Orally dissolving films and methods of making and using same

Abstract

The present invention provides a dissolvable film in the mouth and methods for making and using the same, including: (a) a pharmaceutically active ingredient; (b) a surfactant; (c) a solvent for the pharmaceutically active ingredient; (d) a film matrix; and (e) water, wherein (1) when the pharmaceutically active ingredient is lipophilic or hydrophobic, (i) the surfactant is lipophilic or hydrophobic, and (ii) the solvent for the pharmaceutically active ingredient is lipophilic or hydrophobic; and (2) when the pharmaceutically active ingredient is lipophobic or hydrophilic, (i) the surfactant is lipophobic or hydrophilic, and (ii) the solvent for the pharmaceutically active ingredient is lipophobic or hydrophilic.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 955,484, filed December 31, 2019, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] 2. Background of the Invention The bioavailability of orally administered drugs is relatively low. In addition, sensitive active ingredients (e.g., sensitive to moisture, oxygen, light, pH, and / or heat) present challenges in selecting appropriate dosage forms and routes of administration. This includes dosage forms configured for oral administration.

[0003] Currently, there is a need for pharmaceutical formulations that have increased barriers against moisture, oxygen, light, pH, and heat, thereby protecting sensitive active ingredients.There is also a need to improve the bioavailability of less potent and less bioavailable active ingredients, thereby allowing less potent active ingredients to be used at lower doses.In addition, when using various pharmaceutical formulations, there is a need to increase the penetration and crossing of mucus layers by active ingredients, thereby allowing active ingredients to enter systemic circulation.The above is desirable while reducing liver / GI toxicity. Summary of the Invention [Means for solving the problem]

[0004] SUMMARY OF THE PRESENT APPLICATION The present invention provides an orally dissolvable film comprising (a) a pharmacologic active ingredient, (b) a surfactant, (c) a solvent for the pharmacologic active ingredient, (d) a film matrix, and (e) water, wherein (1) when the pharmacologic active ingredient is lipophilic or hydrophobic, (i) the surfactant is lipophilic or hydrophobic, and (ii) the solvent for the pharmacologic active ingredient is lipophilic or hydrophobic, and (2) when the pharmacologic active ingredient is lipophobic or hydrophilic, (i) the surfactant is lipophobic or hydrophilic, and (ii) the solvent for the pharmacologic active ingredient is lipophobic or hydrophilic.

[0005] The present invention also provides an orally dissolvable film comprising: (a) a lipophilic pharmacologic active ingredient; (b) an oil carrier for the lipophilic pharmacologic active ingredient; (c) a self-emulsifying lipophilic surfactant for the lipophilic pharmacologic active ingredient; (d) one or more co-surfactants; (e) one or more hydrophilic surfactants; (f) a film matrix; and (g) water.

[0006] The present invention also provides an orally dissolvable film comprising: (a) a hydrophilic pharmacologic active ingredient; (b) a water carrier for the hydrophilic pharmacologic active ingredient; (c) a hydrophilic surfactant for the hydrophilic pharmacologic active ingredient; (d) one or more co-surfactants; (e) one or more self-emulsifying surfactants; (f) a film matrix; and (g) water.

[0007] The invention also provides a method of forming an in-mouth dissolving film comprising the steps of: (a) dissolving a medicament in a first solvent system to form a first mixture, (i) if the medicament is lipophilic or hydrophobic, the medicament is dissolved in a lipophilic or hydrophobic solvent, a lipophilic or hydrophobic surfactant, or a combination thereof, or (ii) if the medicament is hydrophilic or lipophobic, the medicament is dissolved in a hydrophilic or lipophobic solvent, a hydrophilic or lipophobic surfactant, or a combination thereof; (b) contacting the first mixture and the lipophilic or hydrophobic surfactant to form a second mixture; (c) contacting the second mixture with water and a hydrophilic or lipophobic surfactant to form a third mixture; (d) contacting the third mixture with film-forming ingredients to form a slurry; and (e) casting the slurry onto a substrate and allowing to harden to form a in-mouth dissolving film. In certain embodiments, for example, the following items are provided: (Item 1) (a) a medicament active ingredient, (b) a surfactant, (c) a solvent for the pharma- ceutical active ingredient; (d) a film matrix, and (e) water A dissolving film in the mouth comprising: When the pharmacoactive ingredient is lipophilic or hydrophobic, (i) the surfactant is lipophilic or hydrophobic, (ii) the solvent for the pharmacoactive ingredient is lipophilic or hydrophobic, If the pharmacoactive ingredient is lipophobic or hydrophilic, (i) the surfactant is lipophobic or hydrophilic, and (ii) the solvent for the pharmacoactive ingredient is lipophobic or hydrophilic. Dissolvable film in the mouth. (Item 2) 2. The mouth-dissolving film of claim 1, wherein the surfactant is lipophilic or hydrophobic and the solvent for the pharma- ceutical active ingredient is lipophilic or hydrophobic. (Item 3) 3. The mouth-dissolving film of any one of items 1 to 2, wherein the lipophilic or hydrophobic surfactant comprises at least one of glyceryl monocaprylate, propylene glycol monocaprylate, glyceryl monooleate, propylene glycol monolaurate, glyceryl caprylate / caprate, glyceryl monolinoleate, sorbitan monooleate (Span 80), glyceryl dibehenate, propylene glycol dilaurate, glyceryl tricaprylate / tricaprate, glyceryl tricaprylate / caprate, decaglyceryl mono- and dioleate, oleoyl macrogolglycerides, lauroyl macrogolglycerides, stearoyl macrogolglycerides, stearoyl polyoxylglycerides, polyoxyethylene, and glyceryl caprylate / caprate. (Item 4) 4. The in-mouth dissolving film according to any one of items 1 to 3, wherein the lipophilic or hydrophobic surfactant is present in an amount of 0.5 to 40 wt %. (Item 5) 2. The mouth-dissolving film of claim 1, wherein the surfactant is lipophobic or hydrophilic and the solvent for the pharma- ceutical active ingredient is lipophobic or hydrophilic. (Item 6) 6. The orally dissolving film of any one of items 1 and 5, wherein the lipophobic or hydrophilic surfactant comprises at least one of poloxamer, polyoxyl castor oil, polyethylene-polypropylene glycol, polyoxyethylene sorbitan monolaurate (Tween 20), Tween 80, polyoxyethylene sorbitan monostearate (Tween 60), decyl glucoside, lauryl glucoside, octyl glucoside, Triton X-100, nonoxynol 9, sodium lauryl sulfate, potassium lauryl sulfate, Brij, glyceryl laurate, phospholipids, n-dodecylphosphocholine, and cholesteryl esters. (Item 7) 7. The in-mouth dissolving film according to any one of items 1 and 5-6, wherein the lipophobic or hydrophilic surfactant is present at 0.5-40 wt %. (Item 8) 4. The orally dissolving film of any one of items 1 to 3, wherein the lipophilic or hydrophobic solvent for the pharma- ceutical active ingredient comprises at least one of medium chain triglyceride oil, coconut oil, corn oil, olive oil, palm oil, canola oil, safflower oil, sesame oil, propylene glycol monocaprylate, propylene glycol monolaurate, glyceryl monolinoleate, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol. (Item 9) 9. The orally dissolving film according to any one of items 1 to 3 and 8, wherein the lipophilic or hydrophobic solvent for the pharma- ceutical active ingredient is present at 0.5 to 40 wt%. (Item 10) 8. The mouth-dissolving film of any one of items 1 and 5-7, wherein the lipophobic or hydrophilic solvent for the pharma- ceutical active ingredient comprises water. (Item 11) 11. The orally dissolving film of any one of items 1, 5-7, and 10, wherein the lipophobic or hydrophilic solvent for the pharma- ceutical active ingredient is present at 0.5-20 wt%. (Item 12) 12. The orally dissolving film according to any one of items 1 to 11, wherein the medicamentously active ingredient is lipophilic or hydrophobic. (Item 13) 12. The orally dissolving film according to any one of items 1 to 11, wherein the medicamentously active ingredient is lipophobic or hydrophilic. (Item 14) 14. The oral dissolving film according to any one of items 1 to 13, wherein the pharma- ceutical active ingredient comprises a cannabinoid, a terpene, a flavonoid, or a combination thereof. (Item 15) 14. The orally dissolving film according to any one of items 1 to 13, wherein the pharmacoactive ingredient comprises at least one of cyclosporine, ritonavir, saquinavir, amprenavir, valproic acid, calcitriol, bexarotene, tretinoin, isotretinoin, tipranavir, and pharmacologic acceptable salts thereof. (Item 16) 14. The orally dissolving film according to any one of items 1 to 13, wherein the medicamentously active ingredient comprises a hallucinogen. (Item 17) 14. The oral dissolving film of any one of items 1 to 13, wherein the pharmacoactive ingredient comprises a hallucinogen comprising at least one of lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), N,N-dimethyltryptamine (DMT), psilocybin, mescaline, and ibogaine. (Item 18) 14. The orally dissolving film according to any one of items 1 to 13, wherein the medicamentously active ingredient comprises ivermectin. (Item 19) 19. The orally dissolving film according to any one of items 1 to 18, comprising at least 10 wt % of the medicamentously active ingredient. (Item 20) 20. The in-mouth dissolving film according to any one of the preceding claims, wherein the film matrix comprises a plasticizer and a film former. (Item 21) 21. The in-mouth dissolving film of any one of the preceding claims, wherein the film matrix comprises a plasticizer comprising at least one of propylene glycol, glycerin, triacetin, triethyl citrate, and polyethylene glycol. (Item 22) 22. The in-mouth dissolving film of any one of the preceding claims, wherein the film matrix comprises a plasticizer present at 0.5-20 wt%. (Item 23) 24. The mouth-dissolving film of any one of the preceding claims, wherein the film matrix comprises a film former comprising at least one of pullulan, gum arabic, guar gum, maltodextrin, microcrystalline cellulose, chitosan, pectin, carrageenan, HPMC, HPC, modified corn starch, Carbopol 974P, Carbopol 934P, Kollidon 25, Soluplus, Lycoat NG73, Kollicoat, Polyox N-10, Polyox N-80, Polyox N-750, Methocel E4M, Methocel E10M, and sodium CMC. (Item 24) 24. The in-mouth dissolving film according to any one of the preceding claims, wherein the film matrix comprises a film former present at 1-60 wt%. (Item 25) 25. The in-mouth dissolvable film according to any one of items 1 to 24, further comprising a co-solvent. (Item 26) 26. The mouth-dissolving film of any one of the preceding claims, further comprising a co-solvent comprising at least one of diethylene glycol monoethyl ether and caprylocaproyl polyoxyl-8 glyceride. (Item 27) 27. The in-mouth dissolvable film according to any one of the preceding items, further comprising a co-solvent present at 0.5-40 wt %. (Item 28) 28. The mouth-dissolving film of any one of the preceding claims, further comprising at least one of an antioxidant, an antibacterial agent, a flavoring agent, a coloring agent, and a sweetener. (Item 29) (a) a lipophilic pharmacologic active ingredient; (b) an oil carrier for the lipophilic pharma- ceutical active ingredient; (c) a self-emulsifying lipophilic surfactant for said lipophilic pharma- ceutical active ingredient; (d) one or more co-surfactants; (e) one or more hydrophilic surfactants; (f) film matrix, and (g) water 2. The mouth-dissolving film according to item 1, comprising: (Item 30) (a) a hydrophilic medicament active ingredient; (b) an aqueous carrier for said hydrophilic pharma- ceutical active ingredient; (c) a hydrophilic surfactant for the hydrophilic pharmacoactive ingredient; (d) one or more co-surfactants; (e) one or more self-emulsifying surfactants; (f) film matrix, and (g) water 2. The mouth-dissolving film according to item 1, comprising: (Item 31) 31. The orally dissolvable film of any one of items 1 to 30, configured to self-emulsify within 20 seconds upon contact with the oral mucosal surface of a subject. (Item 32) 32. The in-mouth dissolving film of any one of items 1 to 31, configured to form an oil-in-water (O / W) emulsion within 20 seconds upon contact with the oral mucosal surface of a subject. (Item 33) 33. The orally dissolvable film of any one of items 1 to 32, configured to form an oil-in-water (O / W) emulsion having an average droplet size of 0.1 microns to 120 microns within 20 seconds upon contact with the oral mucosal surface of a subject. (Item 34) Upon contact with the oral mucosal surface of a subject, within 20 seconds d(10): 0.5 to 10 microns, d(50): 1 to 20 microns, and d(90): 15 to 100 microns 34. The in-mouth dissolving film of any one of the preceding items, configured to form an oil-in-water (O / W) emulsion having an average droplet size of (Item 35) 35. The orally dissolving film according to any one of items 1 to 34, suitable for oral administration (PO), buccal administration, sublingual administration, or mucosal administration. (Item 36) 36. The film dissolving in the mouth according to any one of items 1 to 35, having a water content of 3 to 13 wt %. (Item 37) 37. The orally dissolving film according to any one of items 1 to 36, which is configured to disintegrate within 15 minutes when buccally administered to a subject. (Item 38) 37. The mouth-dissolving film of any one of items 1 to 36, configured to disintegrate within 30 seconds when administered orally (PO) to a subject. (Item 39) Constructed to disintegrate in vitro within 30 seconds (USP <701> In-vitro disintegration method), the orally dissolving film according to any one of items 1 to 36. (Item 40) (i) a Tmax between about 45 minutes and about 120 minutes, (ii) a Cmax of at least 3.5 ng / ml, and (iii) an AUC of at least 13 ng / hr / ml. 0-t 40. The oral dissolving film according to any one of items 1 to 39, exhibiting at least one pharmacokinetic parameter selected from the group consisting of: (Item 41) (i) a Tmax of 1.5 hours, (ii) a Cmax of 4.4 ng / ml, and (iii) an AUC of 13.5 ng / hr / ml. 0-t 41. The orally dissolving film according to any one of items 1 to 40, exhibiting at least one pharmacokinetic parameter selected from the group consisting of: (Item 42) 42. The orally dissolvable film according to any one of items 1 to 41, exhibiting an in vivo dissolution time of 20 minutes or less. (Item 43) 43. The in-mouth dissolving film according to any one of items 1 to 42, exhibiting an in vivo dissolution time of between about 10 minutes and about 15 minutes. (Item 44) 44. The orally dissolving film according to any one of items 1 to 43, which exhibits a bioavailability of at least 15%. (Item 45) 44. The orally dissolving film according to any one of items 1 to 43, which exhibits a bioavailability of at least 18%. (Item 46) 46. ​​The orally dissolvable film according to any one of items 1 to 45, exhibiting at least about 96% stability after 9 months when measured under accelerated conditions of 40° C. / 75% RH. (Item 47) 46. ​​The orally dissolvable film according to any one of items 1 to 45, which exhibits 100% stability after 3 months when measured under accelerated conditions of 25° C. / 60% RH or 40° C. / 75% RH. (Item 48) 1. A method for forming an in-mouth dissolving film, comprising: (a) dissolving a medicament active ingredient in a first solvent system to form a first mixture, (i) if the pharmacoactive ingredient is lipophilic or hydrophobic, dissolving the pharmacoactive ingredient in a lipophilic or hydrophobic solvent, a lipophilic or hydrophobic surfactant, or a combination thereof; or (ii) if the pharmacoactive ingredient is hydrophilic or lipophobic, dissolving the pharmacoactive ingredient in a hydrophilic or lipophobic solvent, a hydrophilic or lipophobic surfactant, or a combination thereof; (b) contacting the first mixture and a lipophilic or hydrophobic surfactant to form a second mixture; (c) contacting the second mixture with water and a hydrophilic or lipophobic surfactant to form a third mixture; (d) contacting the third mixture with a film-forming component to form a slurry; (e) casting the slurry onto a substrate and allowing it to harden to form the mouth-dissolvable film; A method comprising: (Item 49) 49. The method of claim 48, wherein the film-forming component comprises at least one of mucoadhesive polymers, plasticizers, binders, fillers, bulking agents, saliva stimulants, stabilizers and thickeners, gelling agents, flavors, taste masking agents, colorants, pigments, lubricants, release modifiers, adjuvants, sweeteners, solubilizers and emulsifiers, fragrances, emulsifiers, surfactants, pH adjusters, buffers, lipids, glidants, stabilizers, antioxidants, anti-adherents, humectants, solvents, penetration enhancers, and preservatives. (Item 50) 50. The method according to any one of items 48 to 49, wherein the lipophilic or hydrophobic solvent comprises an oil. (Item 51) 50. The method according to any one of items 48 to 49, wherein the hydrophilic or oleophobic solvent comprises an aqueous liquid. (Item 52) 52. The method according to any one of items 48 to 51, wherein the curing is carried out in a hot air oven at an air temperature between about 38°C and about 110°C. (Item 53) 53. The method according to any one of items 48 to 52, wherein the curing is carried out in a hot air oven at an air temperature between about 45°C and about 80°C. (Item 54) 54. The method according to any one of items 48 to 53, wherein the curing is carried out in a hot air oven (air temperature between 50°C and 70°C). (Item 55) 55. The method of any one of items 48 to 54, wherein the curing is carried out at a speed between about 0.8 feet / minute and about 2.5 feet / minute. (Item 56) 56. The method of any one of items 48 to 55, wherein the curing is carried out at a speed between about 0.8 ft / min and about 1.0 ft / min. (Item 57) 57. The method of any one of items 48 to 56, wherein the curing is carried out at a speed between about 2.0 feet / minute and about 2.5 feet / minute. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Detailed Description of the Invention The present invention provides dissolving films in the mouth and methods of making and using the dissolving films in the mouth.

[0009] definition The following terms have the meanings ascribed to them unless specified otherwise.

[0010] The words "comprise," "comprising," "include," "including," and "includes," when used in this specification and claims, are intended to specify the presence of stated substances, features, integers, components, or steps, but do not exclude the presence or addition of one or more other substances, features, integers, components, steps, or combinations thereof.

[0011] The mouth-dissolving film described herein comprises a polymer matrix formed from a pharmaceutical active ingredient, a surfactant, a solvent for the pharmaceutical active ingredient, a film matrix, and water.The optional additional excipients (alternatively called "additives") used to manufacture the mouth film can include, for example, one or more of mucoadhesive polymers, plasticizers, binders, fillers, bulking agents, saliva stimulants, stabilizers and thickeners, gelling agents, flavoring agents, taste masking agents, coloring agents, pigments, lubricants, release modifiers, adjuvants, sweeteners, solubilizers and emulsifiers, fragrances, emulsifiers, surfactants, pH adjusters, buffers, lipids, glidants, stabilizers, antioxidants, anti-tacking agents, humectants, solvents, penetration enhancers, and preservatives. Suitable excipients or additives that can be used in the oral film formulations are described, for example, in Lachman, et al., "The Theory and Practice of Industrial Pharmacy," 4th Edition (2013), Rowe et al., "Handbook of Pharmaceutical Excipients," 8th Edition (2017), and Remington, "The Science and Practice of Pharmacy," 22nd Edition (2015). From a regulatory perspective, all excipients and additives used in the oral film formulations described herein should preferably be approved for use in oral pharmaceutical dosage forms.

[0012] As used herein, the term "dissolvable film" refers to a unit dosage form that is a substantive material, is composed of pharmaceutical or food grade ingredients, is relatively flat and has a discrete dimension, and is configured to dissolve in liquid (e.g., liquid present on a mucosal surface). Also preferably, the dissolvable film is self-supporting, or in other words, can maintain its integrity and structure in the absence of a separate support. Prior to being sized to the appropriate dimensions (thereby providing a unit dosage form), the dissolvable film can be in either an unrolled form (e.g., a sheet) or a rolled form (e.g., a bulk roll).

[0013] The dissolvable films described herein can have any desired shape and size, provided that when administered, they can be effectively administered to a mucosal surface of the body, such as the oral mucosa, tongue, eye, vagina, or rectum. For example, the dissolvable films described herein can be made into the form of an article, such as a strip, tape, patch, sheet, or any other suitable form known to those of skill in the art.

[0014] Specifically, the dissolvable film can be relatively thin, having a thickness of about 0.025 mm to about 0.30 mm, or thicker, having a thickness of about 0.30 mm to about 0.775 mm. For some dissolvable films, the thickness can be even greater, for example, greater than about 0.775 mm. In addition, the term "dissolvable film" includes monolayer compositions (e.g., monolayer laminate films), bilayer compositions (e.g., bilayer laminate films), and multilayer compositions (e.g., multilayer laminate films).

[0015] Dissolvable films can effectively maintain the necessary stability of the ingredients (inactive and active) present thereon over the extended periods typically involved in packaging, shipping and storage. Dissolvable films can also effectively maintain a relatively uniform distribution of such ingredients over the extended periods typically involved in packaging, shipping and storage. From a regulatory standpoint, dissolvable films only have a permissible variation in active ingredient per unit area of ​​film.

[0016] The dissolving film can be administered to a subject (e.g., a human patient) in need of treatment of a particular disease or disorder. The selection of active ingredients in the unit dosage form described herein depends on the particular disease or disorder to be treated. The Physician's Desk Reference, 2018 Edition; The Merck Index, 15th Edition (2013), United States Pharmacopeia (USP) (2018), National Formulary as the USP-NF (2018), and the International Pharmacopoeia (Pharmacopoeia Internationalis, Ph. Int.) (2017) provide descriptions of diseases or disorders for which a particular active ingredient has been approved (e.g., by the US FDA or EMA) for marketing and selling the product (e.g., in the United States or Europe). Thus, one skilled in the art can look to such references for guidance in selecting the active ingredient to be present in the unit dosage form based on the treatment of a particular disease or disorder of particular interest (and vice versa).

[0017] Orally dissolving films (alternatively known as orally dissolving films, ODFs, orally dissolving film strips, edible films, edible strips, oral film strips, oral drug strips, buccal films, sublingual films, orally soluble films, etc.) are unit dosage forms in which the dissolving film is specifically configured to be administered in the oral cavity and disintegrates over a desired period of time.

[0018] The term "orally dissolving film" refers to a dissolving film specifically configured for oral administration. Orally dissolving films are composed of edible or ingestible pharma- ceutically acceptable ingredients. Orally dissolving films can be configured for multi-directional or unidirectional release. Orally dissolving films, similar in size and shape to a postage stamp, are designed for oral administration, with the user placing a strip on the tongue (enteral), under the tongue (sublingual), through the oral mucosa (mucosal), against the inside of the cheek (buccal), or on the gums (gingival). With the exception of the enteral route, these drug delivery options allow the drug to bypass first-pass metabolism, making it more bioavailable. Once the film dissolves, the drug can enter the bloodstream enterally, mucosally, buccal, gingival, and / or sublingually. Thus, in certain embodiments, an orally dissolving film can be prepared using a hydrophilic polymer that dissolves on the tongue or in the buccal oral cavity and delivers the drug to the systemic circulation by dissolving upon contact with bodily fluids. Thus, oral film drug delivery uses dissolvable films to administer drugs via oral absorption (buccal, sublingual, or gingival) and / or the small intestine (enteral). Particularly for drugs that are extensively metabolized by the first-pass effect, the oral films described herein offer the opportunity to provide a more rapid action and better absorption profile.

[0019] When systemic delivery (e.g., transmucosal delivery) is desired, the treatment site may include any area where the adhesive films described herein are capable of maintaining a desired level of pharmaceutical agent in the blood, lymph, or other bodily fluids. Typically, such treatment sites include the oral mucosa (e.g., tongue, sublingual, gums, inner cheeks, etc.).

[0020] When the dissolving film is rectangular in shape, it typically has a two dimensional profile with a length of up to about 65 mm and a width of up to about 35 mm. Regardless of shape, the dissolving film typically has a profile whose maximum length, width, diameter, or cross-sectional dimension is less than about 75 mm.

[0021] Oral dissolving films typically include a polymer matrix formed from one or more of a strip-forming polymer (e.g., a mucoadhesive polymer), an active pharmaceutical ingredient (API), and a solvent. Optional additional excipients (alternatively referred to as "additives") used to manufacture oral films may include, for example, one or more of plasticizers, binders, fillers, extenders, saliva stimulants, stabilizers and thickeners, gelling agents, flavors, taste masking agents, colorants, pigments, lubricants, release modifiers, adjuvants, sweeteners, solubilizers and emulsifiers, fragrances, emulsifiers, surfactants, pH adjusters, buffers, lipids, glidants, stabilizers, antioxidants, anti-tack agents, humectants, and preservatives. Suitable excipients that can be used in the formulation of oral films are described, for example, in Lachman, et al., "The Theory and Practice of Industrial Pharmacy," 4 th Edition (2013), Rowe et al., "Handbook of Pharmaceutical Excipients," 8th Edition (2017), and Remington, "The Science and Practice of Pharmacy," 22nd Edition (2015). From a regulatory standpoint, all excipients used in the oral film formulations described herein should preferably be approved for use in oral pharmaceutical dosage forms.

[0022] The term "oral thin film" (OTF) refers to an oral dissolving film having certain performance characteristics and physical dimensions, as described elsewhere herein. Specifically, an OTF is an oral dissolving film having a thickness of less than about 0.400 mm (typically less than about 0.250 mm), can be configured to be mucoadhesive regardless of drug loading, and is configured to dissolve and / or disintegrate very quickly upon contact with saliva. Specifically, an OTF can disintegrate in the oral cavity (e.g., at the oral mucosal surface) with a relatively short in vitro disintegration time (e.g., about 120 seconds or less).

[0023] Conflicting forces come into play in the development of OTFs. On the one hand, existing OTFs typically do not have high drug loading (e.g., more than 200 mg or 40 wt % active ingredient) because they are "thin". Similarly, by increasing the thickness of an OTF to increase drug loading, the resulting film would at some point no longer be considered "thin". Such films risk losing the aesthetic and performance characteristics of the OTF. Specifically, by increasing the thickness of an existing OTF to support high drug loading, the resulting film may not be able to erode, dissolve, and / or disintegrate quickly and effectively upon contact with saliva. The resulting film may not have the necessary mucoadhesive properties desired for the film, which would allow it to "stick" and remain on the mucosal surface as it erodes. In addition, the resulting film may not retain the necessary mechanical properties over the long periods that typically accompany product packaging, shipping, and storage. Furthermore, the resulting film may not possess the ability to deliver a therapeutically effective amount of active ingredient to a subject as intended.

[0024] The dissolvable film described herein is typically formed from a slurry. The term "slurry" refers to a mixture of solids suspended and / or dissolved in a liquid, suitable for extrusion, casting onto a substrate, and curing to form a dissolvable film. The solids and liquids will include the materials used to produce the dissolvable film in the mouth as expected. The solid materials used in the production of the dissolvable film in the mouth can be dissolved and / or suspended in the liquid. The dissolvable film in the mouth can be formed by curing the cast slurry, where the curing can be performed at an elevated temperature for a period of time. To perform the curing, a large amount of solvent (e.g., water) will be removed.

[0025] The present invention relates to dissolvable films that can be used to administer a desired predetermined substance, referred to herein as an "active pharmaceutical ingredient" (API) (and equivalent terms, e.g., "active ingredient"), in a sufficient or effective amount to (1) obtain a desired result, e.g., treatment of a subject; (2) obtain a desired level of an API in a subject (e.g., as evidenced by plasma levels of the API); and / or (3) obtain a desired level of an active metabolite of the API in a subject (e.g., as evidenced by plasma levels of an active metabolite of the API).

[0026] The term "pharmaceutical active ingredient" or "active ingredient" is used to include any "drug," "bioactive agent," "preparation," "medicine," "therapeutic agent," "physiological agent," "nutraceutical," or "pharmaceutical product," including substances for use in the treatment of a disease or disorder. Dietary supplements, vitamins, functional foods (e.g., ginger, green tea, lutein, garlic, lycopene, capsaicin, etc.) are also included within the term.

[0027] Standard references, such as The Physician's Desk Reference, 2018 Edition; The Merck Index, 15th Edition (2013), and the United States Pharmacopeia (USP) (2018), provide descriptions of specific pharmaceutical active ingredients and pharma- ceutically acceptable salts thereof that are suitable for use with the dissolvable films described herein.

[0028] As used herein, the term "surfactant" refers to a substance that reduces the surface tension (or interfacial tension) between two liquids, between a gas and a liquid, or between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsifiers, foaming agents, or dispersing agents. Surfactants may be anionic, cationic, zwitterionic, or nonionic.

[0029] The term "solvent" refers to a substance that dissolves a solute to provide a solution. In the mouth-dissolving films described herein, the solute may include, for example, a film-forming polymer, an active ingredient, and excipients, such as plasticizers, sweeteners, flavorings, binders, preservatives, colorants, and pH adjusters. In addition, in the mouth-dissolving films described herein, the slurry may be a solution. Thus, a solvent is used to form a slurry by dissolving the desired substances to be included in the slurry (and then the mouth-dissolving film). The solvent may be an aqueous solvent, thereby including water. Alternatively, the solvent may include an organic liquid, such as ethanol. The water present in the mouth-dissolving films described herein may function as a solvent. In addition, water may further function as a plasticizer, a processing aid, or a combination thereof, as required. The term "solvent" also encompasses "co-solvents," which are substances present with the solvent that aid, facilitate, or enhance the dissolution of the solute to provide a solution (e.g., a slurry). The co-solvent typically includes an organic liquid, such as glycerin, propylene glycol, polyethylene glycol, or combinations thereof.

[0030] As used herein, the term "solvent for a pharmaceutical active ingredient" refers specifically to a solvent as described herein that is capable of dissolving the pharmaceutical active ingredient.

[0031] The term "matrix", "film matrix" or "polymer matrix" refers to a matrix of a film-forming polymer in which an active ingredient is embedded. The polymer matrix can further include additional substances embedded therein in addition to the active ingredient. These can include any one or more of the substances used to form the slurry. The cast slurry is cured to provide a dissolvable film, thus forming a polymer matrix containing the embedded active ingredient (and optionally one or more additional substances). For example, if the slurry contains an active ingredient, a film-forming polymer, a solvent, a binder, and a plasticizer, when cast and cured to provide a dissolvable film, a polymer matrix is ​​formed that can contain each of the active ingredient, the film-forming polymer, the solvent, the binder, and the plasticizer. Alternatively, a polymer matrix containing each of the active ingredient, the film-forming polymer, the binder, and the plasticizer (i.e., no solvent) can be formed.

[0032] The dissolving-in-the-mouth films described herein can include a single film matrix. Alternatively, the dissolving-in-the-mouth films can include multiple (e.g., two, three, four, etc.) film matrices.

[0033] As used herein, the term "lipophilic" refers to the ability of a compound to dissolve in fats, oils, lipids, and non-polar solvents, such as hexane or toluene. Such non-polar solvents are themselves lipophilic (translated as "fat-loving" or "fat-liking"), and the axiom "like dissolves like" generally holds. Thus, lipophilic substances tend to dissolve in other lipophilic substances, while hydrophilic ("water-loving") substances tend to dissolve in water and other hydrophilic substances. Lipophilic, hydrophobic, and non-polar, as the terms are often used interchangeably, can describe the same tendency to participate in London dispersion forces. However, the terms "lipophilic" and "hydrophobic" are not synonymous, as can be seen from silicones and fluorocarbons, which are hydrophobic but not lipophilic.

[0034] As used herein, the term "hydrophobic" is the physical property of a molecule (known as a hydrophobe) that is seemingly repelled from a mass of water. (Strictly speaking, there is no repulsion involved, just a lack of attraction). In contrast, hydrophilic substances are attracted to water. Hydrophobic molecules tend to be non-polar, and therefore prefer other neutral molecules and non-polar solvents. Because water molecules are polar, hydrophobic substances dissolve poorly in them. Hydrophobic molecules in water often cluster together to form micelles. Water on hydrophobic surfaces exhibits high contact angles. Examples of hydrophobic molecules include alkanes, oils, fats, and generally fatty substances. Hydrophobic materials are used for the removal of oil from water, oil spill management, and chemical separation processes to remove non-polar substances from polar compounds. Hydrophobic is often used interchangeably with lipophilic "very soluble in fats". However, these two terms are not synonymous. Hydrophobic substances are usually lipophilic, with exceptions such as silicones and fluorocarbons. The term hydrophobic material comes from the Ancient Greek word "water-fearing," which is composed of the Ancient Greek word "water" and the Ancient Greek word "fear."

[0035] As used herein, the term "oleophobic", sometimes also called lipophobia (from Greek "fat" and "fear"), is a chemical property of a compound that means "fat rejection", literally "fear of fat". An oleophobic compound is a compound that is not soluble in lipids or other non-polar solvents. From another perspective, an oleophobic compound does not absorb fat. "Oleophobic" (from Latin "oil", Greek "oil" and "fear") refers to the physical property of a molecule that is seemingly repelled from oil. (Strictly speaking, there is no repulsion involved, it is the lack of attraction). The most common oleophobic substance is water.

[0036] As used herein, the term "hydrophilic" refers to the ability of a compound to dissolve in water. Such polar protic solvents are themselves hydrophilic (translated as "highly soluble in water" or "water-liking"), and the axiom "like dissolves like" generally holds true. Thus, hydrophilic substances tend to dissolve in water and other hydrophilic substances.

[0037] As used herein, the term "lipophilic or hydrophobic" refers to a substance that is (i) lipophilic, (ii) hydrophobic, or (iii) both lipophilic and hydrophobic.

[0038] As used herein, the term "oleophobic or hydrophilic" refers to a material that is (i) oleophobic, (ii) hydrophilic, or (iii) both oleophobic and hydrophilic.

[0039] As used herein, the term "cannabinoid" refers to a class of diverse compounds that act on cannabinoid receptors on cells to inhibit the release of neurotransmitters in the brain. These receptor proteins include endocannabinoids (naturally produced in the body by humans and animals), phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (chemically manufactured). The most notable cannabinoid is the phytocannabinoid Δ9-tetrahydrocannabinol (THC), which is the main psychoactive compound in cannabis. Cannabidiol (CBD) is another major constituent of the plant, making up to 40% of the plant's resin extract. There are at least 85 different cannabinoids that have been isolated from cannabis, which exhibit diverse effects. Cannabinoids can be synthetically prepared (or bio-synthesized) or alternatively obtained naturally (e.g., from plant material). In either case, the cannabinoids can have the required purity. For example, when sold as a nutritional or dietary supplement, the cannabinoid may have a purity of at least 80 wt%, at least 85 wt%, or at least 90 wt%. Additionally, when sold as a pharmaceutical product, the cannabinoid may have a purity of at least 95 wt%, at least 98 wt%, at least 99 wt%, or at least 99.5 wt%. [Table 1-1] [Table 1-2] [Table 1-3] [Table 2-1] [Table 2-2]

[0040] Commercially available, synthetically prepared cannabinoids (e.g., Purisys™, Athens, GA) are provided below. [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0041] As used herein, the term "terpene" refers to a hydrocarbon or derivative thereof found as a natural product and biosynthesized by oligomerization of isoprene units. Terpenes can be acyclic, monocyclic, bicyclic, or polycyclic. Examples include, for example, sesquiterpenes (e.g., (-)-β-caryophyllene, humulene, vetivezulene, guaiazulene, longifolene, copaene, and patchoulol), monoterpenes (e.g., limonene and pulegone), monoterpenoids (e.g., carvone), diterpenes (e.g., taxadiene), and triterpenes (e.g., squalene, betulin, betulinic acid, lupane, lupeol, betulin-3-caffeate, allobetulin, and cholesterol). Terpenes can be synthetically prepared (or biosynthesized) or, alternatively, obtained naturally (e.g., from plant material). In any case, the terpenes can have the required purity. For example, when sold as a nutritional or dietary supplement, the terpene may have a purity of at least 80 wt%, at least 85 wt%, or at least 90 wt%. Additionally, when sold as a pharmaceutical product, the terpene may have a purity of at least 95 wt%, at least 98 wt%, at least 99 wt%, or at least 99.5 wt%. [Table 8-1] [Table 8-2] [Table 8-3]

[0042] Commercially available, synthetically prepared terpenes (eg, Purisys™, Athens, GA) are provided below. [Table 9]

[0043] As used herein, the term "flavonoid" refers to a wide variety of plant natural products with various polyphenolic structures. Flavonoids can be extracted from fruits, vegetables, grains, bark, roots, stems, flowers and tea leaves, or produced by biosynthesis. The role of flavonoids in plants includes UV protection, aiding plant growth, defense against mottle, and providing flower color and fragrance.

[0044] Flavonoids can be divided into several classes (e.g., anthocyanins, chalcones, flavones, flavonols, isoflavones, and flavonones) and several subclasses, depending on the carbon in the C ring to which the B ring is attached and the degree of unsaturation and oxidation of the C ring. [ka] [Table 10] [Table 11]

[0045] Research on flavonoids has revealed an increasing number of health benefits exhibiting antioxidant, anti-inflammatory, antimutagenic, and anti-carcinogenic properties by inhibiting a number of pro-inflammatory and pro-oxidant enzymes (e.g., xanthine oxidase (XO), cyclo-oxygenase (COS), lipoxygenase, phosphoinositide 3-kinase, and acetylcholinesterase). This can have benefits against a number of diseases and conditions (e.g., pain, cancer, arthersclerosis, Alzheimer's disease). There is growing interest in the medicinal properties of cannabis (Cannabis sativa, Cannabis indica, Cannabis ruderalis). Studies have shown that the prenylated flavones Cannaflavin A and Cannaflavin B have anti-inflammatory properties that exceed those of aspirin. Cannaflavin A and B can be isolated from Cannabis sativa and biosynthesized. A recent report showed that the flavonoid FBL-03G was shown to increase the survival rate of subjects suffering from pancreatic cancer.

[0046] Commercially available, synthetically prepared flavonoids (eg, Cannflavin B from Toronto Research Chemicals) are provided below. [Table 12]

[0047] Flavonoids can be synthetically prepared or alternatively obtained naturally (e.g., from plant material). In either case, the flavonoids can have a required purity (e.g., at least 95 wt% pure, at least 98 wt% pure, at least 99 wt% pure, or at least 99.5 wt% pure).

[0048] As used herein, the term "pharmacologically acceptable" refers to compounds, counterions, salts, excipients, active ingredients, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / loss ratio. This can include, for example, substances present in the FDA's Inactive Ingredients Database (IID) (https: / / www.accessdata.fda.gov / scripts / cder / iig / index.Cfm) and substances considered to be Generally Recognized as Safe (GRAS).

[0049] As used herein, the term "psychedelic agent" or "psychedelic" refers to the hallucinogenic class of psychoactive drugs whose primary effect is to induce unusual states of consciousness (known as hallucinatory experiences or "trips") through serotonin 2A receptor agonism. This causes certain psychological, visual and auditory changes, and often substantial alterations of the state of consciousness. "Classical" hallucinogenic drugs include mescaline, LSD, psilocybin, and DMT. Most hallucinogenic drugs fall into one of three families of compounds: tryptamines, phenethylamines, or lysergamides. These chemicals all activate the serotonin 5-HT2A receptor, which modulates the activity of critical circuits in the brain involved in sensory perception and cognition, but the exact nature of how hallucinogens induce changes in perception and cognition through the 5-HT2A receptor is unknown. Hallucinatory experiences are often compared to unusual forms of consciousness, such as meditative experiences, mystical experiences, and near-death experiences. The phenomenon of ego disintegration is often described as a very important feature of hallucinatory experiences. Examples include: · LSD (lysergic acid diethylamide, also known as lysergic acid diethylamic acid) is made from a substance found in ergot, a fungus that infects rye. · Psilocin is a naturally occurring substance found in psilocybin-containing mushrooms and is found in many places around the world. Mescaline is derived from the Mexican peyote and San Pedro cacti and provides effects similar to LSD. DMT (dimethyltryptamine) is structurally similar to psilocin, an alkaloid found in psilocybin-containing mushrooms. DMT can be synthesized in the laboratory but is also a naturally occurring component of several plants. ·DOM is a member of the DOx family of compounds known for their high potency, long duration of action, and mixed hallucinogenic and stimulant effects. 2C-B (4-bromo-2,5-dimethoxyphenethylamine) is a hallucinogenic drug first synthesized in 1974. 2C-B is considered both a hallucinogen and a mild entactogenic. "Entactogen" means "touching within" and is the term used by psychiatrists to classify MDMA and related drugs. Peyote (Lophophora williamsii) is the smallest, slowest growing, yet most well-known potent hallucinogenic cactus. Rather than growing upward to form a cylinder, it grows low to the ground like "buttons". Peyote has been used by Native Americans for 5000 years. 25-NBOMe (N-methoxybenzyl) is the name of a series of drugs that have hallucinogenic effects. Reports indicate that there are several different forms of NBOMe available, all with different effects. Ecstasy (alternatively known as Molly or MDMA) is 3,4-methylenedioxymethamphetamine. Ecstasy is a laboratory-created drug that provides a "high" similar to the stimulants called amphetamines. Ecstasy also provides hallucinogenic effects similar to the hallucinogens mescaline and LSD.

[0050] The term "unit dose" or "unit dosage form" refers to an orally dissolvable film that has been sized to an appropriate size such that each individual film contains a desired amount of active ingredient. Prior to being sized to an appropriate size (thereby providing a unit dosage form), the dissolvable film can be in either an unrolled form (e.g., a sheet) or a rolled form (e.g., a bulk roll).

[0051] The term "plasticizer" refers to a substance that, when added to a polymer, makes the polymer more flexible and soft, enhancing the flexibility and pliability of the film while reducing brittleness. Plasticizers are believed to penetrate the polymer structure, disrupt intramolecular hydrogen bonds, and permanently lower the intermolecular attractions. Plasticizers can be used to enable initial film formation, reduce brittleness, and improve the processability and flexibility of the resulting film, thereby avoiding cracking, for example, during the curing process. Suitable plasticizers include, for example, glycerin, water, polyethylene glycol, honey, propylene glycol, monoacetin, triacetin, triethyl citrate, sorbitol, 1,3-butanediol, D-glucono-1,5-lactone, diethylene glycol, castor oil, and combinations thereof.

[0052] As used herein, the term "antimicrobial agent" refers to an agent that kills or prevents the growth of microorganisms.

[0053] As used herein, the term "self-emulsifying" refers to the ability of the dissolvable films described herein to form an emulsion after being contacted with an oral mucosal surface (e.g., when placed in the oral cavity) for oral (PO), buccal, sublingual, enteral, or gingival administration. The emulsion may be formed, for example, within 120 seconds, 90 seconds, 60 seconds, or 30 seconds of contacting the oral mucosal surface.

[0054] As used herein, the term "subject" refers to an organism, such as humans, dogs, cats, and other mammals. The administration of the medicament contained in the oral dissolving film of the present invention can be performed in an amount and for a period of time effective to treat the subject. In some embodiments, the subject is a human. Unless otherwise specified, the human subject can be male or female, and can be an adult, adolescent, child, infant, or toddler.

[0055] The term "particle size distribution" or "PSD" refers to a list of values ​​or a mathematical function that defines the relative amount, typically by mass, of particles present according to size. For example, the mass median diameter (MMD) (e.g., expressed as d10, d50, d90, etc.) refers to the mass median diameter of a log-normal distribution. The MMD is considered to be the average particle size by mass. Particle size distributions can be obtained using a Malvern Mastersizer.

[0056] Particle size distribution D10 (or d10) is also written as X10, D(0.1) or X(0.1). It represents the particle size corresponding to the 10% cumulative (0-100%) undersieve particle size distribution. In other words, if the particle size D10 is 7.8um, then 10% of the particles in the sample being tested are smaller than 7.8 micrometers, or the percentage of particles smaller than 7.8 micrometers is 10%. D10 is the representative point in particle size distribution analysis. D10 is also divided into Dv10, Dw10 and Dn10. Dv10 means volume D10, Dw10 is mass D10 and Dn10 is number D10.

[0057] Particle size distribution D50 (or d50) is also written as X50, D(0.5) or X(0.5). It represents the particle size corresponding to the 50% cumulative (0-100%) undersieve particle size distribution. In other words, if the particle size D50 is 7.8um, then 50% of the particles in the sample being tested are smaller than 7.8 micrometers or the percentage of particles smaller than 7.8 micrometers is 50%. D50 is the representative point in particle size distribution analysis. D50 is also divided into Dv50, Dw50 and Dn50. Dv50 means volume D50, Dw50 is mass D50 and Dn50 is number D50.

[0058] Particle size distribution D90 (or d90) is also written as X90, D(0.9) or X(0.9). It represents the particle size corresponding to the 90% cumulative (0-100%) undersieve particle size distribution. In other words, if the particle size D90 is 7.8um, then 90% of the particles in the sample being tested are smaller than 7.8 micrometers, or the percentage of particles smaller than 7.8 micrometers is 90%. D90 is the representative point in particle size distribution analysis. D90 is also divided into Dv90, Dw90 and Dn90. Dv90 means volume D90, Dw90 is mass D90 and Dn90 is number D90.

[0059] As used herein, the term "mucosa" (and the related "mucosa" and "mucosal surfaces") refers to membranes that cover or line various cavities in the body. Mucosa consist of one or more layers of epithelial cells overlying a layer of loose connective tissue. Mucosa are mostly of endodermal origin and are continuous with the skin in various openings of the body, such as the eyes, ears, inside the nose, inside the mouth, lips, vagina, urethral opening, and anus. Some mucosa secrete mucus, a thick, protective fluid. The function of the membrane is to prevent pathogens and dirt from entering the body and to prevent body tissues from dehydrating. Mucosal surfaces specifically include, for example, the oral mucosa, tongue, vaginal mucosa, nasal mucosa, and anal canal.

[0060] As used herein, the term "mucosal" as used herein refers to any route of administration through a mucous membrane or mucosal surface. Examples include, but are not limited to, buccal, sublingual, nasal, intravaginal, and rectal.

[0061] As used herein, the term "buccal administration" refers to a topical administration route in which the drug that is held or applied to the buccal area (in the cheek) diffuses through the oral mucosa (the tissue that covers the mouth) and directly enters the bloodstream.Buccal administration can provide better bioavailability and faster onset of action of some drugs compared to oral administration, since the drug does not pass through the digestive system, thereby avoiding first-pass metabolism.Liver and GI toxicity can also be avoided.

[0062] As used herein, the term "buccal space" (also referred to as buccal space) refers to the fascial space (sometimes referred to as fascial tissue space or tissue space) of the head and neck. The buccal spaces are potential spaces within the cheeks, paired on each side. They are superficial to the buccal muscle and deep to the platysma muscle and skin. The buccal space is part of the subcutaneous space that runs from the head to the toes.

[0063] As used herein, the term "oral cavity" or "mouth" or "buccal cavity" refers to the opening through which many animals ingest food and vocalize. This opening is also a cavity at the upper end of the digestive tract, connected externally by the lips and internally by the pharynx, and which in higher vertebrates contains the tongue and teeth. In human anatomy, the mouth is the beginning of the digestive tract that receives food and produces saliva. The oral mucosa is the mucosal epithelium that lines the inside of the mouth. The mouth consists of two regions: the vestibule and the oral cavity proper. The mouth is normally moist, lined with mucous membrane, and contains teeth. The lips mark the transition from the mucous membrane to the skin that covers most of the body.

[0064] As used herein, the term "oral mucosa" refers to the mucosa lining the inside of the mouth and is composed of stratified squamous epithelium, referred to as the oral epithelium, and an underlying connective tissue, referred to as the lamina propria. The oral mucosa can be divided into three main classifications based on function and histology: (1) masticatory mucosa, which is keratinized stratified squamous epithelium and found on the dorsum of the tongue, the hard palate, and the attached gingiva; (2) non-keratinized stratified squamous epithelium, which is found almost everywhere else in the oral cavity and includes the following covering mucosa: (a) buccal mucosa, which refers to the inner lining of the cheeks and floor of the mouth and is part of the covering mucosa; (b) labial mucosa, which refers to the inner lining of the lips and is part of the covering mucosa; and (c) alveolar mucosa, which refers to the lining between the buccal and labial mucosa. This covering mucosa is smooth, shiny, lighter red in color, rich in blood vessels, and is not connected to the underlying tissue by interpapillary processes (rete pegs); and (3) a specialized mucosa on the dorsal surface of the tongue, specifically in the region of the taste buds above the lingual papillae, which contains nerve endings for general sensory reception and taste perception.

[0065] As used herein, the term "oral mucosal surface" refers to the surface of the oral mucosa.

[0066] As used herein, the term "sublingual administration" is derived from the Latin for "under the tongue" and refers to a pharmacological route of administration in which a substance diffuses into the blood through the sublingual tissue. When a drug comes into contact with the mucous membrane just below the tongue, it is absorbed. The connective tissue just below the epithelium contains numerous capillaries, so the substance then diffuses into the capillaries and enters the venous circulation. In contrast, substances absorbed in the intestine undergo first-pass metabolism in the liver before entering the systemic circulation. Sublingual administration has certain advantages over oral administration. More directly, sublingual administration is often more rapid and only risks the substance being degraded by salivary enzymes before entering the bloodstream, whereas orally administered drugs must survive and pass through the harsh environment of the gastrointestinal tract, which ensures that the drug is at risk of being degraded by either stomach acid or bile, or by enzymes such as monoamine oxidase (MAO). Furthermore, after absorption from the gastrointestinal tract, such drugs must reach the liver, where they may be significantly altered. This is known as the first-pass effect of drug metabolism. Due to the digestive activity of the stomach and intestines, the oral route is not suitable for certain substances.

[0067] As used herein, the term "gingival administration" refers to a pharmacological route of administration in which a substance diffuses into the blood through the tissue of the gums. Gums or gingiva (plural: gingivae) consist of the mucosal tissue that lies over the mandible and maxilla in the mouth.

[0068] As used herein, the term "enteral administration" refers to drug administration via the human gastrointestinal tract. Enteral administration involves the esophagus, stomach, and small and large intestines (i.e., the gastrointestinal tract). Methods of administration include oral and rectal. Enteral administration can be divided into three different classifications depending on the point of entry into the GI tract: oral (by mouth), gastric (through the stomach), and rectal (from the rectum). (Introduction into the stomach involves the use of a tube through the nostrils (NG tube) or a tube in the abdomen that leads directly to the stomach (PEG tube). Rectal administration usually involves a rectal suppository). Enteral medications come in a variety of forms including, for example, tablets that are swallowed, chewed, or dissolved in water, capsules and chewable capsules (having a coating that dissolves in the stomach or intestine where it releases the medication), mouth-soluble films, sustained or extended release tablets and capsules (which release the medication gradually), osmotic delivery systems, powders or granules, and liquid medications or syrups.

[0069] As used herein, the term "oral administration" or "PO" refers to a route of administration where a substance is taken via the mouth. Many medicines are taken orally because they are intended to have a systemic effect that reaches various parts of the body via the bloodstream.

[0070] As used herein, the term "water content" refers to the amount of water contained in the dissolvable film described herein. Water content can include bound water and unbound water. Water content is expressed as a ratio that can range from 0 (completely dry) to the value of the porosity of the dissolvable film in the saturated state. Water content can be given on a volumetric or mass (gravimetric) basis. Typically, water content is expressed as a weight percent (e.g., 10 wt%).

[0071] Moisture content can be measured directly using a drying oven. Other methods for determining the moisture content of a sample include chemical titration (e.g., Karl Fischer titration) to determine the mass loss upon heating (possibly in the presence of an inert gas) or after freeze-drying. The Dean-Stark method is also commonly used. Unless otherwise specified, the loss on drying (LOD) method can be used to calculate the moisture content of the dissolvable films described herein.

[0072] As used herein, the term "disintegrate" refers to a material (e.g., the matrix of an oral dissolvable film) that breaks or falls apart. The material loses cohesion or strength and can break into small pieces. The material breaks apart in saliva when placed in the mouth.

[0073] As used herein, the term "bioavailability" refers to a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. When a drug is administered intravenously, its bioavailability is 100%. However, when a drug is administered via a route other than intravenous, its bioavailability is generally lower than that of intravenous due to intestinal epithelial absorption and first-pass metabolism. Mathematically, bioavailability is therefore equal to the ratio of the area under the plasma drug concentration curve (AUC) versus time for an extravascular formulation compared to the AUC for an intravascular formulation. AUC is utilized because it is proportional to the dose that enters the systemic circulation.

[0074] As used herein, the term "dissolving" refers to a material that is dissolving or being dissolved (e.g., an active ingredient or matrix of an in-mouth dissolving film). When placed in the mouth, the material dissolves in saliva.

[0075] The term "effective amount" is used herein generally to include an amount of an active ingredient present in the orally dissolving film that is effective to treat or prevent a disease, disorder, or condition of a subject as described herein.

[0076] The term "treatment" with respect to a subject refers to the amelioration of at least one symptom of a disease, disorder, or condition in a subject. Treatment includes the cure, improvement, or at least partial amelioration of a disease, disorder, or condition, or any of its symptoms.

[0077] As used herein, "pharmacokinetics", sometimes abbreviated as "PK", refers to the branch of pharmacology dedicated to determining the fate of substances administered to an organism. It seeks to discover the fate of a chemical by analyzing its chemical metabolism from the moment it is administered to the point at which it is completely eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, while pharmacodynamics (PD) is the study of how a drug affects an organism. Together they affect dosing, benefits, and adverse effects together, as seen in the PK / PD model.

[0078] PK therefore refers to the study of the uptake of drugs by the body, the biotransformations that drugs undergo, the distribution of drugs and their metabolites in tissues, and the elimination of drugs and their metabolites from the body over time.

[0079] The following are commonly measured pharmacokinetic criteria: [Table 13]

[0080] As used herein, the term "substrate" refers to the underlying object on which the slurry is cured. Once coated with the slurry, the substrate typically travels through a dryer where the slurry is at least partially cured. Typically, a roll of substrate is placed at an unwinding station and tension is applied to the line. Any suitable substrate can be used, such as polyethylene terephthalate (PET) or siliconized paper. PET is a thermoplastic polymer resin of the polyester family that is used as a substrate when coating and drying products. Similarly, siliconized paper is a stable release paper made of polyethylene on both sides and coated with a silicone polymer on one side that is used as a substrate when coating and drying products.

[0081] As used herein, the term "curing" refers to a chemical process that produces a dissolvable film (as described herein) from a slurry (also described herein). This process can be done by removing the solvent (water), by strengthening or hardening the polymeric material present in the slurry, by crosslinking the polymer chains, etc. The term curing can be used to refer to a process that starts from a liquid (or semi-solid) solution (e.g., a slurry) and results in a solid product (e.g., a dissolvable film). Curing can be induced by heat, radiation, electron beam, or chemical additives. Quoting IUPAC, curing "may or may not require mixing with a chemical hardener." IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by AD McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019-) created by SJ Chalk. ISBN 0-9678550-9-8. https: / / doi.org / 10.1351 / goldbook. Thus, there are two broad classes: (i) curing induced by chemical additives (also called hardeners, curing agents), and (ii) curing in the absence of additives. In between involve mixtures of resins and additives that require an external stimulus (light, heat, radiation) to induce curing.

[0082] As used herein, the term "mucoadhesive" refers to a substance that adheres to a mucosal surface (e.g., oral cavity) upon contact therewith. A mucoadhesive adheres to the mucosa when placed in the oral cavity and in contact with the oral mucosa. A mucoadhesive enhances the adhesion of the composition to the mucosa and promotes the release of active ingredients from the composition, thereby allowing the composition of the oral dissolving film to be in intimate and prolonged contact with the mucosal surface of the subject. The mucoadhesive can be a polymeric compound, such as a cellulose derivative, but can also be a natural gum, alginate, pectin, or similar such polymer. The concentration of the mucoadhesive can be adjusted to alter the length of time the film adheres to the mucosa or to alter the adhesive forces created between the film and the mucosa. Mucoadhesives include, for example, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), polyvinyl alcohol, polyvinylpyrrolidone (povidone), sodium alginate, methylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, carbopol, polycarbophil, carboxyvinyl copolymer, propylene glycol alginate, alginic acid, methyl methacrylate copolymer, tragacanth gum, guar gum, karaya gum, ethylene vinyl acetate, dimethylpolysiloxane, polyoxyalkylene block copolymers, pectin, chitosan, carrageenan, xanthan gum, gellan gum, gum arabic, locust bean gum, and hydroxyethyl methacrylate copolymer.

[0083] As used herein, the term "binder" refers to a substance, typically a polymer, used to hold ingredients together. Binders ensure that an in-mouth dissolving film can be formed with the required mechanical strength. Binders also provide the necessary volume for the small amount of active ingredient present in the dissolving film. The presence of a binder also promotes the formation of a hardened film. Thus, binders include substances that, when present in a cast slurry, effectively provide a hardened film upon hardening. Binders can also be referred to as "film formers" or, more specifically, when the binder is a polymer, as "film-forming polymers." The polymers can be natural or synthetic polymers. Natural polymers include, for example, pullulan, sodium alginate (Na alginate), pectin, gelatin, chitosan, and maltodextrin. Synthetic polymers include, for example, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na), microcrystalline cellulose (MCC), polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), and Kollicoat® (e.g., Kollicoat® Protect or Kollicoat® IR).

[0084] As used herein, the term "filler" or "bulking agent" refers to a substance that adds bulk to a pharmaceutical dosage form, making very few active ingredient components easier for the consumer to ingest. Fillers are added to pharmaceutical dosage forms to aid in the manufacture and stabilization of these products. Fillers bind and stabilize the dosage form. Fillers do not alter or affect the efficacy of the active pharmaceutical ingredient (API). Examples include lactose, glucose, vegetable cellulose, microcrystalline cellulose (MCC), and calcium carbonate.

[0085] As used herein, the term "saliva stimulant" or "saliva stimulant" refers to a substance that can increase the production of saliva and thereby increase saliva flow rate. Suitable saliva stimulants include organic acids (e.g., ascorbic acid and malic acid), parasympathomimetic drugs (e.g., choline esters such as pilocarpine hydrochloride and cholinesterase inhibitors), physostigmine, and other substances (e.g., xylitol, xylitol / sorbitol, and nicotinamide).

[0086] As used herein, the term "stabilizers and thickeners" or "gelling agents" refers to materials used to improve the viscosity and consistency of the slurry before casting. The uniformity of the content of active ingredients is often a requirement for all dosage forms, especially those that contain low doses of highly potent active ingredients. To uniquely meet this requirement, the mouth-dissolving film formulation can contain a uniform dispersion of active ingredients throughout the manufacturing process. Examples of stabilizers and thickeners include, for example, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, agar, carrageenan, locust bean gum, pectin, and gelatin.

[0087] As used herein, the term "flavoring agent" refers to a substance used to impart flavor, for example to improve appeal and acceptability to a subject. The basic tastes are salty, sweet, bitter, sour, and umami. Flavors may be selected from natural and synthetic flavoring substances. An exemplary list of such agents includes volatile oils, synthetic flavor oils, flavor aromatics, oils, liquids, oleoresins, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. Flavoring agents may include, for example, one or more of honey, anise, cherry, mint, peppermint, spearmint, menthol, levomenthol, watermint, gingermint, lemongrass, cardamom, sage, cinnamon, ginger, allspice, clove, eugenol, orange, wintergreen, lemon, lime, tangerine, ginger, and nutmeg. Flavoring agents may be available as solids (e.g., powders), liquids (e.g., oils), or combinations thereof.

[0088] As used herein, the term "taste masking agent" refers to a substance used to mask the unpleasant taste of a substance present in the formulation to improve its appeal and acceptability to subjects. For example, a taste masking agent can refer to a substance used to mask the bitter taste of an active ingredient. In the mouth-dissolving film described herein, the taste masking agent can include, for example, at least one of honey, anise, mint, peppermint, cinnamon, magna sweet, citrus, and fruit (e.g., cherry). In addition to imparting flavor, the flavoring agent can also mask the taste of any unpleasant or bitter substance (e.g., active ingredient) present in the mouth-dissolving film, if necessary. In such an embodiment, the same substance can act as both a flavoring agent and a taste masking agent.

[0089] As used herein, the term "colorant," "coloring agent," or "pigment" refers to a substance that is used to impart color, for example, to improve the attractiveness and acceptability to a subject. Color consistency can be important because it makes it easier for a subject to identify a medicine. In addition, color often improves the aesthetic look and feel of a medicine. By increasing these organoleptic properties, a subject is more likely to adhere to a schedule, and treatment objectives also provide a better outcome to the subject.

[0090] As used herein, the term "release modifier" refers to a substance used to modulate the release of an active ingredient from an orally dissolving film and / or modulate the absorption of an active ingredient when administered to a subject. Modified drug release can be contrasted with immediate release (IR), and includes, for example, extended release (XR) or delayed release (DR).

[0091] As used herein, the term "adjuvant" refers to a substance (eg, a pharmacological or immunological agent) that modulates (eg, enhances) the effect or effectiveness of an active ingredient.

[0092] As used herein, the term "sweetener" or "sweetening agent" refers to a substance that provides a sweet taste. Sweeteners may be natural or artificial. Suitable sweeteners include sugars (e.g., glucose, corn syrup, fructose, and sucrose) and sugar substitutes (e.g., honey, granulated honey, aspartame, neotame, acesulfame potassium (Ace-K), saccharin, sodium saccharin, advantame, sucralose, monk fruit extract (mogrosides), stevia, rebaudioside A, sorbitol, xylitol, and lactitol).

[0093] As used herein, the term "solubilizer and emulsifier" or "emulsifier" refers to a substance that can form or promote an emulsion. With particular reference to the mouth-dissolving films described herein, emulsifiers can promote separation of phases (e.g., aqueous and lipid) while allowing the phases to mix. Suitable emulsifiers include, for example, polysorbate 80, glycerin, propylene glycol, and polyethylene glycol.

[0094] The term "emulsion" refers to a mixture of two or more liquids that are normally immiscible (unmixable or unblendable) due to liquid-liquid phase separation. Two liquids can form different types of emulsions. As an example, oil and water can first form an oil-in-water emulsion, where the oil is the dispersed phase and the water is the continuous phase. They can then form a water-in-oil emulsion, where the water is the dispersed phase and the oil is the continuous phase. Multiple emulsions are also possible, including "water-in-oil-in-water" and "oil-in-water-in-oil" emulsions. Emulsions are liquids and do not exhibit a static internal structure. The droplets dispersed in the continuous phase (sometimes called "dispersion medium") are usually assumed to be statistically distributed to produce roughly spherical droplets. If the molecules are ordered during liquid-liquid phase separation, they form liquid crystals rather than emulsions. Lipids, used by all living organisms, are an example of molecules that can form either emulsions (e.g., spherical micelles, lipoproteins) or liquid crystals (lipid bilayer membranes).

[0095] The droplets may be amorphous, liquid-crystalline, or any mixture thereof. The diameter of the droplets constituting the dispersed phase is usually in the range of approximately 10 nm to 100 μm, i.e., the droplets may exceed the normal acceptable size limit for colloidal particles. Emulsions are called oil / water (o / w) emulsions when the dispersed phase is an organic material and the continuous phase is water or an aqueous solution, and water / oil (w / o) emulsions when the dispersed phase is water or an aqueous solution and the continuous phase is an organic liquid ("oil").

[0096] Two special classes of emulsions, microemulsions and nanoemulsions, with droplet sizes less than 100 nm, appear translucent. This property is due to the fact that light waves are scattered by the droplets only if their size exceeds about one-quarter of the wavelength of the incident light. Since the visible light spectrum consists of wavelengths from 390 to 750 nanometers (nm), if the droplet size in an emulsion is less than about 100 nm, the light can penetrate into the emulsion without being scattered. Translucent nanoemulsions and microemulsions are frequently confused because of their similar appearance. Unlike translucent nanoemulsions, which require specialized equipment to be produced, microemulsions are formed spontaneously by "solubilizing" oil molecules with a mixture of surfactants, cosurfactants, and cosolvents. However, the concentration of surfactant required in microemulsions is several times higher than in translucent nanoemulsions and significantly exceeds the concentration of the dispersed phase. Due to the many undesirable side effects caused by surfactants, their presence is disadvantageous or prohibited in many applications. In addition, the stability of microemulsions is often easily compromised by dilution, heating, or changes in pH level.

[0097] The term "lipid" refers to a group of naturally occurring molecules including fats, waxes, sterols, fat-soluble vitamins (e.g., vitamins A, D, E, and K), monoglycerides, diglycerides, triglycerides, phospholipids, and the like. "Lipid" can also refer to ethoxylated fatty alcohols, such as oleth-10 and laureth-10, and mixtures of ethoxylated mono- and diglycerides, such as PEG-16 macadamia glyceride and PEG-10 sunflower glyceride. The compounds are small molecules that are hydrophobic or amphiphilic. The amphiphilic nature of some lipids allows them to form structures such as vesicles, liposomes, or membranes in aqueous environments. Biological lipids are derived in whole or in part from two distinct types of biochemical subunits or "building blocks", ketoacyl groups and isoprene groups. Using this approach, lipids can be divided into eight categories: fatty acids, glycerolipids, glycerophospholipids, sphingolipids, glycolipids, and polyketides (derived from the condensation of ketoacyl subunits), as well as sterol lipids and prenol lipids (derived from the condensation of isoprene subunits). The term lipid is sometimes used as a synonym for fat, which is a subgroup of lipids called triglycerides. Lipids also encompass fatty acids and their derivatives (including triglycerides, diglycerides, monoglycerides, and phospholipids), as well as other sterol-containing metabolites, such as molecules such as cholesterol. Suitable lipids include, for example, almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, palm oil, rapeseed oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, marula oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, and watermelon seed oil.

[0098] As used herein, the term "fragrance" (alternatively known as odorant or fragrance compound) refers to substances used to impart a desired scent or odor.

[0099] As used herein, the term "pH adjuster" refers to a substance that changes the pH when added to an aqueous solution (e.g., a slurry). For example, the pH adjuster can be an acid that lowers the pH when added to an aqueous solution (e.g., a slurry). Alternatively, the pH adjuster can be a base that raises the pH when added to an aqueous solution (e.g., a slurry). The base can be an organic base (e.g., sodium bicarbonate) or an inorganic base (e.g., sodium hydroxide), and the acid can be at least one of an inorganic acid (e.g., hydrochloric acid) and / or an organic acid (e.g., citric acid, malic acid, tartaric acid, etc.).

[0100] As used herein, the term "buffer" refers to a weak acid or base used to maintain the pH (e.g., acidity or basicity) of a solution (e.g., a slurry) near a selected value after the addition of another acid or base. That is, the function of a buffer is to prevent rapid changes in pH when an acid or base is added to a solution (e.g., a slurry). Buffers have various properties, some are more soluble than others, some are acidic while others are basic. The acid can be an organic acid, a mineral acid, or a combination thereof. Similarly, the base can be an organic base, an inorganic base, or a combination thereof.

[0101] The term "lubricant" or "glidant" refers to a substance added to a formulation (e.g., a slurry) to improve processing characteristics. For example, a lubricant can enhance slurry flow by reducing interparticulate friction. Suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils (e.g., Sterotex, Lubritab, and Cutina), mineral oil, polyethylene glycol 4000-6000 (PEG), sodium lauryl sulfate (SLS), sodium hyaluronate, sucrose esters, stelliesters, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, tributyl citrate, triethyl citrate, acetyl citrate, triacetin, dioctyl adipate, diethyl adipate, di(2-methylethyl) adipate, dihexyl adipate, partial fatty acid esters of sugars, polyethylene glycol fatty acid esters, polyethylene glycol fatty alcohol ethers, polyethylene glycol sorbitan fatty acid esters, 2-ethoxyethanol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, dibutyl tartrate, castor oil, or any combination thereof.

[0102] As used herein, the term "stabilizer" refers to a substance used to prevent the degradation of any one of a number of substances present in the slurry and / or in-mouth dissolving film, which may include any of the active and inactive ingredients (e.g., excipients or additives).

[0103] As used herein, the term "antioxidant" refers to a substance that inhibits or prevents the oxidation of any one of a number of substances present in the slurry and / or the mouth dissolving film. The number of substances can include any of the active and inactive ingredients (e.g., excipients or additives). Examples of antioxidants include, for example, ascorbic acid (vitamin C), vitamin A, alpha-tocopherol (vitamin E), beta-carotene, glutathione, ubiquinol (coenzyme Q), and selenium.

[0104] As used herein, the term "anti-blocking agent" refers to a substance used to prevent the formation of clumps (caking) of powdered or granulated materials. The use of an anti-blocking agent can result in easier flow of the solid powders used to form the slurry. Crystalline solids often caking due to the formation of liquid bridges and subsequent fusion of crystallites. Amorphous materials may caking due to glass transitions and viscosity changes. Polymorphic phase transitions may also induce caking. Examples include, for example, calcium silicate, calcium carbonate, and magnesium carbonate.

[0105] As used herein, the term "humectant" refers to a substance used to keep the slurry and / or the mouth dissolving film moist. A humectant attracts and holds moisture in the nearby air by absorption, drawing water vapor to or under the surface of the mouth dissolving film. This is the opposite use of a hygroscopic material when used as a desiccant used to draw away moisture. A humectant can be used in the mouth dissolving film to increase the solubility of the active ingredient and increase the ability of the active ingredient to penetrate the mucosal surface or its activity time. Examples include, for example, propylene glycol, hexylene glycol, butylene glycol, aloe vera gel, alpha hydroxy acids (e.g., lactic acid), glyceryl triacetate, and sugar alcohols or polyols (e.g., glycerol, sorbitol, xylitol, and maltitol).

[0106] As used herein, the term "penetration enhancer" refers to a substance that, when administered in vivo (e.g., orally), is used to increase the delivery of an active ingredient across a desired body surface (e.g., oral mucosa, e.g., buccal, sublingual, mucosal or gingival, or intestinal surfaces), resulting in increased absorption of the active ingredient.

[0107] As used herein, the term "preservative" refers to a substance that is added to prevent degradation due to microbial growth or undesirable chemical changes.Some typical preservatives used in pharmaceutical formulations include antioxidants, such as vitamin A, vitamin E, vitamin C, vitamin C palmitate, retinyl palmitate, and selenium; amino acids cysteine ​​and methionine; citric acid and sodium citrate; synthetic preservatives, such as parabens methylparaben and propylparaben.In the mouth-dissolving film described herein, preservatives can include, for example, any one or more of sodium benzoate, benzoic acid, sodium nitrite, sodium sorbate, potassium sorbate, and ascorbic acid.

[0108] As used herein, the term "oil" refers to any non-polar chemical that is a viscous liquid at ambient temperature and is hydrophobic (does not mix with water, literally "fears water") and lipophilic (mixes with other oils, literally "dissolves very well in fat"). Oils have a high carbon and hydrogen content, are usually flammable, and are surface active. Most oils are unsaturated lipids that are liquid at room temperature. The general definition of oil includes classes of compounds that may otherwise be unrelated in structure, properties, and use. Oils may be of animal or vegetable origin and may be volatile or non-volatile. Oils are typically used in food (e.g., olive oil).

[0109] As used herein, the term "oil carrier" refers to an oil, as described herein, that is useful as a solvent.

[0110] As used herein, the term "aqueous liquid" refers to a liquid that contains water.

[0111] As used herein, the term "hot air oven" refers to an oven that radiates convection heat.

[0112] The term "convection heat" refers to heat obtained by convection. "Convection" refers to the transfer of heat from one place to another by the movement of a fluid (e.g., a gas, e.g., air). Convection is usually the primary form of heat transfer in liquids and gases. Although convection heat transfer is often discussed as a separate heat transfer method, it involves a combined process of unknown conduction (thermal diffusion) and advection (heat transfer by bulk fluid flow). Two types of convection heat transfer can be distinguished: (1) free or natural convection, and (2) forced convection. The convection heat used in the method of the present invention can include (1) free or natural convection, and / or (2) forced convection.

[0113] Free or natural convection occurs when fluid motion is driven by buoyancy forces resulting from density variations due to thermal temperature variations in the fluid. When a fluid is brought into contact with a hot surface in the absence of an internal source, the fluid molecules separate and scatter, decreasing the density of the fluid. As a result, the fluid is displaced and at the same time the cooler fluid increases in density and sinks. Thus, the warmer volume transfers heat towards the cooler volume of the fluid. Well-known examples are the upward flow of air caused by a fire or a hot object, and the circulation of water in a pot heated from below. In contrast, forced convection occurs when a fluid is forced to flow over a surface by an internal source, such as a fan, by stirring, and by a pump, or by creating artificially induced convection.

[0114] The term "thickness" refers to the distance between the two sides of the mouth-dissolving film. Thickness is the smallest of the three dimensions (length, width, and thickness). Film thickness can be measured by a micrometer screw gauge or a calibrated digital vernier caliper. Thickness can be evaluated at five different locations (four corners and one point at the center) and in certain embodiments can be important to ensure the uniformity of the film thickness, as it can directly relate to the accuracy of the dose distribution in the film.

[0115] The term "mass" refers to a measurement of how much of a substance is present in an object. Mass is a combination of the total number of atoms, the density of the atoms, and the types of atoms in an object. Mass is usually measured in grams (abbreviated as g) or milligrams (abbreviated as mg).

[0116] The term "drug loading" or "loading of active ingredient" refers to the amount of pharmacologic active ingredient present in an orally dissolving film (or slurry). For example, in certain embodiments, an orally dissolving film can have a high drug loading such that the pharmacologic active ingredient is present in a relatively large amount in the film (e.g., greater than 30 wt% of the orally dissolving film).

[0117] The term "density" refers to the mass per unit volume of an object (e.g., a dissolving mouth film). Density is calculated by dividing the mass of an object by the volume of the object. The volume of an object can be described as cubic centimeters or milliliters, since both are equivalent.

[0118] The term "Loss on Drying (LOD)" refers to the weight loss, expressed as a w / w percentage, resulting from the water and / or volatiles that can be released from an object (e.g., a dissolving film in the mouth) under certain conditions. In this technique, a sample of the material (e.g., a dissolving film in the mouth) is weighed, heated in an oven for a suitable time, cooled in a dry atmosphere in a desiccator, and then weighed again. The weight difference is the Loss on Drying (LOD). For example, a dissolving film in the mouth can have a Loss on Drying (LOD) of 10±2 wt%.

[0119] The term "tacky" refers to the tenacity with which the mouth-dissolving film adheres to an attachment (such as a piece of paper) that is compressed in contact with the film.

[0120] The term "tensile strength" refers to the maximum stress applied to the point where a dissolvable-in-mouth film specimen breaks. Tensile strength is calculated by dividing the applied burst load by the cross-sectional area of ​​the dissolvable-in-mouth film as given by the following equation: Tensile strength = breaking load x 100 / film thickness x film width

[0121] The term "percent elongation" refers to the amount of relative increase in length upon application of stress. When stress is applied on a film sample, the film stretches. This is called strain. Strain is essentially the deformation of the film before it breaks due to stress. Strain can be measured by using a Hounsfield universal testing machine. In general, the elongation of a film increases with increasing plasticizer content. Elongation is calculated by the following formula: Elongation % = Increase in film length x 100 / initial film length

[0122] The term "tear resistance" refers to the resistance that a film exhibits when some load or force is applied to a film specimen. Specifically, tear resistance is the maximum force required to tear the specimen. The load applied primarily can be applied at a very slow speed (e.g., 51 mm / min). The units of tear resistance are Newtons or pounds-force.

[0123] The term "Young's modulus" or "elastic modulus" refers to a measure of the stiffness of a dissolvable film. It is expressed as the ratio of applied stress to strain in the region of elastic deformation as follows: Young's modulus = slope x 100 / film thickness x crosshead speed The hard brittle strips demonstrate high tensile strength and Young's modulus with low elongation.

[0124] The term "folding strength" refers to the number of times a film can be folded back without breaking or having any visible cracks. Folding strength gives the brittleness of a film. The method followed to determine the strength value is to repeatedly fold a film specimen in the same place until it breaks or until a visible crack is observed. The number of times a film can be folded back without breaking or having any visible cracks is the calculated folding strength.

[0125] The terms "drug content uniformity," "dosage unit uniformity," or "CU" refer to the degree of uniformity of the amount of drug substance among dosage units and, unless otherwise specified, are defined in USP-NF General Chapter <905> It is described in Uniformity of Dosage Units.

[0126] The preparation of dissolvable-in-the-mouth films can be accomplished by a variety of methods, including (1) casting (e.g., solvent casting or semi-solid casting), (2) extrusion (e.g., hot melt extrusion or solid dispersion), and (3) calendering. These methods of preparing dissolvable-in-the-mouth films are generally well known to those skilled in the art. For example, "Manufacturing Techniques of Orally Dissolving Films," Pharmaceutical Technology, Volume 35, Issue 1 (Jan 02, 2011), "Current Advances in Drug Delivery Through Fast Dissolving / Disintegrating Dosage Forms," ​​Vikas Anand Saharan, pp. 318-356 (39) (2017), A short review on "A novel approach in oral fast dissolving drug delivery system and their patents," MN Siddiqui, G. Garg, PK Sharma, Adv. Biol. Res., 5 (2011), pp. 291-303, "Orally disintegrating films: A modern expansion in drug delivery system," Ifran et al., Saudi Pharmaceutical Journal, Volume 24, Issue 5, pp. 537-546 (September 2016), "Development and characterization of pharmacokinetic parameters of fast-dissolving films containing levocetirizine," DR Choudhary, VA Patel, UK Chhalotiya, HV Patel, AJ Kundawala; Sci. Pharm., 80 (2012), pp.779-787; "Orally disintegrating preparations: recent advancement in formulation and technology," RR Thakur, DS Rathore, S. Narwal; J. Drug Deliv. Therap., 2 (3) (2012), pp. 87-96; "Development of innovative orally fast disintegrating film dosage forms: a review," BP Panda, NS Dey, MEB Rao; Int. J. Pharm. Sci. Nanotechnol., 5 (2012), pp. 1666-1674.

[0127] Across multiple embodiments, the substance present in the mouth dissolving film is characterized by the amount of the substance present therein. This substance can be any one or more of the medicament active ingredient and / or excipient. Unless otherwise expressly stated, the amount of the substance present in the film is based on anhydrous film (e.g., mouth dissolving film that does not contain water). The obvious exception is the amount of water (moisture) present in the dissolving film. As an example, refer to the product illustrated in the table below (amounts calculated for a batch of 100 strips). The dissolving film can be prepared from a slurry in which the active ingredient (CBD isolate) is present at 50 mg (21.66 wt%) per 230.82 mg strip. This can be calculated as follows:

number

[0128] To arrive at this calculation, the mass of the dry weight (anhydrous) of the strip does not include water. This is in contrast to a slurry where the active ingredient (CBD isolate) is present at 6.5 wt%. When arriving at this calculation, water is included in the mass of the slurry. This can be calculated as follows:

number

[0129] The mass of the slurry (769.4 mg) is calculated by adding the mass of the dry (anhydrous) weight of the strip (230.82 mg) to the mass of purified water added to the slurry (538.58 mg). [Table 14]

[0130] As used herein, the term "glyceryl monocaprylate" refers to the compound having the IUPAC name 1,3-dihydroxypropan-2-yl octanoate, CAS number 4228-48-2, chemical formula C 11 H 22 O4, and a molar mass of 218.29 g mol-1. When present in the orally dissolving films described herein, glyceryl monocaprylate can function, at least, as a lipophilic or hydrophobic surfactant.

[0131] As used herein, the term "propylene glycol monocaprylate" refers to the compound having the IUPAC name 2-hydroxypropyl octanoate, CAS number 23794-30-1, 68332-79-6, chemical formula C 11 H 22 O3, and a molar mass of 202.29 g mol-1. When present in the orally dissolving films described herein, propylene glycol monocaprylate can function, at a minimum, as a lipophilic or hydrophobic surfactant.

[0132] As used herein, the term "glyceryl monooleate" refers to glyceryl monooleate, which has the IUPAC name 2,3-dihydroxypropyl (Z)-octadec-9-enoate, CAS numbers 111-03-5, 25496-72-4, 67701-32-0, 37220-82-9, and the chemical formula C 21 H 40O4, and a molar mass of 356.5 g mol-1. When present in the mouth dissolving films described herein, glyceryl monooleate can function, at a minimum, as either a lipophilic or hydrophobic surfactant.

[0133] As used herein, the term "propylene glycol monolaurate" refers to propylene glycol ester having the IUPAC name 2-hydroxypropyl dodecanoate, CAS number 142-55-2, 27194-74-7, chemical formula C 15 H 30 O3, and a molar mass of 258.4 g mol-1. When present in the mouth dissolving films described herein, propylene glycol monolaurate can function, at a minimum, as either a lipophilic or hydrophobic surfactant.

[0134] As used herein, the term "glyceryl caprylate / caprate" refers to glyceryl caprylate, which has the IUPAC name 11-(2,3-dihydroxypropoxycarbonyl)heptadecanoate, CAS number 73398-61-5, chemical formula C 21 H 39 O6, and a molar mass of 387.5 g mol-1. When present in the orally dissolving films described herein, glyceryl caprylate / caprate can function, at a minimum, as a lipophilic or hydrophobic surfactant.

[0135] As used herein, the term "glyceryl monolinoleate" refers to the compound having the IUPAC name 2,3-dihydroxypropyl(9E,12E)-octadeca-9,12-dienoate, CAS number 2277-28-3, and chemical formula C 21 H 38 O4, and a molar mass of 354.52 g mol-1. When present in the mouth dissolving films described herein, glyceryl monolinoleate can function, at least, as a lipophilic or hydrophobic surfactant.

[0136] As used herein, the term "sorbitan monooleate (Span 80)" refers to the compound having the IUPAC name [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl](Z)-octadec-9-enoate, CAS numbers 1338-43-8, 9015-08-1, chemical formula C 24 H 44 O6, and a molar mass of 428.6 g mol-1. When present in the mouth dissolving films described herein, sorbitan monooleate (Span 80) can function at least as a lipophilic or hydrophobic surfactant.

[0137] As used herein, the term "glyceryl dibehenate" refers to glyceryl dibehenate, which has the IUPAC name docosanoic acid; propane-1,2,3-triol, CAS number 99880-64-5, and chemical formula C 25 H 52 O5, and a molar mass of 432.7 g mol-1. When present in the mouth dissolving films described herein, glyceryl dibehenate can function, at least, as a lipophilic or hydrophobic surfactant.

[0138] As used herein, the term "propylene glycol dilaurate" refers to the compound having the IUPAC name 2-dodecanoyloxypropyl dodecanoate, CAS number 22788-19-8, chemical formula C 27 H 52 O4, and a molar mass of 440.7 g mol-1. When present in the mouth dissolving films described herein, propylene glycol dilaurate can function, at least, as a lipophilic or hydrophobic surfactant.

[0139] As used herein, the term "glyceryl tricaprylate / tricaprate" refers to the compound having the IUPAC name 2,3-di(octanoyloxy)propyl octanoate, CAS number 538-23-8, chemical formula C 27 H 50O6, and a molar mass of 470.7 g mol-1. When present in the mouth dissolving films described herein, glyceryl tricaprylate / tricaprate can function, at a minimum, as either a lipophilic or hydrophobic surfactant.

[0140] As used herein, the term "glyceryl tricaprylate / caprate" refers to glyceryl tricaprylate, which has the IUPAC name 11-(2,3-dihydroxypropoxycarbonyl)heptadecanoate, CAS number 73398-61-5, chemical formula C 21 H 39 O6, and a molar mass of 387.5 g mol-1. When present in the mouth dissolving films described herein, glyceryl tricaprylate / caprate can function, at a minimum, as either a lipophilic or hydrophobic surfactant.

[0141] As used herein, the term "decaglyceryl monooleate" has the IUPAC name (Z)-octadec-9-enoic acid; propane-1,2,3-triol; CAS number; chemical formula C 48 H 114 O 32 and a molar mass of 1203.4 g mol-1. When present in the mouth dissolving films described herein, decaglyceryl monooleate can function as at least a lipophilic or hydrophobic surfactant.

[0142] As used herein, the term "decaglyceryl dioleate" has the IUPAC name [2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[2-hydroxy-3-[(Z)-octadec-9-enoyl]oxypropoxy]propoxy]propoxy]propoxy]propoxy]propyl](Z)-octadec-9-enoate, CAS number 33940-99-7, chemical formula C 66 H126 O 23 and a molar mass of 1287.7 g mol-1. When present in the mouth-dissolving films described herein, decaglyceryl dioleate can function, at least, as a lipophilic or hydrophobic surfactant.

[0143] As used herein, the term "oleoyl macrogol glycerides" refers to components obtained from apricot kernel oil. Oleoyl macrogol glycerides include a complex mixture composed of monoglycerides (MG), diglycerides (DG) and triglycerides (TG), as well as monoPEG-6 esters (MPEGE) and diPEG-6 esters (DPEGE) of oleic acid (18:1). When present in the mouth-dissolving films described herein, oleoyl macrogol glycerides can function as at least a lipophilic or hydrophobic surfactant.

[0144] As used herein, the term "lauroyl macrogol glycerides" refers to ingredients derived from corn oil. Lauroyl macrogol glycerides include a complex mixture composed of monoglycerides (MG), diglycerides (DG) and triglycerides (TG), as well as monoPEG-6 esters (MPEGE) and diPEG-6 esters (DPEGE) of linoleic acid (18:2). When present in the mouth-dissolving films described herein, lauroyl macrogol glycerides can function as at least a lipophilic or hydrophobic surfactant.

[0145] As used herein, the term "stearoyl macrogol glycerides" refers to mixtures of mono-, di- and triesters of glycerol and mono- and diesters of polyethylene glycol. The polyethylene glycols used have an average molecular weight between 300 and 4000. They are produced by partial alcoholysis of saturated oils containing primarily triglycerides of stearic acid with polyethylene glycol, by esterification of glycerol and polyethylene glycol with fatty acids, or as mixtures of glycerol esters and ethylene oxide condensates of hydrogenated oils with fatty acids. The hydroxyl value is greater than or equal to 85 percent and less than or equal to 115 percent of the labeled nominal value, and the saponification value is greater than or equal to 90 percent and less than or equal to 110 percent of the labeled nominal value. Stearoyl macrogol glycerides may contain free polyethylene glycol. When present in the mouth-dissolving films described herein, stearoyl macrogol glycerides can function as at least lipophilic or hydrophobic surfactants.

[0146] As used herein, the term "stearoyl polyoxylglycerides" refers to mixtures of mono-, di- and triesters of glycerol and mono- and diesters of polyethylene glycol. The polyethylene glycols used have an average molecular weight between 300 and 4000. They are produced by partial alcoholysis of saturated oils containing primarily triglycerides of stearic acid with polyethylene glycol, by esterification of glycerol and polyethylene glycol with fatty acids, or as mixtures of glycerol esters and ethylene oxide condensates of hydrogenated oils with fatty acids. The hydroxyl value is greater than or equal to 85 percent and less than or equal to 115 percent of the labeled nominal value, and the saponification value is greater than or equal to 90 percent and less than or equal to 110 percent of the labeled nominal value. Stearoyl polyoxylglycerides may contain free polyethylene glycol. When present in the mouth-dissolving films described herein, stearoyl polyoxylglycerides can function at least as lipophilic or hydrophobic surfactants.

[0147] As used herein, the term "polyoxyethylene" refers to the compound having the IUPAC name 1-(2-methoxyethoxy)hexadecane, CAS number, and chemical formula C 19 H 40 O2, and a molar mass of 300.5 g mol-1. When present in the orally dissolvable films described herein, polyoxyethylene can function at least as a lipophilic or hydrophobic surfactant.

[0148] As used herein, the term "caprylic / capric glyceryl" refers to an oily liquid made from palm kernel or coconut oil. Caprylic / capric glyceryl includes mixed esters made up of caprylic and capric fatty acids attached to a glycerin backbone. Caprylic / capric glyceryl is made primarily from triglycerides whose fatty acids are chains of carbon atoms ranging from 6-12, in this case the esters are made up of capric acid (10 carbon atoms) and caprylic acid (8 carbon atoms). Caprylic / capric glyceryl occurs naturally at low levels in coconut and palm kernel oils. Caprylic / capric glyceryl can also be obtained when the oil is separated and the specific fatty acids (capric and caprylic acids) are isolated and recombined with the glycerin backbone to form pure caprylic / capric glyceryl, which is then further refined (bleached and deodorized) using clay, heat and steam. When present in the mouth-dissolving films described herein, caprylic / capric glyceryl can function, at a minimum, as a lipophilic or hydrophobic surfactant.

[0149] As used herein, the term "poloxamer" refers to a block copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), which has amphiphilic characteristics and useful association and adsorption properties resulting therefrom. Poloxamers are used in many applications requiring compound solubilization or stabilization, and also have noteworthy physiological properties, including low toxicity. When present in the mouth-dissolving films described herein, poloxamers can function as at least a lipophobic or hydrophilic surfactant.

[0150] As used herein, the term "polyoxyl castor oil" refers to a mixture of triricinoleic acid esters of ethoxylated glycerol with small amounts of polyethylene glycol (macrogol) ricinoleate and the corresponding free glycols. When present in the mouth-dissolving films described herein, polyoxyl castor oil can function at least as a lipophobic or hydrophilic surfactant.

[0151] As used herein, the term "polyethylene-polypropylene glycol" refers to a non-ionic polyoxyethylene-polyoxypropylene copolymer that is primarily used as an emulsifier or solubilizer. The polyoxyethylene segments are hydrophilic, while the polyoxypropylene segments are hydrophobic. Polyethylene-polypropylene glycols are chemically similar in composition, differing only in the relative amounts of propylene oxide and ethylene oxide added during manufacture. Their physical and surface active properties vary over a wide range. When present in the mouth-dissolving films described herein, polyethylene-polypropylene glycols can function at least as lipophobic or hydrophilic surfactants.

[0152] As used herein, the term "polyoxyethylene sorbitan monolaurate (Tween® 20)" refers to a polysorbate-type nonionic surfactant formed by the ethoxylation of sorbitan followed by the addition of lauric acid. Due to its stability and relative non-toxicity, it is used as a cleaning agent and emulsifier in several scientific applications. When present in the mouth-dissolving films described herein, polyoxyethylene sorbitan monolaurate (Tween 20) can function as at least a lipophobic or hydrophilic surfactant.

[0153] As used herein, the term "Tween 80" refers to a polysorbate-type nonionic surfactant formed by the ethoxylation of sorbitan followed by the addition of lauric acid. Due to its stability and relative non-toxicity, it is used as a cleaning agent and emulsifier in several scientific applications. When present in the mouth-dissolving films described herein, Tween 80 can function as at least a lipophobic or hydrophilic surfactant.

[0154] As used herein, the term "polyoxyethylene sorbitan monostearate (Tween 60)" refers to a polysorbate-type nonionic surfactant formed by the ethoxylation of sorbitan followed by the addition of lauric acid. Due to its stability and relative non-toxicity, it is used as a cleaning agent and emulsifier in several scientific applications. When present in the mouth-dissolving films described herein, polyoxyethylene sorbitan monostearate (Tween 60) can function as at least a lipophobic or hydrophilic surfactant.

[0155] As used herein, the term "decyl glucoside" refers to the compound having the IUPAC name (3R,4S,5S,6R)-2-decoxy-6-(hydroxymethyl)oxane-3,4,5-triol, CAS numbers 54549-25-6, 68515-73-1, and chemical formula C 16 H 32 O6, and a molar mass of 320.42 g mol-1. When present in the orally dissolving films described herein, decyl glucoside can function, at least, as either a lipophobic or hydrophilic surfactant.

[0156] As used herein, the term "lauryl glucoside" refers to the compound having the IUPAC name (2R,3R,4S,5S,6R)-2-dodecoxy-6-(hydroxymethyl)oxane-3,4,5-triol, CAS number 59122-55-3, and chemical formula C 18 H 36O6, and a molar mass of 348.5 g mol-1. When present in the orally dissolving films described herein, lauryl glucoside can function, at least, as a lipophobic or hydrophilic surfactant.

[0157] As used herein, the term "octylglucoside" refers to the compound having the IUPAC name 2-(hydroxymethyl)-6-octoxyoxane-3,4,5-triol, CAS number 4742-80-7, and chemical formula C 14 H 28 O6, and a molar mass of 292.37 g mol-1. When present in the orally dissolving films described herein, octylglucoside can function, at least, as either a lipophobic or hydrophilic surfactant.

[0158] As used herein, the term "Triton X-100" refers to a non-ionic surfactant having a hydrophilic polyethylene oxide chain (having an average of 9.5 ethylene oxide units) and a lipophilic or hydrophobic aromatic hydrocarbon group. The hydrocarbon group is a 4-(1,1,3,3-tetramethylbutyl)-phenyl group. This material has the IUPAC name 2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol, CAS numbers 2315-67-5, 63869-93-2, 9002-93-1, and the chemical formula C 16 H 26 O2, and a molar mass of 250.38 g mol-1. When present in the mouth dissolving films described herein, Triton X-100 can function, at least, as either a lipophobic or a hydrophilic surfactant.

[0159] As used herein, the term "nonoxynol 9" (sometimes abbreviated as N-9) refers to ethanol, having the IUPAC name 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(4-nonylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol, CAS numbers 26571-11-9, 26027-38-3, 14409-72-4, and chemical formula C33 H 60 O 10 , and a molar mass of 616.8 g mol-1. When present in the mouth-dissolving films described herein, nonoxynol 9 can function, at a minimum, as either an oleophobic or hydrophilic surfactant.

[0160] As used herein, the term "sodium lauryl sulfate" refers to sodium dodecyl sulfate, IUPAC name, CAS numbers 151-21-3, 1335-72-4, 8012-56-4, chemical formula NaSO4C 12 H 25 or C 12 H 25 O4S.Na or C 12 H 25 NaO4S, and refers to a substance having a molar mass of 288.38 g mol-1. When present in the mouth dissolving films described herein, sodium lauryl sulfate can function, at least, as either an oleophobic or hydrophilic surfactant.

[0161] As used herein, the term "potassium lauryl sulfate" refers to potassium dodecyl sulfate, IUPAC name, CAS number 4706-78-9, chemical formula C 12 H 25 K04S, and a molar mass of 304.49 g mol-1. When present in the orally dissolving films described herein, potassium lauryl sulfate can function as at least a lipophobic or hydrophilic surfactant.

[0162] As used herein, the term "Brij" or "Brij®" refers to a family of non-ionic surfactants. Suitable Brij surfactants include, for example, Brij 78 (C 18 H 37 E 20 ), Brij 98(C 18 H 35 E 20 ) and Brij 700(C 18 H 37E 100 ), where E represents the OCH2CH2 unit of the poly(ethylene oxide) chain. Additional Brij surfactants include, for example, Brij 23, Brij 30, Brij 35, Brij® S20, Brij® O20, Brij® O10, Brij® C10, Brij® C20, Brij® L4, Brij® S2, Brij® S20 and other Brij® products. Specific polyoxyethylene alkyl ethers include Brij® L4 and Brij® S20. Brij® products are commercially available from Sigma-Aldrich (St. Louis, MO) and Croda (East Yorkshire, UK). When present in the mouth-dissolving films described herein, Brij can function as at least an oleophobic or hydrophilic surfactant.

[0163] As used herein, the term "glyceryl laurate" refers to the compound having the IUPAC name 1,3-diacetyloxypropan-2-ylundecanoate, CAS number 120602-37-1, and chemical formula C 18 H 32 O6, and a molar mass of 344.4 g mol-1. When present in the mouth dissolving films described herein, glyceryl laurate can function, at least, as a lipophobic or hydrophilic surfactant.

[0164] As used herein, the term "phospholipid" refers to the IUPAC [2-[decyl(hydroxy)phosphoryl]oxy-3-(10-methoxy-10-oxodecoxy)propyl]2-(trimethylazaniumyl)ethyl phosphate, CAS number, chemical formula C 29 H 61 NO 10P2, and a molar mass of 645.7 g·mol-1, or a derivative thereof. When present in the mouth dissolving films described herein, the phospholipids can function, at least, as either lipophobic or hydrophilic surfactants.

[0165] As used herein, the term "n-dodecylphosphocholine" refers to the compound having the IUPAC name dodecyl 2-(trimethylazaniumyl)ethyl phosphate, CAS number 29557-51-5, and chemical formula C 17 H 38 NO4P, and refers to a substance having a molar mass of 351.5 g mol-1. When present in the orally dissolving films described herein, n-dodecylphosphocholine can function, at least, as a lipophobic or hydrophilic surfactant.

[0166] As used herein, the term "cholesteryl ester" refers to the compound having the IUPAC name [(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl](Z)-heptadec-9-enoate, CAS number, chemical formula C 44 H 76 O2, and materials such as the 17:1 cholesteryl ester having a molar mass of 637.1 g mol-1, or derivatives thereof, including but not limited to, 17:0, 15:0, 22:4, 20:3, and 22:3 cholesteryl esters. When present in the mouth dissolving films described herein, the cholesteryl esters can function at least as lipophobic or hydrophilic surfactants.

[0167] As used herein, the term "medium chain triglyceride oil" refers to a material having triglycerides with 2-3 fatty acids with an aliphatic end of 6-12 carbon atoms. Medium chain triglyceride oils include, but are not limited to, fatty acids such as hexanoic or caproic acid, octanoic or caprylic acid, decanoic or capric acid, dodecanoic or lauric acid. When present in the mouth-dissolving films described herein, medium chain triglyceride oils can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for active ingredients.

[0168] As used herein, the term "coconut oil" refers to the oil having the IUPAC name (1-decanoyloxy-3-octanoyloxypropan-2-yl) dodecanoate, CAS number 68991-68-4, chemical formula C 33 H 62 O6, and a molar mass of 554.8 g mol-1. When present in the mouth-dissolving films described herein, coconut oil can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredients.

[0169] As used herein, the term "corn oil" refers to materials extracted from the germ of corn and physically modified derivatives thereof. Corn oil includes, but is not limited to, the glycerides of the fatty acids linoleic, oleic, palmitic and stearic acids, having the IUPAC name, CAS number 8001-30-7, chemical formula, and molar mass g·mol-1. When present in the mouth-dissolving films described herein, corn oil can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for active ingredients.

[0170] As used herein, the term "olive oil" refers to an oil having the IUPAC names hexadecanoic acid; (9Z,12Z)-octadeca-9,12-dienoic acid; octadecanoic acid; (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid; (Z)-octadec-9-enoic acid, CAS number 92044-96-7, chemical formula C 88 H 164 O 10 , and a molar mass of 1382.2 g mol-1. When present in the mouth-dissolving films described herein, olive oil can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredients.

[0171] As used herein, the term "palm oil" refers to palm oil, which has the IUPAC name 1-hydroxypropane-2-oleate; 3-oxododecanoic acid; CAS number 91052-70-9, chemical formula C 15 H 29 O5 - and a molar mass of 289.39 g mol-1. When present in the mouth-dissolving films described herein, palm oil can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredients.

[0172] As used herein, the term "canola oil" refers to a material derived from various rapeseeds that is low in erucic acid. Canola oil includes oils produced from the seeds of any of several cultivars of the Brassica family. For example, canola oil includes oils extracted from the seeds of Brassica napus, Brassica rapa, or Brassica juncea, which contain less than 2% erucic acid in their fatty acid profile, and the solid components contain less than 30 micromoles of any one of 3-butenyl glucosinolate, 4-pentenyl glucosinolate, 2-hydroxy-3butenyl glucosinolate, and 2-hydroxy-4-pentenyl glucosinolate, or any mixture thereof, per gram of oil-free air-dried solids. When present in the mouth-dissolving film described herein, canola oil can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for active ingredients.

[0173] As used herein, the term "safflower oil" refers to a material extracted from the seeds of the safflower plant. When present in the mouth-dissolving films described herein, safflower oil can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for active ingredients.

[0174] As used herein, the term "sesame oil" refers to a material extracted from sesame seeds. When present in the mouth-dissolving films described herein, sesame oil can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for active ingredients.

[0175] As used herein, the term "propylene glycol monocaprylate" refers to the compound having the IUPAC name 2-hydroxypropyl octanoate, CAS number 23794-30-1, 68332-79-6, chemical formula C 11 H 22O3, and a molar mass of 202.29 g mol-1. When present in the orally dissolving films described herein, propylene glycol monocaprylate can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredient.

[0176] As used herein, the term "propylene glycol monolaurate" refers to propylene glycol ester having the IUPAC name 2-hydroxypropyl dodecanoate, CAS number 142-55-2, 27194-74-7, chemical formula C 15 H 30 O3, and a molar mass of 258.4 g mol-1. When present in the orally dissolving films described herein, propylene glycol monolaurate can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredient.

[0177] As used herein, the term "glyceryl monolinoleate" refers to the compound having the IUPAC name 2,3-dihydroxypropyl(9E,12E)-octadeca-9,12-dienoate, CAS number 2277-28-3, and chemical formula C 21 H 38 O4, and a molar mass of 354.5 g mol-1. When present in the mouth-dissolving films described herein, glyceryl monolinoleate can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredient.

[0178] As used herein, the term "cetyl alcohol" refers to the compound having the IUPAC name hexadecan-1-ol, CAS number 2277-28-3, and chemical formula C 16 H 34 O, and a molar mass of 242.44 g mol-1. When present in the mouth-dissolving films described herein, cetyl alcohol can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredients.

[0179] As used herein, the term "stearyl alcohol" refers to the compound having the IUPAC name octadecan-1-ol, CAS number 112-92-5, 68911-61-5, and chemical formula C 18 H 38 O, and a molar mass of 270.5 g mol-1. When present in the mouth-dissolving films described herein, stearyl alcohol can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredient.

[0180] As used herein, the term "cetostearyl alcohol" refers to the compound having the IUPAC name hexadecan-1-ol; octadecane-1-ol, CAS number 67762-27-0, chemical formula C 34 H 72 O2, and a molar mass of 512.9 g mol-1. When present in the mouth-dissolving films described herein, cetostearyl alcohol can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredient.

[0181] As used herein, the term "oleyl alcohol" refers to the IUPAC name (Z)-octadec-9-en-1-ol, CAS number 143-28-2, chemical formula C 18 H 36 O, and a molar mass of 268.5 g mol-1. When present in the orally dissolvable films described herein, oleyl alcohol can function at least as an oil carrier or as a lipophilic or hydrophobic solvent for the active ingredient.

[0182] As used herein, the term "cyclosporine" refers to cyclosporine, which has the IUPAC name 30-ethyl-33-[(E)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecaone, CAS number 59865-13-3, and chemical formula C 62 H 111 N 11 O 12 and a molar mass of 1202.6 g mol-1. When present in the orally dissolving films described herein, cyclosporine can function at least as a pharmaceutical active ingredient.

[0183] As used herein, the term “ritonavir” has the IUPAC name 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate, CAS number 155213-67-5, chemical formula C 37 H 48 N6O5S2, and a substance having a molar mass of 875.106 g mol-1. When present in the orally dissolving films described herein, ritonavir can function, at least, as an active pharmaceutical ingredient.

[0184] As used herein, the term "saquinavir" refers to the compound of formula C, which has the IUPAC name (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinoline-2-carbonylamino)butanediamide, CAS number 127779-20-8, and chemical formula C38 H 50 N6O5, and a substance having a molar mass of 670.8 g mol-1. When present in the orally dissolving films described herein, saquinavir can function, at least, as an active pharmaceutical ingredient.

[0185] As used herein, the term "amprenavir" refers to the compound having the IUPAC name [(3S)-oxolan-3-yl]N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate, CAS number 161814-49-9, chemical formula C 25 H 35 N3O6S, and refers to a substance having a molar mass of 505.6 g mol-1. When present in the orally dissolving films described herein, amprenavir can function, at least, as an active pharmaceutical ingredient.

[0186] As used herein, the term "valproic acid" refers to the compound having the IUPAC name 2-propylpentanoic acid, CAS number 99-66-1, chemical formula CH 16 O2, and a molar mass of 144.21 g mol-1. When present in the orally dissolving films described herein, valproic acid can function, at a minimum, as a pharmaceutical active ingredient.

[0187] As used herein, the term "calcitriol" refers to calcitriol, which has the IUPAC name (1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol, CAS number 32222-06-3, chemical formula C 27 H 44 O3, and a molar mass of 416.6 g mol-1. When present in the orally dissolving films described herein, calcitriol can at least function as a pharmaceutical active ingredient.

[0188] As used herein, the term "bexarotene" refers to the compound having the IUPAC name 4-[1-(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)ethenyl]benzoic acid, CAS number 153559-49-0, chemical formula C 24 H 28 O2, and a molar mass of 348.5 g mol-1. When present in the orally dissolving films described herein, bexarotene can at least function as a pharmaceutical active ingredient.

[0189] As used herein, the term "tretinoin" refers to a compound having the IUPAC name (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid, CAS numbers 302-79-4, 4759-48-2, 97950-17-9, and chemical formula C 20 H 28 O2, and a molar mass of 300.4 g mol-1. When present in the orally dissolving films described herein, tretinoin can function, at a minimum, as a pharmaceutical active ingredient.

[0190] As used herein, the term "isotretinoin" refers to isotretinoin having the IUPAC name (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid, CAS numbers 4759-48-2, 97950-17-9, and chemical formula C 20 H 28 O2, and a molar mass of 300.44 g mol-1. When present in the orally dissolving films described herein, isotretinoin can at least function as a pharmaceutical active ingredient.

[0191] As used herein, the term “tipranavir” refers to the compound of the IUPAC name N-[3-[(1R)-1-[(2R)-4-hydroxy-6-oxo-2-(2-phenylethyl)-2-propyl-3H-pyran-5-yl]propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide, CAS number 174484-41-4, and chemical formula C 31 H 33 F3N2O5S, and a molar mass of 602.7 g mol-1. When present in the orally dissolving films described herein, tipranavir can function, at a minimum, as an active pharmaceutical ingredient.

[0192] As used herein, the term "lysergic acid diethylamide (LSD)" refers to the compound having the IUPAC name (6aR,9R)-N,N-diethyl-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide, CAS number 50-37-3, chemical formula C 20 H 25 NO, and a substance having a molar mass of 323.4 g mol-1. When present in the orally dissolving films described herein, lysergic acid diethylamide (LSD) can function, at a minimum, as a pharmaceutical active ingredient.

[0193] As used herein, the term "3,4-methylenedioxymethamphetamine (MDMA)" refers to MDMA, which has the IUPAC name 1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine, CAS number 42542-10-9, chemical formula C 11 H 15 NO2, and a molar mass of 193.24 g mol-1. When present in the orally dissolving films described herein, 3,4-methylenedioxymethamphetamine (MDMA) can function as at least one pharmacoactive ingredient.

[0194] As used herein, the term "N,N-dimethyltryptamine (DMT)" refers to DMT, which has the IUPAC name 2-(1H-indol-3-yl)-N,N-dimethylethanamine, CAS number 61-50-7, chemical formula C 12 H 16 N2, and a molar mass of 188.269 g·mol-1. DMT is a chemical that occurs in many plants and animals and is both a derivative and structural analog of tryptamine. DMT may be consumed as a hallucinogenic drug and has historically been prepared by various cultures for ritual purposes as an entheogen. DMT is a functional and structural analog of other hallucinogenic tryptamines, such as O-acetylpsilocin (4-AcO-DMT), 5-MeO-DMT, psilocybin (4-PO-DMT), psilocin (4-HO-DMT), and bufotenin (5-HO-DMT). The structure of DMT occurs in some important biomolecules, such as serotonin and melatonin, which make them structural analogs of DMT. When present in the orally dissolving films described herein, N,N-dimethyltryptamine (DMT) can function, at least, as a pharmaceutical active ingredient.

[0195] As used herein, the term "psilocybin" refers to psilocybin, which has the IUPAC name [3-(2-dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, CAS number 520-52-5, and chemical formula C 12 H 17Psilocybin refers to a substance with a molar mass of 284.252 g·mol-1 and a N2O4P. Psilocybin is a naturally occurring hallucinogenic prodrug compound produced by over 200 species of fungi. The most potent are members of the genus Psilocybe, such as P. azurescens, P. semilanceata, and P. cyanescens, but psilocybin has also been isolated from about a dozen other genera. As a prodrug, psilocybin is rapidly converted by the body to psilocin, which in some embodiments has psychoactive effects similar to those of LSD, mescaline, and DMT. In general, the effects include euphoria, visual and mental hallucinations, altered perception, a distorted sense of time, and perceived spiritual experiences, and may include possible adverse reactions such as nausea and panic attacks.

[0196] As used herein, the term "mescaline" refers to the compound having the IUPAC name 2-(3,4,5-trimethoxyphenyl)ethanamine, CAS number 54-04-6, and chemical formula C 11 H 17 NO3, and a molar mass of 211.261 g mol-1. Mescaline is a naturally occurring hallucinogenic protoalkaloid of the substituted phenethylamine class known for its hallucinogenic effects comparable to those of LSD and psilocybin. Mescaline occurs naturally in the peyote cactus (Lophophora williamsii), San Pedro cactus (Echinopsis pachanoi), Peruvian torch (Echinopsis peruviana), and other cactus species. It is also found in small amounts in certain members of the legume family Fabaceae, including Acacia berlandieri.

[0197] As used herein, the term "ibogaine" refers to a compound having the IUPAC name 12-methoxyibogamine, CAS number 83-74-9, and chemical formula C 20 H 26N2O, and a substance with a molar mass of 310.441 g mol-1. Ibogaine is a naturally occurring psychoactive substance found in plants of the Apocynaceae family, such as Tabernanthe iboga, Voacanga africana, and Tabernaemontana undulata. Ibogaine is a hallucinogenic substance with dissociative properties.

[0198] As used herein, the term "ivermectin" has the IUPAC name 22,23-dihydroavermectin B 1a +22,23-Dihydroavermectin B 1b , CAS numbers 70288-86-7 and 71827-03-7, chemical formula C 48 H 74 O 14 (22,23-dihydroavermectin B 1a ) and C 47 H 72 O 14 (22,23-dihydroavermectin B 1b ), and a molar mass of 875.106 g mol-1 (22,23-dihydroavermectin B 1a ) and 861.079 g mol-1 (22,23-dihydroavermectin B 1b When present in the orally dissolving films described herein, ivermectin can function at least as a pharmaceutical active ingredient.

[0199] As used herein, the term "propylene glycol" refers to a substance having the IUPAC name propane-1,2-diol, CAS numbers 57-55-6, 25322-68-3, 63625-56-9, chemical formula C3H8O2 or CH3CHOHCH2OH, and molar mass 76.09 g mol-1. When present in the mouth-dissolving films described herein, propylene glycol can function, at least, as a plasticizer.

[0200] As used herein, the term "glycerin" refers to a substance having the IUPAC name propane-1,2,3-triol, CAS numbers 56-81-5, 8043-29-6, 25618-55-7, 8013-25-0, chemical formula C3H8O3 or CH2OH-CHOH-CH2OH, and molar mass 92.09 g mol-1. When present in the mouth-dissolving films described herein, glycerin can function, at least, as a plasticizer.

[0201] As used herein, the term "triacetin" refers to the compound having the IUPAC name 2,3-diacetyloxypropyl acetate, CAS number 102-76-1, chemical formula CH 14 O6 or C3H5(OCOCH3)3, and a molar mass of 218.2 g mol-1. When present in the mouth-dissolving films described herein, triacetin can function, at a minimum, as a plasticizer.

[0202] As used herein, the term "triethyl citrate" refers to the compound having the IUPAC name triethyl 2-hydroxypropane-1,2,3-tricarboxylate, CAS number 77-93-0, and chemical formula C 12 H 20 O7 or (CH2COOC2H5)2COHCOOC2H5, and a molar mass of 276.28 g mol-1. When present in the mouth-dissolving films described herein, triethyl citrate can function, at a minimum, as a plasticizer.

[0203] As used herein, the term "polyethylene glycol" refers to a polymer of material having the IUPAC name ethane-1,2-diol, CAS number 107-21-1, 25322-68-3, chemical formula C2H6O2 or (C2H4O)nH2O (n=number of ethylene oxide units, approximately 140, corresponding to a molecular weight of 6000) or HOCH2CH2OH or CH2OHCH2OH, and a molar mass of 62.07 g mol-1. When present in the mouth-dissolving films described herein, polyethylene glycol can function, at least, as a plasticizer.

[0204] As used herein, the term "pullulan" refers to the compound having the IUPAC name [(2R,3S,4R,5R,6S)-4,5-dihydroxy-3-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-[(2R,3S,4R,5R,6S)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-2-yl]methoxy]oxan-2-yl]methyl hexadecanoate, CAS number 53572-58-0, chemical formula C 40 H 72 O 22 and a molar mass of 905 g mol-1. When present in the mouth-dissolving films described herein, pullulan can function, at least, as a film former.

[0205] As used herein, the term "gum arabic" refers to gum arabic, which has the IUPAC name 17-acetyl-3,7-dihydroxy-4,4,10,13,14-pentamethyl-2,3,5,6,7,12,16,17-octahydro-1H-cyclopenta[a]phenanthrene-11,15-dione, CAS number 97653-92-4, and chemical formula C 24 H 34O5, and a molar mass of 402.5 g mol-1. When present in the mouth-dissolving films described herein, gum arabic can function, at least, as a film former.

[0206] As used herein, the term "guar gum" has the IUPAC name disodium;[[[5-(6-aminopurin-9-yl)-3-hydroxyoxolan-2-yl]oxy-methoxyphosphoryl]oxy-oxidophosphoryl]hydrogen phosphate, CAS number 9000-30-0, chemical formula C 10 H 14 N5Na2O 12 P3, and a molar mass of 535.15 g mol-1. When present in the mouth dissolving films described herein, guar gum can function, at least, as a film former.

[0207] As used herein, the term "maltodextrin" refers to maltodextrin having the IUPAC name (3R,4S,5S,6R)-2-[(2R,3S,4R,5R)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2R,3S,4R,5R,6S)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol, CAS number 9004-53-9, and chemical formula C 18 H 32 O 16 and a molar mass of 504.4 g mol-1. When present in the mouth-dissolving films described herein, maltodextrin can function, at least, as a film former.

[0208] As used herein, the term "microcrystalline cellulose" refers to cellulose having the IUPAC name 2-[4,5-dihydroxy-2-(hydroxymethyl)-6-methoxyoxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol, CAS number 9004-34-6, chemical formula C 14 H26 O 11 and a molar mass of 370.35 g mol-1. When present in the mouth-dissolving films described herein, microcrystalline cellulose can function, at least, as a film former.

[0209] As used herein, the term "chitosan" refers to chitosan having the IUPAC name methyl N-[(2S,3R,4R,5S,6R)-5-[(2S,3R,4R,5S,6R)-3-amino-5-[(2S,3R,4R,5S,6R)-3-amino-5-[(2S,3R,4R,5S,6R)-3-amino-5-[(2S,3R,4R,5S,6R)-3-amino-5-[(2S,3R,4R,5S,6R)-3-amino-5-[(2S,3R,4R,5S,6R)-3-amino-5-[(2S,3R,4R,5S,6R)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4- ... methyl)oxan-2-yl]oxy-4-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2-[(2R,3S,4R,5R,6S)-5-amino-6-[(2R,3S,4R,5R,6R)-5-amino-4,6-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4-hydroxy-6-(hydroxymethyl)oxan-3-yl]carbamate, CAS number 9012-76-4, chemical formula C 56 H 103 N9O 39 and a molar mass of 1526.5 g mol-1. When present in the mouth-dissolving films described herein, chitosan can function, at least, as a film former.

[0210] As used herein, the term "pectin" refers to pectin having the IUPAC name (2S,3R,4S,5R,6R)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid, CAS number 18968-14-4, chemical formula CH 10 O7, and a molar mass of 194.14 g mol-1. When present in the mouth-dissolving films described herein, pectin can function, at least, as a film-forming agent.

[0211] As used herein, the term "carrageenan" refers to the IUPAC name zinc; 1-(5-cyanopyridin-2-yl)-3-[(1S,2S)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea; diacetate, CAS number 9000-07-1, chemical formula C 23 H 23 FN4O7Zn, and a molar mass of 551.8 g mol-1. When present in the mouth-dissolving films described herein, carrageenan can at least function as a film-forming agent.

[0212] As used herein, the term "HPMC" or "hydroxypropyl methylcellulose" or "hypromellose" refers to a semi-synthetic, inert viscoelastic polymer having CAS number 9004-65-3. When present in the mouth-dissolving films described herein, HPMC can function, at least, as a film former.

[0213] As used herein, the term "HPC" or "hydroxypropyl cellulose" refers to cellulose derivatives having the IUPAC name 1-[[(2R,3R,4S,5R)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan-3-yl]oxyoxan-2-yl]methoxy]propan-2-ol or analogs or derivatives thereof, CAS number, chemical formula C 36 H 70 O19 and a molar mass of 806.9 g mol-1. When present in the mouth dissolving films described herein, HPC can function, at least, as a film former.

[0214] As used herein, the term "modified corn starch" refers to corn starch having the IUPAC name 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol or an analog or derivative thereof, a CAS number, a chemical formula C 27 H 48 O 20 and a molar mass of 692.7 g mol-1. When present in the mouth-dissolving films described herein, the modified cornstarch can function, at least, as a film former.

[0215] As used herein, the term "carbopol 974P" refers to a member of the carbomer family, including high molecular weight cross-linked polyacrylic acid polymers or derivative analogs thereof. Carbopols include, but are not limited to, carbopol homopolymers: acrylic acid cross-linked with allyl sucrose or allyl pentaerythritol, carbopol copolymers: acrylic acid cross-linked with allyl pentaerythritol and C10-C30 alkyl acrylates, and carbopol interpolymers: carbomer homopolymers or copolymers containing block copolymers of polyethylene glycol and long chain alkyl acid esters. When present in the mouth-dissolving films described herein, carbopol 974P can function at least as a film former.

[0216] As used herein, the term "carbopol 934P" refers to a member of the carbomer family, including high molecular weight cross-linked polyacrylic acid polymers or derivative analogs thereof. Carbopols include, but are not limited to, carbopol homopolymers: acrylic acid cross-linked with allyl sucrose or allyl pentaerythritol, carbopol copolymers: acrylic acid cross-linked with allyl pentaerythritol and C10-C30 alkyl acrylates, and carbopol interpolymers: carbomer homopolymers or copolymers containing block copolymers of polyethylene glycol and long chain alkyl acid esters. When present in the mouth-dissolving films described herein, carbopol 934P can function at least as a film former.

[0217] As used herein, the term "kollidon 25" refers to a member of the polyvinylpyrrolidone family, including high molecular weight cross-linked polymers or their derivative analogs. When present in the mouth-dissolving films described herein, kollidon 25 can function, at a minimum, as a film former.

[0218] As used herein, the term "soluplus" refers to the compound having the IUPAC name 2-hydroxyethyl 12-hydroxyoctadecanoate or an analog or derivative thereof, CAS number 105109-85-1, 6284-41-9, chemical formula C 20 H 40 O4, and a molar mass of 344.5 g mol-1. When present in the in-mouth dissolving films described herein, soluplus can function, at least, as a film former.

[0219] As used herein, the term "lycoat NG73" refers to a member of the hydroxypropyl bean starch family, e.g., a polymer or an analog or derivative thereof. When present in the mouth-dissolving films described herein, lycoat NG73 can function, at a minimum, as a film former.

[0220] As used herein, the term "Kollicoat" or "Kollicoat®" refers to commercially available products from BASF (Florham Park, NJ). These include, for example, Kollicoat® Protect and Kollicoat® IR. The term "Kollicoat® Protect" refers to a commercial product containing (i) 35-45 wt% polyvinyl alcohol (PVA), (ii) 55-65 wt% polyvinyl alcohol (PVA)-polyethylene glycol (PEG) graft copolymer, and (iii) 0.1-0.3 wt% silicon dioxide. Kollicoat® Protect is a combination of water-soluble Kollicoat® IR and polyvinyl alcohol, where Kollicoat® IR is a polyvinyl alcohol (PVA)-polyethylene glycol (PEG) graft copolymer. The PEG portion of Kollicoat® IR is PEG 6000. Kollicoat® Protect has the chemical name polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol (PVA). Kollicoat® Protect has the CAS numbers: Kollicoat® IR 96734-39-3, polyvinyl alcohol 9002-89-5, and silicon dioxide 7631-86-9. When present in the mouth-dissolving film described herein, the Kollicoat® product can at least function as a film former.

[0221] As used herein, the term "polyox N-10" refers to a compound having the IUPAC name 2-methyloxirane; oxirane or analogs or derivatives thereof, CAS numbers 691397-13-4, 9003-11-6, 106392-12-5, chemical formula CH 10 O2, and a member of the polyoxalene family of polymers of material having a molar mass of 102.13 g mol-1. When present in the mouth-dissolving films described herein, polyox N-10 can function, at a minimum, as a film former.

[0222] As used herein, the term "polyox N-80" refers to a compound having the IUPAC name 2-methyloxirane; oxirane or analogs or derivatives thereof, CAS numbers 691397-13-4, 9003-11-6, 106392-12-5, chemical formula CH 10 O2, and a member of the polyoxalene family of polymers of material having a molar mass of 102.13 g mol-1. When present in the mouth-dissolving films described herein, polyox N-80 can function, at a minimum, as a film former.

[0223] As used herein, the term "polyox N-750" refers to a compound having the IUPAC name 2-methyloxirane; oxirane or analogs or derivatives thereof, CAS numbers 691397-13-4, 9003-11-6, 106392-12-5, chemical formula CH 10 O2, and a member of the polyoxalene family of polymers of material having a molar mass of 102.13 g mol-1. When present in the mouth-dissolving films described herein, polyox N-750 can function, at a minimum, as a film former.

[0224] As used herein, the term "methocel E4M" refers to the compound having the IUPAC name 6-(hydroxymethyl)-5-methoxy-2-[4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxan-3,4-diol or an analog or derivative thereof, CAS number 99638-59-2, chemical formula C 17 H 32 O 11 and a member of the methylcellulose ether family, such as a polymer of material having a molar mass of 412.4 g mol-1. When present in the mouth-dissolving films described herein, methocel E4M can function, at a minimum, as a film former.

[0225] As used herein, the term "methocel E10M" refers to a compound having the IUPAC name 6-(hydroxymethyl)-5-methoxy-2-[4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxan-3,4-diol or an analog or derivative thereof, CAS number 99638-59-2, chemical formula C 17 H 32 O 11 and a member of the methylcellulose ether family, such as a polymer of material having a molar mass of 412.4 g mol-1. When present in the mouth-dissolving films described herein, methocel E10M can function, at a minimum, as a film former.

[0226] As used herein, the term "sodium CMC" or "sodium carboxymethylcellulose" has the IUPAC name Sodium; 2,3,4,5,6-pentahydroxyhexanal; acetate or analogs or derivatives thereof, CAS number 9004-32-4, chemical formula CH 15 NaO8, and a substance having a molar mass of 262.19 g mol-1. When present in the mouth-dissolving films described herein, sodium CMC can function, at a minimum, as a film former.

[0227] As used herein, the term "diethylene glycol monoethyl ether" has the IUPAC name 2-(2-ethoxyethoxy)ethanol, CAS number 111-90-0, chemical formula CH 14 O3 or CH3CH2OCH2CH2OCH2CH2OH, and a molar mass of 134.17 g mol-1. When present in the mouth-dissolving films described herein, diethylene glycol monoethyl ether can function, at a minimum, as a film former.

[0228] As used herein, the term "caprylocapryol polyoxyl-8 glyceride" refers to any of the IUPAC names 2,3-dihydroxypropyl decanoate; 2,3-dihydroxypropyl octanoate or analogs or derivatives thereof, CAS numbers, chemical formula C 24 H 48 O8, and a molar mass of 464.6 g mol-1. When present in the mouth-dissolving films described herein, caprylocaproyl polyoxyl-8 glyceride can function, at least, as a film former.

[0229] Specific Ranges, Values, and Embodiments The specific embodiments setting forth the ranges and values ​​provided below are for illustrative purposes only and do not otherwise limit the scope of the presently disclosed subject matter, as defined by the claims.

[0230] In certain embodiments, the mouth dissolving film comprises a pharmaceutical active ingredient that is lipophilic or hydrophobic.

[0231] In certain embodiments, the mouth dissolving film comprises a pharmaceutical active ingredient that is both lipophilic and hydrophobic.

[0232] In certain embodiments, the mouth dissolving film includes a surfactant that is lipophilic or hydrophobic.

[0233] In certain embodiments, the mouth dissolving film comprises a surfactant that is both lipophilic and hydrophobic.

[0234] In certain embodiments, the mouth dissolving film comprises a solvent for the pharmaceutical active, which solvent is lipophilic or hydrophobic.

[0235] In certain embodiments, the mouth dissolving film comprises a solvent for the pharmaceutical active, which solvent is both lipophilic and hydrophobic.

[0236] In certain embodiments, the mouth dissolving film comprises (1) a pharmaceutical active ingredient, which is lipophilic or hydrophobic, (2) a surfactant, which is lipophilic or hydrophobic, and (3) a solvent, which is lipophilic or hydrophobic.

[0237] In certain embodiments, the mouth dissolving film comprises (1) a pharmaceutical active ingredient that is lipophilic and hydrophobic, (2) a surfactant that is lipophilic and hydrophobic, and (3) a solvent that is lipophilic and hydrophobic.

[0238] In certain embodiments, the mouth-dissolving film comprises a pharmaceutical active ingredient that is lipophobic or hydrophilic.

[0239] In certain embodiments, the mouth-dissolving film comprises a pharmaceutical active ingredient that is both lipophobic and hydrophilic.

[0240] In certain embodiments, the mouth dissolving film comprises a surfactant that is lipophobic or hydrophilic.

[0241] In certain embodiments, the mouth dissolving film comprises a surfactant that is both oleophobic and hydrophilic.

[0242] In certain embodiments, the mouth dissolving film comprises a solvent for the pharmaceutical active, which solvent is oleophobic or hydrophilic.

[0243] In certain embodiments, the mouth dissolving film comprises a solvent for the pharmaceutical active, which solvent is both oleophobic and hydrophilic.

[0244] In certain embodiments, the mouth-dissolving film comprises (1) a pharmacoactive ingredient, which is lipophobic or hydrophilic, (2) a surfactant, which is lipophobic or hydrophilic, and (3) a solvent for the pharmacoactive ingredient, which is lipophobic or hydrophilic.

[0245] In certain embodiments, the mouth-dissolving film comprises (1) a pharmacoactive ingredient that is both lipophobic and hydrophilic, (2) a surfactant that is both lipophobic and hydrophilic, and (3) a solvent for the pharmacoactive ingredient that is both lipophobic and hydrophilic.

[0246] In certain embodiments, the surfactant is lipophilic or hydrophobic and the solvent for the pharmaceutical active ingredient is lipophilic or hydrophobic.

[0247] In certain embodiments, the lipophilic or hydrophobic surfactant comprises at least one of glyceryl monocaprylate, propylene glycol monocaprylate, glyceryl monooleate, propylene glycol monolaurate, glyceryl caprylate / caprate, glyceryl monolinoleate, sorbitan monooleate (Span 80), glyceryl dibehenate, propylene glycol dilaurate, glyceryl tricaprylate / tricaprate, glyceryl tricaprylate / caprate, decaglyceryl mono- and dioleate, oleoyl macrogolglycerides, lauroyl macrogolglycerides, stearoyl macrogolglycerides or stearoyl polyoxylglycerides, and polyoxyethylene glyceryl caprylate / caprate.

[0248] In certain embodiments, the lipophilic or hydrophobic surfactant comprises at least one of glyceryl monocaprylate, propylene glycol monocaprylate, glyceryl monooleate, propylene glycol monolaurate, glyceryl caprylate / caprate, glyceryl monolinoleate, sorbitan monooleate (Span 80), glyceryl dibehenate, propylene glycol dilaurate, glyceryl tricaprylate / tricaprate, glyceryl tricaprylate / caprate, decaglyceryl mono- and dioleate, oleoyl macrogolglycerides, lauroyl macrogolglycerides, stearoyl macrogolglycerides, stearoyl polyoxylglycerides, polyoxyethylene, and glyceryl caprylate / caprate.

[0249] In certain embodiments, the lipophilic or hydrophobic surfactant comprises at least one of glyceryl monocaprylate, propylene glycol monocaprylate, glyceryl monooleate, propylene glycol monolaurate, glyceryl monolinoleate, sorbitan monooleate (Span 80), propylene glycol dilaurate, and decaglyceryl mono- and dioleate.

[0250] In certain embodiments, the lipophilic or hydrophobic surfactant comprises at least one of propylene glycol monocaprylate, glyceryl monooleate, propylene glycol monolaurate, glyceryl monolinoleate, and sorbitan monooleate (Span 80).

[0251] In certain embodiments, the lipophilic or hydrophobic surfactant is present at 0.5-40 wt %.

[0252] In certain embodiments, the lipophilic or hydrophobic surfactant is present at 3-25 wt%.

[0253] In certain embodiments, the lipophilic or hydrophobic surfactant is present at 8-14 wt%.

[0254] In a particular embodiment, the lipophilic or hydrophobic surfactant is present at 11 wt %.

[0255] In certain embodiments, the lipophilic or hydrophobic surfactant comprises one or more of the substances set forth below: In further embodiments, the lipophilic or hydrophobic surfactant comprises one or more of the substances set forth below in the amounts / ranges. [Table 15-1] [Table 15-2]

[0256] In certain embodiments, the surfactant is lipophobic or hydrophilic and the solvent for the pharmaceutical active ingredient is lipophobic or hydrophilic.

[0257] In certain embodiments, the lipophobic or hydrophilic surfactant comprises at least one of poloxamer, polyoxyl castor oil, polyethylene-polypropylene glycol, polyoxyethylene sorbitan monolaurate (Tween 20), Tween 80, polyoxyethylene sorbitan monostearate (Tween 60), decyl glucoside, lauryl glucoside, octyl glucoside, Triton X-100, nonoxynol 9, sodium lauryl sulfate, potassium lauryl sulfate, Brij, glyceryl laurate, phospholipids, n-dodecylphosphocholine, and cholesteryl esters.

[0258] In certain embodiments, the lipophobic or hydrophilic surfactant comprises at least one of poloxamer, polyethylene-polypropylene glycol, polyoxyethylene sorbitan monolaurate (Tween 20), Tween 80, polyoxyethylene sorbitan monostearate (Tween 60), Triton X-100, sodium lauryl sulfate, Brij, phospholipids, n-dodecylphosphocholine, and cholesteryl esters.

[0259] In certain embodiments, the lipophobic or hydrophilic surfactant comprises at least one of a poloxamer, a polyethylene-polypropylene glycol, a polyoxyethylene sorbitan monolaurate (Tween 20), a phospholipid, and n-dodecylphosphocholine.

[0260] In certain embodiments, the lipophobic or hydrophilic surfactant comprises at least one of poloxamer, polyoxyl castor oil, polyethylene-polypropylene glycol, polyoxyethylene sorbitan monolaurate (Tween 20), Tween 80, polyoxyethylene sorbitan monostearate (Tween 60), decyl glucoside, lauryl glucoside, octyl glucoside, Triton X-100, nonoxynol 9, sodium lauryl sulfate, potassium lauryl sulfate, Brij, glyceryl laurate, phospholipids, n-dodecylphosphocholine, and cholesteryl esters.

[0261] In certain embodiments, the lipophobic or hydrophilic surfactant is present at 0.5-40 wt %.

[0262] In certain embodiments, the lipophobic or hydrophilic surfactant is present at 0.5-25 wt %.

[0263] In certain embodiments, the lipophobic or hydrophilic surfactant is present at 3-7 wt%.

[0264] In certain embodiments, the lipophobic or hydrophilic surfactant is present at 5 wt %.

[0265] In certain embodiments, the lipophobic or hydrophilic surfactant comprises one or more of the substances set forth below: In further embodiments, the lipophobic or hydrophilic surfactant comprises one or more of the substances set forth below in the amounts / ranges. [Table 16-1] [Table 16-2]

[0266] In certain embodiments, the lipophilic or hydrophobic solvent for the pharma- ceutical active ingredient comprises at least one of medium chain triglyceride oil, coconut oil, corn oil, olive oil, palm oil, canola oil, safflower oil, sesame oil, propylene glycol monocaprylate, propylene glycol monolaurate, glyceryl monolinoleate, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol.

[0267] In certain embodiments, the lipophilic or hydrophobic solvent for the pharmaceutical active ingredient comprises at least one of medium chain triglyceride oil, coconut oil, olive oil, sesame oil, propylene glycol monocaprylate, propylene glycol monolaurate, and glyceryl monolinoleate.

[0268] In certain embodiments, the lipophilic or hydrophobic solvent for the pharmaceutical active ingredient comprises at least one of medium chain triglyceride oil, olive oil, sesame oil, propylene glycol monocaprylate, propylene glycol monolaurate, and glyceryl monolinoleate.

[0269] In certain embodiments, the lipophilic or hydrophobic solvent for the pharma- ceutical active ingredient comprises at least one of medium chain triglyceride oil, coconut oil, corn oil, olive oil, palm oil, canola oil, safflower oil, sesame oil, propylene glycol monocaprylate, propylene glycol monolaurate, glyceryl monolinoleate, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol.

[0270] In certain embodiments, the lipophilic or hydrophobic solvent for the pharmaceutical active ingredient is present at 0.5-40 wt %.

[0271] In certain embodiments, the lipophilic or hydrophobic solvent for the pharmaceutical active ingredient is present at 3-25 wt %.

[0272] In certain embodiments, the lipophilic or hydrophobic solvent for the pharmaceutical active ingredient is present at 8-14 wt %.

[0273] In certain embodiments, the lipophilic or hydrophobic solvent for the pharmaceutical active ingredient is present at 11 wt %.

[0274] In certain embodiments, the lipophobic or hydrophilic solvent for the pharmaceutical active ingredient comprises water.

[0275] In certain embodiments, the lipophobic or hydrophilic solvent for the pharmaceutical active ingredient is present at 0.5-20 wt %.

[0276] In certain embodiments, the lipophobic or hydrophilic solvent for the pharmaceutical active comprises one or more of the substances set forth below: In further embodiments, the lipophobic or hydrophilic solvent for the pharmaceutical active comprises one or more of the substances set forth below in the amounts / ranges. [Table 17-1] [Table 17-2]

[0277] In certain embodiments, the pharmaceutical active ingredient is lipophilic or hydrophobic.

[0278] In certain embodiments, the pharmaceutical active ingredient is lipophobic or hydrophilic.

[0279] In certain embodiments, the active pharmaceutical ingredient comprises a cannabinoid, a terpene, a flavonoid, or a combination thereof.

[0280] In a particular embodiment, the flavonoid comprises FBL-03G.

[0281] In certain embodiments, the active pharmaceutical ingredient comprises at least one of cyclosporine, ritonavir, saquinavir, amprenavir, valproic acid, calcitriol, bexarotene, tretinoin, isotretinoin, tipranavir, and pharma- ceutically acceptable salts thereof.

[0282] In certain embodiments, the pharmaceutical active ingredient comprises a hallucinogen.

[0283] In certain embodiments, the active pharmaceutical ingredient comprises a hallucinogen, including at least one of lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA).

[0284] In certain embodiments, the active pharmaceutical ingredient comprises ivermectin.

[0285] In certain embodiments, the pharma- ceutical active ingredient is present at 0.5-40 wt%.

[0286] In certain embodiments, the pharma- ceutical active ingredient is present at 0.5-30 wt%.

[0287] In certain embodiments, the pharma- ceutical active ingredient is present at 0.5-20 wt%.

[0288] In certain embodiments, the pharma- ceutical active ingredient is present at 0.5-10 wt%.

[0289] In certain embodiments, the active pharmaceutical ingredient is present at at least 10 wt%.

[0290] In certain embodiments, the pharma- ceutical active ingredient is present at 10-40 wt%.

[0291] In certain embodiments, the pharma- ceutical active ingredient is present at 10-35 wt%.

[0292] In certain embodiments, the pharma- ceutical active ingredient is present at 10-30 wt%.

[0293] In certain embodiments, the pharma- ceutical active ingredient is present at 10-25 wt%.

[0294] In certain embodiments, the pharma- ceutical active ingredient is present at 10-20 wt%.

[0295] In certain embodiments, the pharma- ceutical active ingredient is present at 0.01-5 wt%.

[0296] In certain embodiments, the pharma- ceutical active ingredient is present at 0.01-2.5 wt%.

[0297] In certain embodiments, the pharma- ceutical active ingredient is present at 0.01-1.0 wt%.

[0298] In certain embodiments, the pharma- ceutical active ingredient is present at 0.01-0.5 wt%.

[0299] In certain embodiments, the active pharmaceutical ingredient is present at up to 2.5 wt%.

[0300] In certain embodiments, the active pharmaceutical ingredient is present at up to 1.5 wt%.

[0301] In certain embodiments, the active pharmaceutical ingredient is present at up to 1.0 wt%.

[0302] In certain embodiments, the active pharmaceutical ingredient is present at up to 0.5 wt%.

[0303] In certain embodiments, the film matrix of the mouth-dissolving film comprises a plasticizer and a film former.

[0304] In certain embodiments, the film matrix of the mouth-dissolving film comprises a plasticizer comprising at least one of propylene glycol, glycerin, triacetin, triethyl citrate, and polyethylene glycol.

[0305] In certain embodiments, the film matrix of the mouth-dissolving film comprises a plasticizer comprising at least one of propylene glycol, glycerin, and polyethylene glycol.

[0306] In certain embodiments, the film matrix of the mouth-dissolving film comprises a plasticizer comprising at least one of glycerin and polyethylene glycol.

[0307] In certain embodiments, the film matrix of the mouth-dissolving film comprises a plasticizer present at 0.5-20 wt %.

[0308] In certain embodiments, the film matrix of the mouth-dissolving film comprises a plasticizer present at 3-20 wt %.

[0309] In certain embodiments, the film matrix of the mouth-dissolving film comprises a plasticizer present at 8-14 wt%.

[0310] In a particular embodiment, the film matrix of the mouth-dissolving film comprises a plasticizer present at 12 wt %.

[0311] In certain embodiments, the plasticizer comprises one or more of the substances set forth below: In further embodiments, the plasticizer comprises one or more of the substances in the amounts / ranges set forth below. [Table 18]

[0312] In certain embodiments, the film matrix of the mouth-dissolving film comprises a film former comprising at least one of pullulan, gum arabic, guar gum, maltodextrin, microcrystalline cellulose, chitosan, pectin, carrageenan, HPMC, HPC, modified corn starch, Carbopol 974P, Carbopol 934P, Kollidon 25, Soluplus, Lycoat NG73, Kollicoat, Polyox N-10, Polyox N-80, Polyox N-750, Methocel E4M, Methocel E10M, and sodium CMC.

[0313] In certain embodiments, the film matrix of the mouth-dissolving film comprises a film-forming agent comprising at least one of pullulan, gum arabic, microcrystalline cellulose, chitosan, pectin, carrageenan, HPMC, modified corn starch, Kollidon 25, and Soluplus.

[0314] In certain embodiments, the film matrix of the mouth-dissolving film comprises a film-forming agent comprising at least one of pullulan, microcrystalline cellulose, chitosan, pectin, HPMC, modified corn starch, Kollidon 25, and Soluplus.

[0315] In certain embodiments, the film matrix of the mouth dissolving film comprises a film former present at 1-60 wt %.

[0316] In certain embodiments, the film matrix of the mouth dissolving film comprises a film-forming agent present at 5-40 wt%.

[0317] In certain embodiments, the film matrix of the mouth dissolving film comprises a film former present at 10-20 wt%.

[0318] In certain embodiments, the film matrix of the mouth dissolving film comprises a film former present at 1-20 wt %.

[0319] In certain embodiments, the film matrix of the mouth dissolving film comprises a film former present at 3-7 wt %.

[0320] In a particular embodiment, the film matrix of the mouth dissolving film comprises a film former present at 14 wt %.

[0321] In certain embodiments, the film matrix of the mouth dissolving film comprises a film former present at 5 wt %.

[0322] In certain embodiments, the film former comprises one or more of the substances set forth below: In further embodiments, the film former comprises one or more of the substances in the amounts / ranges set forth below. [Table 19-1] [Table 19-2]

[0323] In certain embodiments, the mouth-dissolvable film further comprises a co-solvent.

[0324] In certain embodiments, the mouth-dissolving film further comprises a co-solvent comprising at least one of diethylene glycol monoethyl ether and caprylocaproyl polyoxyl-8 glyceride.

[0325] In certain embodiments, the mouth-dissolving film further comprises a co-solvent present at 0.5-40 wt %.

[0326] In certain embodiments, the mouth-dissolving film further comprises a co-solvent present at 0.5-25 wt %.

[0327] In certain embodiments, the mouth-dissolving film further comprises a co-solvent present at 3-7 wt %.

[0328] In certain embodiments, the mouth-dissolving film further comprises a co-solvent present at 5 wt %.

[0329] In certain embodiments, the co-surfactant comprises one or more of the materials set forth below: In further embodiments, the co-surfactant comprises one or more of the materials in the amounts / ranges set forth below. [Table 20]

[0330] In certain embodiments, the mouth-dissolving film further comprises at least one of an antioxidant, an antimicrobial agent, a flavoring agent, a coloring agent, and a sweetening agent.

[0331] In certain embodiments, the orally dissolvable film is configured to self-emulsify within 120 seconds upon contact with a subject's oral mucosal surface.

[0332] In certain embodiments, the orally dissolvable film is configured to self-emulsify within 100 seconds upon contact with the oral mucosal surface of a subject.

[0333] In certain embodiments, the mouth-dissolving film is configured to self-emulsify within 90 seconds upon contact with a subject's oral mucosal surface.

[0334] In certain embodiments, the mouth-dissolving film is configured to self-emulsify within 75 seconds upon contact with a subject's oral mucosal surface.

[0335] In certain embodiments, the orally dissolvable film is configured to self-emulsify within 60 seconds upon contact with a subject's oral mucosal surface.

[0336] In certain embodiments, the orally dissolvable film is configured to self-emulsify within 45 seconds upon contact with a subject's oral mucosal surface.

[0337] In certain embodiments, the mouth-dissolving film is configured to self-emulsify within 30 seconds upon contact with a subject's oral mucosal surface.

[0338] In certain embodiments, the mouth-dissolving film is configured to self-emulsify within 20 seconds upon contact with the oral mucosal surface of a subject.

[0339] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion within 120 seconds upon contact with the oral mucosal surface of a subject.

[0340] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion within 100 seconds upon contact with the oral mucosal surface of a subject.

[0341] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion within 90 seconds upon contact with a subject's oral mucosal surface.

[0342] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion within 75 seconds upon contact with the oral mucosal surface of a subject.

[0343] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion within 60 seconds upon contact with the oral mucosal surface of a subject.

[0344] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion within 45 seconds upon contact with a subject's oral mucosal surface.

[0345] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion within 30 seconds upon contact with the oral mucosal surface of a subject.

[0346] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion within 20 seconds upon contact with the oral mucosal surface of a subject.

[0347] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion having an average droplet size of 0.1 microns to 120 microns within 20 seconds upon contact with the oral mucosal surface of a subject.

[0348] In certain embodiments, the orally dissolvable film is configured to form an oil-in-water (O / W) emulsion upon contact with a subject's oral mucosal surface within 20 seconds having average droplet sizes of d(10): 0.5-10 microns, d(50): 1-20 microns, and d(90): 15-100 microns.

[0349] In certain embodiments, the in-mouth dissolving film is configured to form an oil-in-water (O / W) emulsion having average droplet sizes of d(10): 0.5-5 microns, d(50): 1-10 microns, and d(90): 15-50 microns.

[0350] In certain embodiments, the mouth dissolving film is configured to form an oil-in-water (O / W) emulsion having average droplet sizes of d(10): 0.5-2 microns, d(50): 1-5 microns, and d(90): 15-30 microns.

[0351] In certain embodiments, the mouth dissolving film is configured to form an oil-in-water (O / W) emulsion having an average droplet size as shown below. [Table 21]

[0352] In certain embodiments, the orally dissolvable films are suitable for oral (PO), buccal, sublingual, or mucosal administration.

[0353] In certain embodiments, the mouth-dissolving film has a moisture content of 3-13 wt%.

[0354] In certain embodiments, the mouth-dissolving film has a moisture content of 5-13 wt%.

[0355] In certain embodiments, the mouth-dissolving film has a moisture content of 5-12 wt%.

[0356] In certain embodiments, the mouth-dissolving film has a moisture content of 5-11 wt%.

[0357] In certain embodiments, the mouth-dissolving film has a moisture content of 5-10 wt%.

[0358] In certain embodiments, the mouth-dissolving film has a moisture content of 5-9 wt%.

[0359] In certain embodiments, the mouth-dissolving film has a moisture content of 6-13 wt %.

[0360] In certain embodiments, the mouth-dissolving film has a moisture content of 6-12 wt%.

[0361] In certain embodiments, the mouth-dissolving film has a moisture content of 6-11 wt%.

[0362] In certain embodiments, the mouth-dissolving film has a moisture content of 6-10 wt%.

[0363] In certain embodiments, the orally dissolving film is configured to disintegrate within 20 minutes when buccally administered to a subject.

[0364] In certain embodiments, the orally dissolving film is configured to disintegrate within 15 minutes when buccally administered to a subject.

[0365] In certain embodiments, the orally dissolving film is configured to disintegrate within 10 minutes when buccally administered to a subject.

[0366] In certain embodiments, the orally dissolving film is configured to disintegrate within 5 minutes when buccally administered to a subject.

[0367] In certain embodiments, the mouth-dissolving film is configured to disintegrate within 120 seconds when administered orally (PO) to a subject.

[0368] In certain embodiments, the mouth-dissolving film is configured to disintegrate within 100 seconds when administered orally (PO) to a subject.

[0369] In certain embodiments, the mouth-dissolving film is configured to disintegrate within 90 seconds when administered orally (PO) to a subject.

[0370] In certain embodiments, the mouth-dissolving film is configured to disintegrate within 70 seconds when administered orally (PO) to a subject.

[0371] In certain embodiments, the mouth-dissolving film is configured to disintegrate within 60 seconds when administered orally (PO) to a subject.

[0372] In certain embodiments, the mouth-dissolving film is configured to disintegrate within 45 seconds when administered orally (PO) to a subject.

[0373] In certain embodiments, the mouth-dissolving film is configured to disintegrate within 30 seconds when administered orally (PO) to a subject.

[0374] In certain embodiments, the mouth-dissolving film is configured to disintegrate within 20 seconds when administered orally (PO) to a subject.

[0375] In certain embodiments, the mouth-dissolving film is configured to disintegrate in vitro within 120 seconds (USP <701> In-vitro disintegration method).

[0376] In certain embodiments, the mouth-dissolving film is configured to disintegrate in vitro within 100 seconds (USP <701> In-vitro disintegration method).

[0377] In certain embodiments, the mouth-dissolving film is configured to disintegrate in vitro within 90 seconds (USP <701> In-vitro disintegration method).

[0378] In certain embodiments, the mouth-dissolving film is configured to disintegrate in vitro within 75 seconds (USP <701> In-vitro disintegration method).

[0379] In certain embodiments, the mouth-dissolving film is configured to disintegrate in vitro within 60 seconds (USP <701> In-vitro disintegration method).

[0380] In certain embodiments, the mouth-dissolving film is configured to disintegrate in vitro within 40 seconds (USP <701> In-vitro disintegration method).

[0381] In certain embodiments, the mouth-dissolving film is configured to disintegrate in vitro within 30 seconds (USP <701> In-vitro disintegration method).

[0382] In certain embodiments, the mouth-dissolving film is configured to disintegrate in vitro within 20 seconds (USP <701> In-vitro disintegration method).

[0383] In certain embodiments, the orally dissolving film has (i) a Tmax between about 45 minutes and about 120 minutes, (ii) a Cmax of at least 3.5 ng / ml, and (iii) an AUC of at least 13 ng / hr / ml. 0-t The present invention shows at least one pharmacokinetic parameter selected from the following:

[0384] In certain embodiments, the orally dissolving film has (i) a Tmax of 1.5 hours, (ii) a Cmax of 4.4 ng / ml, and (iii) an AUC of 13.5 ng / hr / ml. 0-t The present invention shows at least one pharmacokinetic parameter selected from the following:

[0385] In certain embodiments, the mouth-dissolving film exhibits an in vivo dissolution time of 20 minutes or less.

[0386] In certain embodiments, the mouth-dissolving film exhibits an in vivo dissolution time of between about 10 minutes and about 15 minutes.

[0387] In certain embodiments, the mouth dissolving film exhibits a bioavailability of at least 10%.

[0388] In certain embodiments, the mouth-dissolving film exhibits a bioavailability of at least 12.5%.

[0389] In certain embodiments, the mouth-dissolving film exhibits a bioavailability of at least 15%.

[0390] In certain embodiments, the mouth dissolving film exhibits a bioavailability of at least 18%.

[0391] In certain embodiments, the mouth dissolving film exhibits a bioavailability of at least 20%.

[0392] In certain embodiments, the mouth dissolving film exhibits a bioavailability of at least 25%.

[0393] In certain embodiments, the mouth-dissolving film exhibits at least about 96% stability after 9 months when measured under accelerated conditions of 40° C. / 75% RH.

[0394] In certain embodiments, the mouth-dissolving film exhibits 100% stability after 3 months when measured under accelerated conditions of 25° C. / 60% RH or 40° C. / 75% RH.

[0395] In certain embodiments involving methods of forming a dissolvable film in the mouth, the film-forming components include at least one of mucoadhesive polymers, plasticizers, binders, fillers, bulking agents, saliva stimulants, stabilizers and thickeners, gelling agents, flavors, taste masking agents, colorants, pigments, lubricants, release modifiers, adjuvants, sweeteners, solubilizers and emulsifiers, fragrances, emulsifiers, surfactants, pH adjusters, buffers, lipids, glidants, stabilizers, antioxidants, anti-adherents, humectants, solvents, penetration enhancers, and preservatives.

[0396] In certain embodiments involving methods of forming a dissolvable film in the mouth, the lipophilic or hydrophobic solvent comprises an oil.

[0397] In certain embodiments involving methods of forming a dissolvable film in the mouth, the hydrophilic or oleophobic solvent comprises an aqueous liquid.

[0398] In certain embodiments involving methods of forming a dissolvable-in-the-mouth film, curing is carried out in a hot air oven at an air temperature between about 38°C and about 110°C.

[0399] In certain embodiments involving methods of forming a dissolvable-in-the-mouth film, curing is carried out in a hot air oven at an air temperature between about 45°C and about 80°C.

[0400] In certain embodiments involving methods of forming a dissolvable-in-the-mouth film, curing is carried out in a hot air oven (air temperature between 50° C. and 70° C.).

[0401] In certain embodiments involving methods of forming a dissolvable film in the mouth, curing occurs at a speed between about 0.8 feet / minute and about 2.5 feet / minute.

[0402] In certain embodiments involving methods of forming a dissolvable film in the mouth, curing occurs at a speed between about 0.8 feet / minute and about 1.0 feet / minute.

[0403] In certain embodiments involving methods of forming a dissolvable film in the mouth, curing occurs at a speed between about 2.0 feet / minute and about 2.5 feet / minute.

[0404] Numbered embodiments The specific numbered embodiments [1]-

[57] provided below are for illustrative purposes only and do not otherwise limit the scope of the disclosed subject matter as defined by the claims. These numbered embodiments include all combinations, subcombinations, and multiple reference (e.g., multiple dependent) combinations described herein.

[0405] Embodiment [1] The present invention relates to (a) a medicament active ingredient, (b) a surfactant, (c) a solvent for a pharmaceutical active ingredient; (d) a film matrix, and (e) water A dissolving film in the mouth comprising: If the medicament is lipophilic or hydrophobic, (i) the surfactant is lipophilic or hydrophobic, and (ii) the solvent for the medicament is lipophilic or hydrophobic; If the pharmacoactive ingredient is lipophobic or hydrophilic, (i) the surfactant is lipophobic or hydrophilic, and (ii) the solvent for the pharmacoactive ingredient is lipophobic or hydrophilic; A dissolvable film in the mouth is provided.

[0406] Embodiment [2] The present invention provides an orally dissolving film of embodiment [1], wherein the surfactant is lipophilic or hydrophobic, and the solvent for the medicamentously active ingredient is lipophilic or hydrophobic.

[0407] Embodiment [3] The present invention provides the orally dissolving film of any one of embodiments [1] to [2], wherein the lipophilic or hydrophobic surfactant comprises at least one of glyceryl monocaprylate, propylene glycol monocaprylate, glyceryl monooleate, propylene glycol monolaurate, glyceryl caprylate / caprate, glyceryl monolinoleate, sorbitan monooleate (Span 80), glyceryl dibehenate, propylene glycol dilaurate, glyceryl tricaprylate / tricaprate, glyceryl tricaprylate / caprate, decaglyceryl mono- and dioleate, oleoyl macrogolglycerides, lauroyl macrogolglycerides, stearoyl macrogolglycerides, stearoyl polyoxylglycerides, polyoxyethylene, and glyceryl caprylate / caprate.

[0408] Embodiment [4] The present invention provides an in-mouth dissolving film according to any one of embodiments [1] to [3], wherein the lipophilic or hydrophobic surfactant is present in an amount of 0.5 to 40 wt %.

[0409] Embodiment [5] The present invention provides an orally dissolvable film of embodiment [1], wherein the surfactant is lipophobic or hydrophilic, and the solvent for the pharma- ceutical active ingredient is lipophobic or hydrophilic.

[0410] Embodiment [6] The present invention provides the orally dissolving film of any one of embodiments [1] and [5], wherein the lipophobic or hydrophilic surfactant comprises at least one of poloxamer, polyoxyl castor oil, polyethylene-polypropylene glycol, polyoxyethylene sorbitan monolaurate (Tween 20), Tween 80, polyoxyethylene sorbitan monostearate (Tween 60), decyl glucoside, lauryl glucoside, octyl glucoside, Triton X-100, nonoxynol 9, sodium lauryl sulfate, potassium lauryl sulfate, Brij, glyceryl laurate, phospholipids, n-dodecylphosphocholine, and cholesteryl esters.

[0411] Embodiment [7] The present invention provides an in-mouth dissolving film according to any one of embodiments [1] and [5] to [6], wherein the lipophobic or hydrophilic surfactant is present in an amount of 0.5 to 40 wt %.

[0412] Embodiment [8] The present invention provides an orally dissolving film according to any one of embodiments [1] to [3], wherein the lipophilic or hydrophobic solvent for the medicament active ingredient comprises at least one of medium chain triglyceride oil, coconut oil, corn oil, olive oil, palm oil, canola oil, safflower oil, sesame oil, propylene glycol monocaprylate, propylene glycol monolaurate, glyceryl monolinoleate, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol.

[0413] Embodiment [9] The present invention provides an orally dissolvable film according to any one of embodiments [1] to [3] and [8], wherein a lipophilic or hydrophobic solvent for a medicament active ingredient is present in an amount of 0.5 to 40 wt %.

[0414] Embodiment

[10] The present invention provides an orally dissolvable film according to any one of embodiments [1] and [5] to [7], wherein the lipophobic or hydrophilic solvent for the medicament active ingredient comprises water.

[0415] Embodiment

[11] The present invention provides an orally dissolvable film according to any one of embodiments [1], [5] to [7], and

[10] , wherein the lipophobic or hydrophilic solvent for the medicament active ingredient is present in an amount of 0.5 to 20 wt %.

[0416] Embodiment

[12] The present invention provides an orally dissolvable film according to any one of the embodiments [1] to

[11] , wherein the medicamentously active ingredient is lipophilic or hydrophobic.

[0417] Embodiment

[13] The present invention provides an orally dissolvable film according to any one of the embodiments [1] to

[11] , wherein the medicamentously active ingredient is lipophobic or hydrophilic.

[0418] Embodiment

[14] The present invention provides an orally dissolving film according to any one of embodiments [1] to

[13] , wherein the medicamentously active ingredient comprises a cannabinoid, a terpene, a flavonoid, or a combination thereof.

[0419] Embodiment

[15] The present invention provides an orally dissolving film according to any one of embodiments [1] to

[13] , wherein the medicamentously active ingredient comprises at least one of cyclosporine, ritonavir, saquinavir, amprenavir, valproic acid, calcitriol, bexarotene, tretinoin, isotretinoin, tipranavir, and a pharma- ceutically acceptable salt thereof.

[0420] Embodiment

[16] The present invention provides an orally dissolving film according to any one of the embodiments [1] to

[13] , wherein the medicamentously active ingredient comprises a hallucinogen.

[0421] Embodiment

[17] The present invention provides an orally dissolving film according to any one of embodiments [1] to

[13] , wherein the medicamentous active ingredient comprises a hallucinogen comprising at least one of lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), N,N-dimethyltryptamine (DMT), psilocybin, mescaline, and ibogaine.

[0422] Embodiment

[18] The present invention provides an orally dissolving film according to any one of the embodiments [1] to

[13] , wherein the medicamentously active ingredient comprises ivermectin.

[0423] Embodiment

[19] The present invention provides an orally dissolvable film according to any one of the embodiments [1] to

[18] , which contains at least 10 wt % of a medicament active ingredient.

[0424] Embodiment

[20] The present invention provides an in-mouth dissolving film according to any one of the embodiments [1] to

[19] , wherein the film matrix contains a plasticizer and a film forming agent.

[0425] Embodiment

[21] The present invention provides an orally dissolving film according to any one of embodiments [1] to

[20] , wherein the film matrix comprises a plasticizer comprising at least one of propylene glycol, glycerin, triacetin, triethyl citrate, and polyethylene glycol.

[0426] Embodiment

[22] The present invention provides a dissolvable-in-the-mouth film according to any one of embodiments [1] to

[21] , wherein the film matrix comprises a plasticizer present in an amount of 0.5 to 20 wt %.

[0427] Embodiment

[23] The present invention provides the orally dissolving film of any one of embodiments [1] to

[23] , wherein the film matrix comprises a film former comprising at least one of pullulan, gum arabic, guar gum, maltodextrin, microcrystalline cellulose, chitosan, pectin, carrageenan, HPMC, HPC, modified corn starch, Carbopol 974P, Carbopol 934P, Kollidon 25, Soluplus, Lycoat NG73, Kollicoat, Polyox N-10, Polyox N-80, Polyox N-750, Methocel E4M, Methocel E10M, and sodium CMC.

[0428] Embodiment

[24] The present invention provides an in-mouth dissolving film according to any one of the embodiments [1] to

[23] , wherein the film matrix comprises a film-forming agent present in an amount of 1 to 60 wt %.

[0429] Embodiment

[25] The present invention provides an in-mouth dissolvable film according to any one of embodiments [1] to

[24] , further comprising a cosolvent.

[0430] Embodiment

[26] The present invention provides the mouth-dissolving film of any one of embodiments [1] to

[25] , further comprising a co-solvent comprising at least one of diethylene glycol monoethyl ether and caprylocaproyl polyoxyl-8 glyceride.

[0431] Embodiment

[27] The present invention provides the in-mouth dissolvable film of any one of embodiments [1] to

[26] , further comprising a co-solvent present in an amount of 0.5 to 40 wt %.

[0432] Embodiment

[28] The present invention provides a dissolvable-in-the-mouth film according to any one of embodiments [1] to

[27] , further comprising at least one of an antioxidant, an antibacterial agent, a flavoring agent, a coloring agent, and a sweetener.

[0433] Embodiment

[29] The present invention relates to (a) a lipophilic pharmacologic active ingredient; (b) an oil carrier for a lipophilic pharmacoactive ingredient; (c) self-emulsifying lipophilic surfactants for lipophilic pharmaceutical active ingredients; (d) one or more co-surfactants; (e) one or more hydrophilic surfactants; (f) film matrix, and (g) water The present invention provides an oral dissolving film according to embodiment [1], comprising:

[0434] Embodiment

[30] The present invention relates to (a) a hydrophilic medicament active ingredient; (b) an aqueous carrier for a hydrophilic pharmacoactive ingredient; (c) hydrophilic surfactants for hydrophilic pharmaceutical active ingredients; (d) one or more co-surfactants; (e) one or more self-emulsifying surfactants; (f) film matrix, and (g) water The present invention provides an oral dissolving film according to embodiment [1], comprising:

[0435] Embodiment

[31] The present invention provides an in-mouth dissolving film according to any one of embodiments [1] to

[30] , which is configured to self-emulsify within 20 seconds upon contact with the oral mucosal surface of a subject.

[0436] Embodiment

[32] The present invention provides an in-mouth dissolving film according to any one of embodiments [1] to

[31] , which is configured to form an oil-in-water (O / W) emulsion within 20 seconds upon contact with the oral mucosal surface of a subject.

[0437] Embodiment

[33] The present invention provides an in-mouth dissolving film according to any one of embodiments [1] to

[32] , which is configured to form an oil-in-water (O / W) emulsion having an average droplet size of 0.1 microns to 120 microns within 20 seconds upon contact with the oral mucosal surface of a subject.

[0438] Embodiment

[34] The present invention, upon contact with the oral mucosal surface of a subject, d(10): 0.5 to 10 microns, d(50): 1 to 20 microns, and d(90): 15 to 100 microns The present invention provides a dissolvable film in the mouth according to any one of embodiments [1] to

[33] , wherein the film is configured to form an oil-in-water (O / W) emulsion having an average droplet size of

[0439] Embodiment

[35] The present invention provides an orally dissolvable film according to any one of embodiments [1] to

[34] , which is suitable for oral administration (PO), buccal administration, sublingual administration, or mucosal administration.

[0440] Embodiment

[36] The present invention provides an in-mouth dissolvable film according to any one of the embodiments [1] to

[35] , which has a water content of 3 to 13 wt %.

[0441] Embodiment

[37] The present invention provides an orally dissolvable film according to any one of embodiments [1] to

[36] , which is configured to disintegrate within 15 minutes when buccally administered to a subject.

[0442] Embodiment

[38] The present invention provides an orally dissolvable film according to any one of embodiments [1] to

[36] , which is configured to disintegrate within 30 seconds when orally (PO) administered to a subject.

[0443] Embodiment

[39] The present invention is configured to disintegrate in vitro within 30 seconds (USP <701> In-vitro disintegration method), an orally dissolvable film according to any one of embodiments [1] to

[36] is provided.

[0444] Embodiment

[40] The present invention provides a method for treating rheumatoid arthritis with: (i) a Tmax between about 45 minutes and about 120 minutes; (ii) a Cmax of at least 3.5 ng / ml; and (iii) an AUC of at least 13 ng / hr / ml. 0-t The present invention provides an oral dissolving film according to any one of embodiments [1] to

[39] , which exhibits at least one pharmacokinetic parameter selected from the following:

[0445] Embodiment

[41] The present invention provides a medicament for the treatment of rheumatoid arthritis with (i) a Tmax of 1.5 hours, (ii) a Cmax of 4.4 ng / ml, and (iii) an AUC of 13.5 ng / hr / ml. 0-t The present invention provides an oral dissolving film according to any one of embodiments [1] to

[40] , which exhibits at least one pharmacokinetic parameter selected from the following:

[0446] Embodiment

[42] The present invention provides an in-mouth dissolving film according to any one of the embodiments [1] to

[41] , which exhibits an in vivo dissolution time of 20 minutes or less.

[0447] Embodiment

[43] The present invention provides an in-mouth dissolving film according to any one of the embodiments [1] to

[42] , which exhibits an in vivo dissolution time of about 10 minutes to about 15 minutes.

[0448] Embodiment

[44] The present invention provides an orally dissolving film according to any one of the embodiments [1] to

[43] , which exhibits a bioavailability of at least 15%.

[0449] Embodiment

[45] The present invention provides an orally dissolving film according to any one of embodiments [1] to

[43] , which exhibits a bioavailability of at least 18%.

[0450] Embodiment

[46] The present invention provides the orally dissolvable films of embodiments [1] to

[45] , which exhibit a stability of at least about 96% after 9 months when measured under accelerated conditions of 40° C. / 75% RH.

[0451] Embodiment

[47] The present invention provides the orally dissolvable films of embodiments [1] to

[45] , which exhibit 100% stability after 3 months when measured under accelerated conditions of 25°C / 60% RH or 40°C / 75% RH.

[0452] Embodiment

[48] The present invention provides a method for forming an in-mouth dissolving film, comprising the steps of: (a) dissolving a medicament active ingredient in a first solvent system to form a first mixture, (i) if the pharmacoactive ingredient is lipophilic or hydrophobic, dissolving the pharmacoactive ingredient in a lipophilic or hydrophobic solvent, a lipophilic or hydrophobic surfactant, or a combination thereof; or (ii) if the pharmacoactive ingredient is hydrophilic or lipophobic, dissolving the pharmacoactive ingredient in a hydrophilic or lipophobic solvent, a hydrophilic or lipophobic surfactant, or a combination thereof; (b) contacting the first mixture and a lipophilic or hydrophobic surfactant to form a second mixture; (c) contacting the second mixture with water and a hydrophilic or oleophobic surfactant to form a third mixture; (d) contacting the third mixture with a film-forming component to form a slurry; (e) casting the slurry onto a substrate and curing to form a dissolvable film in the mouth; The present invention provides a method comprising:

[0453] Embodiment

[49] The present invention provides a method of forming a dissolvable in-mouth film of embodiment

[48] , wherein the film-forming components include at least one of mucoadhesive polymers, plasticizers, binders, fillers, bulking agents, saliva stimulants, stabilizers and thickeners, gelling agents, flavors, taste masking agents, colorants, pigments, lubricants, release modifiers, adjuvants, sweeteners, solubilizers and emulsifiers, fragrances, emulsifiers, surfactants, pH adjusters, buffers, lipids, glidants, stabilizers, antioxidants, anti-adherents, humectants, solvents, permeation enhancers, and preservatives.

[0454] Embodiment

[50] The present invention provides a method for forming an in-mouth dissolvable film according to any one of embodiments

[48] to

[49] , wherein the lipophilic or hydrophobic solvent comprises an oil.

[0455] Embodiment

[51] The present invention provides a method for forming an in-mouth dissolvable film according to any one of the embodiments

[48] to

[49] , wherein the hydrophilic or lipophobic solvent comprises an aqueous liquid.

[0456] Embodiment

[52] The present invention provides a method for forming a dissolvable-in-the-mouth film according to any one of embodiments

[48] to

[51] , wherein curing is carried out in a hot air oven at an air temperature between about 38°C and about 110°C.

[0457] Embodiment

[53] The present invention provides a method for forming a dissolvable-in-the-mouth film according to any one of the embodiments

[48] to

[52] , wherein curing is carried out in a hot air oven at an air temperature between about 45°C and about 80°C.

[0458] Embodiment

[54] The present invention provides a method for forming a dissolvable-in-the-mouth film according to any one of the embodiments

[48] to

[53] , wherein curing is carried out in a hot air oven (air temperature of 50°C to 70°C).

[0459] Embodiment

[55] The present invention provides a method of forming a dissolvable-in-the-mouth film of any one of embodiments

[48] to

[54] , wherein curing is performed at a speed between about 0.8 ft / min and about 2.5 ft / min.

[0460] Embodiment

[56] The present invention provides a method of forming a dissolvable-in-the-mouth film of any one of embodiments

[48] to

[55] , wherein curing is performed at a speed between about 0.8 ft / min and about 1.0 ft / min.

[0461] Embodiment

[57] The present invention provides a method of forming a dissolvable-in-the-mouth film of any one of embodiments

[48] to

[56] , wherein curing is performed at a speed between about 2.0 feet / minute and about 2.5 feet / minute.

[0462] All publications, patents, and patent documents are incorporated herein by reference as if they were individually incorporated by reference.The present invention has been described with reference to various specific preferred embodiments and techniques.However, it should be understood that many changes and modifications can be made without departing from the spirit and scope of the present invention.The present invention can also be described by reference to the following examples and experiments, which do not otherwise limit the scope of the present invention. EXAMPLES

[0463] Examples and Experiments Dissolving film formulations can include an active ingredient and a polymer. Formulation of thin films can be difficult due to the following factors (1-3): (1) lack of stability of certain active ingredients, which can complicate the formulation of oral thin films (OTF) or other thin films, (2) low bioavailability of the active ingredient, or (3) low permeability of the active ingredient.

[0464] Regarding factor (1), the presence of heat, moisture, light, and / or oxygen may degrade active ingredients that are sensitive to heat, moisture, light, or oxygen. Oral thin film (OTF) systems may exhibit (i) polymorphic transitions of the active ingredient, (ii) hydration of the polymer of the formulation containing the active ingredient, and (iii) degradation and / or oxidation of the active ingredient via photolytic or hydrolytic processes. Hygroscopicity (i.e., adsorbing or absorbing water) is a factor that affects the formulation of thin films. Adsorbed or absorbed moisture in thin films may affect the mechanical strength, adhesive properties, and friability of the thin film. In addition to the hygroscopicity of the active ingredient, the level of water in the formulation of the thin film may be elevated by (i) the polymer and the solvent used to dissolve the polymer, and (ii) the manufacturing technique. The stability of the active ingredient may be further affected by (i) the amount of heat applied to dry the film used during the manufacturing technique, and (ii) the drying time (i.e., the length of time the wet thin film is exposed to heat to dry).

[0465] With regard to factor (2), the use of thin films involves difficulties such as (i) low drug loading capacity for less potent drugs administered at high doses, or (ii) low bioavailability for more potent drugs.

[0466] Regarding factor (3), the mucus layer covering the epithelial cells filters substances such as small molecule active pharmaceutical ingredients, limiting their penetration into the epithelial cells, and the thickness of the mucus layer slows the diffusion of substances.

[0467] Exemplary Advantages of the Invention The systems and methods described herein are directed to self-emulsifying thin films containing active ingredients. Self-emulsifying thin film formulations, in certain embodiments, provide the following advantages: (1) increased barrier against moisture, oxygen, light, pH, and heat, thereby protecting the active ingredient against moisture, oxygen, light, pH, and heat; (2) improved bioavailability of less potent and less bioavailable active ingredients, thereby allowing less potent active ingredients to be used at lower doses; (3) potential reduction in liver / GI toxicity; and (4) increased penetration and crossing of the mucus layer by the active ingredient, thereby allowing the active ingredient to enter the systemic circulation.

[0468] Regarding advantage 3, the active ingredient of the self-emulsifying thin film is administered by (i) facilitating binding receptors for transport through enterocytes (i.e., transcellular process) or (ii) loosening tight intercellular junctions for (a) transport between cells and (b) transport of the active ingredient of small molecule drugs for systemic circulation (i.e., paracellular process). The systems and methods described herein provide the advantages of thin films that can be obtained in specific combinations or as a single modality.

[0469] Specific combination 1 The system and method described herein features higher bioavailability, where the thin film can rapidly self-emulsify when (i) contacted with a solvent in the oral cavity and (ii) gently stirred by the mouth of the patient consuming the thin film. A fine oil / water (o / w) emulsion is formed. The bioavailability of the active ingredient released from the self-emulsifying thin film is increased and the permeability is increased for buccal administration of the thin film, and to a lesser extent for oral administration, i.e., Per Os (PO). In addition, the film matrix of the self-emulsifying thin film has mucoadhesive properties that allow the direct absorption of the active ingredient that enters the blood via the oral cavity.

[0470] Specific combination 2 The system and method described herein are characterized by higher stability, where the OTF can self-emulsify.The formulation of self-emulsifying OTF has thermal gelation properties, thus creating a physically stable formulation.The formulation of self-emulsifying OTF can protect active ingredients against degradation due to exposure to high temperature in response to (i) exposure to heat during the gelatinization process of forming the self-emulsifying OTF, (ii) emulsification of ingredients, and (iii) subsequent cooling.

[0471] A specific example using Vitamin D3 as the active ingredient Vitamin D3 is a sensitive and lipophilic pharmaceutical active ingredient (API).Vitamin D3 is used as a model drug, and is formulated using the above formulation, and vitamin D3 oral thin film is tested for 4-week stability study.Under normal circumstances, high heat and high humidity will cause vitamin D3 to decompose, but in this formulation, the inventors have observed significant protection and stability of vitamin D3 in OTF. [Table 22]

[0472] Examples of using cannabidiol (CBD) as an active ingredient Similarly, the active ingredient, the cannabinoid CBD, was tested for T=3M stability. We observed better stability and significant protection of the API in the film formulation. [Table 23]

[0473] Single style Thin films containing drugs as active ingredients can self-emulsify to provide (i) a more consistent drug absorption profile over time, (ii) selective drug targeting to specific absorption time in the gastrointestinal (GI) tract, and (iii) protection of drugs from degradation in the intestine. The intestine is acidic and can impose harsh conditions that can biochemically disrupt (i.e., degrade) drugs. More specifically, drugs that are lipophilic compounds exhibit dissolution rate-limited absorption. Thin films containing drugs can provide (i) increased absorption rate and extent of drugs, and (ii) more reproducible blood time profiles. Thin films containing active ingredients can self-emulsify, where the active ingredient is lipophilic, lipophobic, hydrophilic, or hydrophobic.

[0474] When the self-emulsifying thin film containing the active ingredient disintegrates, the active ingredient is released into the oral cavity and turns into an o / w emulsion. More specifically, the active ingredient can pass through the oral cavity quickly, thereby facilitating the widespread distribution of the active ingredient, such as small molecule drugs, throughout the oral cavity or GI tract. The disintegrated self-emulsifying thin film can thereby minimize the irritation frequently encountered during the long contact time between the bulk drug substance and the intestinal / oral cavity walls. [Table 24]

[0475] Further advantages of the systems and methods described herein directed to thin films include avoiding (i) the need for water / drinking to swallow the pill, (ii) exposure of the drug to stomach acid and tissue irritation, (iii) drug absorption via the intestine, and (iv) liver metabolism and potential injury.

[0476] Preferred Embodiments If the active ingredient is lipophilic, 1) A lipophilic active ingredient, an oil carrier, and one self-emulsifying lipophilic surfactant 2) One or more co-surfactants and a hydrophilic surfactant 3) Ingredients that create the film matrix 4)Water

[0477] If the active ingredient is hydrophilic, 1) Hydrophilic active ingredients in water and hydrophilic surfactants 2) One or more co-surfactants and a self-emulsifying surfactant 3) Ingredients that create the film matrix 4)Water

[0478] The thin films of the systems and methods described herein utilize (i) at least one self-emulsifying surfactant, (ii) one or more co-surfactants, (iii) an oil or aqueous solution containing an active ingredient, and (iv) a matrix. The active ingredient can be a pharmaceutical active ingredient, a lipophilic active ingredient, or a hydrophilic active ingredient. The thin films contain a self-emulsifying system embedded in a film-forming system.

[0479] More specifically, the thin film has the following features: (1) the absence of an emulsion that results in the embedding of the active ingredient in the film, (2) the matrix and components for the construction of the film derived from the initial emulsion, and (3) the active ingredient protected by the matrix.

[0480] Regarding feature (2) above, the following steps are carried out to obtain a matrix and then a thin film.

[0481] Step 1: Dissolve the active ingredient in a suitable solvent system to obtain Mix 1, wherein a) if the active ingredient is lipophilic, dissolving the lipophilic active ingredient in an oil carrier or a lipophilic surfactant, or b) When the active ingredient is hydrophilic, the hydrophilic active ingredient is dissolved in water or water containing a hydrophilic surfactant.

[0482] Step 2: A lipophilic surfactant is added to Mix 1 to obtain Mix 2.

[0483] Step 3: Add a hydrophilic surfactant to the water to obtain Mix 3.

[0484] Step 4: Forming ingredients are added to Mix 3 to obtain a wet but homogenous slurry, where the ingredients include water, matrix forming ingredients, plasticizers, flavors, and colorants. When the slurry is wet, the active ingredients are covered by the lipophilic and / or hydrophilic surfactant system.

[0485] Step 5: Cast the slurry and dry the slurry in a hot air oven (38°C-110°C) to obtain a thin film.

[0486] Step 6: After drying the thin film, peeling, cutting and packing of the thin film are performed, thereby obtaining strips derived from the thin film. During drying of the thin film, the matrix, which is a construction of lipophilic and hydrophilic surfactants and film-forming components, provides protection for the active ingredient and helps to improve the stability of the thin film.

[0487] The matrix can be a gel derived from the gelation phenomenon. The gelation phenomenon is due to interactions between hydrophobic polymer chains. By increasing the temperature, the hydrophobic polymer chains start to aggregate into micellar structures. The formation of the micellar structure is the result of the dehydration of the hydrophobic repeating units in the hydrophobic polymer chains. This gelation phenomenon is reversible and can be characterized by the solution-gel transition temperature (Tsol-gel).

[0488] If the temperature of the thin film is lower than the T sol-gel, the self-emulsifying hydrophilic-hydrophobic surfactant remains in a fluid state. If the temperature of the thin film is higher than the T sol-gel, the solution phase material in the slurry turns into a semi-solid material.

[0489] The systems and methods described herein increase the following properties (1 and 2): (1) the stability of the thin film, and (2) the bioavailability of the active ingredient. Then, upon dissolution of the thin film, more of the active ingredient can be released to reach the target area. The systems and methods described herein do not need to compensate for the degradation or loss of the active ingredient in the GI. Based on properties 1 and 2, the systems and methods described herein can (i) reduce the amount of active ingredient required by an individual consuming the thin film, (ii) reduce the amount of side effects that may occur due to consumption of the active ingredient, and (iii) reduce the manufacturing cost of the thin film containing the active ingredient.

[0490] More specifically, the thin films may be subject to (i) polymorphic transitions of the active ingredient, (ii) hydration of the intraoral thin film polymer, and (iii) degradation and oxidation of the active ingredient due to photolytic or hydrolytic degradation.

[0491] More specifically, the self-emulsions of the systems and methods described herein can enhance properties 1 and 2. Based on properties 1 and 2, the systems and methods described herein can (i) effectively protect active ingredients from damage during the manufacturing process and (ii) impart reversibility during the gelling phenomenon in self-emulsifying oral thin films.

[0492] Regarding property 1, the emulsions and matrices shown in Figure 1 can stabilize intraoral thin films containing active ingredients by insulating the active ingredient from water, light, and heat. In the beaker 105, there are two immiscible layers: a bottom water layer with dissolved hydrophilic surfactant (H) and an oil layer with dissolved lipophilic surfactant (L) and active ingredient.

[0493] Upon vigorously mixing the contents in beaker 105, the lipophilic surfactant (L) and hydrophilic surfactant (H) create an emulsion that can surround the active ingredient, as illustrated in beaker 110. Due to the active ingredient's lipophilicity, high solubility in organic solvents, and low solubility in water, the active ingredient is near L in beaker 110 (i.e., L is attracted to the active ingredient) and far away from H (i.e., H is repelled by the active ingredient). A film-forming ingredient (F), listed in the table below, is added to beaker 110, thus resulting in beaker 115.

[0494] When light or heat is applied, certain active ingredients, such as vitamin D3, may undergo cycloaddition reactions with some of the film-forming ingredients. When light and heat are applied, electrons in the pi-system of dienes, such as those found in vitamin D3, can become excited and undergo Diels-Alder reactions with electron-deficient alkenes of sorbic acid, one of the film-forming ingredients (F). The resulting Diels-Alder adducts are undesirable by-products that are difficult to remove during the manufacturing process, while at the same time reducing the overall yield of the active ingredient to be administered and missing out on the individual consuming the OTF.

[0495] The emulsion, with L near the active ingredient and H far from the active ingredient, surrounds the active ingredient and thus becomes a chemical-physical barrier to light, water, heat, oxidation, and other degradative processes. After mixing the contents of beaker 115, F can be converted to a film (F') for building the matrix in the early stages of slurry formation, as illustrated in beaker 120. As illustrated by the dotted lines, the emulsion begins to break down into precursors that will become embedded in F'.

[0496] To shield the active ingredient from water, the active ingredient is surrounded by a lipophilic surfactant so that the interaction between water and the active ingredient is reduced or eliminated (i.e., hygroscopicity is reduced).To shield the active ingredient from light, the self-emulsion becomes an additional layer that is a physical barrier that can prevent the penetration of light.To shield the active ingredient from heat, the gelation phenomenon (i.e., the gel matrix) dissipates heat, thereby reducing the thermal interaction with the active ingredient (i.e., reducing the thermal decomposition of the active ingredient). [ka]

[0497] Regarding property 2, the composition of the self-emulsifying oral thin film can improve the bioavailability of the active ingredient. As shown in FIG. 2, after completing the mixing and heating, the emulsion of FIG. 1 does not exist in either the top or bottom diagram. The top diagram of FIG. 2 is a slurry of 70% water (by weight) and film-forming ingredients converted into a matrix. The active ingredient is surrounded by micelles, where the active ingredient is dissolved in oil. The head of the micelle is a lipophilic surfactant (L) in direct contact with the oil, and the tail of the micelle is a hydrophilic surfactant (H) in direct contact with the water. After heating the slurry in an oven, the dried OTF is formed in the bottom diagram of FIG. 2. The amount of water in the bottom diagram of FIG. 2 is reduced to 10% water (by weight). The concentration of the active ingredient and micelles is increased in the bottom diagram of FIG. 2 compared to the top diagram of FIG. 2. This helps to increase the bioavailability of the active ingredient before and during administration of the OTF. [ka]

[0498] Further to property 2, upon administration of this oral thin film that is hydrated by the oral mucosa, the oral thin film begins to disintegrate and enter the oral mucosa as illustrated in Figure 3. For example, the surfactant system (e.g., lipophilic and hydrophilic surfactants) of the OTF can self-emulsify in the mouth and facilitate the release of the active ingredient to the systemic circulation via transcellular transport (lipophilic surfactants) and / or paracellular transport (hydrophilic surfactants) as illustrated in Figure 4.

[0499] Further with regard to characteristic 2, as illustrated in FIG. 4, transcytosis refers to the passage of a substance through epithelial cells by transcytosis. Transcytosis is a process in which particles are taken up by cells depending on various physicochemical properties of the particles, such as lipophilicity. The self-emulsifying oral thin film of the system and method described herein can adjust the lipophilicity of the active ingredient and can facilitate the movement of the active ingredient via the transcellular diffusion pathway. As illustrated in FIG. 4, the oral thin film disintegrates, thus releasing the active ingredient for transcellular diffusion. Transcellular diffusion involves the movement of the active ingredient based on a diffusion gradient, moving from an area of ​​high concentration to an area of ​​low concentration. [ka]

[0500] Further with regard to property 2, as illustrated in FIG. 4, paracellular transport refers to the transport of a substance, such as an active ingredient or food ingredient, across an epithelium by passing through the intercellular space between cells. The intercellular space between cells may be minimal, thus making the intercellular space a tight bond. Transport of the substance may require modulation of the tight bond. The components of the self-emulsifying thin film may modulate the tight bond. More specifically, the first fatty acid chain of the surfactant system may attach the active ingredient to the epithelial cell surface for a longer period of time than observed in the absence of the surfactant system. In addition, the second fatty acid chain of the surfactant system may inhibit the mechanism for contracting the intercellular space. Inhibition of the mechanism for attachment and contracting the intercellular space may loosen the tight bond to obtain a less tight bond, facilitating the penetration of the active ingredient into the epithelium. The loosening mechanism is reversible, thus allowing the intercellular space between cells to return to a tight bond. As illustrated in FIG. 4, the oral thin film disintegrates, thus releasing the active ingredient for modulating tight bonds. [ka]

[0501] The system and method described herein is a platform technology that can be integrated into multiple products. However, slight differences in ingredients and / or addition order may occur while maintaining features 1-3 without departing from the scope of the claims. Applications of platform technology are transdermal / topical patches, creams, balms, semi-solid products, and processes that do not retain a significant amount of water. A significant amount of water is an amount of water by weight percentage that may have a detrimental effect on the efficacy of the thin film. Exemplary embodiments and combinations [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4]

[0502] Example 1 [Table 26]

[0503] Experimental procedure 1) Vitamin D3 and BHT are dissolved in MCT oil by warming to 40°C ± 5°C, thereby obtaining Mix 1. 2) Span 80 is added to Mix 1, thereby obtaining Mix 2. 3) Tween 20 is added to Mix 2 together with purified water (20% of 70% as before), thereby obtaining Mix 3, where the temperature of the water is 40°C ± 5°C. 4) Mix 3 with mechanical stirring. 5) Add the remaining water to Mix 3, where the temperature of the water is 80°C ± 5°C. 6) Food modified starch, pullulan, glycerin, potassium sorbate, Red 40, sucralose, and berry flavor are added to Mix 3, thereby obtaining Mix 4. 7) Mix 4 until it reaches a homogenous state, thereby obtaining a slurry. 8) Casting the slurry for a film casting process, thereby obtaining a thin film. 9) After casting, dry the thin film in a drying oven at 160°F-180°F for 15 minutes or less or until dry. Measure the thickness of the thin film, where the specification of the thin film is 0.12mm-0.20mm. This can be adjusted during the casting process. 10) After drying, cut the thin film to obtain strips of 22 mm x 36 mm, which can be adjusted according to the dosage.

[0504] Example 2 [Table 27]

[0505] Experimental procedure 1) Vitamin D3 and BHT are dissolved in MCT oil by warming the MCT oil to 40° C.±5° C., thereby obtaining Mix 1. 2) Span 80 is added to Mix 1, thereby obtaining Mix 2. 3) Kolliphor RH40 is added along with purified water (20% out of 70%), thereby obtaining Mix 3, wherein the temperature of the water is 40°C ± 5°C. 4) Mix 3 with mechanical stirring. 5) Add the remaining water to Mix 3, where the temperature of the water is 80°C ± 5°C. 6) Food modified starch, pullulan, glycerin, potassium sorbate, Red 40, sucralose, and berry flavor are added to Mix 3, thereby obtaining Mix 4. 7) Mix 4 until it reaches a homogenous state, thereby obtaining a slurry. 8) Casting the slurry for a film casting process, thereby obtaining a thin film. 9) After casting, dry the thin film in a drying oven at 160°F-180°F for up to 15 minutes or until dry. Measure the thickness of the thin film, where the thin film specification is 0.12mm-0.20mm. (This can be adjusted during the casting process.) 10) After drying, cut the thin film to obtain strips of 22 mm x 36 mm. (This can be adjusted according to the dosage.)

[0506] Example 3 [Table 28]

[0507] Experimental procedure 1) Vitamin D3 and BHT are dissolved in MCT oil by warming the MCT oil to 40° C.±5° C., thereby obtaining Mix 1. 2) Span 80 is added to Mix 1, thereby obtaining Mix 2. 3) Poloxamer 407 is added to Mix 2 together with purified water (20% of 70% as above), thereby obtaining Mix 3, where the temperature of the water is 40°C ± 5°C. 4) Mix 3 with mechanical stirring. 5) Add the remaining water to Mix 3, where the temperature of the water is 80°C ± 5°C. 6) Food modified starch, pullulan, glycerin, potassium sorbate, Red 40, sucralose, and berry flavor are added to Mix 3, thereby obtaining Mix 4. 7) Stir Mix 4 until it reaches a homogenous mixture, thereby obtaining a slurry. 8) Casting the slurry for a film casting process, thereby obtaining a thin film. 9) After casting, dry the thin film in a drying oven at 160°F-180°F for up to 15 minutes or until dry. Measure the thickness of the thin film, where the thin film specification is 0.12mm-0.20mm. (This can be adjusted during the casting process.) 10) After drying, cut the thin film to obtain strips of 22 mm x 36 mm. (This can be adjusted according to the dosage.)

[0508] Example 4 [Table 29]

[0509] Experimental procedure 1) CBD isolate is dissolved in propylene glycol monocaprylate by warming the propylene glycol monocaprylate to 55°C ± 5°C, thereby obtaining Mix 1. 2) Span 80 is added to Mix 1, thereby obtaining Mix 2. 3) Tween 20 is added to Mix 2 together with purified water (20% of the 70% of the aforementioned amount), thereby obtaining Mix 3, wherein the temperature of the water is 55°C ± 5°C. 4) Mix 3 with mechanical stirring. 5) Add the remaining water to Mix 3, where the temperature of the water is 80°C ± 5°C. 6) Food modified starch, pullulan, glycerin, potassium sorbate, Red 40, sucralose, and berry flavor are added to Mix 3, thereby obtaining Mix 4. 7) Stir Mix 4 until it reaches a homogenous mixture, thereby obtaining a slurry. 8) Casting the slurry for a film casting process, thereby obtaining a thin film. 9) After casting, dry the thin film in a drying oven at 160°F-180°F for up to 15 minutes or until dry. Measure the thickness of the thin film, where the thin film specification is 0.12mm-0.20mm. (This can be adjusted during the casting process.) 10) After drying, cut the thin film to obtain strips of 22 mm x 36 mm. (This can be adjusted according to the dosage.)

[0510] Example 5 [Table 30]

[0511] Experimental procedure 1) CBD isolate is dissolved in propylene glycol monocaprylate by warming the propylene glycol monocaprylate to 55°C ± 5°C, thereby obtaining Mix 1. 2) Span 80 is added to Mix 1, thereby obtaining Mix 2. 3) Tween 20 is added to Mix 2 together with purified water (20% of the 70% of the aforementioned amount), thereby obtaining Mix 3, wherein the temperature of the water is 55°C ± 5°C. 4) Mix 3 with mechanical stirring. 5) Add the remaining water to Mix 3, where the temperature of the water is 80°C ± 5°C. 6) Food modified starch, pectin, chitosan, glycerin, potassium sorbate, Red 40, sucralose and berry flavor are added to Mix 3, thereby obtaining Mix 4. 7) Stir Mix 4 until it reaches a homogenous mixture, thereby obtaining a slurry. 8) Casting the slurry for a film casting process, thereby obtaining a thin film. 9) After casting, dry the thin film in a drying oven at 160°F-180°F for up to 15 minutes or until dry. Measure the thickness of the thin film, where the thin film specification is 0.12mm-0.20mm. (This can be adjusted during the casting process.) 10) After drying, cut the thin film to obtain strips of 22 mm x 36 mm. (This can be adjusted according to the dosage.)

[0512] Stability Studies and Data [Table 31] 1) The main application of this technology is to provide better stability of active ingredients and increase their bioavailability. 2) Self-emulsifying delivery compositions can be incorporated into OTFs and other applications (ie, semi-solid), such as patches.

[0513] Alternative Embodiments Sandimmune® (Cyclosporin A / I) Indicated for the prevention of organ rejection in kidney, liver, and heart allografts Corn oil, linoleoyl macrogolglycerides, and sorbitol Neora® (cyclosporine) Systemic immunosuppressants Corn Oil-Mono-Di-Triglycerides, Polyoxyl 40 Hydrogenated Castor Oil NF, DL-α Tocopherol USP Gengraf® (Cyclosporin A / III) Systemic immunosuppressants Polyethylene Glycol NF, Polyoxyl 35 Castor Oil NF, Polysorbate 80 NF, Propylene Glycol USP, Sorbitan Monooleate NF, Titanium Dioxide Norvir® (ritonavir) Combination with other antiretroviral agents for the treatment of HIV-1 infection Butylated hydroxytoluene, ethanol, oleic acid, polyoxyl 35, and castor oil Fortovase® (saquinavir) Human immunodeficiency virus (HIV) protease inhibitors Medium chain mono- and diglycerides, povidone, and dl-alpha-tocopherol Agenerase® (amprenavir) Human immunodeficiency virus (HIV) protease inhibitors d-Alpha Tocopherol PEG 1000 Succinate (TPGS), PEG 400, and Propylene Glycol Depakene® (valproic acid) Monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures occurring alone or in association with other types of seizures Corn Oil, Glycerin, Methylparaben, and Propylparaben Rocaltrol® (Calcitriol) Management of secondary hyperparathyroidism and management of hypocalcemia Coconut oil triglyceride Targretin® (Bexarotene) Treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy Polyethylene glycol 400, NF, Polysorbate 20, NF, Povidone, USP, and Butylated Hydroxyanisole, NF Vesanoid® (tretinoin) Retinoids induce maturation of acute promyelocytic leukemia (APL) Beeswax, butylated hydroxyanisole, disodium edetate, hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Accutane® (isotretinoin) Severe resistant nodular acne Beeswax, butylated hydroxyanisole, disodium edetate, hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Aptivus® (tipranavir) Combination antiretroviral treatment for HIV-1 Absolute alcohol (7% w / w or 0.1 g per capsule), polyoxyl 35 castor oil, propylene glycol, caprylic / capric mono / diglycerides

[0514] Experimental Data Pharmacokinetic Studies and Data In a single-dose, open-label, randomized, crossover and balanced study, the described delivery system has improved bioavailability of CBD compared to the administration of commercially available softgels.The study was performed in healthy adults in the fasting state with equal representation of gender (8 / 6 males and females). [Table 32] [Table 33] [Table 34] [ka]

Claims

1. 1. A method for forming an in-mouth dissolving film, comprising: (a) dissolving a medicament active ingredient in a first solvent system to form a first mixture, wherein the medicament active ingredient is lipophilic or hydrophobic, and the medicament active ingredient is dissolved in a lipophilic or hydrophobic solvent, or a combination comprising the lipophilic or hydrophobic solvent and a lipophilic or hydrophobic surfactant, and the lipophilic or hydrophobic solvent comprises an oil; (b) contacting the first mixture and a lipophilic or hydrophobic surfactant to form a second mixture; (c) contacting the second mixture with water and a hydrophilic or oleophobic surfactant to form a third mixture; (d) contacting the third mixture with film-forming ingredients including a film-forming polymer to form a slurry; (e) casting the slurry onto a substrate and allowing it to harden to form the mouth-dissolvable film; A method comprising:

2. The method of claim 1, wherein step (d) is carried out by contacting the third mixture with the film-forming components, the film-forming components including the film-forming polymer and at least one of mucoadhesive polymers, plasticizers, binders, fillers, bulking agents, saliva stimulants, stabilizers and thickeners, gelling agents, flavors, taste masking agents, colorants, pigments, lubricants, release modifiers, adjuvants, sweeteners, solubilizers and emulsifiers, fragrances, emulsifiers, surfactants, pH adjusters, buffers, lipids, glidants, stabilizers, antioxidants, anti-adherents, humectants, solvents, penetration enhancers, and preservatives.

3. The method of claim 1, wherein the curing is carried out in a hot air oven at an air temperature between about 38°C and about 110°C.

4. The method of claim 1, wherein the curing is carried out in a hot air oven at an air temperature between about 45°C and about 80°C.

5. The method of claim 1, wherein the curing is carried out in a hot air oven (air temperature between 50° C. and 70° C.).

6. The method of claim 1, wherein the curing is carried out at a speed between about 0.8 feet / minute and about 2.5 feet / minute.

7. The method of claim 1, wherein the curing is carried out at a speed between about 0.8 feet / minute and about 1.0 feet / minute.

8. The method of claim 1, wherein the curing is carried out at a speed between about 2.0 feet / minute and about 2.5 feet / minute.

9. 10. The method of claim 1, wherein the orally dissolving film is suitable for oral (PO), buccal, sublingual, or mucosal administration.

10. The method of claim 1, wherein the mouth-dissolving film has a moisture content of 3 to 13 wt %.

11. 10. The method of claim 1, wherein the orally dissolving film is configured to disintegrate within 15 minutes when buccally administered to a subject.

12. 10. The method of claim 1, wherein the mouth-dissolving film is configured to disintegrate within 30 seconds when administered orally (PO) to a subject.

13. 10. The method of claim 1, wherein the mouth-dissolving film is configured to disintegrate in vitro within 30 seconds (USP <701> In-vitro Disintegration Method).

14. The orally dissolving film has (i) a Tmax between about 45 minutes and about 120 minutes, (ii) a Cmax of at least 3.5 ng / ml, and (iii) an AUC of at least 13 ng / hr / ml. ０－ｔ The method of claim 1, wherein the at least one pharmacokinetic parameter is selected from the group consisting of:

15. (i) a Tmax of 1.5 hours, (ii) a Cmax of 4.4 ng / ml, and (iii) an AUC of 13.5 ng / hr / ml. ０－ｔ The method of claim 1, wherein the at least one pharmacokinetic parameter is selected from the group consisting of:

16. 10. The method of claim 1, wherein the mouth-dissolving film exhibits an in vivo dissolution time of 20 minutes or less.

17. 10. The method of claim 1, wherein the mouth-dissolving film exhibits a bioavailability of at least 15%.

18. 10. The method of claim 1, wherein the mouth-dissolving film exhibits a stability of at least about 96% after 9 months when measured under 40°C / 75% RH accelerated conditions.

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