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WO2025043236A1 - Films oraux comestibles, compositions, procédé de fabrication et systèmes d'emballage - Google Patents

Films oraux comestibles, compositions, procédé de fabrication et systèmes d'emballage Download PDF

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Publication number
WO2025043236A1
WO2025043236A1 PCT/US2024/043779 US2024043779W WO2025043236A1 WO 2025043236 A1 WO2025043236 A1 WO 2025043236A1 US 2024043779 W US2024043779 W US 2024043779W WO 2025043236 A1 WO2025043236 A1 WO 2025043236A1
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WO
WIPO (PCT)
Prior art keywords
film
sheet
nicotine
films
oil
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/US2024/043779
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English (en)
Inventor
Joseph Fuisz
Madhu Hariharan
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Individual
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Individual
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Filing date
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Publication of WO2025043236A1 publication Critical patent/WO2025043236A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

  • an “oral thin film” (OTF) or “oral soluble film” is a thin film composed of a mono or multi-layer polymeric matrix that is applied in the mouth. They can be water-based soluble polymers designed to rapidly deliver drugs systemically. Depending on the drug candidate and the targeted indication, they can be formulated either as orodispersible films or a transmucosal film. Orodispersible films (ODF’s) work like conventional orodispersible tablets. An ODF typically disintegrates or dissolves in seconds in the mouth and the drug substance is swallowed. With a transmucosal film, the active substance directly enters the systemic circulation via the buccal mucosa.
  • Thin-film drug delivery uses a dissolving film or oral drug strip to administer drugs via absorption in the mouth (i.e., buccally or sublingually) and/or via the small intestines (i.e., enterically).
  • a film is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made.
  • Thin-film drug delivery has emerged as an alternative to the traditional tablets, capsules and liquids often associated with prescription and OTC medications. Similar in size, shape and thickness to a postage stamp, thin-film strips are typically designed for oral administration.
  • a user places the strip on or under the tongue (i.e., sublingual) or along the inside of the cheek (i.e., buccal). As the strip dissolves, the drug can enter the blood stream PATENT JF1-001WO enterically, buccally or sublingually. For systemic transmucosal drug delivery, the buccal mucosa is generally preferred compared to the sublingual mucosa.
  • wet casting or solvent casting of films has been the dominant method of manufacture of commercially available oral soluble films. Solvent casting is discussed in US 7,897,080 which describes a method of making films by deposition as an alternative to the solvent casting process. In contrast, “hot melt extrusion” to manufacture edible, soluble films and sheets is described in the art.
  • Listerine PocketPaks® an edible oral film and edible oral film dispenser that was first launched in October 2001.
  • Listerine PocketPaks® are small, rectangular, single- chambered cassettes that hold a stack of multiple orally soluble films in a compartment that is accessible by a flip-top lid on the front of the cassette.
  • the cassettes are stored in a secondary blister package composed of Aclar® film which provides barrier protection to the orally soluble films until the cassette is removed from the secondary blister package.
  • the orally soluble films use pullulan as the primary film former.
  • pullulan has severe loading limitations and so the behavior and attributes of primarily-pullulan based films is sui generis.
  • the film-facing interior wall of the cassette is smooth-textured to allow easy sliding of the orally soluble films from the cassette without blockage or adhesion.
  • Various companies have manufactured products with similar packaging, as unit dose sachets, wherein the film is packed as a unit dose, typically in a foil-foil laminate.
  • Such products include approved ethical drugs sold in soluble films; over-the-counter (OTC) drug products; nutraceutical products as well as films containing cannabinoids.
  • oral soluble film ethical drugs include Suboxone® (unit dose pouch), Sympazam® (unit dose pouch), Igalmi® (unit dose pouch), Kynmobi® (unit dose pouch), Zuplenz® (unit dose pouch), etc.
  • OTC drug products include oral soluble films previously marketed under Triaminic® (unit dose pouch), Benadryl® (unit dose pouch) and Gas-x® (unit dose pouch).
  • Nutraceutical oral films include Sanofi’s Unisom® dissolving strips (multi-dose cassette).
  • Cannabinoid containing films include KinSlips® (unit dose pouch).
  • Schiraldi et al. (U.S. RE33,093) describes bioadhesive monolayer extruded films, under 10 millimeters in thickness (10 thousandths of an inch), composed principally of PATENT JF1-001WO polyethylene oxide together with HPC, a water insoluble polymer; a plasticizer and a medicament.
  • U.S. Pat. No.6,072,100 describes compositions extruded films and sheets comprising PEO or HPC, a water polymer derived from a carboxylic aid, 30-80% plasticizer and up to 10% of a medicament.
  • the film is made from a precursor composition containing a water soluble or water swellable thermoplastic polymer (e.g,, HPC and/or PEO) and a bioadhesive polymer.
  • the film does not contain a conventional plasticizer or a material that is recognized as a plasticizer.
  • Repka et al. describes films that include up to 10% active agent.
  • U.S. Patent Publication 2006/0257463 describes transmucosal film compositions for delivery of tetrahydrocannabinol (THC). Examples include hot melt molding, solvent casting and hot melt extrusion. Hot melt extrusion examples comprise PEO and 8% w/w THC or 8% w/w THC-HS.
  • Example #5 and #6 were prepared using hot-melt extrusion techniques.
  • the PEO, PVP and Vitamin E TPGS were blended in a V-blender.
  • the THC and the THC-HS were solubilized in the PEG 400 and immediately sprayed into the dry blend with continuous mixing.
  • the resulting blend was then hot-melt extruded into films.
  • the highest extrusion temperature was 150°C and residence time in the barrel was approximately two minutes.
  • Example #1 was PATENT JF1-001WO prepared by hot-melt molding.
  • THC Tetrahydrocannabinol
  • Example 1 Ingredients for the inner layer of this Eloshly Example 1 include: Klucel TM (EF grade), Polycarbophil, PEG 400, tartaric acid, BT and TJC.
  • the “outer backing layer” comprises Klucel TM (EF Grade), Ethyl Cellulose, Eudragit and PEG 3350.
  • the ‘872 patent provides examples of hot melt extruded sheets containing up to 30% tobacco (Bruton Snuff) (See Example G describing an extruded hot melt sheet of 13 mils.
  • the ‘872 patent Example O describes a clinical study with a sheet containing 75 mg of tobacco, with an implied sheet piece weight of 300 mg.
  • U.S. Patent No.8,613,285 issued December 24, 2013, describes extruded sheets containing bioactive agents.
  • the ‘285 patent further describes the use of a drug in an ion exchange in an extrudable composition, and the ability of the ion exchange complex to remain bonded through the hot melt extrusion process.
  • the films or sheets described herein are formulated for oral delivery (i.e., oromucosal or orodispersible) of an active agent (e.g., nicotine or a cannabinoid).
  • the films or sheets have a length to height ratio of about 2.0 – 4.0 to 1.
  • the films or sheets are not tacky and do not tack together when packaged together in a container with loose films subjected to ambient conditions (e.g., 30 days or longer at 25°C/60% relative humidity (RH)). In certain embodiments, the films or sheets are not tacky and do not tack together (i.e., stick together) when packaged together in a container with loose films subjected to 90 days of 25°C/60% relative humidity (RH).
  • a round cassette is particularly suitable for longer and thinner films with length by width aspect ratios greater than 1.5 to 1.
  • the films or sheets described herein have dimensional stability. Dimensional stability can be determined by exposing the films or sheets to a temperature of about 30°C and about 65% relative humidity (RH) for 24 hours and determining that the films or sheets bend less than 3% in either length or height direction. The films/sheets are not in barrier packaging.
  • RH relative humidity
  • the film or sheet includes a form of nicotine, and/or a cannabinoid.
  • each chamber of the cassette can move within the cassette and stop in alignment with an aperture or opening on the cassette. This allows for removal of a film or sheet contained in each chamber.
  • the cassette has a single chamber with multiple films or sheets arranged sequentially within the chamber using clips, brushes or pins to hold the films or sheets in place.
  • the cassette includes a desiccant.
  • the desiccant may be a single desiccant pack (or area) or multiple packs or areas.
  • the desiccant is not in direct, physical contact with the films or sheets.
  • the desiccant is housed in PATENT JF1-001WO an area of the cassette which has one or more air channels to allow for the transfer of moisture from the film/sheet area to the desiccant area or areas.
  • the cassette is packaged with an overwrap (i.e. a packaging film over the cassette).
  • the overwrap can provide a moisture barrier to ensure stability of the films or sheets. While many types of material are suitable, a preferred overwrap material is polypropylene, including biaxially-oriented polypropylene (BOPP).
  • the cassette can be entirely or partially overwrapped.
  • the “joints” or “seams” of the cassette are covered.
  • a suitable moisture barrier film is employed.
  • the cassette has multiple chambers with multiple films or sheets arranged sequentially within the chamber using clips, brushes, pegs or pins to hold the films or sheets in place.
  • the cassette is a round container with rotational or other movement capability such that no chamber can move until a film or sheet is removed from the chamber aligned with the aperture.
  • a container or cassette cover has rotational capability, such that the container or cassette cover can rotate to align with an aperture in the cover and stop at a given chamber to allow for the removal of a film or sheet contained in the corresponding chamber aligned with the aperture.
  • rotation of the cassette, chamber, opening, or aperture is effected through the use of a dial.
  • rotation of the cassette, chamber, opening or aperture is achieved with a push button actuator that creates rotation through a gear. Comparable and equivalent mechanisms known in the art may also be employed to effect rotation of the cassette, chamber, opening or aperture of the present invention.
  • the container includes a rectangular cassette which slides linearly within a larger rectangular case or container cover which has an aperture. The cassette may be pushed along the case to align each chamber with the aperture to allow removal of individual films within each chamber of the cassette.
  • the invention includes a container cover with rotational capability, such that the container cover is capable of rotating to align an aperture in the cover to stop at a given chamber to allow for the removal of a film or sheet contained in the corresponding chamber.
  • the invention contemplates a container capable of dispensing individual films or sheets to a user by gravity. More specifically, the individual films or sheets may be dispensed by dropping from the container through an aperture due to the force of gravity when used as intended. In other embodiments, tapping or bumping of the container against a surface may be required to shake loose a film via an aperture.
  • a film or sheet manufactured by dynamic roll molding comprising a breath freshener or mint containing menthol, eugenol, peppermint oil, eucalyptol, thyme, fennel or other breath freshening agents.
  • a film or sheet optionally, manufactured by dynamic roll molding, wherein said film dissolves, when placed in the buccal cavity, in three to seventy minutes, preferably in ten to forty-five minutes, more preferably in ten to thirty-five minutes; most preferably fifteen to thirty minutes.
  • PATENT JF1-001WO One of more large sides/ faces may be textured; optionally, only one large side/face is textured.
  • the invention includes a container for dispensing individual films or sheets to a user by mechanical force applied to an individual film or sheet to raise, present, or eject the individual film or sheet from the container.
  • containers of the invention are assembled from four pieces of fewer, preferably three pieces or fewer, more preferably two pieces or fewer (in each case not including overwrap). In embodiments, such pieces are injection molded.
  • the films are loosely packaged within a tin or puck type package made of polymeric or other resin or metal which may or may not be airtight. These tins or pucks can contain a cone or reverse cone shaped insert to allow easy sliding removal of the films within the package.
  • the top of the cone may reach the height of the interior space.
  • the top of the cone reaches at least one half of the height of the interior space, more preferably at least two thirds, still more preferably, at least three fourths, and most preferably at least four fifths.
  • the films are arranged within slots on the cone-shaped insert which can be arranged radially like spokes to allow easy removal of a single film by pinching a film between two fingers and sliding or lifting. Other non-radial slot configurations are similarly contemplated.
  • the insert can be a separately made material that is placed in the container, or the insert can be manufactured as part of the container or puck.
  • the invention includes a non-smooth surface within a dispensing container.
  • the non-smooth surface provides a non-smooth texture to retard the sticking of the films or sheets to the non-smooth surface.
  • a non-smooth surface resembling a grate may be employed to reduce the contacting surface area exposed to the films or sheets.
  • Other surface textures contemplated include a pocked texture, a rough texture, a knurled texture, an uneven texture, a studded texture, a combination of any of the aforementioned and any equivalent texture or texture combinations that are known in the art.
  • the inside surface of the dispensing container is coated with (or made from) a hydrophobic material.
  • the hydrophobic coating can be silicone, or any other oily hydrophobic substance.
  • the hydrophobic material can be admixed with the PATENT JF1-001WO polymeric material of construction of the dispensing container.
  • the container may be opaque, translucent or transparent.
  • a low-surface-energy substrate is paired with a rough or pocked surface texture.
  • the substrate and surface texture can be parallel to each other, orthogonal, opposing, adjacent, or in any configuration within the grasp of a skilled artisan.
  • the textures, surface energy and other attributes discussed above may equally apply to a puck style container.
  • the bottom of the chamber is sloped upwards, akin to an inverted cone
  • the bottom of the chamber may further include a single upward planar surface.
  • the bottom of the chamber may include two or more upward planar surfaces.
  • the planar surfaces may include a constant slope, but concave, convex and other curved surfaces are also contemplated.
  • the cone shape may have a dessicant underneath, with air channels to connect airflow between the space under the cone and the rest of the container.
  • Low surface energy contact areas and rough or pocked textures are particularly suitable for use with films or sheets that include oily active ingredients. Examples include nicotine oil, or cannabinoids.
  • Product tackiness for a film or sheet may increase as the film matrix comprises more than 3% of an oily ingredient (e.g. nicotine oil). Such tackiness typically increases with increased oil percentages (i.e.5% or greater, and still more tackiness at 7.5% or greater).
  • Cannabinoids show similar properties; increased product tack above the prior percentages.
  • Nicotine and cannabinoid containing films and sheets at these loading levels are expressly contemplated.
  • “dusting” is employed to reduce tackiness where films or sheets to reduce product tackiness (i.e. placing a powder in the container, optionally hydrophobic, that reduces tackiness of the films or sheets one with the other).
  • corn starch may be suitable for dusting.
  • PATENT JF1-001WO a chamber of the invention contains multiple films or sheets.
  • the chamber is sized to encourage the movement of multiple films or sheets. The chamber may be taller, shorter, or equal to the height of the film or sheet.
  • the chamber or container or puck may be segmented with areas for films of different strength of active ingredient, or flavor
  • the chamber size is such that there is minimization of contact of the flat surface of the film with the surfaces of the chamber.
  • the chamber is rectangular and has sides with a smaller width than the film or sheet so that the film or sheets can only be placed along the diagonal width of the chamber, ensuring that only the edges of the film or sheet make contact with the corners of the chamber.
  • the container employs gaskets to reduce air and vapor flux. Ideally, the container is airtight, or substantially airtight.
  • Child resistance features may be incorporated in the lid of the container or aperture or by any other suitable means such as pin-actuated enablement of cassette rotation, or pressure actuated enablement. Such features may apply to all containers described or contemplated herein.
  • the aperture of the container is configured to push or pull out the individual film or sheet from the chamber, including through physical contact (i.e., grasping and pulling or pushing) with the film or sheet.
  • the cassette/container of the invention includes nylon brush hairs within the chambers.
  • Each chamber can include protruding brush hairs such that each film or sheet may be emplaced within the brush hair fibers in a radial arrangement to hold the film or sheets firmly in place while ensuring minimal contact of the film or sheet with brush hairs while also allowing removal of film or sheet embedded in the brush hair when presented at the aperture.
  • the fibers can protrude from or along any of the walls of the chamber.
  • the fibers can also be parallel to the plane of the film or sheet or perpendicular to the plane of the film or sheet or at any angle there between.
  • the container/cassette includes brush fibers that can be used to hold each film or sheet in lieu of the use of chambers.
  • Each film or sheet can be PATENT JF1-001WO embedded within the brush hairs of the rotating or sliding cassettes/containers of the invention.
  • processing temperatures do not exceed 120°C, preferably do not exceed 110°C, more preferably do not exceed 95°C, and most preferably do not exceed 85°C; where the film or sheet comprises less than 20% active ingredient, preferably less than 15% active ingredient, more preferably less than 10% active ingredient, most preferably less than 5% active ingredient.
  • compositions and process suitable for manufacturing a film or sheet wherein the certain ingredients are melted and certain ingredients remain unmelted during the manufacturing process.
  • molten inactive components comprise 40% to 90% of the composition, more preferably 50%-80% and most preferably 60-70% of the composition.
  • a film or sheet comprising nicotine with a pH of greater than 7, preferably greater than 8, and most preferably greater than 9.
  • said nicotine film does not comprise sodium carbonate or sodium bicarbonate, or other similar basic salts.
  • a film or sheet that is sufficiently non-hygroscopic, to allow for stable bulk packaging in a container.
  • 10-40 films or sheets may be placed loosely in a container.
  • Film stiffness as described here is similar to bending strength and flexural strength in engineering material characterization.
  • ASTM American Society of Testing and Materials
  • ASTM D2344 and D790 are two examples of standards used to calculate these types of properties. The stiffness of the film was quantified using an apparatus similar to that described for a 3-point test in the ASTM standards.
  • films of 0.4 mm thickness, 11 mm wide and 33 mm long were considered as a beam and tested on a 3-point testing apparatus wherein the film was supported on two points at the end and the force in milliNewtons (mN) was measured as a third point crosshead probe pushed at the center of the film to deflect it by 1mm at 1.1 mm/min speed.
  • the average force required to bend the film is 100-600 mN, more preferably 200-500 mN and most preferably 300-400 mN.
  • the peak force required to bend a film of 0.3 mm thickness is 50-400 mN, more preferably 75-300 mN and most preferably 100-200 mN.
  • the film has adequate structural memory to return after bending to its original flat position. For example, a film bent at the middle at 30 degrees will return to the original position within 10 degrees.
  • the products may have reduced bendability PATENT JF1-001WO as compared with typical cast films, where the film web is rolled up after drying prior to being cut into pieces.
  • films for oral use are rectangular or square shaped with typical length by width ratios no greater than 1.5 to 1. In contrast, the films described herein can have a minimum length by width ratio of 2 to 1 or higher.
  • the films or sheets do not tack or stick together when the packaging container with loose films is subjected to 30 days of 25°C/60% relative humidity (RH). 60 days, 90 days and 180 days are also contemplated at these same stability conditions. [0087] In certain embodiments, the films or sheets do not tack or stick together when the packaging container with loose films is subjected to 30 days of 40 °C/75% relative humidity (RH). 60 days, 90 days and 180 days are also contemplated at these same stability conditions. [0088] Stability of the film or sheet can be thought of in a number of ways. These include chemical stability of the active ingredient, as well as physical stability of the dosage form itself.
  • the film or sheet retaining its form, i.e. not curling, bending or melting or otherwise deforming; the propensity of the film or PATENT JF1-001WO sheet to increase in moisture (typically considered under accelerated stability conditions), and when relevant to the packaging configuration, propensity of films or sheets to increase in tackiness and tend to stick together.
  • the film or sheet maintains its form without deforming after 5 days, preferably 10 days, more preferably 30 days at one or more of the following conditions: 25 °C/60% relative humidity (RH); 30 °C/65% RH; 30 °C/75% RH; or 40 °C/75% RH.
  • the films or sheets when packaging in a multi-film/sheet chamber, do not stick together and/or to container surfaces after 5 days, preferably 10 days, more preferably 30 days at one or more of the following conditions: 25 °C/60% relative humidity (RH); 30 °C/65% RH; 30 °C/75% RH; or 40 °C/75% RH.
  • 5 days is considered a reasonable time in which to consume the contents of a unit dose container after removing an overwrap. In other cases, a user will consume the fill contents within two days, in which case the moisture uptake discussed above may be considered in a forty-eight-hour period.
  • a film or sheet capable of releasing perceptible levels of flavor and/or sweetener, when used in the buccal cavity, sublingual cavity, supralingually, or in the upper lip, for greater than ten minutes, preferably greater than fifteen minutes, more preferably greater than twenty minutes, and most preferably for greater than thirty minutes.
  • Nicotine compositions will generally range from 1 mg per film or sheet, to up to 30 mg per film or sheet. A preferred nicotine dose range is 2 mg to 12 mg per film or sheet.
  • the film or sheet may comprise polymers of 50% or greater, preferably 75% or greater, more preferably 85% or greater, most preferably 90% or greater particularly (though not exclusively) where the film or sheet contains a nicotine active ingredient.
  • Cannabinoid compositions will generally range from 5 mg per film or sheet, to up to 50 mg per film or sheet.
  • a preferred cannabinoid dose range is 10 mg to 30 mg per film or sheet.
  • the films described herein allow constant (or substantially constant) release of an active agent (e.g., nicotine) through the mucosa of a user.
  • an active agent e.g., nicotine
  • PATENT JF1-001WO PATENT JF1-001WO
  • the active agent is released as the film dissolves for a period of about, for example, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 12 minutes, 15 minutes, 20 minutes or longer.
  • embodiments include an orally dissolvable film or sheet that includes (a) about 3% or more nicotine oil, (b) about 3 – 15% of a water-soluble non-melting polymer, (c) about 0.2 – 5% w/w of an oil absorbent agent and (d) a basic amino acid as a pH modifier.
  • the water-soluble non-melting polymer is selected from hydroxypropyl cellulose, povidone, starch and CMC.
  • the film has a pH of 7 or higher and the oil absorbent agent is silicone dioxide, talc, oat fibers, rice flour, calcium silicate, magnesium stearate, magnesium silicate or microcrystalline cellulose.
  • Embodiments also include an orally dissolvable film or sheet that includes (a) about 3% or more nicotine oil, (b) about 3 – 15% of a water-soluble non-melting polymer or water- dispersible polymer and (c) about 0.2 – 5% w/w of an oil absorbent agent.
  • the non-melting melting water-soluble or water-dispersible polymer is selected from hydroxypropyl cellulose, povidone, starch and CMC.
  • Embodiments also include methods a method of making an orally dissolvable film.
  • FIG.1 is a side view of a paddle wheel according to embodiments of the invention.
  • FIG.2 is a perspective view of the paddle wheel embodiment of FIG.1.
  • FIG.3 is a cross-sectional view of a paddle wheel embodiment.
  • FIG.4 is a cross-sectional view of a paddle wheel embodiment along line 4-4 of FIG.3.
  • FIG.5 is a perspective view of a turbofan embodiment of the present invention.
  • FIG.6 is a top view of a turbofan embodiment of the present invention.
  • FIG.7 is a perspective view of a turbofan embodiment without a cylindrical case present.
  • FIG.8 is a cross-sectional view of a turbofan embodiment along line 8-8 of FIG.7.
  • FIG.9 is a cross-sectional view of a turbofan embodiment of the present invention.
  • FIG.10 is a perspective view of a multi-chambered rotating cassette which includes arrowhead-shaped features to center the film position within the chamber.
  • FIG.11 is a top view of a multi-chambered rotating cassette which includes arrowhead-shaped features to center the film position within the chamber.
  • FIG.12 is a perspective view of a shaped film or sheet intended for use over teeth, with approximately 90-degree angles at two bend points.
  • FIG.13 is a perspective view of a shaped film or sheet intended for use over teeth, with an approximately continuous curve.
  • FIG.14 is a perspective view of a shaped film intended for use over teeth, with a non-continuous curve.
  • FIG.15 is a flow-chart of steps in dynamic roll molding according to certain embodiments of the present invention.
  • FIG.16 is a perspective view of the lower component of a puck with a conical insert.
  • the insert in Figure 16 is smooth (not scalloped like Fig.17).
  • the user can slide a film up the cone to a point where the top of the film is presented with two sides of the top of the film available to be grabbed by the user.
  • the optional flat top of the cone makes more of the film presented when slid up.
  • FIG.17 is a perspective view of the lower component of a puck with a conical insert.
  • the insert is scalloped, with a series of adjoining sections that are optionally concave as depicted in Figure 17. The scalloped feature allows the user to slide the film up, to a point where the film is presented with the upper end of the film above the center of the cone where it can be grabbed easily.
  • FIG.18 is a side perspective of the lower component of a puck with a conical insert shown in Figure 16.
  • FIG.19 is a perspective view of a multi-chambered rotating cassette which includes arrowhead-shaped features with an outer case and aperture.
  • FIG.20 is a perspective view of an outer case of the multi-chambered rotating cassette of FIG.19.
  • Reference in this specification to "one embodiment/aspect” or “an embodiment/aspect” means that a particular feature, structure, or characteristic described in connection with the embodiment/aspect is included in at least one embodiment/aspect of the disclosure.
  • the term “substantially” as used herein in the specification and appended claims, unless otherwise indicated, means a margin of +/- 10%. It is to be PATENT JF1-001WO appreciated that not all uses of the above terms are quantifiable such that the referenced ranges can be applied.
  • the term “medicament,” “active agent” or “active ingredient” refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to.
  • active agent or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed.
  • An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed.
  • An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed.
  • the term “nicotine” refers a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and Duboisia hopwoodii) and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used for smoking cessation to relieve withdrawal symptoms.
  • Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits (nAChR ⁇ 9 and nAChR ⁇ 10) where it acts as a receptor antagonist.
  • nAChRs nicotinic acetylcholine receptors
  • nAChR ⁇ 9 and nAChR ⁇ 10 nicotinic receptor subunits
  • the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.
  • an effective amount refers to the amount of the defined component sufficient to achieve the desired chemical composition or the desired biological and/or therapeutic result.
  • that result can be the desired pH or chemical or biological characteristic, e.g., stability of the formulation.
  • the desired result is the alleviation or amelioration of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • the effective amount will vary depending upon the specific disease or symptom to be treated or alleviated, the age, gender and weight of the subject to be treated, the dosing regimen of the formulation, the severity of the disease condition, the manner of administration and the like, all of which can be determined readily by one of skill in the art.
  • a PATENT JF1-001WO desired effect may, without necessarily being therapeutic, also be a cosmetic effect, in particular for treatment for disorders of the skin or muscles.
  • the terms “treating,” “treatment” and the like are used herein to mean obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and/or may be therapeutic in terms of amelioration of the symptoms of the disease or infection, or a partial or complete cure for a disorder and/or adverse effect attributable to the disorder.
  • bioavailability refers to the fraction of an administered dose of unchanged drug that reaches the systemic circulation.
  • oral thin film refers to a thin film composed of a mono or multi-layer polymeric matrix that is applied in the mouth. OTFs can be water-based soluble polymers designed to rapidly deliver drugs systematically.
  • OTF can be formulated either as orodispersible films or a transmucosal film.
  • the term “tackiness” generally refers to the proclivity of one film or sheet to adhere to another surface.
  • film or “sheet” or “oral film” or “oral sheet” or “oral film product” or “oral sheet product” or “oral drug product” or “film product” or “sheet product” or “drug product” or “product” can be used interchangeably.
  • Orodispersible films work like conventional orodispersible tablets. In this case, OTF dissolves within seconds in the mouth and the drug substance is swallowed together with the saliva and takes the same route as a tablet.
  • the active substance directly enters the systemic circulation via the buccal mucosa, avoiding the hepatic first-pass effect.
  • PATENT JF1-001WO The active ingredient can be either dissolved or suspended in the polymeric matrix.
  • the OTF dosage form presents several advantages, among which: (a) an easy drug intake therefore high acceptance by young and old patients (b) no swallowing difficulties and no beverages requirement for intake, (c) flexible manufacturing with area proportional dosage (different doses from one base bulk), (d) potential avoidance of the first-pass effect and improved bioavailability, (e) innovative and appealing design offering more options for differentiating a product range and (f) a discreet and pain-free application.
  • Soluplus® refers to an amphiphilic graft copolymer studied as a micellar solubilizer for drugs.
  • SOL is a unique water-soluble graft copolymer constructed from hydrophilic and lipophilic portions.
  • the hydrophilic moiety is composed of PEG residue corresponding to 13% of the polymer, whereas the polyvinyl caprolactam and polyvinyl acetate act as the lipophilic backbone in the polymer structure.
  • This amphiphilic polymer can be used above the critical micelle concentration (CMC) to dissolve certain drugs via micelle formation.
  • CMC critical micelle concentration
  • HPC hydroxypropyl cellulose
  • DS degree of substitution
  • HPMC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose
  • hypromellose it has been used as an excipient in oral tablet and capsule formulations, where, depending on the grade, it functions as controlled release agent to delay the release of a medicinal compound.
  • Various grades are available based on molecular weight and the degree of substitution which is the average level of methoxy substitution on the cellulose chain. It is considered a water soluble, non-heat-meltable polymer generally not useful in hot extrusion, or molding.
  • the term “hot extrusion” refers to the act of extruding an article, while the article is currently being heated, or was previously heated, such that the article is at an PATENT JF1-001WO elevated temperature during the extruding process.
  • the extruding process typically includes forcing the article through a die, thereby obtaining a desired cross-section.
  • the term “casting” or “film easting” refers to the act of removing liquid (e.g., water and/or solvent) from a mixture (e.g., slurry), such that a film is produced.
  • the term “condensing” refers to the act of removing liquid (e.g., water and/or solvent).
  • the term “packaging material” refers to those materials and substances employed to package the product (e.g., thin film). Such materials are widely known to those of skill in the art.
  • the term “enclosing” refers to the packaging materials containing or holding the product (e.g., thin film) by surrounding the product with the packaging material.
  • the packaging materials can partially surround the product or can completely surround the product.
  • the packaging materials can form a relatively vapor impermeable enclosure of the product.
  • LSE low surface energy
  • substrates or plastics made of materials such as vinyl, polyethylene and polystyrene and have unique surface characteristics making them harder for pressure sensitive adhesives to stick. These plastics are generally soft and have low density which helps in lightweighting applications.
  • All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are to be understood as approximations in accordance with common practice in the art. When used herein, the term “about” may connote variation (+) or (-) 1%, 5% or 10% of the stated amount, as appropriate given the context.
  • “Dynamic roll molding,” refers generally to (1) milling and mixing the feedstock with or without spraying of liquid componenents ; (2) pelletizing the feedstock; (3) softening the feedstock at processing temperatures and passing the feedstock through rollers, die or orifice; (4) controlling the thickness resulting material by stretching and rolling (and adding optional features like texture, embossing, debossing), and (5) die-cutting individual pieces.
  • the final product is a film or sheet whether single or multi-layer.
  • the initial feedstock is preferably a substantially non-aqueous feedstock.
  • substantially non-aqueous it is meant that the only water is that of moisture that is typically present in the compositional ingredients.
  • the initial feedstock may be produced by direct blending of excipients and drugs in a V-blender type mixer with an i-bar or chopper bar with or without a spray capability; or by spray granulation; or high shear granulation; or spray drying; or spray congealing; or low shear granulation; or microencapsulation.
  • the feedstock may then be further wet or dry granulated by pelletizing or roller compaction and milling.
  • the initial feedstock is comprised of a mixture of excipients and actives wherein some excipients melt at processing temperatures and other excipients may be non-melting.
  • the contact surface area of the container may include a low-surface-energy substrate that possesses a surface energy of 40 dynes/cm or less. In other embodiments, the contact surface area of the container may include a low-surface-energy substrate that possesses a surface energy of 30 dynes/cm or less. [00192] In other embodiments, the contact surface area of the container may include a low-surface-energy substrate that possesses a surface energy of 20 dynes/cm or less. [00193] In embodiments, more than 50% of the chamber surface area may include low-surface-energy substrate. In other embodiments, more than 75% of the chamber surface area is composed of low-surface-energy substrate.
  • Additional useful polymers include, stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers of polyurethane and (poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of ⁇ -amino acids, copolymers of ⁇ -amino acids and caproic acid, copolymers of ⁇ -benzyl glutamate and polyethylene glycol, copolymers of succinate and poly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixtures thereof.
  • lactide/glycolide 100 L believed to be 100% glycolide having a melting point within the range of 437°-455° F. (225°-235° C.); lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolide with a melting point within the range of 338°-347° F. (170°-175° C.); and lactide/glycolide 50/50, believed to be a copolymer of 50% lactide and 50% glycolide with a melting point within the range of 338°- 347° F. (170°-175° C.).
  • the Biodel materials represent a family of various polyanhydrides which differ chemically.
  • polymers that provide mucoadhesive properties to the film or sheet, as well as a desired dissolution and/or disintegration rate.
  • the time period for which it is desired to maintain the film or sheet in contact with the mucosal tissue depends on the type of active contained in the composition. Some actives may only require a few minutes for delivery through the mucosal tissue, whereas other actives may require up to several hours or even longer. Accordingly, in some embodiments, one or more water-soluble polymers, as described above, may be used to form the film.
  • the films may include polyethylene oxide alone or in combination with a second polymer component. In some embodiments, the films may include polymers other than polyethylene oxide.
  • the second polymer may be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer or any combination thereof.
  • Suitable water-soluble polymers include, PATENT JF1-001WO without limitation, any of those provided above.
  • the water-soluble polymer may include hydrophilic cellulosic polymers, such as hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose.
  • water soluble polymers include, but are not limited to, polyethylene oxide (PEO), pullulan, hydroxypropyl cellulose, polydextrose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, propylene glycol alginate, carrageenan, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, 38erpin gum, polyacrylic acid, methylmethacrylate copolymer, poloxamer polymers, copolymers of acrylic acid and alkyl acrylate (available as Pemulen® polymers), carboxyvinyl copolymers, starch, gelatin, pectin, and combinations thereof.
  • PEO polyethylene oxide
  • pullulan pullulan
  • hydroxypropyl cellulose polydextrose
  • polyvinyl pyrrolidone carboxymethyl cellulose
  • polyvinyl alcohol sodium alginate
  • propylene glycol alginate carrageen
  • water insoluble polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, acrylic polymers, vinyl acetate, sodium sulphonated polyesters, carboxylated acrylics, trimethylpentanediol/adipic acid/glycerin cross polymer, polyglycerol-2-diisostearate/IPDI copolymer, carboxylated vinyl acetate copolymer, vinylpyrrolicone/vinyl acetate/alkylaminoacrylate terpolymers, vinylpyrrolidone/vinyl acetate copolymer, and combinations thereof.
  • polyethylene oxide may range from about 20% to 100% by weight in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight.
  • one or more water-swellable, water-insoluble and/or biodegradable polymers also may be included in the polyethylene oxide-based film. Any of the water- swellable, water-insoluble or biodegradable polymers provided above may be employed.
  • the second polymer component may be employed in amounts of about 0% to about 80% by weight in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight.
  • the molecular weight of the polyethylene oxide also may be varied.
  • high molecular weight polyethylene oxide such as about 4 million
  • the molecular weight may range from about 100,000 to 900,000, more specifically from about 100,000 to 600,000, and even more specifically from about 100,000 to 300,000.
  • Pore formers are soluble organic materials to adjust the disintegration time of the film composition in the buccal cavity.
  • the pore formers are typically incorporated in the film as non-molten components and remain dispersed as particles throughout the film matrix.
  • Preferred ratio of pore formers to film formers is 1:10 to 1:2, more preferably 1:8 to 1:3, most preferably 1:6 to 1:4.
  • Applicants have determined that corn syrup solids are highly useful for embodiments of the present invention. Corn syrup solids can be used to accelerate disintegration of the film or sheet. In addition, corn syrup solids have a low propensity to absorb moisture and can be useful to promote dimensional stability of the film or sheet. A preferred range of corn syrup solids is 1 to 20%, preferably 3% to 15%.
  • a preferred pore former is corn syrup solids.
  • corn syrup solids reduce the gummy mouth feel of the product in the buccal cavity, and to help control disintegration time in the mouth.
  • Rice syrup solids are an alternative to corn syrup solids and can provide a similar function. A preferred range of rice syrup solids is 2% to 20%, preferably 5% to 15%. Other (i.e. non corn, non rice) syrup solids can be used in these same ranges.
  • Another non-limitative example of an ingredient that may function as a pore former is isomalt. A preferred range of isomalt is 5 to 20%, preferably 8% to 15%.
  • pH modifiers may be used to control pH (acidic or base), including without limitation, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, dipotassium phosphate, potassium citrate, sodium phosphate, Formic Acid/Sodium Formate, Hydrogen Chloride/Potassium Chloride, Hydrogen Chloride/Glycine, Hydrogen Chloride/Potassium Hydrogen Phthalate, Citric Acid/Sodium Citrate, Acetic Acid/Sodium Acetate, Citric Acid/Disodium Hydrogen Phosphate, Citric Acid/Trisodium Citrate Dihydrate, etc., and any other such buffer system.
  • the buffer system may be designed to dynamically control the pH of the product taking into consideration the effect of saliva during use, i.e., a dynamic buffer system.
  • PATENT JF1-001WO While sodium bicarbonate and similar basic salts may be used, salts are not preferred for certain embodiments, particularly nicotine containing films.
  • the nicotine film does not comprise a sodium or a potassium as a pH modifier.
  • Meglumine has surprisingly been found to be an adequate pH modifier, with particular suitability for use with nicotine films, including nicotine films made by dynamic roll molding with a pH greater than 6, preferably greater than 7, more preferably greater than 8, most preferably greater than 9.
  • Meglumine can be incorporated without deleterious effects to film properties, including physical stability, dimensional stability and targeted disintegration time.
  • a preferred range of meglumine concentration is 0.25-9%, preferably .4% to 5%, most preferably 1-3%.
  • a preferred amount of meglumine per film or sheet is .25 mg to 14 mg, preferable .4 mg to 7.5 mg, most preferably 1 mg to 4 mg.
  • Other non-limitative examples of pH adjusters are triethanolamine, arginine, histidine, asparagine or lysine.
  • a preferred range for basic amino acids as pH modifiers is 0.25-9%, preferably .4% to 5%, most preferably 1-3%.
  • Arginine is a preferred basic acid used in a range from 1.25% to 5%. In addition to pH, arginine counters the vasoconstriction caused by nicotine, thereby enhancing local blood flow and absorption, and thus may act as a permeation enhancer. Preferred amounts of arginine in an individual film or sheet are 1.25 mg to 6, preferably 1 to 3mg.
  • Non limitative, examples of buffer systems to obtain a pH include dibasic sodium phosphate and monobasic sodium phosphate. Both are FDA accepted buffer materials used and listed in the inactive ingredients list.
  • the ratio of monobasic/dibasic can be 4.6/8.6; for a pH of 7.5 the ratio of monobasic/dibasic can be 1.9/11.9; and for a pH of 8.0 the ratio of monobasic/dibasic can be 0.6/13.4.
  • this dynamic buffer range is adjusted in the dosage unit by the amount s of the buffer system since saliva is freshly renewable in the mouth. See U.S. Patent Application Publication Nos.2009/0098192 A1 and US 2011/0318390 A1 PATENT JF1-001WO discussing dynamic buffering and incorporated herein by reference.
  • the dynamic buffer systems of the present invention may be acidic or basic.
  • Surfactants and Penetration Enhancers [00243] Several surfactants (surface active agents) and non-surfactant penetration enhancers have been found to improve the absorption of actives. [00244] Applicants have found that meglumine acts as a penetration enhancer, particularly for nicotine. A preferred range of meglumine concentration is 0.25-9%, preferably .4% to 5%, most preferably 1-3%.
  • Gelucire may be used as a penetration enhancer as well as a surfactant.
  • a preferred range of gelucire is 0.01% to 5%, preferably 0.01% to 2%, more preferably 0.075% to .35%.
  • a preferred amount of gelucire per film or strip is 0.1 mg to 7 mg, preferably, 0.75 mg to 4.5 mg.
  • sodium caprate is a useful absorption enhancer, including without limitation for cannabinoids.
  • a preferred range for sodium caprate is 3% to 20%, preferable 5% to 15%.
  • triglyceryl monooleate Caprol 3GO
  • a preferred range for Caprfol 3GO is 0.5% to 5%, more preferably 1-4% and most preferably 2-3%.
  • Other penetration enhancers are expressly contemplated.
  • a penetration enhancer is a substance that enhances absorption through the mucosa, mucosal coating and epithelium (otherwise known (see U.S. Patent Application Publication No. 2006/0257463) as a “penetration enhancer” or “permeability enhancer”).
  • the mucosal absorbing enhancer may include but is not limited to polyethylene glycol (PEG), diethylene glycol monoethyl ether (Transcutol), 23-lauryl ether, aprotinin, azone, , dextran sulfate, sodium caprate, salcaprazoate sodium, lauric acid, lauric acid/propylene glycol, lysophosphatilcholine, menthol, methoxysalicylate, oleic acid, phosphaidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycholated, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, sulfoxides, and various alkyl glycosides or, as described in U.S.
  • PEG polyethylene glycol
  • Transcutol diethylene glycol monoethyl ether
  • 23-lauryl ether 23-lau
  • bile salts such as sodium deoxycholate, sodium glycodeoxycholate, sodium taurocholate and sodium glycocholate
  • surfactants such as PATENT JF1-001WO sodium lauryl sulfate, polysorbate 80, laureth-9, benzalkonium chloride, cetylpyridinium chloride and polyoxyethylene monoalkyl ethers such as the BRIJ® and MYRJ® series, Kolliphors®, Gelucires®
  • benzoic acids such as sodium salicylate and methoxy salicylate, fatty acids, such as lauric acid, oleic acid, undecanoic acid and methyl oleate, fatty alcohols, such as octanol and nonanol, laurocapram, the polyols, propylene glycol and glycerin, cyclodextrins, the sulfoxides, such as dimethyl sulfoxide and dodecy
  • the mucosal absorbing enhancer is a polyol, e.g., polyethylene glycol (PEG), glycerin, maltitolsorbitol and other similar compounds.
  • Preferred surfactants include, without limitation, Pluronics, Kolliphors and propylene glycol.
  • Non limiting surfactants may also include non-ionic surfactants, like polyol esters (e.g., glycol or glycerol esters, sorbitan derivatives); polyoxyethylene esters (e.g., polyethylene glycol (the “PEGs”; and poloxamers.
  • Table 1 below sets forth additional surfactants which may be used in suitable amounts.
  • the plasticizer may be present in an amount up to 30% based on the weight of the thermoplastic polymer.
  • the plasticizer can be, without limitation, at least one of polyethylene oxide, polypropylene PATENT JF1-001WO glycol, polyethylene glycol, glycerin, edible polyols, glycerol, polyols, maltitol, and reduced sugars.
  • Polyethelene oxide (PEO) is a preferred plasticizer, particularly where the product is intended to be packed loosely in a container.
  • a preferred range of PEO is 0.01 to 10%, more preferably 0.05-2 most preferably .7-1.25%.
  • PEO N10 is a preferred grade.
  • Mucoadhesive agents may be included to enhance mucoadhesion of the film or sheet. Mucoadhesive agents, may include, without limitation, propylene glycol, high molecular weight polyethylene oxides, sodium alginate, carbomer and polycarbophil, and other known mucoadhesive agents.
  • a preferred range of mucoadhesive agents is 0.2-5%, preferably 0.5-3%, most preferably 1-2%.
  • Oil Absorbent Agents are particularly relevant where oils are used in the composition, typically as one or more active ingredients.
  • Oil absorbent agents may include, without limitation, silicone dioxide, calcium silicate, magnesium stearate, magnesium silicate, soluble fibers (e.g., Polydex/Maltodextrin), rice flour, corn flour and gums (e.g., Arabic, agar, etc).
  • a preferred range of oil absorbent agents is 0.2-10%, preferably 1-8%, most preferably 2-3%.
  • a coloring agent may be added to color the film or sheet.
  • Food safe coloring agents are preferred.
  • Colorants may include FD&C pigments or lakes as well as iron oxide pigments.
  • the film/sheet is color-coded to flavor, e.g. an orange flavored film is orange in color, a cherry flavored film is red in color, a mint flavored film may be blue or green in color, etc.
  • white may be used to denote mint.
  • Embossed or color printed flavor identifiers may also be used.
  • Flavor Agents [00263] Flavor agents are typically employed. In addition, masking agents are useful where the active ingredient has a bitter taste profile.
  • bitter maskers or bitter blockers may be employed in effective amounts.
  • a preferred range of bitter blocker agents is 0.01-2%, preferably 0.1-1.5%, most preferably 0.2-1%.
  • Sweeteners are typically employed. Non-limitative examples include sucralose, glycyrrhizinates, acesulfame potassium, aspartame, neotame, neohesperidine, steviosides and monk fruit extract as well as natural sugars.
  • Opacifiers [00266] Any known opacifier may be employed to opacify the film or sheet (i.e., make the substance opaque and/or prevent/slow the rate of yellowing).
  • Non-limitative examples include titanium dioxide and calcium carbonate.
  • a clear film or sheet is preferred.
  • an opaque film or sheet is preferred.
  • the film or sheet may be semi-opaque or semi-translucent.
  • the opacifier may be a whitening agent.
  • Glidants and Anti-Tacking Agents [00267] Glidants may be employed to facilitated flow and feed of the feedstock. Suitable, non-limitative examples of glidants include silicone dioxide and silicates like calcium silicate. Fumed silicone dioxide may be employed; a preferred grade is Aeroperl 300. Rice and corn flour may also help reduce tackiness by absorbing oils.
  • oils and oily surfactants may help reduce tackiness by virtue of their hydrophobicity.
  • PATENT JF1-001WO Applicants have found gelucire to be suitable for use as an anti-tacking agent. Low levels of Gelucires® are employed, preferably less than 0.3% dry weight of the feedstock to prevent films packaged together from sticking to each other. Higher levels above 0.5% may tend to weaken the matrix undesirably. Gelucire 48/16 is a preferred grade.
  • MCT Oil medium-chain triglycerides
  • MCT oil is used from .1% to 8%, preferably 0.5% to 2.5%, more preferably 0.75% to 1.5%, and most preferable 0.1% to 1.2%.
  • a combination of gelucire and MCT oil may be employed for anti-tacking.
  • a preferred level of glidants or flow/ anti-tacking agents is 1 – 5%.
  • Printed Indicia [00273] The film or sheet stock is optionally printed with ink. Printed indicia may include active ingredient, strength, brand. [00274] Alternatively, indicia may be applied through debossing/embossing.
  • a preferred method is through rollers, which may be heated, chilled or ambient temperature.
  • Stabilizers, diluents, release modifiers, bulking agents, fillers, adhesives, anti- adherents, softeners, disintegrants, emulsifiers, elastomers may all be employed, preferably in effective amounts.
  • Active Ingredients [00276] Films or sheets of the present invention may include one or more active ingredients.
  • Nicotine compositions may comprise nicotine that is tobacco derived, or synthetic nicotine. It is expressly contemplated that any blend of stereoisomers, i.e., S- PATENT JF1-001WO nicotine and R-nicotine.
  • Nicotine polacrilex or similar ion exchange complexes may be employed; however, nicotine oil is a preferred embodiment, in part due to the low assay of nicotine polacrilex making higher nicotine loads harder to achieve.
  • Nicotine compositions may comprise free base nicotine, nicotine bitartrate, nicotine hydrochloride, nicotine benzoate, nicotine lactate or any other nicotine salt.
  • Certain actives, such as nicotine oil may have a tendency to sublime off at elevated temperatures. For this reason, the use of a closed system to soften the composition may be desirable, i.e. the material is heated in an otherwise unvented system apart from the exit opening.
  • the initial formula be overloaded relative to the intended film dose by 1-50%, preferably 5-25%, more preferably 5- 10% most preferably 1% to 10%.
  • the peak processing temperature for nicotine oil is under 125°C, preferably under 110 °C, more preferably under 100°C, and most preferably under 95°C. Such temperatures may similarly be employed with other actives prone to sublimation or degradation.
  • Other nicotine substitutes are contemplated, including without limitation, Imotine®. By nicotine substitutes, we mean molecules that are structurally similar to, but chemically different from nicotine.
  • Nicotine and nicotine-substitute embodiments are contemplated for use as consumer products, as well as for use as pharmaceutical products (including smoking cessation and other non-cessation therapeutic uses).
  • Cannabinoid formulations may comprise phyto-cannabinoids as well as synthetic cannabinoids. Phyto-cannabinoids are typically derived from hemp, but may also be derived from cannabis (i.e., marijuana) or from other plant sources.
  • the cannabinoid may be present as plant material, a plant extract or essential oil, as a resin, a distillate or as an isolate. In certain cases the cannabinoid is solubilized in a carrier during the mixing phase. PATENT JF1-001WO [00284] Typically, the cannabinoid is present in a therapeutically effective amount. [00285] In some embodiments, the cannabis plant material provided to the composition is obtained from a cannabis plant selected from the non-limitative group consisting of Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Hemp may be used as a source.
  • the composition provided herein includes a cannabinoid such as, for example, delta 9 tetrahydrocannabinol (Delta 9 THC), iso- tetrahydrocannabinol (iso-THC), delta 9 tetrahydrocannabinolic acid (Delta (THCA), delta 8 tetrahydrocannabinol (Delta 8 THC), delta 8 tetrahydrocannabinolic acid (Delta 8 THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol-C4 (CBN-C4), cannabinol-CZ (CBN-C2), cannabiorcol (CBN-C1), cannabinodiol (C
  • CBD cannabidio
  • Composites of cannabinoids are also contemplated; unrefined or semi-refined oils or extracts, including without limitation full spectrum oils and partial spectrum oils.
  • Compositions can include purely synthetic cannabinoids or mixtures thereof.
  • Synthetic cannabinoids are drugs that bind to endocannabinoid receptors and/or other receptors to which phytocannabinoids also bind. Typically, the cannabinoid is present in a therapeutically effective amount.
  • PATENT JF1-001WO Synthetic cannabinoids may be of from any category such as classical cannabinoids, non- classical cannabinoids, hybrid cannabinoids, aminoalkylindoles, and eicosanoids.
  • the cannabinoids may include any specific stereoisomer or a combination or racemic mixture.
  • Non limitative examples include 4-nonylphenyl boronic acid, palmitoylsulfonyl fluoride, Cyclohexyl [I,G- biphenyl]-3-ylcarbamate.
  • the film or sheet composition includes synthetic cannabinoids in combination with phytocannabinoids.
  • the film or sheet is sold as a dietary supplement, food, medical food, medical supplement or as a pharmaceutical.
  • the composition provided herein is formulated in the form a pharmaceutical composition, a nutraceutical, a cosmeceutical, a nutricosmetic, a cosmetic composition, a body care product, a personal hygiene product or a food product.
  • a bi-layer film can include a single layer with at least one cannabinoid, and a second layer with at least one cannabinoid.
  • a film composition can include at least one cannabinoid, and at least one non- cannabinoid drug.
  • a film composition includes at least one cannabinoid, and at least one non-cannabinoid bioactive agent.
  • the non-cannabinoid bioactive agent can include any bioactive agent, where the bioactive agent is not a drug.
  • a preferred embodiment includes a supplement combined within a single film composition with more than one cannabinoid to use or take advantage of the entourage effect between cannabinoids as well as a synergistic effect with non-cannabinoid supplements.
  • the entourage effect is a mechanism by which other cannabinoid compounds modulate or attenuate the overall psychoactive effects of delta 9 THC (or other forms of THC like delta 8 THC).
  • a preferred embodiment includes a drug molecule combined within a film or sheet composition with more than one cannabinoid to take advantage of the entourage effect between cannabinoids as well as a synergistic effect with non-cannabinoid drugs via different pharmacological mechanisms of action.
  • a preferred embodiment includes combining a drug molecule with delta 9 THC and cannabidiol to modulate or attenuate the psychoactivity of delta 9 THC.
  • a preferred embodiment includes combining a drug molecule with delta 9 THC and terpenes like pinene and limonene to modulate or attenuate the psychoactivity of delta 9 THC.
  • a preferred embodiment includes combining a drug molecule with delta 9 THC and cannabidiol and terpenes like pinene and limonene to modulate or attenuate the psychoactivity of delta 9 THC.
  • Other embodiments include breath freshener and oral health actives.
  • Breath freshener active ingredients are well known, and in some cases simple flavors and sweeteners are used for breath freshening compositions.
  • a non-limitative list of active ingredients useful for breath freshening applications include: botanical extracts, and essential oils (anise, fennel, basil, mint, thymol, eucalyptol, menthol, spearamint, peppermint, tea tree, bergamont, cinnamon, clove, coriander, laurel, lavender, lemon, marjoram, mustard, orange, orris, parsley, pimento, pine, rosemary, sage, sassafras, thyme, etc).
  • the film or sheet adheres to the teeth.
  • the film may comprise agents necessary to adhere the film or sheet to the teeth in the matrix, or such agents may be applied to the film or sheet after processing.
  • Vaginal films may have appropriate actives for lubrication, spermicide or other birth control, hormonal actives, or other suitable active ingredients for vaginal use. Anti- spasmodics may be used. It is expressly contemplated that actives may be incorporated for preferential delivery to the uterus via the uterine first pass effect.
  • PATENT JF1-001WO Other embodiments include nutraceutical products (like vitamins, minerals and dietary supplements). Caffeine is a preferred active ingredient.
  • Non-cannabinoid botanical ingredients are contemplated.
  • a preferred embodiment is tobacco. Tobacco is typically ground, and preferred embodiments employ tobacco with a moisture content below 12%, more preferably below 10% and most preferably below 8%.
  • the tobacco’s nicotine content is 2.5% or greater, preferably 3% or greater, more preferably 4% or greater, most preferably 5% or greater.
  • the tobacco is pasteurized.
  • Non-limitative examples of useful active pharmaceutical ingredients include ace-inhibitors, antianginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti- diarrhea preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplastics, anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators
  • Examples of active ingredients contemplated for use in the present invention include antacids, H 2 -antagonists, and analgesics.
  • antacid dosages can be prepared using the ingredients calcium carbonate alone or in combination with magnesium hydroxide, and/or aluminum hydroxide.
  • antacids can be used in combination with H 2 -antagonists.
  • Analgesics include opiates and opiate derivatives, such as oxycodone (available as Oxycontin®), ibuprofen, aspirin, acetaminophen, and combinations thereof that may optionally include caffeine. NaV1.8 inhibitors may be used.
  • anti-diarrheals such as immodium AD, anti-histamines, anti- tussives, decongestants, vitamins, and breath fresheners.
  • Common drugs used alone or in combination for colds, pain, fever, cough, congestion, runny nose and allergies, such as acetaminophen, chlorpheniramine maleate, dextromethorphan, pseudoephedrine HCl and diphenhydramine may be included in the film and sheet compositions of the present invention.
  • anxiolytics such as alprazolam (available as Xanax®); anti-psychotics such as clozopin (available as Clozaril®) and haloperidol (available as Haldol®); non-steroidal anti-inflammatories (NSAID's) such as dicyclofenacs (available as Voltaren®) and etodolac (available as Lodine®), anti-histamines such as loratadine (available as Claritin®), astemizole (available as HismanalTM), nabumetone (available as Relafen®), and Clemastine (available as Tavist®); anti-emetics such as granisetron hydrochloride (available as Kytril®) and nabilone (available as CesametTM); bronchodilators such as Bentolin®, albuterol sulfate (available as Proventil®); anti-depressants such as fluoxetine
  • Erectile dysfunction therapies include, but are not limited to, drugs for facilitating blood flow to the penis, and for effecting autonomic nervous activities, such as increasing parasympathetic (cholinergic) and decreasing sympathetic (adrenergic) activities.
  • useful non-limiting drugs include sildenafils, such as Viagra®, tadalafils, such as Cialis®, vardenafils, apomorphines, such as Uprima®, yohimbine hydrochlorides such as Aphrodyne®, and alprostadils such as Caverject®.
  • H 2 -antagonists which are contemplated for use in the present invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine and aceroxatidine.
  • Active antacid ingredients include, but are not limited to, the following: aluminum hydroxide, dihydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodium carbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth subsilysilate, calcium carbonate, calcium phosphate, citrate ion (acid or salt), amino acetic acid, hydrate magnesium aluminate sulfate, magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, aluminum mono-ordibasic calcium phosphate, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminosilicates, tartaric acids and salts.
  • Anti-inflammatory agents include steroidal anti-inflammatory drugs, such as cortisone, triamcinalone, prednisone, prednisolone, and the like.
  • Dental care products are expressly contemplated, including films or sheets with fluoride, local anesthetics, locally acting steroids or antifungals/antibiotics for local infections. Active ingredients such as lidocaine, benzocaine, chlorhexidine, peroxide and clove oil may be employed.
  • Tooth de-sensitizers may be employed, including inter alia, potassium citrate, potassium chloride, potassium nitrate, strontium chloride, strontium acetate, arginine, calcium carbonate, hydroxyapatite, and calcium sodium phosphosilicate.
  • Veterinary application and use are expressly contemplated, for livestock and companion animals.
  • Stability Certain embodiments are largely non-hygroscopic, and can be packed using non-oxygen barrier materials with relatively high water vapor permeability, without sticking together.
  • a nitrogen (or other gaseous) blanket may be optionally employed. Nitrogen may be used in combination with a composition that includes an anti-oxidant.
  • the film/sheets are packaged loosely without being clumping together (i.e., not individually packed) in a container with a water vapor permeability of 10 ⁇ 7 at 22°C or greater, preferably 10 ⁇ 8 at 22°C or greater (cm 2 *s -1 @25 °C).
  • a water vapor permeability 10 ⁇ 7 at 22°C or greater, preferably 10 ⁇ 8 at 22°C or greater (cm 2 *s -1 @25 °C).
  • the container and container components include, but are not limited to: spherical shapes, tear-drop shapes, pear shapes, crescent shapes, cuboid shapes, prismatic shapes, polygonal shapes, and other shapes suitable for the purposes of the present invention and known in the art.
  • the film/sheets have shapes that are not flat. Bent, or curved shapes, such as those of Figures 13, 14 and 15 may be particularly suitable for use over the teeth, for suitable applications such as teeth whitening, teeth de-sensitization and other tooth and/or gum issues.
  • the film-sheet product is a multi-layer composition inclusive of one or more films or sheets (i.e., different layers).
  • Multi- layer compositions may comprise two or more layers. Layers may be co-formed, i.e. simultaneously formed, optionally in two different forming vessels, and then joined together when still warm, optionally using rollers to compress the films.
  • layers may be PATENT JF1-001WO joined after initial manufacture, in which heat, compression and solvents may be used to join the layers together. Water is a preferred solvent. In one embodiment, moisture is applied to one or more layers prior to joining the two layers with compression (typically rollers). [00330] Thickness of the layers may be the same or different.
  • one layer is at least 15% thicker than at least one other layer, preferably at least 20% thicker, more preferably at least 30% thicker.
  • one or more layers are textured at the seam of lamination.
  • Disintegration times of the layers – which may be considered with the two films when apart (i.e. prior to being joined), or also considered when the two films are together – may vary.
  • layer disintegrates at least 15% faster than at least one other layer, preferably at least 20% faster, more preferably at least 30% faster.
  • Compositions of the layers may differ in the multi-layer composition.
  • the layers may have different colors, different flavors, and may comprise different active ingredients (layers without actives may be included).
  • the layers will have the same geometry (i.e. same shape) even if thickness optionally differs, in certain embodiments, layers may have differing geometries.
  • Optional functionalities include a mucoadhesive layer, and a backing layer to retard salivary flow.
  • a three layer film containing a flavor layer laminated between two nicotine containing layer is expressly contemplated.
  • the layers may be laminated by heat, solvent and pressure.
  • the product may also be supplied as a long tape wound around itself which may be unwound and from which individual pieces may be cut or torn off by the end user.
  • the film or sheet is used to form a pouch, optionally in conjunction with a non-dissolvable material, optionally a fabric material. In preferred embodiments, no non-dissolvable material is used.
  • the pouch may contain a dry blend, a liquid blend, or a dry and liquid blend.
  • the pouch may have one or more compartments.
  • a tubular shape may be flattened between rollers and further compressed or laminated at the edges to form a pouch like structure.
  • the length of a film or sheet is no more than 5% the length of the container it is housed within. In other embodiments, the length of the film or sheet is no more than 10% the length of the container it is housed within. In other embodiments, the length of the film or sheet is no more than 15%, no more than 20%, no more than 25%, no more than 30%, no more than 35%, no more than 40%, no more than 45%, no more than 50%, no more than 55%, no more than 60%, no more than 65%, no more than 70%, no more than 75%, no more than 80%, no more than 85%, no more than 90%, no more than 95%, no more than 100%, no more than 105%, no more than 110%, no more than 115%, no more than 120%, no more than 125%, no more than 130%, no more than 140% or no more than 150% the length of the container it is housed within.
  • the length of a film or sheet is about 5% the length of the container it is housed within. In other embodiments, the length of the film or sheet is about 10% the length of the container it is housed within. In other embodiments, the length of the film or sheet is about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 140% or about 150% the length of the container it is housed within.
  • the length of a film or sheet is at least 5% the length of the container it is housed within. In other embodiments, the length of the film or sheet is at least 10% the length of the container it is housed within. In other embodiments, the length of the film or sheet is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 105%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 140% or at least 150% the length of the container it is housed within.
  • the container of the present invention includes at least one aperture, at least two apertures, at least three apertures, at least four apertures, at least five apertures, at least six apertures, at least seven apertures, at least eight apertures, at least nine apertures, at least 10 apertures, at least 11 apertures, at least 12 apertures, at least 13 apertures, at least 15 apertures, at least 20 apertures or more.
  • the container of the present invention includes no more than one aperture, no more than two apertures, no more than three apertures, no more than four apertures, no more than five apertures, no more than six apertures, no more than seven apertures, no more than eight apertures, no more than nine apertures, no more than 10 apertures, no more than 11 apertures, no more than 12 apertures, no more than 13 apertures, no more than 15 apertures, or no more than 20 apertures.
  • the dispenser of the present invention dispenses at least one product per actuation, at least two products per actuation, at least three products per actuation, at least four products per actuation, at least five products per actuation, at least six products per actuation, at least seven products per actuation, at least eight products per actuation, at least nine products per actuation, at least ten products per actuation or more.
  • the dispenser of the present invention dispenses no more than one product per actuation, no more than two products per actuation, no more than three products per actuation, no more than four products per actuation, no more than five products per actuation, no more than six products per actuation, no more than seven products per actuation, no more than eight products per actuation, no more than nine products per actuation, or no more than ten products per actuation.
  • the chamber of the present invention holds at least one product, at least two products, at least three products, at least four products, at least five products, at least six products, at least seven products, at least eight products, at least nine products, at least 10 products, at least 11 products, at least 12 products, at least 13 products, at least 14 products, at least 15 products, at least 20 products, at least 25 products, at least 30 products, at least 35 products, at least 40 products, at least 45 products, at least 50 products, at least 55 products, at least 60 products, at least 65 products, at least 70 products, at least 75 products, at least 80 products, at least 90 products, at least 100 products, at least 110 products, at least 125 products, at least 150 products, at least 200 products, at least 250 products or more.
  • the chamber of the present invention holds about one product, about two products, about three products, about four products, about five products, about six products, about seven products, about eight products, about nine products, about 10 products, about 11 products, about 12 products, about 13 products, about 14 products, about 15 products, about 20 products, about 25 products, about 30 products, about 35 products, about 40 products, about 45 products, about 50 products, about 55 products, about 60 products, about 65 products, about 70 products, about 75 products, about 80 PATENT JF1-001WO products, about 90 products, about 100 products, about 110 products, about 125 products, about 150 products, about 200 products, about 250 products or more.
  • the chamber of the present invention holds no more than one product, no more than two products, no more than three products, no more than four products, no more than five products, no more than six products, no more than seven products, no more than eight products, no more than nine products, no more than 10 products, no more than 11 products, no more than 12 products, no more than 13 products, no more than 14 products, no more than 15 products, no more than 20 products, no more than 25 products, no more than 30 products, no more than 35 products, no more than 40 products, no more than 45 products, no more than 50 products, no more than 55 products, no more than 60 products, no more than 65 products, no more than 70 products, no more than 75 products, no more than 80 products, no more than 90 products, no more than 100 products, no more than 110 products, no more than 125 products, no more than 150 products, no more than 200 products, no more than 250 products or no more than 500 products.
  • an individual chamber of the present invention includes one protrusion, two protrusions, three protrusions, four protrusions, five protrusions, six protrusions, seven protrusions, eight protrusions, nine protrusions, ten protrusions or more.
  • an individual chamber of the present invention includes at least one protrusion, at least two protrusions, at least three protrusions, at least four protrusions, at least five protrusions, at least six protrusions, at least seven protrusions, at least eight protrusions, at least nine protrusions, at least 10 protrusions or more.
  • an individual chamber of the present invention includes no more than one protrusion, no more than two protrusions, no more than three protrusions, no more than four protrusions, no more than five protrusions, no more than six protrusions, no more than seven protrusions, no more than eight protrusions, no more than nine protrusions, no more than 10 protrusions or no more than 15 protrusions.
  • the height of the chamber containing a film or sheet is no more than 75% of the height of the film or sheet. In other embodiments, the height of the chamber containing a film or sheet is no more than 80% of the height of the film or sheet.
  • the height of the chamber containing a film or sheet is no more than 85%, no more than 90%, no more than 95%, no more than 100%, no more than 105%, PATENT JF1-001WO no more than 110%, no more than 115%, no more than 120%, no more than 125%, no more than 150%, no more than 175%, or no more than 200% of the height of the film or sheet.
  • the height of the chamber containing a film or sheet is about 50% of the height of the film or sheet. In other embodiments, the height of the chamber containing a film or sheet is about 55% of the height of the film or sheet.
  • the height of the chamber containing a film or sheet is about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 150%, about 175%, or about 200% of the height of the film or sheet.
  • the height of the chamber containing a film or sheet is at least 75% of the height of the film or sheet. In other embodiments, the height of the chamber containing a film or sheet is at least 80% of the height of the film or sheet.
  • the height of the chamber containing a film or sheet is at least 85%, at least 90%, at least 95%, at least 100%, at least 105%, at least 110%, at least 115%, at least 120%, at least 125%, at least 150%, at least 175%, or at least 200% of the height of the film or sheet.
  • the non-smooth chamber surface area relative to total chamber surface area of the present invention is at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%.
  • the non-smooth chamber surface area relative to total chamber surface area of the present invention is about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%.
  • the non-smooth chamber surface area relative to total chamber surface area of the present invention is no more than 15%, no more than 20%, no more than 25%, no more than 30%, no more than 35%, no more than 40%, no more than 45%, no more than 50%, no more than 55%, no more than 60%, no more than 65%, no more than 70%, no more than 75%, no more than 80%, no more than 85%, no more than 90%, no more than 95%, no more than 96%, no more than 97%, no more than 98%, no more than 99%, no more than 99.5%.
  • PATENT JF1-001WO Further illustration of the present invention is shown in the working examples produced below.
  • EXAMPLES [00359] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples are intended to be a mere subset of all possible contexts in which the components of the formulation may be combined. Thus, these examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the type and amounts of components of the formulation and/or methods and uses thereof.
  • EXAMPLE A Efficacy of Orally Soluble Nicotine Films [00360] Smoking is a practice in which a substance is combusted and the resulting smoke is inhaled to be tasted and absorbed into the bloodstream of a person.
  • Smoking has negative health effects, because smoke inhalation inherently poses challenges to various physiologic processes such as respiration.
  • Smoking tobacco is among the leading causes of many diseases such as lung cancer, heart attack, COPD, erectile dysfunction, and birth defects.
  • Diseases related to tobacco smoking have been shown to kill approximately half of long-term smokers when compared to average mortality rates faced by non-smokers.
  • Smoking caused over five million deaths a year from 1990 to 2015.
  • Non-smokers account for 600,000 deaths globally due to second-hand smoke.
  • This example illustrates that a nicotine delivery system that provides cigarette-like plasma levels, serves to reduce acute craving, inhibit relapse, and result in higher smoking cessation rates compared with conventional methods.
  • the patient is provided films containing 0.25% w/w nicotine.
  • the patient dispenses an individual film as needed, when he feels the craving to smoke.
  • the film gradually dissolves and nicotine is released.
  • the nicotine is absorbed through the mucosa in a rate comparable to the rate of nicotine absorption through the lungs via conventional cigarette smoking.
  • the patient is able to replace cigarettes with oral films. Gradually, the patient reduces his use of films thereby reducing his reliance on nicotine.
  • an 8 mg nicotine oil containing film or sheet that weighs 125 mg is over 6% nicotine oil in the film/sheet matrix.
  • a 12 mg nicotine film or sheet that weighs 125 mg is over 9% nicotine oil in the film/sheet matrix.
  • films/sheets are intended for buccal use, it is important that a film or sheet have level of stiffness to allow it to be easily placed in the check (a more flexible film is harder to place and harder to manipulate in the mouth). In traditional film manufacture and formulation, flexibility of the film is prized as an attribute, so the film can be readily manipulated when it is rolled up after casting and then in subsequent conversion steps to package the film. [00370] Additionally, absorption of ambient moisture by the film/sheet may increase the tackiness of the film/sheet. The film/sheet may adhere to another film or sheet (where the films or sheets are not separated in the container – see container embodiments, infra), or adhere to the surface of the container (see discussions of container surfaces, infra).
  • the film composition should be resistant to moisture uptake, and the composition, in tandem with features of the container, not stick or adhere to the container surfaces during the expected time the container will be exposed to ambient air without barrier protection. [00371] All of these attributes must be pursued in conjunction with the desired attributes of film/sheet performance, i.e. release of active, release of flavor, disintegration time, lack of film residue, desired mucoadhesion, and other desired attributes. [00372] Table 2 below shows the percentage composition of ingredients and excipients for a synthetic nicotine orally soluble film.
  • the dry feedstock was softened using an extruder at a processing temperature of 90C. The. The resulting material was run through unheated rollers to control thickness and texturize the resulting sheet. [00374] Individual doses were die cut with a piece weight of 150 mg. Weight variation was tight confirming successful thickness control by dynamic roll molding. [00375] A healthy adult volunteer uses the product in the buccal cavity. Observations included: the stiff film was easy to insert; the relatively low height of the product allowed the product to be used in the buccal cavity below the tooth line; there was an initial nicotine “bite” within 45 seconds of insertion (though the user deemed the “bit” to be mold); the film/sheet took approximately twenty-five minutes to dissolve; the user felt the flavor delivery from the product for the entire dissolution period.
  • Example A The volunteer believed that the films of Example A provided greater nicotine delivery than an equivalent, 4 mg nicotine pouch. It was observed that the texture on the film appeared to meaningfully increase surface area.
  • Twenty of the cut films were placed in a plastic container, taken from “On! TM ” nicotine pouch container (which has a rectangular shape). The adult volunteer carried the product in their pocket to determine whether, in real world conditions, product tackiness would be an issue. It was noted in this regard that the interior space was adequate for the film strips to move around while naturally shaken in the pocket. Each dimension of the “On! TM ” container exceeded twice of both the height and width of the film strips.
  • glycerol monooleate was adequate to retard product tackiness for a formulation containing nicotine oil.
  • a preferred amount is less than 0.2%, or a range of 0.1% to 0.2%, preferably less than 0.1% or a range of 0.01% to 0.1%, more preferably less than 0.075% or a range of 0.01% to 0.075%.
  • EXAMPLE B PATENT JF1-001WO Table 3 – Synthetic Nicotine and Excipients Ingredients Percent Synthetic Nicotine 1.6% Klucel ELF (HPC) 81.57% PEO N10 0.05% L-Arginine 3.00% Gelucire 0.20% MCT oil 1.00% Mint 1.50% Aeropearl 300 P 6.00% Sucralose 4.00% Magnasweet 1.00% Blue 1 0.08% TOTAL SOLIDS 100.00% [00379] The inactive ingredients of Example B were mixed using staged mixing. Nicotine was deposited or sprayed on to the inactive ingredients with high intensity mixing. The dry feedstock was softened using an extruder at a processing temperature of 90C.
  • Example A provided greater nicotine delivery than an equivalent, 2 mg nicotine pouch.
  • Film attributes were judged good in terms of product stickness and flexibility.
  • EXAMPLE C TABLE 4 Ingredients Percent Synthetic Nicotine 1.74% Soluplus 21.29% Klucel ELF (HPC) 44.99% Corn Syrup Solids 12.98% PEO N10 0.10% L-Arginine 3.00% Gelucire 0.20% MCT oil 1.00% Blood Orange 3.00% Mint 0.25% Aeropearl 300 P 6.00% Sucralose 4.00% Magnasweet 0.70% Colorants (yellow 5, 6, Red 50) 0.75% PATENT JF1-001WO TOTAL SOLIDS 100.00% staged mixing. high intensity mixing. The dry feedstock was softened in a heated barrel at a processing temperature of 90C.
  • the resulting semi-molten material was run through unheated rollers to control thickness and texturize the resulting sheet.Individual doses were die cut with a piece weight of 125 mg for a dose of 2 mg.
  • the films of this example were deemed to have improved mouthfeel over the films of Example B, resulting in a less “gummy” feel in the buccal pouch.
  • EXAMPLE D TABLE 5 Ingredients Percent Synthetic Nicotine 3.2% Soluplus 8% Klucel ELF 54.2% Corn Syrup Solids 15.5% PEO N10 0.05% L-Arginine 3% Gelucire 0.2% MCT Oil 1% Blood Orange 3% Mint 0.25% Aeropearl 300 P 6% Sucralose 4% Magnasweet 1% Colorants 0.6% TOTAL SOLIDS 100% [00385]
  • the inactive ingredients of Example D were mixed using staged mixing. Nicotine was deposited or sprayed on to the inactive ingredients with high intensity mixing. The dry feedstock was softened in a heated barrel at a processing temperature of 90C. The resulting semi-molten material was run through unheated rollers to control thickness and texturize the resulting sheet.
  • Example E Ingredients Percent PATENT JF1-001WO Synthetic Nicotine Bitartrate 11.40% Klucel ELF 40.45% Erythritol 29.10% L-Arginine 3% MCT oil 0.50% Blood Orange 3.00% Mint 0.25% PEO 1.00% Aerosil 300 P 6.00% Sucralose 4.00% Magnasweet 0.70% Colorants Yellow & Red 0.6% TOTAL SOLIDS 100% [00387] The inactive ingredients of Example E were mixed using staged mixing.
  • Nicotine was deposited or sprayed on to the inactive ingredients with high intensity mixing.
  • the dry feedstock was softened in a heated barrel at a processing temperature of 90C.
  • the resulting semi-molten material was run through unheated rollers to control thickness and texturize the resulting sheet.
  • Individual doses were die cut with a piece weight of 100 mg for a dose of 4 mg.
  • the formulation was adjudged to be too soft.
  • EXAMPLE F TABLE 7 Ingredients Percent Synthetic nicotine 8.00% Klucel ELF 74.85% L-Arginine 2.00% MCT oil 0.50% Blood Orange 3.00% Mint 0.25% PEO 0.10% Ca Silicate 6.00% Sucralose 4.00% Magnasweet 0.70% Colorants – Yellow 5, 6, Red 40 0.55% TOTAL SOLIDS 100% [00390]
  • the inactive ingredients of Example F were mixed using staged mixing. Nicotine was deposited or sprayed on to the inactive ingredients with high intensity mixing. The dry feedstock was softened in an extruder at a processing temperature of 90C. The PATENT JF1-001WO resulting semi-molten material was run through unheated rollers to control thickness and texturize the resulting sheet.
  • Example G TABLE 8 Ingredients Percent Syn Nicotine 2.67% Klucel ELF 83.05% L-Arginine 2% MCT oil 0.5% Menthol 0.5% Clove oil 1.5% Aerosil r972 4% Ca Silicate 2% Sucralose 3% Magnasweet 0.7% Blue 1 .08% TOTAL SOLIDS 100% [00392]
  • the inactive ingredients of Example G were mixed using staged mixing. Nicotine was deposited or sprayed on to the inactive ingredients with high intensity mixing. The dry feedstock was softened in a heated barrel at a processing temperature of 90C.
  • the resulting semi-molten material was run through unheated rollers to control thickness and texturize the resulting sheet. [00394] The pieces were cut to a weight of 150 mg, for a target dose of 8 mg per piece. The Formulation took approximately eighteen minutes to dissolve in the buccal cheek pouch of an adult user. Film properties were good.
  • Example I TABLE 10 Ingredients Percent Delta 8 THC 3.33% Klucel ELF 87.47% PEO N10 6% Caprol PGE-860 0.25% GMO (Peceol) 0.25% Meglumine 0.5% Sucralose 2% Ca Silicate 3% Aerosil R972 2% Magnasweet 0.1% Magna CBD 0.05% Grapefruit Flavor 4% TOTAL SOLIDS 100% [00395]
  • the inactive ingredients of Example I were mixed using staged mixing. Nicotine was deposited or sprayed on to the inactive ingredients with high intensity mixing. The dry feedstock was softened in a heated barrel at a processing temperature of 90C. The resulting semi-molten material was run through unheated rollers to control thickness and texturize the resulting sheet.
  • the formulation comprised a combination of surfactacts – Caprol and Peceol. This is a combination of a high HLB surfactant (10-12)(Caprol PGE-860) with a low HLB surfactant (0-1)(Peceol). In this formulation they are used in a 1-1 ratio; a ratio of 1-3 is also contemplated.
  • PATENT JF1-001WO Label Ingredients Claim Percent (mg) Synthetic Nicotine Oil 4 3.385% E xcipients Klucel Fusion X Pharm 56.595% Corn Syrup Solids 240 (Milled) 15.00% PEO N10 0.070% Pharmacoat 606 7.00% L-Arginine (Milled) 3.00% [00400] The composition Gelucire 48/16 0.20% was mixed M CT Oil 1.00% using staged M int 0.75% mixing.
  • the target film Cab-o-sil 6.00% weight for this experiment Sucralose 5.00% was 130 mg, with an Magnasweet 1.00% intended label claim of 4 mg Calcium Carbonate (CalEssence 0PCC) 1 per film, and 30 .00% an overage TOTAL SOLIDS 100.00% (i.e. active in excess of intended label claim of 10%).
  • the composition was processed akin to Example J, except that the highest processing temperature was 78°C.
  • the film ribbon had good flexibility. Some roughness on the edges of the film was present.
  • PATENT JF1-001WO Label Ingredients Claim Percent (mg) S ynthetic Nicotine Oil 4 3.385% E xcipients Klucel Fusion X Pharm 63.095% C orn Syrup Solids 240 (Milled) 15.50% P EO N10 0.070% P harmacoat 606 – L -Arginine (Milled) 3.00% G elucire 48/16 0.20% M CT Oil 1.00% M int 0.75% C ab-o-sil 6.00% S ucralose 5.00% M agnasweet 1.00% Calcium Carbonate (CalEssence 1.00% 300PCC) T OTAL SOLIDS 100.00% [00402] The composition was mixed using staged mixing.
  • the target film weight for this experiment was 130 mg, with an intended label claim of 4 mg per film, and an overage (i.e. active in excess of intended label claim of 10%).
  • the composition was processed akin to Example J, except that the highest processing temperature was 78 °C.
  • the film ribbon had good flexibility. Some roughness on the edges of the film was present.
  • Example M Table 14 Label Ingredients Claim Percent (mg) PATENT JF1-001WO Synthetic Nicotine Oil 4 3.385% E xcipients Klucel Fusion X Pharm 68.595% Corn Syrup Solids 240 (Milled) 10.00% PEO N10 0.070% Pharmacoat 606 – L-Arginine (Milled) 3.00% Gelucire 48/16 0.20% MCT Oil 1.00% Mint 0.75% Cab-o-sil 6.00% Sucralose 5.00% Magnasweet 1.00% Calcium Carbonate (CalEssence 300PCC) 1.00% TOTAL SOLIDS 100.00% [00404] This example was mixed processed like Example L, with a maximum processing temperature of 78°C, except this Example contained 10% corn syrup solids.
  • Example N Label Ingredients Claim Percent (mg) Synthetic Nicotine 4 3.385% E xcipients Klucel Fusion X Pharm 78.595% Corn Syrup Solids 240 (Milled) – PEO N10 0.070% Pharmacoat 606 – L-Arginine (Milled) 3.00% Gelucire 48/16 0.20% MCT Oil 1.00% Mint 0.75% Cab-o-sil 6.00% PATENT JF1-001WO S ucralose 5.00% Magnasweet 1.00% Calcium Carbonate (CalEssence 300PCC) 1.00% TOTAL SOLIDS 100.00% [00405] The target film weight for this experiment was 130 mg.
  • the overage in the composition prior to processing is less than 10%, preferably less than 7.5%, more preferably less than 5%, and most preferably less than 2.5%.
  • PATENT JF1-001WO Reducing or eliminating venting during processing may be useful in this regard; even more important is the reduction in maximum processing temperatures.
  • the composition may be exposed to maximum processing temperatures in certain embodiments for five minutes or less, preferably three minutes or less, more preferably 2 minutes or less, most preferably 1 minute or less.
  • Klucel Fusion X were relatively quick to dissolve in the cheek. An adult volunteer found the films disintegrated in the buccal cavity in a range of 2.5 to 8 minutes. Disintegration times where similar; 3 to 9 minutes, when used in the upper cheek. [00414] It was further observed that Klucel Fusion X could be combined effectively with other polymers.
  • a preferred embodiment is a composition comprising Klucel Fusion X and Klucel ELF, in a ratio between 1 to 10 and 1 to 3.
  • EXAMPLE Q Table 18 Label Ingredients Claim Percent (mg) Syn Nicotine 4 3.520% E xcipients Klucel ELF (Lot: 234078) 55.408% Corn Syrup Solids 240 (Milled@0.12) 15.50% PEO N10 0.070% Pharmacoat 606 5.000% L-Arginine (Milled@0.12) 3.00% Gelucire 48/16 0.20% Water 2.00% Mint 0.80% Cab-o-sil 6.00% Sucralose 5.00% Magnasweet 1.00% Rice Flour 2.00% Calcium Carbonate (CalEssence 300PCC) 0.50% TOTAL SOLIDS 100.00% PATENT JF1-001WO [00415] The target weight for this composition was 125 mg per film, an intended dose of 4 mg, and an overage of 10% of the active was included; the maximum processing temperature was 95°C.
  • rice flour from 0.25% to 5% as an anti-caking agent, preferably from 0.5% to 3.5%, more preferably from .75% to 3%, and most preferably from 1.25% to 2.75%.
  • rice flour from 0.25% to 5% as an anti-tack agent, preferably from 0.5% to 3.5%, more preferably from .75% to 3%, and most preferably from 1.25% to 2.75%.
  • rice flour from 0.25% to 5% as a whitening agent, preferably from 0.5% to 3.5%, more preferably from .75% to 3%, and most preferably from 1.25% to 2.75%.
  • rice flour may be used as a whitening agent together with calcium carbonate.
  • Preferred embodiments for whitened films include compositions comprising rice flour from 0.5% to 3.5%, and calcium carbonate from 0.2% to 1.2%.
  • Example S Table 20 Label Ingredients Claim Percent (mg) Synthetic Nicotine 4 3.143% E xcipients Klucel ELF 53.088% Corn Syrup Solids 240 (Milled) 10.00% PEO N10 0.070% Pharmacoat 606 10.000% L-Arginine (Milled) 3.00% Gelucire 48/16 0.20% MCT Oil 6.00% Mint 1.00% Cab-o-sil 6.00% Sucralose 5.00% Magnasweet 1.00% Rice Flour 1.00% Calcium Carbonate (CalEssence 300PCC) 0.50% TOTAL SOLIDS 100.00% PATENT JF1-001WO [00423] Films were made from the composition described above, with a maximum processing temperature of 95°C.
  • embodiments of the present invention may be used with dosage forms other than films or sheets; including without limitation, tablets, capsules, gel-caps, lozenges, nicotine pouches, non-nicotine pouches with other actives, and other solid dosage forms.
  • embodiments of the invention include a dispenser for releasing pieces of oral film.
  • the dispenser can include (a) a central hub, (b) a plurality of spokes that protrude from the central hub to a periphery to form individual chambers, and (c) an outer case with an aperture.
  • the central hub is configured to rotate around an axis so that a chamber aligns with an aperture to release a piece of the oral film.
  • each spoke is wider at its periphery (e.g., arrow-shaped) to create positional stability for a single piece of oral film.
  • each piece of the oral film includes an active agent (e.g., nicotine).
  • the dispenser includes a push-button actuator that rotates a first chamber from the aperture to a second chamber.
  • Embodiments also include a dispenser that is shaped like a puck.
  • the puck dispenser can include a central chamber portion that is elevated (i.e., to form a cone shape).
  • the open-ended transitional term “comprising” (and equivalent open-ended transitional phrases thereof like including, containing and having) encompasses all the expressly recited elements, limitations, steps and/or features alone or in combination with unrecited subject matter; the named elements, limitations and/or features are essential, but other unnamed elements, limitations and/or features may be added and still form a construct within the scope of the claim.
  • the meaning of the open-ended transitional phrase “comprising” is being defined as encompassing all the specifically recited elements, limitations, steps and/or features as well as any optional, additional unspecified ones.
  • the meaning of the closed-ended transitional phrase “consisting of” is being defined as only including those elements, limitations, steps and/or features specifically recited in the claim whereas the meaning of the closed-ended transitional phrase “consisting essentially of” is being defined as only including those elements, limitations, steps and/or features specifically recited in the claim and those elements, limitations, steps and/or features that do not materially affect the basic and novel characteristic(s) of the claimed subject matter.
  • the open-ended transitional phrase “comprising” includes within its meaning, as a limiting case, claimed subject PATENT JF1-001WO matter specified by the closed-ended transitional phrases “consisting of” or “consisting essentially of.”
  • embodiments described herein or so claimed with the phrase “comprising” are expressly or inherently unambiguously described, enabled and supported herein for the phrases “consisting essentially of” and “consisting of.”
  • All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention.

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Abstract

Des modes de réalisation comprennent un film ou une feuille fabriqué par moulage par rouleau dynamique. Le film ou la feuille peut comprendre un agent actif (par exemple, de la nicotine) pour une administration orale. Selon des aspects, un agent actif est appliqué à la muqueuse buccale d'un sujet pour une distribution locale ou systémique. Des modes de réalisation comprennent également des récipients et des distributeurs pour films ou feuilles comestibles et solubles par voie orale pour administrer des agents thérapeutiques. Le film ou la feuille peut comprendre un agent actif (par exemple, de la nicotine) pour une administration orale. Selon des aspects, un agent actif est appliqué à la muqueuse buccale d'un sujet pour une distribution locale ou systémique. Des modes de réalisation comprennent également des récipients qui distribuent des films ou des feuilles comestibles et solubles par voie orale par l'intermédiaire de cassettes rotatives qui alignent des chambres contenant un film ou une feuille avec une ouverture ouverte.
PCT/US2024/043779 2023-08-24 2024-08-24 Films oraux comestibles, compositions, procédé de fabrication et systèmes d'emballage Pending WO2025043236A1 (fr)

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