, temperature, concentration, or mixing speed, or a combination thereof can be adjusted to form an aqueous mixture comprising one or more food grade wall materials, wherein the one or more food grade wall materials surround the inner core materials, i.e., the CBD and one or more food grade oils. If there is more than one food grade wall material, i.e., a first and s second food grade wall material are different, complex coacervation may occur between the components to form a coacervate, which further deposits around the inner core materials to form the shell.
- the pH adjustment depends, for example, on the type of wall material to be formed. For example, the pH may be adjusted to a value from about 3.5 to about 5.0, or from about 4.0 to about 5.0. If the pH of the mixture starts in the desired range, then little or no pH adjustment is required. In one example, the pH is adjusted to from about 3.5 to about 4.5, from about 3.6 to about 4.4, or from about 3.7 to about 4.2.
- the shell of the disclosed microcapsules can comprise a complex coacervate.
- the complex coacervate can be formed from the two or more food grade wall materials.
- the outer shell can comprise a complex coacervate between whey protein isolate and agar. All combinations of two or more food grade wall materials are contemplated herein for the complex coacervate and the shell.
- the aqueous mixture can be cooled at a controlled cooling rate and mixing parameters to permit agglomeration of the primary shells to form encapsulated agglomerations of primary shells.
- the encapsulated agglomerations are discrete particles themselves. It is advantageous to control the formation of the encapsulated agglomerations at a temperature above the gel point of the shell material, and to let excess shell material form a thicker shell. It is also possible at this stage to add more polymer (e.g., a third polymer component), where the polymer is the same or different as the shell material being used, in order to thicken the shell and/or produce microcapsules having primary and outer shells of different composition.
- a third polymer component e.g., a third polymer component
- the outer shell encapsulates the agglomeration of primary shells to form a rigid encapsulated agglomeration of microcapsules.
- Cooling the aqueous mixture can be accomplished by methods known in the art, e.g., the use of a chiller.
- the rate of cooling can be about 1 °C per minute to about 1 °C per about 100 minutes.
- the rate of cooling can be about 1 °C per about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 minutes, where any of the stated values can form an upper or lower endpoint when appropriate.
- the rate of cooling can be about 1 °C/5 minutes. Cooling can take place until the mixture reaches a temperature of from about 5 °C to about 25 °C, e.g., about 5 °C.
- Processing aids can be included in the shell material. Processing aids can be used for a variety of reasons. For example, they may be used to promote agglomeration of the microcapsules, stabilize the emulsion or agglomeration system, improve the properties of the shell, control microcapsule size, and/or to act as an antioxidant.
- the processing aid can be an emulsifier, a fatty acid, a lipid, a wax, a microbial cell, e.g., yeast cell lines, a clay, or an inorganic compound, e.g., calcium carbonate.
- these processing aids can improve the barrier properties of the microcapsules.
- ascorbic acid or citric acid can be used to promote agglomeration of the microcapsules, to control microcapsule size, and to act as an antioxidant.
- the antioxidant can be used in an amount of about 100 ppm to about 20,000 ppm, or from about 1,000 ppm to about 5,000 ppm.
- Other processing aids such as, for example, metal chelators, can also be used.
- ethylene diamine tetraacetic acid can be used to bind metal ions, which can reduce oxidation.
- the shell material can also be cross-linked.
- the disclosed methods can further involve the addition of a cross-linker.
- the cross-linker can be added to increase the rigidity of the microcapsules by cross-linking the shell material in the shell and to make the shells insoluble in both aqueous and oily media.
- the cross-linker is added after the shell of the microcapsule is produced. Any suitable cross-linker can be used and the choice of cross-linker can vary depending upon the selection of the first and second polymer component.
- the cross-linkers can be enzymatic cross-linkers, e.g. transglutaminase, aldehydes, e.g. formaldehyde or glutaraldehyde, tannic acid, or alum, or a mixture thereof.
- the cross-linker can be a plant extract or a phenolic compound. It is also contemplated that one or more processing aids, e.g., antioxidants, can be used with the cross-linker.
- processing aids e.g., antioxidants
- the cross-linkers are preferably non-toxic or of sufficiently low toxicity. The amount of cross-linker used depends on the components selected and can be adjusted to provide more or less structural rigidity as desired.
- the amount of cross-linker used is in the amount of about 0.1% to about 5.0%, about 0.5% to about 5.0%, about 1.0% to about 5.0%, about 2.0% to about 4.0%, or about 2.5%, by weight, of one of the food grade wall materials.
- the cross-linker can be added at any stage of the process, e.g., it can be added after the cooling step.
- the use of transglutaminase to crosslink the microcapsules may not be desired because the temperature and pH are too low for effective cross-linking.
- glutaraldehyde can be in the disclosed methods to crosslink the disclosed microcapsules.
- the use of one or more compositions comprising an amino acid or protein can react with residual glutaraldehyde that was totally or partially unreacted from the crosslinking reaction. That is, unreacted and partially-reacted glutaraldehyde, i.e., with one aldehyde group still reactive, can be neutralized by the amino group of lysine or other amino groups on proteins.
- the microcapsules comprising amino acids and/or proteins can improve the microcapsule shell by filling any pores and neutralizing glutaraldehyde from the crosslinking reaction. This can also eliminate the need to wash the microcapsule after crosslinking because the microcapsule will be essentially free of glutaraldehyde.
- Crosslinking can also be accomplished with genipin, e.g., with genipin and carboxylmethyl chitosan, and/or other cross-linking agents.
- the disclosed microcapsules are washed with water and/or dried to provide a free-flowing powder.
- the disclosed methods of preparing microcapsules can comprise a drying step for the microcapsules. Drying can be accomplished by a number of methods known in the art such as, for example, freeze drying, drying with ethanol, or spray drying.
- spray drying is used for drying the microcapsules.
- Spray drying techniques are well known in the art, see, e.g., disclosed in "Spray Drying Handbook", K. Masters, 5th edition, Longman Scientific Technical UK, 1991, the disclosure of which is hereby incorporated by reference at least for its teaching of spray drying methods. Drying agents or anticaking agents can be used to help produce free flowing powders.
- the disclosure provides a method for helping a subject stop smoking, the method comprising administering a therapeutically effective amount of a Microcapsule of the Disclosure, a therapeutically effective amount of a Pharmaceutical Composition of the Disclosure, or a therapeutically effective amount of a Pharmaceutical Formulation of the Disclosure to the subject.
- the disclosure provides a kit comprising a therapeutically effective amount of a Microcapsule of the Disclosure, a therapeutically effective amount of a Pharmaceutical Composition of the Disclosure, or a therapeutically effective amount of a Pharmaceutical Formulation of the Disclosure, and instructions for administering the microcapsule, pharmaceutical composition, or pharmaceutical formulation to a subject attempting to stop smoking.
- the food grade wall material comprises modified starch, gum arabic, gelatin, pectin, lecithin, casein, caseinate, whey protein isolates, pea protein isolates, soy protein isolates, egg proteins, yeast protein, algae protein, hempseed protein, rice protein, barley protein, pumpkin seed protein, almond protein, canola protein, plant-based proteins, insect based proteins, xanthan gum, gellan gum, polyphosphate, alginate, agar, carrageenan, starch, oligofructans, konnyaku, alpha-lactalbumin, beta-lactoglobumin, ovalbumin, polysorbate, maltodextrin, alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, chitosan, chitin, cellulose, methyl cellulose, ethyl cellulose, hydropropylmethyl cellulose, carb
- the emulsion or agglomeration comprises one or more processing aids.
- the one or more processing aids comprise an antioxidant.
- the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, tocopherols, or a mixture thereof.
- the one or more processing aids comprise a transglutaminase enzyme.
- the emulsion or agglomeration further comprises a fragrance and/or flavor oil.
- Embodiment s The microcapsule of Embodiment 2, wherein the food grade oil comprises palm oil or coconut oil.
- Embodiment 4 The microcapsule of any one of Embodiments 1-3, wherein the food grade wall material comprises modified starch, gum arabic, gelatin, pectin, lecithin, casein, caseinate, whey protein isolates, pea protein isolates, soy protein isolates, egg protein, yeast protein, algae protein, hempseed protein, rice protein, barley protein, pumpkin seed protein, almond protein, canola protein, plant-based proteins, insect based proteins, xanthan gum, gellan gum, polyphosphate, alginate, agar, carrageenan, starch, oligofructans, konnyaku, alpha-lactalbumin, beta-lactoglobumin, ovalbumin, polysorbate, maltodextrin, alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, chitosan, chitin, cellulose, methyl cellulose, ethyl cellulose
- Embodiment 6 The microcapsule of any one of Embodiments 1-5, wherein the inner core, the primary shell, and/or the outer shell further comprise one or more processing aids.
- Embodiment 7. The microcapsule of Embodiment 6, wherein the one or more processing aids comprise an antioxidant.
- Embodiment 8 The microcapsule of Embodiment 7, wherein the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, or tocopherols, or a mixture thereof.
- Embodiment 9 The microcapsule of any one of Embodiments 1-8, wherein the primary shell and/or the outer shell comprises cross-linked food grade wall materials.
- Embodiment 11 The microcapsule of any one of Embodiments 1-10, wherein the diameter of the microcapsule is from about 1 pm to about 500 pm.
- Embodiment 12 The microcapsule of any one of Embodiments 1-11, wherein the microcapsule comprises from about 1 wt % to about 60 wt % of CBD and, optionally, nicotine.
- Embodiment 13 A pharmaceutical composition comprising the microcapsule of any one of Embodiments 1-12 and one or more pharmaceutically acceptable excipients.
- Embodiment 14 A pharmaceutical formulation comprising the microcapsule of any one of Embodiments 1-12, or the pharmaceutical composition of Embodiment 13, for oral administration to a subject.
- Embodiment 15 The pharmaceutical formulation of Embodiment 14, wherein said formulation is administered to the subject as a softgel, a tablet, a capsule, a gummie, a lozenge, a chewing gum, a taffy, a film, or an edible product.
- Embodiment 16 An emulsion or agglomeration comprising CBD and, optionally, nicotine, one or more food grade oils, one or more food grade wall materials, and water.
- Embodiment 17 The emulsion or agglomeration of Embodiment 16, wherein the emulsion or agglomeration droplet size is about 2 pm or less.
- Embodiment 18 The emulsion or agglomeration of Embodiments 16 or 17, wherein the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, com oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.
- the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, com oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.
- Embodiment 19 The emulsion or agglomeration of Embodiment 17, wherein the food grade oil comprises palm oil or coconut oil.
- Embodiment 20 The emulsion or agglomeration of any one of Embodiments
- Embodiment 21 The emulsion or agglomeration of Embodiment 20, wherein the food grade wall material comprises gelatin, protein isolate, lecithin, modified starch, or gum Arabic, or a combination thereof.
- Embodiment 22 The emulsion or agglomeration of any one of Embodiments 16-21, further comprising one or more processing aids.
- Embodiment 23 The emulsion or agglomeration of Embodiment 22, wherein the one or more processing aids comprise an antioxidant.
- Embodiment 24 The emulsion or agglomeration of Embodiment 23, wherein the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, or tocopherols, or a mixture thereof.
- Embodiment 25 A method of preparing the microcapsule of Embodiment 1, the method comprising: (i) providing an emulsion or agglomeration comprising CBD and, optionally, nicotine, one or more food grade oils, one or more food grade wall materials, water, and, optionally, one or more processing aids; and (ii) spray drying the emulsion or agglomeration to provide a powder comprising the microcapsule.
- Embodiment 26 A method of preparing the microcapsule of Embodiment 1, the method comprising: (i) providing an emulsion or agglomeration comprising CBD and, optionally, nicotine, one or more food grade oils, one or more food grade wall materials, water, and, optionally, one or more processing aids; and (ii) spray drying the emulsion or agglomeration to provide a powder comprising the microcapsule.
- Embodiment 26 A method of preparing the microcapsule of Embodiment 1, the method comprising: (i) providing an e
- Embodiment 27 The method of Embodiments 25 or 26, wherein the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, com oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.
- the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, com oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.
- Embodiment 28 The method of Embodiment 27, wherein the food grade oil comprises palm oil or coconut oil.
- Embodiment 29 The method of any one of Embodiments 25-28, wherein the food grade wall material comprises modified starch, gum arabic, gelatin, pectin, lecithin, casein, caseinate, whey protein isolates, pea protein isolates, soy protein isolates, egg proteins, yeast protein, algae protein, hempseed protein, rice protein, barley protein, pumpkin seed protein, almond protein, canola protein, plant-based proteins, insect based proteins, xanthan gum, gellan gum, polyphosphate, alginate, agar, carrageenan, starch, oligofructans, konnyaku, alpha-lactalbumin, beta-lactoglobumin, ovalbumin, polysorbate, maltodextrin, alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, chitosan, chitin, cellulose, methyl cellulose, ethyl cellulose
- Embodiment 30 The method of Embodiment 29, wherein the food grade wall material comprises gelatin, protein isolate, lecithin, modified starch, or gum Arabic, or a combination thereof.
- Embodiment 31 The method of any one of Embodiments 25-30, wherein the emulsion or agglomeration comprises one or more processing aids.
- Embodiment 32 The method of Embodiment 31, wherein the one or more processing aids comprise an antioxidant.
- Embodiment 33 The method of Embodiment 32, wherein the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, tocopherols, or a mixture thereof.
- Embodiment 34 The method of any one of Embodiments 25-33, wherein the one or more processing aids comprise a transglutaminase enzyme.
- Embodiment 35 A method of treating or preventing anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, or a metabolic syndrome-related disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of the microcapsule of any one of Embodiments 1-12, a therapeutically effective amount of the pharmaceutical composition of Embodiment 13, or a therapeutically effective amount of the pharmaceutical formulation of Embodiments 14 or 15 to the subject.
- Embodiment 36 The method of Embodiment 35 for treating anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, a metabolic syndrome-related disorder, or nicotine dependence, or a symptom thereof.
- Embodiment 37 The method of Embodiment 35 for preventing anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, a metabolic syndrome-related disorder, or nicotine dependence, or a symptom thereof.
- Embodiment 40 A microcapsule comprising: (a) an emulsion or agglomeration of primary microcapsules, wherein the primary microcapsules comprise an inner core and a primary shell surrounding the inner core; and (b) an outer shell surrounding the agglomeration of primary microcapsules, wherein (i) the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils; (ii) the primary shell comprises one or more food grade wall materials; and (iii) the outer shell comprises one or more food grade wall materials, produced by adjusting the pH, temperature, concentration, or mixing speed, or combination thereof, of the emulsion or agglomeration to form a coacervate slurry comprising an outer shell; and spray drying the coacervate slurry to provide a powder comprising the microcapsule.
- the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils
- the primary shell comprises one or more food grade wall materials
- the outer shell comprises one or more food grade wall
- Embodiment 41 The microcapsule of Embodiments 39 or 40, wherein the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, corn oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.
- the food grade oil comprises coconut oil, palm oil, soy bean oil, mineral oil, olive oil, canola oil, avocado oil, sunflower oil, peanut oil, corn oil, walnut oil, flaxseed oil, sesame oil, almond oil, tea seed oil, grapeseed oil, safflower oil, hemp seed oil, or vegetable oil, or a combination thereof.
- Embodiment 42 The microcapsule of Embodiment 41, wherein the food grade oil comprises palm oil or coconut oil.
- Embodiment 47 The microcapsule of Embodiment 46, wherein the antioxidant is ascorbic acid, rosemary extracts, ascorbyl palmitate, tocopherols, or a mixture thereof.
- Embodiment 48 The microcapsule of any one of Embodiments 39-47, wherein the one or more processing aids comprise a transglutaminase enzyme.
- Embodiment 50 The microcapsule, pharmaceutical composition, or a pharmaceutical formulation of Embodiment 49 for use in treating anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, a metabolic syndrome-related disorder, or nicotine dependence, or a symptom thereof.
- Embodiment 51 The microcapsule, pharmaceutical composition, or pharmaceutical formulation of Embodiment 49 for use in preventing anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, a metabolic syndrome-related disorder, or nicotine dependence, or a symptom thereof.
- Embodiment 52 Use of a microcapsule of any one of Embodiments 1-12, a pharmaceutical composition of Embodiment 13, or a pharmaceutical formulation of Embodiments 14 or 15 in the manufacture of a medicament for treating or preventing anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, a metabolic syndrome-related disorder, or nicotine dependence, in a subject in need thereof.
- Embodiment 53 The use of Embodiment 52 for treating anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, a metabolic syndrome-related disorder, or nicotine dependence, or a symptom thereof.
- Embodiment 54 The use of Embodiment 52 for preventing anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, a metabolic syndrome-related disorder, or nicotine dependence, or a symptom thereof.
- Embodiment 56 The emulsion or agglomeration of any one of Embodiments
- Embodiment 57 The method of any one of Embodiments 25-37, wherein the emulsion or agglomeration further comprises a fragrance and/or flavor oil.
- Embodiment 58 The microcapsule of any one of Embodiments 39-48, further comprising a fragrance and/or flavor oil.
- Embodiment 59 The microcapsule of any one of Embodiments 1-12, wherein the inner core comprises nicotine.
- Embodiment 60 The emulsion or agglomeration of any one of Embodiments
- Embodiment 62 The microcapsule of any one of Embodiments 39-48, wherein the emulsion or agglomeration and inner core comprise nicotine.
- Embodiment 63 The microcapsule of any one of Embodiments 1-12 or 55, wherein the the inner core comprises CBD and one or more food grade oils.
- Embodiment 66 The microcapsule of any one of Embodiments 1-12 or 55, wherein the the inner core comprises CBD and nicotine, and one or more food grade oils.
- Embodiment 68 A pharmaceutical formulation comprising the microcapsule of Embodiment 66 and one or more pharmaceutically acceptable excipients.
- the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils
- the outer shell comprises one or more food grade wall materials.
- Embodiment 72 A method of preparing the microcapsule of Embodiment 69, the method comprising:
- Embodiment 73 A microcapsule comprising:
- the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils
- the primary shell comprises one or more food grade wall materials
- the outer shell comprises one or more food grade wall materials, produced by:
- Embodiment 74 A microcapsule comprising:
- the inner core comprises CBD and, optionally, nicotine, and one or more food grade oils
- the primary shell comprises one or more food grade wall materials
- the outer shell comprises one or more food grade wall materials, produced by:
- range format Various embodiments of this disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range, such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 2, from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 3, from 2 to 4, from 2 to 5, from 2 to 6, from 3 to 4, from 3 to 5, from 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
- the term “or” is understood to be inclusive.
- the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both “A and B,” “A or B,” “A,” and “B.”
- the term “and/or” as used in a phrase such as "A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
- composition or the specified steps of a method, and those additional materials or steps that do not materially affect the basic characteristics of the material or method.
- a "therapeutically effective amount” or “effective amount” of a composition is a predetermined amount calculated to achieve the desired result.
- the activity contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate.
- the specific dose of a compound administered according to this disclosure to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the subject to be treated.
- a therapeutically effective amount of compound of this disclosure is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient. Therapeutically effective amounts may be administered according to any dosing schedule.
- treat refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disease, or disorder, or to obtain beneficial or desired physiological results (e.g., clinical, medical, and/or veterinary results).
- beneficial or desired results include, but are not limited to, alleviation or elimination of the symptoms or signs associated with a condition, disease, or disorder, i.e., anorexia, emesis, pain, inflammation, multiple sclerosis, a neurodegenerative disorder, epilepsy, glaucoma, osteoporosis, schizophrenia, a cardiovascular disorder, cancer, obesity, or a metabolic syndrome-related disorder; diminishment of the extent of a condition, disease, or disorder; stabilization of a condition, disease, or disorder, i.e., where the condition, disease, or disorder is not worsening; delay in onset or progression of the condition, disease, or disorder; amelioration of the condition, disease, or disorder; remission (whether partial or total and whether detectable or undetectable) of the condition, disease, or disorder; or enhancement or improvement of a condition, disease, or disorder.
- Treatment includes eliciting a physiologically significant response without excessive side effects.
- food grade refers to material that is safe for human consumption.
- residue refers to the moiety that is the resulting product of the specified chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the specified chemical species.
- an "amino acid residue” refers to the moiety which results when an amino acid participates in a particular reaction, e.g., the residue can be the product of an amino acid undergoing a transglutaminase catalyzed crosslinking reaction with another amino acid. In this case, the amino acid residue is "derived" from the amino acid.
- this moiety can be obtained by a reaction with a species other than the specified amino acid, for example, by a reaction with a protein or peptide containing the amino acid, and the like.
- This concept applies to other chemical species disclosed herein, such as protein, saccharides like chitosan, lactose, and sucrose, and waxes.
- chemical species disclosed herein such as protein, saccharides like chitosan, lactose, and sucrose, and waxes.
- a weight percent (wt.%) of a component is based on the total weight of the composition in which the component is included.
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Abstract
La présente divulgation concerne des microcapsules chargées de CBD ou chargées de CBD et de nicotine destinées à être utilisées dans le traitement ou la prévention de l'anorexie, des vomissements, de la douleur, de l'inflammation, de la sclérose en plaques, d'un trouble neurodégénératif, de l'épilepsie, du glaucome, de l'ostéoporose, de la schizophrénie, d'un trouble cardiovasculaire, du cancer, de l'obésité, d'un trouble lié au syndrome métabolique, de l'eczéma, du psoriasis ou de la dépendance à la nicotine, chez un sujet en ayant besoin. La divulgation concerne également des compositions pharmaceutiques et des formulations pharmaceutiques comprenant des microcapsules chargées de CBD ou chargées de CBD et de nicotine. La divulgation concerne également des méthodes de fabrication de microcapsules chargées de CBD ou chargées de CBD et de nicotine, avec ou sans arômes ou parfums.
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WO2008017962A2 (fr) * | 2006-06-05 | 2008-02-14 | Ocean Nutrition Canada Ltd. | Microcapsules à enveloppes améliorées |
WO2008085997A2 (fr) * | 2007-01-10 | 2008-07-17 | Ocean Nutrition Canada, Ltd. | Microcapsules végétariennes |
US10080736B2 (en) * | 2014-12-12 | 2018-09-25 | Ojai Energetics Pbc | Microencapsulated cannabinoid compositions |
CA3059908A1 (fr) * | 2018-10-24 | 2020-04-24 | Emanuel Frank Petricoin, Iv | Emulsions huile dans le sirop comestibles, de longue conservation et hydrosolubles de cannabinoides comprenant des microparticules encapsulees et leurs utilisations |
US20200170950A1 (en) * | 2018-11-30 | 2020-06-04 | Canopy Growth Corporation | Compositions comprising a cannabinoid or a cannabis-derived compound, methods of making and use |
AU2020335245A1 (en) * | 2019-08-30 | 2022-03-10 | Evie Sa | Loaded granules, their process of production and their uses |
WO2022081814A1 (fr) * | 2020-10-16 | 2022-04-21 | Michael Ogburn | Formulations de cannabinoïdes inhalables |
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WO2008017962A2 (fr) * | 2006-06-05 | 2008-02-14 | Ocean Nutrition Canada Ltd. | Microcapsules à enveloppes améliorées |
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