Stable film formulations for high loading of low melting point actives

Abstract

An oral film formulation; it has at least one active pharmaceutical ingredient (API) having a melting point below 80°C, wherein the API includes at least 20% by weight of the dry film; a film forming matrix including at least two polymers, wherein the film forming matrix includes at least 20% by weight of the dry film; and wherein at least one polymer has a glass transition temperature (Tg) at least three times higher than the melting point of the API; and a method of preparation thereof.

Description

[0001] The present application claims priority from U.S. provisional patent application No. 63 / 614,075 filed on December 22, 2023, incorporated herein by reference. FIELD OF THE DISCLOSURE

[0002] This disclosure relates to oral dosage forms for administration of an active agent, and more particularly to high loaded films containing an active agent having a low melting point. BACKGROUND OF THE DISCLOSURE

[0003] This disclosure relates to oral film dosage formulations and processes for preparing oral film dosage forms, and more particularly to the preparation of oral film dosage forms that are suitable for high active content films for both human and animal applications. Film-type oral dosage forms are often preferred by subjects that have difficulty swallowing tablets or capsules. Such drug delivery options can allow the medication to bypass the first pass metabolism thereby making the medication more bioavailable. As the strip dissolves, the drug can enter the blood stream enterically, buccally or sublingually. Film-type dosage forms are designed for oral administration, with the user placing the strip on or under the tongue (sublingual) or along the inside of the cheek (buccal). Oral films eliminate some common problems associated with drug administration such as the fear of choking and the need for water intake. Oral films also offer significant benefits to those subjects wanting to administer the medication in a discreet, inconspicuous, unnoticeable and / or private manner, especially while in the company of others. Such oral films are also particularly useful for geriatric, pediatric and veterinary subjects.

[0004] Various active ingredients pose distinct challenges when it comes to their integration into films and maximizing their utility. A prime example of such complexity lies in the case of low melting point actives, which may necessitate high loading within the film matrix to ensure effectiveness.

[0005] Active Pharmaceutical Ingredients (APIs) characterized by a low melting point often present a range of inherent characteristics. They tend to exhibit increased stickiness, lower stiffness, heightened susceptibility to environmental factors such as humidity during manufacturing, and are more prone to deformation when subjected to stress within the film. Additionally, these APIs can display reduced stability when formulated in their amorphous state, adding further complexity to their incorporation into pharmaceutical films. Therefore, there is a need to develop solutions for the formulation of stable and manufactureable oral films with high loading of low melting point APIs.

[0006] On of the biggest advantages of film formulation generally is the capability to formulate the API in an amorphous state, which is significantly more difficult using the tablet approach. However, for molecules with low melting points remaining in amorphous state under different stability conditions might be a challenge as stability studies have to be conducted over a long period of time (24 to 36 months), exposure to high humidity condition (60 to 75%) and temperature close to melting point for some molecule (25 to 40°C) permitting movement of the API and potential reorganization. Prevention of the recrystallization is known in film formulation and is covered in patents and applications like for example JP3674566B2 / US9408809B2 METHOD FOR PREVENTING CRYSTALLIZATION OF A PHARMACEUTICAL IN A POLYMER FILM, the patent disclosed drying above the melting point for a certain amount of time.

[0007] In 20170157119 SOLID ORAL FILM DOSAGE FORMS AND METHODS FOR MAKING SAME, improved solubilization and stabilization of an active ingredient in particle form include at least one primary crystallization inhibitor in an amount that inhibits growth and / or agglomeration of the active ingredient.

[0008] However, in the aforementioned disclosures the emphasis is not placed on APIs with low melting points. SUMMARY OF THE DISCLOSURE

[0009] In certain aspects of this disclosure, at least one API exhibits a low melting point.

[0010] In certain aspects of this disclosure, the oral film will be high loading.

[0011] In certain aspects of this disclosure, the disclosed formulations and excipients are specifically adapted for use in humans.

[0012] In certain aspects of this disclosure, the disclosed formulations and excipients are specifically adapted for use in animals.

[0013] In certain aspects of this disclosure, the disclosed excipients are pharmaceutical or food grade. And the process manufacturing process follows good production practices (GPP) or good manufacturing practices (GMP).

[0014] These and other features, advantages and objects of the various embodiments will be better understood with reference to the following specification and claims.

[0015] In certain aspects of this disclosure, an oral film formulation is provided comprising at least one active pharmaceutical ingredient (API) having a melting point below 80°C, wherein the API comprises at least 20% by weight of the dry film, and a film forming matrix comprising at least two polymers, wherein the film forming matrix comprises at least 20% by weight of the dry film. The formulation is characterized in that at least one polymer has a glass transition temperature (Tg) at least three times higher than the melting point of the API. This configuration provides a stable film formulation capable of maintaining its physical and chemical properties despite the challenges posed by incorporating high loadings of low melting point APIs.

[0016] In certain embodiments, the API may comprise at least 30% by weight of the dry film, and in some embodiments, may comprise at least 40% by weight of the dry film. The API may have a melting point below 60°C, and in some cases, between 20°C and 55°C. These high API loadings are achieved while maintaining the stability and mechanical properties of the film through careful selection of the polymer matrix components and their relative proportions.

[0017] The film forming matrix may comprise multiple polymers serving different functions within the formulation. In certain embodiments, the matrix includes at least one polymer that acts as a crystal inhibitor, at least one polymer that acts as a viscosity enhancer, and at least one polymer that acts as a matrix stiffener with a Tg above 120°C. The crystal inhibitor may comprise hydroxypropyl methylcellulose (HPMC), while the viscosity enhancer may comprise hydroxypropyl cellulose (HPC). This combination of polymers with different functional properties helps maintain the stability of the high-loaded API in its amorphous state while providing appropriate mechanical properties to the film.

[0018] In certain aspects, the formulation contains minimal amounts of traditional plasticizers, specifically less than 5% plasticizer by weight, as the low melting point API itself can function as a plasticizer within the film matrix. Similarly, the residual solvent content is controlled to be less than 5% by weight in the final film product. The film forming matrix typically comprises between 25% and 45% by weight of the dry film, providing sufficient structural support while allowing for high API loading.

[0019] The formulations may be particularly suited for sublingual or buccal administration, taking advantage of these routes of administration for improved bioavailability. Additional components may be incorporated into the formulation, including pH modifiers, stabilizers, flavoring agents, flavor enhancers, sweeteners, and colorants. When present, stabilizers may be selected from the group consisting of ascorbic acid, Vitamin E TPGS, sodium metabisulfite, and BHT.

[0020] Methods of preparing such oral film formulations are also contemplated within this disclosure. These methods generally comprise providing at least one API having a melting point below 80°C, combining the API with a film forming matrix comprising at least two polymers (wherein at least one polymer has a glass transition temperature at least three times higher than the melting point of the API), forming a blend comprising the API and film forming matrix, and casting the blend to form an oral film. The polymers for the film forming matrix are specifically selected to achieve a final glass transition temperature above the melting point of the API, which helps maintain physical stability of the formulation.

[0021] The blending process may involve dissolving the API in a solvent, combining the dissolved API with the polymers, and mixing until uniform. The casting process is controlled to maintain the residual solvent content below 5% by weight in the final oral film. This careful control of the manufacturing process, combined with the specific selection of components and their proportions, results in a stable oral film formulation that maintains its physical stability without recrystallization when exposed to accelerated stability conditions (40°C / 75% RH) for at least one month.

[0022] In certain embodiments, the oral film formulation demonstrates enhanced stability against environmental factors such as heat and moisture while maintaining the API in an amorphous state. The formulation achieves this stability through the specific combination of polymers with different glass transition temperatures and functional properties, rather than through traditional approaches relying on high levels of plasticizers. This innovative approach allows for the successful incorporation of high levels of low melting point APIs while maintaining the necessary mechanical properties and stability of the oral film.

[0023] The stability of these formulations can be attributed to several factors working in concert. First, the selection of polymers with appropriately high glass transition temperatures helps restrict molecular mobility within the film matrix, reducing the tendency for API recrystallization. Second, the minimal use of plasticizers and careful control of residual solvent content helps maintain the desired mechanical properties without compromising stability. Third, the incorporation of crystal inhibitors helps maintain the API in its amorphous state, while viscosity enhancers and matrix stiffeners provide the necessary structural support and mechanical properties.

[0024] In particular embodiments, the film forming matrix may comprise combinations of polymers selected to provide specific functional properties. For example, hydroxypropyl methylcellulose (HPMC) may serve as both a crystal inhibitor and film former, while hydroxypropyl cellulose (HPC) may provide viscosity enhancement and additional filmforming properties. The relative proportions of these polymers can be adjusted to optimize the balance between API loading, stability, and mechanical properties of the final film product.

[0025] The mechanical properties of the resulting films are particularly noteworthy, as they maintain appropriate flexibility and strength despite the high loading of low melting point APIs. This is achieved through the careful balance of polymer types and their relative proportions, along with the minimal use of traditional plasticizers. The films typically exhibit sufficient tensile strength for handling and administration while maintaining enough flexibility to prevent cracking or breaking during normal use.

[0026] The formulations described herein may be particularly advantageous for APIs that benefit from transmucosal delivery, as the stable incorporation of high API loads in an amorphous state can promote rapid dissolution and absorption through the oral mucosa. This can lead to improved bioavailability compared to conventional oral dosage forms, particularly for APIs that undergo significant first-pass metabolism or are poorly absorbed from the gastrointestinal tract. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The invention will be better understood by way of the following detailed description of embodiments of the invention with reference to the appended drawings, in which:

[0028] Figure 1 is a drawing illustrating delamination occurring during an unrolling of a film; and

[0029] Figure 2 is a photograph of several exemplary films. DETAILED DESCRIPTION OF THE DISCLOSURE

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0031] It is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0032] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0033] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range.

[0034] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range. When a range or a list of sequential values is given, unless otherwise specified any value within the range or any value between the given sequential values is also disclosed.

[0035] The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

[0036] A variety of additives that can be integrated into the films herein and may provide a variety of different functions. Examples of classes of additives include excipients, lubricants, buffering agents, stabilizers, blowing agents, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, anti-adherents, antifoaming agents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, taste modifier agents, viscosity enhancer, mucoadhesive agent, anti-tacking agent, basifying agent, anti-microbial agent, chelating agent and mixtures thereof. These additives may be added along with the active ingredient(s).

[0037] Film systems embody a field of technology that has major advantages in areas of administering various actives to an individual in need thereof. The present disclosure relates to oral films and methods for forming film products that include at least one active with a low melting point.

[0038] The term “film” refers to a type of dosage form that is distinctly different from pills, tablets, caplets, and capsules, and in which the dosage form is a thin strip of material. It will be understood that the term “film” includes delivery systems of various thickness, including films, film strips, discs, sheets, stamp, and the like, in any shape. Such films are typically rapidly disintegrating or rapidly dissolving, but can also exhibit longer disintegration times when required. The films are generally sufficiently flexible to allow bending or even folding without breaking. For example, the films typically have length and width dimensions on the order of 5 to 40 mm, although larger or smaller dimensions are possible and may be desirable in particular circumstances, and a thickness on the order of 5 to 300 pm, although larger or smaller thicknesses are possible and may be desirable in certain circumstances.

[0039] The terms “oral dissolving film,” “oral dissolvable film”, “oral disintegrating film”, OSF, “oral soluble film”, “ODF”, “oral chewable film”, “OCF”, “oral thin film”, “OTF,” “oral wafer”, “oral drug strip” or “oral strip” refer to a product used to administer a predetermined amount of active ingredient(s) via oral administration such as oral transmucosal absorption, sublingual delivery or buccal delivery and will be referred to throughout as oral film(s), denoted “OF”.

[0040] The term “acidifier” refers to a substance or compound incorporated into the formulation to lower the pH (acidity) of the environment. An acidifier falls into the category of pH modifier.

[0041] In the context of oral films, the term “agglomeration” refers to the undesired formation of clusters or clumps of particles or components within the film matrix. These clusters can consist of active pharmaceutical ingredients (APIs), excipients, or other substances present in the formulation. Agglomeration can occur during various stages of the film preparation process, such as mixing, dispersion, or drying, and it results in the non-uniform distribution of components within the film. This uneven distribution can lead to inconsistency in drug content, altered mechanical properties, uneven drug release, and compromised performance or efficacy of the oral film. Controlling agglomeration is crucial to ensure the homogeneity and quality of the final oral film product.

[0042] An agglomeration inhibitor in the context of oral films refers to a substance or ingredient that is added to the formulation of the film to prevent or minimize the formation of agglomerates or clusters of particles. Agglomerates are formed when small particles stick together, which can negatively impact the quality, uniformity, and effectiveness of the oral film. Agglomeration inhibitors help maintain the desired properties of the film, such as its texture, appearance, and the even distribution of active ingredients. Examples include butare not limited to the following and their derivatives: Polyvinylpyrrolidone and Hydroxypropylmethylcellulose (HPMC) where the polymer structure combines both hydrophobic (methoxy group) and hydrophilic substitutions (hydroxypropoxy group) and have aqueous viscosity up to 15000 mPas (2% ,20C), employed alone or mixed with 5 Methyl cellulose (MC) of aqueous viscosity up to 5040 mPas (2% ,20C).

[0043] As used herein, the term “animal” is meant to indicate mammals, and to exclude humans. This disclosure contemplates oral film formulations suitable for both humans and animals.

[0044] The term “active agent(s)” or “API” refers mainly to active pharmaceutical io ingredients, drugs, pharmaceuticals, but may also refer generally to any agent(s) that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body subject.

[0045] There are many active pharmaceutical ingredients (APIs) known for their low 15 melting points, including but not limited to the following as categorized by their respective drug classes: Common Name Indication MP (°C) Bupropion Antidepressant 25 Desipramine Antidepressant 25 Trifluoperazine Antipsychotic 25 Valproic Acid Anticonvulsant 25 Verapamil Antihypertensive 25 Ampyzine Sulfate Nootropic 26 Carbantel Lauryl Sulfate Anthelminithic 27 Isaxonine Nootropic 27 Ethanolamine Hydrofluoride Dermatologic 28 Furethidine Antihypertensive 28 Tranylcypromine Antidepressant 28 Dixanthogen Ectoparasiticide 29 Pentrinitrol Vasodilator 29 Etafedrine Adrenergic 29 Norletimol Unclassified 30 Dinoprost Oxytocic 30 Temefos Ectoparasiticide 30 Meparfynol Sedative 31 Ambuphylline Bronchodilator 31 Fluphenazine Antipsychotic 31 Decanoate Sulfiram Ectoparasiticide 31 Paramethadione Anticonvulsant 32 Carmustine Antineoplastic 32 Guaiacol Expectorant 32 Bioresmethrin Dermatologic 33 Clofibride Antihyperlipidemic 34 Pilocarpine Antiglaucoma 34 Metoprolol Antihypertensive 35 Racementhol Decongestant 35 Thiphenamil Muscle Relaxant 36 (Skeletal) Etofenprox Antiinflammatory 36 Olvanil Analgesic 36 Ditolamide Antibiotic 37 Permethrin Dermatologic 37 Prenylamine Vasodilator 37 Monoctanoin Anticholelithogenic 38 Prilocaine Anesthetic 38 Ephedrine Bronchodilator 38 Ammonium Sedative 38 Valerate Levmetamfetamine Decongestant 38 Tibenzate Unclassified 39 Methyl Nicotinate Dermatologic 39 Phenoxybenzamine Antihypertensive 39 Dexpanthenol Cholinergic 40 Methyl Salicylate Dermatologic 40 Orlistat Antiobesity 41 Phenol Dermatologic 41 Camphorated Bu ramate Anticonvulsant 41 Fluoresone Anticonvulsant 41 Myrophine Analgesic 41 Fenpiprane Antispasmodic 41 Dimorpholamine Nootropic 42 Phenyl Salicylate Analgesic 42 Chlorthalidone Diuretic 42 Colfosceril Respiratory 42 Palmitate Stimulant Levomenthol Dermatologic 42 Pecilocin Antibiotic 42 Chlorpyrifos Ectoparasiticide 42 Amolanone Anesthetic 44 Enazadrem Dermatologic 44 Phosphate Ifosfamide Antineoplastic 44 Methyl Palmoxirate Antidiabetic 44 Calcium Carbimide Alcohol Deterrant 45 Rolicyclidine Cholinergic 45 Zofenopril Calcium Antihypertensive 45 Diisopropanolamine Decongestant 45 Clofexamide Antiinflammatory 45 Trimipramine Antidepressant 45 Butanilicaine Anesthetic 46 Pridefine Antidepressant 46 Phencyclidine Anesthetic 46 Methoxypromazine Antipsychotic 46 Maleate Octacaine Anesthetic 46 Pirifibrate Antihyperlipidemic 46 Quinocide Anti malarial 46 Trimecaine Anesthetic 46 Trimethadione Anticonvulsant 46 Cyclophosphamide Antineoplastic 47 Ubidecarenone Antihypertensive 47 Cetyl Myristate Dermatologic 47 Cotinine Antidepressant 48 Octabenzone Dermatologic 48 Ibrotamide Sedative 48 Urethane Antineoplastic 48 Cloridarol Vasodilator 49 Dibemethine Antineoplastic 49 Isoflurane Anesthetic 49 Nicofibrate Antihyperlipidemic 49 Phencarbamide Antispasmodic 49 Pyrrobutamine Antihistaminic 49 Phosphate Ristianol Phosphate Immunomodulator 49 Bunaprolast Bronchodilator 49 Esmolol Antiarrhythmic 49 Cyclandelate Vasodilator 49 Formetorex Anorexic 50 Gemcabene Antihyperlipidemic 50 Calcium Idebenone Nootropic 50 Triethylamine Antiinflammatory 50 Tybamate Anxiolytic 50 Zuclomiphene Pituitary 50 Itazigrel Anticoagulant 51 Salcolex Analgesic 51 Enilconazole Antifungal 51 Propatyl Nitrate Vasodilator 52 Thymol Antibacterial 52 Benactyzine Antispasmodic 52 Butibufen Antiinflammatory 52 Perazine Antipsychotic 52 Simfibrate Antihyperlipidemic 52 Binedaline Antidepressant 53 Bromofos Antineoplastic 53 Fomocaine Anesthetic 53 Methsuximide Anticonvulsant 53 Cloforex Anorexic 53 Thiotepa Antineoplastic 53 Chlorpromazine Antiemetic 53 Deximafen Antidepressant 53 Petrichloral Sedative 53 Ibudilast Vasodilator 54 Chlornaphazine Antineoplastic 54 Mequinol Dermatologic 54 Thioctic Acid Hepatic Protectant 54 Tolboxane Antianginal 54 Torcetrapib Antihyperlipidemic 54 Butixirate Analgesic 55 Ethopropazine Antiparkinsonian 55 Ethosuximide Anticonvulsant 55 Carboprost Methyl Oxytocic 56 Hydrocotarnine Hemostatic 56 Nortriptyline Antidepressant 56 Dothiepin Antidepressant 56 Elmustine Antineoplastic 56 Propacetamol Analgesic 56 Emylcamate Anxiolytic 56 Chlordimorine Unclassified 57 Depramine Antidepressant 57 Hydroxyphenamate Anxiolytic 57 Nonivamide Nootropic 57 Pentylenetetrazol Nootropic 57 Arildone Antiviral 57 Dextilidine Antihistaminic 57 Diethylcarbamazine Anthelminithic 57 Xibenolol Antiarrhythmic 57 Fenaclon Antipsychotic 57 Chloral Hydrate Sedative 58 (Chloral Betaine) Butamben Anesthetic 58 Methohexital Anesthetic 58 Prothixene Antipsychotic 58 Prenderol Unclassified 59 Scopolamine Antispasmodic 59 Roxatidine Acetate Antiulcerative 60 Flestolol Sulfate Antihypertensive 60 Hexapradol Unclassified 60 Ipronidazole Antiprotozoal 60 N Myristyl 3 Unclassified 60 Hydroxybutylamine Proclonol Anthelminithic 60 Promethazine Antihistaminic 60 Triprolidine Antihistaminic 60 Viquidil Vasodilator 60 Ethylenediamine Urologic 61 Gemfibrozil Antihyperlipidemic 61 Malotilate Hepatic Protectant 61 Gemcadiol Antihyperlipidemic 61 Eptastigmine Cholinergic 61 Erythrityl Vasodilator 61 Tetranitrate Nicoclonate Nootropic 61 Procaine Anesthetic 61 Butobendine Antiarrhythmic 63 Crufomate Anthelminithic 63 Suloctidil Vasodilator 63 Bucricaine Analgesic 63 Dexibuprofen Analgesic 63 Didrovaltrate Sedative 63 Feneritrol Antihypertensive 63 Hopantenic Acid Nootropic 63 Thiethylperazine Antiemetic 63 Ubisindine Unclassified 63 Cetalkonium Antibacterial 64 Chloride Chlorambucil Antineoplastic 64 Isosorbide Antianginal 64 Tipepidine Antitussive 64 Dibucaine Anesthetic 65 Guaietolin Expectorant 65 Isobutamben Anesthetic 65 Lucanthone Anthelminithic 65 Tiropramide Antispasmodic 65 Triclofenol Anthelminithic 65 Piperazine Phensuximide Anticonvulsant 66 Pipazethate Antitussive 66 Methixene Muscle Relaxant 66 (Skeletal) Naepaine Anesthetic 66 Oxybenzone Dermatologic 66 Tolazoline Vasodilator 66 Dimefadane Analgesic 67 Dimethyl Sulfoxide Urologic 67 Etomidate Sedative 67 Fluanisone Antipsychotic 68 Carbenzide Antipsychotic 68 Dioxybenzone Dermatologic 68 Lidocaine Anesthetic 68 Methylchromone Antispasmodic 68 Tradecamide Unclassified 68 Hexylresorcinol Anthelminithic 68 Chaulmoogric Acid Antibacterial 68 Morsuximide Anticonvulsant 69 Pivhydrazine Antidepressant 69 Dizocilpine Maleate Nootropic 69 Caroverine Antispasmodic 69 Dioxaphetyl Antispasmodic 69 Butyrate Etalocib Antineoplastic 69 Mephenesin Muscle Relaxant 69 (Skeletal) Pyrithione Antibacterial 69 Valdipromide Analgesic 69 Butoconazole Antifungal 69 Coumarin Anticoagulant 69 Capsaicin Analgesic 70 Propentofylline Nootropic 70 Ranitidine Antiulcerative 70 Tiadenol Antihyperlipidemic 70 Guacetisal Analgesic 70 Bufenadrine Antihistaminic 70 Cloquinozine Diuretic 70 Isosorbide Dinitrate Antianginal 70 Methenolone Steroid 70 Enanthate Oxprenolol Antihypertensive 70 Penbutolol Sulfate Antianginal 70 Pramiverine Antispasmodic 70 Zucapsaicin Analgesic 70 Ridog rel Antithrombotic 70 Butylphenamide Antiglaucoma 71 Dimethadione Anticonvulsant 71 Disulfiram Alcohol Deterrant 71 Eucaine Analgesic 71 Pirmenol Antiarrhythmic 71 Betaxolol Antianginal 71 Ecadotril Antihypotensive 71 Exalamide Antifungal 71 Hexacyprone Mydriatic 71 Levobetaxolol Antihypertensive 71 Tertatolol Antihypertensive 71 Dexpropranolol Antiarrhythmic 72 Ipazilide Fumarate Antiarrhythmic 72 Croconazole Antifungal 73 Difeterol Adrenergic 73 Phenaglycodol Sedative 73 Thioridazine Antipsychotic 73 Piconol Decongestant 73 Terofenamate Antiinflammatory 73 Stiripentol Anticonvulsant 74 Taltirelin Pituitary 74 Tracazolate Sedative 74 Arformoterol Bronchodilator 74 Tartrate Azaperone Sedative 74 Darunavir Antiviral 74 Emetine Antiamebic 74 Enclomiphene Steroid 74 Methylphenidate Nootropic 74 Neocinchophen Analgesic 74 Risocaine Anesthetic 74 Sulfonethylmethane Sedative 74 Venlafaxine Antidepressant 74 Cinnamedrine Antispasmodic 75 Etamiphyllin Bronchodilator 75 Levopropoxyphene Antitussive 75 Clonitazene Analgesic 76 Nizofenone Nootropic 76 Propoxyphene Analgesic 76 Cannabinol Antiemetic 76 Hexobendine Vasodilator 76 Ibuprofen Antiinflammatory 76 Mitotane Antineoplastic 76 Norfenefrine Antihypotensive 76 Pento rex Anorexic 76 Phenadoxone Analgesic 76 Salmeterol Bronchodilator 76 Secnidazole Antiamebic 76 Soblidotin Antineoplastic 76 Toliprolol Antianginal 76 Toloxatone Antidepressant 76 Treosulfan Antineoplastic 76 Guaifenesin Expectorant 76 Cathine Anorexic 77 Fenpentadiol Antidepressant 77 Mupirocin Antibacterial 77 Dimercaprol Antidote 77 Ethylestrenol Steroid 77 Mebutamate Antihypertensive 77 Menoctone Anti malarial 77 Cronidipine Antihypertensive 78 Dexketoprofen Analgesic 78 Ornidazole Antibacterial 78 Racephedrine Bronchodilator 78 Clofoctol Antibiotic 78 Etisazole Antifungal 78 Etosalamide Antifungal 78 Firocoxib Antiinflammatory 78 Glutethimide Sedative 78 Methylene Blue Hemantic 78 Olradipine Antiparkinsonian 78 Sifaprazine Sedative 78 Difemerine Antispasmodic 78 Flamenol Antiarrhythmic 78 Etaqualone Sedative 79 Moxaverine Antispasmodic 79 Oxisu ran Antineoplastic 79 Suplatast Tosilate Antihistaminic 79 Methitural Sedative 79 Nisobamate Sedative 79 Salicyl Alcohol Anesthetic 79 Trimebutine Antispasmodic 79 Trichlormethiazide Diuretic 79 Alpha Cypermethrin Ectoparasiticide 80 Anileridine Analgesic 80 Fenofibrate Antihyperlipidemic 80 Flurazepam Anticonvulsant 80 Allylestrenol Progestogen 80 Methyprylon Sedative 80 Lysergide Antidepressant 80 Nabumetone Antiinflammatory 80 Naphthalene Anthelminithic 80 Valdetamide Sedative 80 Bamifylline Bronchodilator 80 Gacyclidine Anticonvulsant 81 Dalcotidine Antiulcerative 81 Metrifonate Anthelminithic 81 Artemotil Anti malarial 81 Metitepine Antipsychotic 81 Tribromoethanol Anesthetic 81 Ramifenazone Analgesic 81 Anastrozole Antineoplastic 82 Clorprenaline Bronchodilator 82 Cyclobutyrol Choleretic 82 Pipradrol Nootropic 82 Racemethorphan Antitussive 82 Guanoxyfen Sulfate Antihypertensive 82 Levomoprolol Antihypertensive 82 Quipazine Maleate Antidepressant 82 Benzylpenicillin Antibiotic 83 Cinanserin Antidepressant 83 Cliprofen Antiinflammatory 83 Cloranolol Antiarrhythmic 83 Fantofarone Antihypertensive 83 Moprolol Antihypertensive 83 Cyclomenol Antiarrhythmic 83 Carbantel Lauryl Anthelminithic 83 Sulfate Pentifylline Vasodilator 83 Pyrrocaine Anesthetic 83 Zipeprol Antitussive 83 Nefazodone Antidepressant 83 Felipyrine Antiinflammatory 84 Bucolome Antiinflammatory 84 Ibandronate Bone Resorption 84 Inhibito Ibufenac Analgesic 84 Isopropamide Antispasmodic 84 Parsalmide Antifungal 84 Phenyramidol Analgesic 84 Visnadine Vasodilator 84 Zetidoline Antipsychotic 84 Salicylic Anhydride Antiinflammatory 84 Diacetate Broxaterol Bronchodilator 85 Niludipine Antianginal 85 Clorethate Sedative 85 Amfetaminil Nootropic 85 Flomoxef Antibiotic 85 Fotemustine Antineoplastic 85 Homatropine Mydriatic 85 Hydrobromide Methoxamine Antihypotensive 85 Zafuleptine Antidepressant 85 Fentanyl Analgesic 85 Cicrotoic Acid Choleretic 86 Efetozole Antidepressant 86 Talosalate Analgesic 86 Procyclidine Antiparkinsonian 86 Tipranavir Antiviral 86 Amitraz Ectoparasiticide 87 Piprozolin Choleretic 87 Sisomicin Antibacterial 87 Artemether Anti malarial 87 Fospirate Anthelminithic 87 Methdilazine Dermatologic 87 Phenamazoline Antibiotic 87 Trazodone Antidepressant 87 Chloramphenicol Antibiotic 88 Palmitate Flavoxate Antispasmodic 88 Flucarbril Analgesic 88 Fludiazepam Anxiolytic 88 llepcimide Anticonvulsant 88 Methylephedrine Nootropic 88 Nonabine Antiemetic 88 Tiprenolol Antihypertensive 88 Acetohydroxamic Antiurolithic 88 Acid Carfimate Sedative 88 Chloroquine Anti malarial 88 Diproxadol Analgesic 88 Disoxaril Antiviral 88 Ethambutol Antibacterial 88 Irindalone Antihypertensive 88 Isosorbide Vasodilator 88 Mononitrate Oxazidione Analgesic 88 Butofilolol Antihypertensive 89 Capecitabine Antineoplastic 89 Cycrimine Antispasmodic 89 Indenolol Antiarrhythmic 89 Guaiacol Carbonate Expectorant 89 Benzocaine Anesthetic 89 Chlorphenesin Muscle Relaxant 89 Carbamate (Skeletal) Hexazole Unclassified 89 Lomustine Antineoplastic 89 Lufironil Dermatologic 89 Racecadotril Antidiarrheal 89 Ritodrine Tocolytic 89 Tulobuterol Bronchodilator 89 U rede pa Antineoplastic 89 Alamifovir Antiviral 90 Cinromide Anticonvulsant 90 Dichloroxylenol Anesthetic 90 Dihydrocodeine Analgesic 90 Bitartrate Imidazole Salicylate Antiinflammatory 90 Omoconazole Antifungal 90 Nitrate Ragaglitazar Antidiabetic 90 Emorfazone Antiinflammatory 90 Hydroxychloroquine Anti malarial 90 Isoprofen Antiinflammatory 90 Naproxol Antiinflammatory 90 Oxanamide Anxiolytic 90 Phenindamine Antihistaminic 90 Pyrithyldione Sedative 90 Tetramisole Anthelminithic 90 Vinylbital Sedative 90 Epirizole Analgesic 91 Metindizate Antispasmodic 91 Zotepine Antipsychotic 91 Alclofenac Analgesic 91 Fenimide Antipsychotic 91 Buclosamide Antifungal 91 Carisoprodol Muscle Relaxant 91 (Skeletal) Etifoxine Anxiolytic 91 Gliamilide Antidiabetic 91 Haloxon Anthelminithic 91 Fenbenicillin Antibiotic 92 Metochalcone Choleretic 92 Morclofone Antitussive 92 Chlorindanol Contraceptive 92 Coumaphos Antineoplastic 92 Ketamine Anesthetic 92 Thenalidine Antihistaminic 92 Homidium Bromide Anthelminithic 92 Nicorandil Vasodilator 93 Sulbentine Antifungal 93 Tetrydamine Analgesic 93 Iproclozide Antidepressant 93 Lonapalene Dermatologic 93 Maprotiline Antidepressant 93 Mephenesin Muscle Relaxant 93 Carbamate (Skeletal) Mepiroxol Antiinflammatory 93 Tolciclate Antifungal 93 Benmoxin Antidepressant 94 Danosteine Antitussive 94 Proligestone Progestogen 94 Propetamide Antidiabetic 94 Beclamide Anticonvulsant 94 Ethotoin Anticonvulsant 94 Fosfomycin Antibiotic 94 Indecainide Antiarrhythmic 94 Ketoprofen Antiinflammatory 94 Pholcodine Antitussive 94 Quingestrone Progestogen 95 Tolindate Antifungal 95 Nifurmerone Antibiotic 95 Clobetasone Glucocorticoid 95 Butyrate Dehydroemetine Antiamebic 95 Dimeth azan Antidepressant 95 Estradiol Enanthate Estrogen 95 Hepronicate Vasodilator 95 Loprodiol Muscle Relaxant 95 (Skeletal) Mebhydrolin Antihistaminic 95 Mepindolol Antianginal 95 Mexenone Dermatologic 95 Orestrate Unclassified 95 Piribedil Vasodilator 95 Stevaladil Unclassified 95 Xibornol Antibacterial 95 Nandrolone Androgen 95 Phenpropionate Alibendol Choleretic 96 Disopyramide Antiarrhythmic 96 Esonarimod Antiarrhythmic 96 Fostedil Vasodilator 96 Propranolol Antihypertensive 96 Propyperone Antipsychotic 96 Azintamide Choleretic 96 Ethinamate Sedative 96 Fananserin Antipsychotic 96 Methocarbamol Muscle Relaxant 96 (Skeletal) Oxyphenbutazone Antiinflammatory 96 Tamoxifen Antineoplastic 96 Tiopronin Antidote 96 Trenbolone Acetate Steroid 96 Chlorobutanol Analgesic 96 Cetamolol Antihypertensive 97 Ethamivan Nootropic 97 Rodocaine Anesthetic 97 Tropicamide Mydriatic 97 Bipenamol Antidepressant 97 Ditazole Antiinflammatory 97 Docarpamine Cardiotonic 97 Ethaverine Antispasmodic 97 Panomifene Steroid 97 Piberaline Antidepressant 97 Perphenazine Antipsychotic 97 Chlorprothixene Antipsychotic 98 Diethadione Anticonvulsant 98 Tazarotene Dermatologic 98 Dibenzothiophene Dermatologic 98 Cocaine Anesthetic 98 Diminazene Analgesic 98 Dinoprostone Oxytocic 98 Etocrylene Dermatologic 98 Indanorex Anorexic 98 Mepitiostane Oxytocic 98 Nifenalol Antiarrhythmic 98 Selodenoson Antiarrhythmic 98 Tinoridine Analgesic 98 Ace perone Adrenergic 99 Cysteamine Antidote 99 Hexapropymate Sedative 99 Palmidrol Oxytocic 99 Secobarbital Sedative 99 Etazepine Anticonvulsant 99 Medazepam Sedative 99 Narasin Antibacterial 99 Phenanthrene Antineoplastic 99 Phenoxyacetic Acid Dermatologic 99 Pimetremide Anticonvulsant 99 Pirprofen Antiinflammatory 99 Praxadine Antibiotic 99 Quinestradol Estrogen 99 Clorotepine Antipsychotic 100 Etofibrate Antihyperlipidemic 100 Metaproterenol Bronchodilator 100 Methadone Analgesic 100 Ormeloxifene Bone Resorption 100 Inhibitor Stearylsulfamide Diuretic 100 Trapidil Vasodilator 100 Sufentanil Analgesic 100

[0046] A pharmaceutical composition can include one or more pharmaceutically active components. The pharmaceutically active component can be a single pharmaceutical component or a combination of pharmaceutical components. The pharmaceutically active component can be an anti-inflammatory analgesic agent, a steroidal anti-inflammatory agent, an antihistamine, a local anesthetic, a bactericide, a disinfectant, a vasoconstrictor, a hemostatic, a chemotherapeutic drug, an antibiotic, a keratolytic, a cauterizing agent, an antiviral drug, an antirheumatic, an antihypertensive, a bronchodilator, an anticholinergic, an anti-anxiety drug, an antiemetic compound, a hormone, a peptide, a protein or a vaccine. The pharmaceutically active component can be the compound, pharmaceutically acceptable salt of a drug, a prodrug, a derivative, a drug complex or analog of a drug.

[0047] In some embodiments herein, the oral film formulation includes more than one API, wherein at least one has a low melting point. Further examples of pharmaceutically active agents include ACE-inhibitors, antianginal drugs, anti-arrhythmics, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, antidiabetic agents, anti-diarrhea preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, antistroke 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, cardiovascular agents, central nervous system stimulates, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis management agents, enzymes, erectile dysfunction therapies such as sildenafil citrate, tadalafil, and vardenafil, fertility agents, gastrointestinal agents, homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, antimigraine preparations such as rizatriptan, eletriptan and zolmitriptan, motion sickness treatments, muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives such as lorazepam or diazepam, smoking cessation aids such as bromocryptine or nicotine, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents such as alprazolam, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anticoagulants, anti-thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anticonvulsants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and antithyroid preparations, diuretics, anti-spadmodics, terine relaxants, anti-obesity drugs, erythropoietic drugs, anti-astmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof. Examples of nutraceutically active agents include various dietary supplements, vitamins, minerals, herbs and nutrients.

[0048] "Amorphous" refers to a state in which the molecules of the active pharmaceutical ingredient (API) or other components within the film lack a defined, ordered crystalline structure. Instead of a regular and repeating molecular arrangement found in crystalline substances, amorphous materials have a disordered or random molecular arrangement.

[0049] For oral films, the amorphous state of an API or film-forming excipient is often desirable for several reasons: 1) Enhanced Solubility: Amorphous forms of APIs tend to have higher solubility compared to their crystalline counterparts. This property can potentially improve the dissolution rate of the drug upon administration, leading to faster onset of action and improved bioavailability. 2) Improved Stability: Some APIs exhibit better stability in their amorphous form, particularly when the crystalline form is prone to degradation or exhibits polymorphism (multiple crystalline forms). 3) Uniform Distribution: Amorphous APIs can be more uniformly dispersed within the film matrix, ensuring better homogeneity and consistency in dosing across individual oral film units. However, amorphous materials, including APIs, can be more thermodynamically unstable compared to their crystalline counterparts. They tend to have a higher propensity to revert to a more stable crystalline form, a process known as recrystallization, especially under certain conditions like temperature variations, humidity exposure, or over time during storage.

[0050] The terms “blend” or “blending media” and variations thereof generally refers to the combination of the OF formulation with the presence of at least one solvent.

[0051] The term “bioavailability” will have its meaning as prescribed in the art, as the ability of a drug or other substance to be absorbed and used by the body. Bioavailability is an important factor in oral film technology. The sublingual mucosa has high membrane permeability due to its thin membrane structure and high vascularization. Due to this rapid blood supply, it offers very good bioavailability. Enhanced systemic bioavailability is owing to skipping the first-pass effect and better permeability is owing to high blood flow and lymphatic circulation. In addition, the oral mucosa is a very effective and selective route of systemic drug delivery because of the large surface area and ease of application for absorption. In studies, thin films have shown their abilities such as improving the initial effect of the drug and duration of this effect, decreasing the frequency of dosing, and increasing the effectiveness of the drug. A measure of demonstrating permeability and therefore bioavailability is with permeability data through pig mucosa testing. In this context, conducting permeability studies using pig mucosa serves as a reliable method to assess the ability of the oral film formulation to penetrate biological membranes, simulating human oral mucosa conditions. Such studies provide valuable insights into the formulation's ability to facilitate drug absorption across mucosal barriers, aiding in predicting and evaluating the oral film's bioavailability potential and effectiveness in delivering the active pharmaceutical ingredients (APIs) to the systemic circulation.

[0052] The term “colorants” and variations thereof generally refers to any dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived, with or without intermediate or final change of identity, from a vegetable, animal, mineral or other source and that, when added or applied, can impart color to a food, drug, or cosmetic or to the human body. Color makes products attractive, appealing, appetizing, and informative. Examples of colorants include but are not limited to Brilliant blue FCF, Indigotine, Alphazurine FG, Indigo, Indanthrene blue, Resorcin brown, Fast green FCF, Alizarin cyanine green F, Quinizarine green SS, Pyranine, Dibromofluorescein, Diiodofluorescein, Erythrosine yellowish Na, Copper phthalocyanine, Erythrosine, Ponceau SX, Lithol rubin B, Lithol rubin B Ca, Toney red, Tetrabromo fluorescein, Eosine, Tetrachlorotetra—bromofluorescein, Yellow Iron Oxide, Ultramarine Blue, Zinc Ferrite, Chromium Oxide Green, Titanium Dioxide, Zinc Oxide, Phloxine, Helindone pink CN, Brilliant lake red R, Acid fuchsine, Lake bordeaux B, Flaming red, Alba red, Allura red AC, Alizurol purple SS, Alizarin violet, Tartrazine, Sunset yellow FCF, Fluorescein, Napthol yellow S, Uranine, Quinoline yellow WS, Quinoline yellow SS and others or mixtures thereof.

[0053] The term a “crystal” refers to a substance or ingredient added to the formulation to prevent or minimize the formation and growth of crystals, particularly for active pharmaceutical ingredients (APIs) prone to crystallization. These inhibitors play a crucial role in maintaining the amorphous or non-crystalline state of the API within the film matrix, thereby enhancing the stability and solubility of the drug, as well as ensuring uniformity and consistency in drug delivery. Common crystal inhibitors used in oral films include: Polymers such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG); Surfactants like polysorbates (e.g., Polysorbate 80), sodium lauryl sulfate (SLS), and lecithin; Complexing agents such as cyclodextrins (e.g., hydroxypropyl-beta-cyclodextrin); Solubilizers including various types of cosolvents or co-solubilizers, such as propylene glycol and glycerin, and; pH modifiers or buffering agents to maintain a suitable pH that discourages crystallization. These crystal inhibitors are employed to ensure the stability and efficacy of the active pharmaceutical ingredient within the oral film, preventing the formation of crystals that could otherwise impact drug performance and uniformity. Agglomeration inhibitors can be included in this definition, but relate to a different part of the process. An agglomeration inhibitor in the context of oral films refers to a substance or ingredient that is added to the formulation of the film to prevent or minimize the formation of agglomerates or clusters of particles. Agglomerates are formed when small particles stick together, which can negatively impact the quality, uniformity, and effectiveness of the oral film. Agglomeration inhibitors help maintain the desired properties of the film, such as its texture, appearance, and the even distribution of active ingredients. Examples include butare not limited to the following and their derivatives: Polyvinylpyrrolidone and Hydroxypropylmethylcellulose (HPMC) where the polymer structure combines both hydrophobic (methoxy group) and hydrophilic substitutions (hydroxypropoxy group) and have aqueous viscosity up to 15000 mPas (2% ,20C), employed alone or mixed with Methyl cellulose (MC) of aqueous viscosity up to 5040 mPas (2% ,20C).

[0054] The term “film matrix” or “matrix” and variations thereof generally refers to the polymer component or mixture of polymers, which creates the film-forming matrix supporting the API within the oral film dosage form. It refers to the structural framework or the continuous phase of the film in which the active pharmaceutical ingredients (APIs) and other components are dispersed or embedded. The matrix forms the backbone or scaffold of the oral film, providing cohesion and integrity to the final product. It consists of polymeric materials or a combination of polymers and excipients that are responsible for holding the API and other additives together in a homogeneous and stable manner. The matrix plays a pivotal role in determining the mechanical properties, drug release kinetics, solubility, and overall performance of the oral film as it governs the dispersion, distribution, and release of the active ingredients upon administration in the oral cavity.

[0055] The term “flavor” and variations thereof generally refers to the entire range of sensations evoked by a substance in the mouth when we eat a food or drink a beverage. Flavor encompasses a substance’s taste, smell, and any physical feeling we perceive in our mouths, such as “heat” (for example, cinnamon) or “cold” (for example, spearmint).

[0056] The term “flavoring agents” and variations thereof generally refers to concentrated preparations, with or without flavor adjuncts required in their manufacture, used to impart flavor, with the exception of salt, sweet, or acid tastes. Flavoring agents may be classified as natural, artificial, or natural and artificial (N&A) by combining the all-natural and synthetic flavors or other forms known in the art. Flavoring agents are categorized by their physical classification as solid flavoring agents and liquid flavoring agents, with or without encapsulation to preserve the heat sensitive or volatile flavoring agents during drying process.

[0057] The term “flavor enhancer” and variations thereof generally refers to compounds that particularly enhance certain tastes or reduce undesirable flavors without having an especially strong taste of their own. They harmonize taste components and make food / drug preparations more palatable. Examples include but are not limited to maltol, ethyl maltol and monosodium glutamate, glutamic acid, glutamates, purine-5_-ribonucleotides, inosine, guanosine, adenosine 5_-monophosphates, sugars, sweetener, carboxylic acids (e.g., citric, malic, and tartaric), common salt (NaCI), amino acids, some amino acid derivatives (e.g., monosodium glutamate—MSG), and spices (e.g., peppers) are most often employed, yeast, yeast extract, dried yeast and others or mixtures thereof.

[0058] Other known techniques used to cover the perceived unpleasant taste of active agents include the addition of taste maskers.

[0059] The term “Taste Masker” and variations thereof generally refers to an ingredient capable of covering or at least making more acceptable an unpleasant odor or taste in a food or pharmaceuticals. Of the many tastes that must be masked in pharmaceuticals, bitterness is most often encountered; to mask it completely is challenging. Examples of bitter maskers include but are not limited to licorice, coffee, chocolate, mint, grapefruit, cherry, peach, raspberry, orange, lemon, lime, advantame and others or mixtures thereof. Syrups of cinnamon, orange, citric acid, cherry, cocoa, wild cherry, raspberry, or glycyrrhiza elixir, raspberry and other fruit syrups can be used to effectively mask salty and bitter tastes in a number of drug products. Metallic tastes in oral liquid products (e.g., iron) are often masked by extracts of guarana, a tropical fruit, but can be masked by other extracts and agents.

[0060] There can be a correlation between using flavors and taste maskers in high loading films, especially in pharmaceutical formulations where taste masking is crucial due to the presence of bitter or unpleasant-tasting active pharmaceutical ingredients (APIs) at high concentrations. As the drug load increases within the formulation, there may arise a critical need to extend the residence time of the product on the mucosal surface, ensuring optimal permeation for effective drug absorption. However, this imperative extension in residence time might consequently lead to an increased duration of exposure to the inherent bitterness of certain active pharmaceutical ingredients (APIs). Balancing the necessity for enhanced permeation with the management of potential taste-related challenges becomes pivotal in formulating oral films, calling for nuanced approaches to maintain both efficacy and palatability.

[0061] "High loading" refers to the practice of incorporating a significant amount or a high concentration of active pharmaceutical ingredient (API) within a dosage form while maintaining the required physical and chemical characteristics of the final product. In the context of oral films, high loading refers to the incorporation of a substantial quantity of the API into the film matrix without compromising the film's structural integrity, mechanical properties, and dissolution characteristics. The term “high loading” as used herein can describe a film with a high amount of API such as a film in, around or above 30-50 mg of API. High loading can also be described in terms of film composition such as up to 2540% of the film being composed of an API.

[0062] The term “permeation enhancer” and variations thereof generally refers to is a chemical compound which is added into the formulation along with the target drug in order to improve permeation through the biological membrane such as the skin, nasal, and intestinal mucosae. Examples comprising but not limited to bile salts, fatty acids and derivatives, glycerides, chitosan, surfactants, cyclodextrins derivatives, pH modulators, and mucoadhesive excipients.

[0063] The term “plasticizer” refers to a component that reduces the glass-transition temperature of the film forming polymers (e.g., the water-soluble polymer or water-soluble polymers in the film). The plasticizer increases flexibility, enhances elasticity and reduces brittleness of the film. Examples of plasticizers that can be used in the disclosed film oral dosage forms include but are not limited to triacetin, triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, trioctyl citrate, acetyl trioctyl citrate, trihexyl citrate, dibutyl sebacate, etc. Usually, plasticizers may be added in an amount up to 25% of the total mass of the film oral dosage form, such as from 0.5% to 25%, 1% to 20%, 2% to 15% or 5% to 10%. However, low melting point API will act as plasticizer and significantly reduce the need for it in the formulation. In fact, in presence of low melting point API which act as plasticizer, a stiffening agent will be required to compensate for the softness promoted by the API.

[0064] The term “pH modifier” refers to a substance or compound included in the formulation to adjust and control the acidity or alkalinity level of the film-forming solution or the resulting oral film. These modifiers are utilized to maintain a specific pH range that is optimal for the stability, solubility, permeability and effectiveness of the active pharmaceutical ingredients (APIs) within the film matrix. pH modifiers can be acids, bases, or buffering agents that help regulate and stabilize the pH of the formulation to ensure the desired properties of the oral film, such as improved drug stability, controlled release, and compatibility with the physiological environment of the oral cavity. In fact, most common polymers are slightly acidic and will, without the use of additional acidic agent, create an acidic environment.

[0065] The term “preservative” refers to an agent that extends the storage life of food and non-food products by retarding or preventing deterioration of flavor, odor, color, texture, appearance, nutritive value, or safety. A preservative need not provide a lethal, irreversible action resulting in partial or complete microbial cell destruction or incapacitation. Sterilants, sanitizers, disinfectants, sporicides, viracides and tuberculocidal agents provide such an irreversible mode of action, sometimes referred to as “bactericidal” action. In contrast, a preservative can provide an inhibitory or bacteriostatic action that is reversible, in that the target microbes can resume multiplication if the preservative is removed. The principal differences between a preservative and a sanitizer primarily involve mode of action (a preservative prevents growth rather than killing microorganisms) and exposure time (a preservative has days to months to act whereas a sanitizer has at most a few minutes to act). In specific embodiments, the preservative includes but is not limited to at least one of following or their derivatives such as sodium benzoate, methyl paraben, propyl paraben, and sodium sorbate.

[0066] The term “film former polymers” refers to water-soluble or water dispersible polymers of common pharmaceutical use that conform to the required properties, including, but not limited to, film instant hydration potential, mucoadhesion and solubility over time. Examples of film forming polymers include cellulose derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, carboxymethyl cellulose, hydroxypropyl cellulose, starches, polyacrylates, gums (xanthan gum, arabic gum, guar gum, etc.) and / or mixtures thereof. Film forming polymers may be used in combinations chosen based on the desired characteristics of the delivery form (e.g., rapid disintegration, higher mucoadhesion, longer residence time, etc.). Some of the film forming polymers may also act as emulsifier, and or viscosity modifier and or solubilizer.

[0067] The term “stable” refers to a product which exhibits no changes in the dissolution profile or remains within the established specifications and recovery when the product is exposed to normal (long term) and accelerated stability conditions (e.g., 25°C / 60% RH and 40°C / 75% RH) for an extended period of time while also demonstrating no chemical degradation or degradation that conforms to the established specification limits. The term “stable” can also refer also to mechanical stability, such as in the case where the product is recrystallizing, there will be a change in flexibility and other mechanical properties. The term “stable” can also refer also to chemical stability and refers to a product which exhibits changes in the assay and impurity profile that remains within the established specifications when the product is exposed to standard stability conditions (e.g., 24 months at 25°C / 60% RH and 6 months at 40°C / 75% RH) demonstrating chemical degradation within established specifications.

[0068] The term “stabilizer” refers to a molecule that prevent chemical degradation such as, D-a-tocopheryl polyethylene glycol succinate (TPGS), citric acid, vitamin E, ascorbic acid, Ethylenediaminetetraacetic acid (EDTA), glutathione, L-Cysteine, Tocobiol, BHT (butylated hydroxytoluene), BHA (beta hydroxy acid), sodium metabisulfite or a combination thereof.

[0069] “Recrystallization” refers to the phenomenon where the active pharmaceutical ingredient (API) that is dissolved or amorphously dispersed in the film matrix reforms into crystalline structures over time, especially during storage or exposure to specific conditions. Recrystallization can occur due to various factors. 1) Thermal Variations: Fluctuations in temperature during manufacturing, storage, or transportation can prompt the API to undergo recrystallization. Temperature changes might induce the previously dissolved or amorphous API to revert to its more stable crystalline form. 2) Moisture Exposure: Absorption of moisture from the environment or inadequate protection against humidity can lead to recrystallization. Moisture absorption may alter the physical state of the API, causing it to crystallize within the film. 3) Chemical Interactions: Interactions between the API and other excipients in the film matrix might promote recrystallization. 4) Time: Amorphous state is a metastable state and will slowly revert to the more stable crystalline form. This will happened at different rate depending on the environment of the product. Incompatibilities between components can induce crystallization of the API. Recrystallization in oral films can be problematic for several reasons. Recrystallization can lead to uneven distribution of the API within the film, causing variations in dosage from one film unit to another. This inconsistency can impact the efficacy and safety of the medication. The formation of crystalline structures within the film matrix might alter the film's mechanical properties, affecting its flexibility, solubility, and disintegration characteristics. Crystallization of the API can modify its dissolution rate, affecting the release profile and bioavailability of the drug when the oral film is administered.

[0070] The term “residence time” and variations thereof generally refers to a time necessary for complete erosion / disintegration of the dosage form. This test is usually performed to assess the average time the product will last in the mouth when provided to human.

[0071] The term "softness" in the context of oral films refers to the mechanical property that describes the film's flexibility, pliability, and the degree to which it yields or deforms under stress, gravity or pressure. Softness is a crucial attribute for oral films as it directly impacts patient acceptability, comfort during administration, and the film's ability to conform to the oral mucosa for efficient drug delivery. It is also critical during manufacturing as a lack of it may render the product unpackageable. Softness can be quantified by the time a specific length of film takes to bend by 20 degrees when held straight between 2 fingers.

[0072] The term “solubility enhancer” refers to excipients used to solubilize low solubility drugs via non-covalent interactions, and permit dissolution and bioavailability enhancement of the said drug. Non-covalent interactions include van der Waals forces, hydrogen bonding, dipole-dipole and ion-dipole interactions, and in certain cases favorable electromagnetic interactions. In this disclosure, the solubility enhancer involves one or combination of two types of excipients: type (I) of amphiphilic structure having both hydrophobic and hydrophilic constituents and type (II) of non-amphiphilic structure having either a majority of hydrophilic constituents or a majority of hydrophobic constituents. Solubility enhancers are divided into two categories, the first being the amphiphilic solubility enhancers type (I): A) Cellulosic derivative such as but not limited to HPMC having aqueous viscosity of Not More Than (NMT) 500mPas (2%, 25C) and HPC of low Molecular Weight (MW) Hydroxypropyl Cellulose (HPC) (up to 95.000) having aqueous viscosity of Not More Than (NMT) 150 mPas (5% , 25C), and B) Surfactant(s) of HLB from 3 to 7 (category I) or of an HLB equal to 7 and above or a combination of the two categories: examples include but are not limited to sodium lauryl sulfate, copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) i.e poloxamer having MW up to 14.600 and viscosity up to 3100 mPas (77C); PEG 300 oleic glycerides, PEG 300 linoleic glycerides; Sorbitan Esters (Sorbitan Fatty Acid Esters) such as: Sorbitan monoisostearate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan monostearate, Sorbitan sesquioleate; Polyoxyethylene Sorbitan Fatty Acid Esters such as: Polyoxyethylene 20 sorbitan monolaurate, Polyoxyethylene (4) sorbitan monolaurate, Polyoxyethylene 20 sorbitan monopalmitate, Polyoxyethylene 20 sorbitan monostearate, Polyoxyethylene (4) sorbitan monostearate, Polyoxyethylene 20 sorbitan tristearate, Polyoxyethylene 20 sorbitan monooleate, Polyoxyethylene (5) sorbitan monooleate, Polyoxyethylene 20 sorbitan trioleate, Polyoxyethylene 20 sorbitan monoisostearate Propylene glycol monocaprylate type I and type II, Caprylocaproyl polyoxyl-8 glycerides, C) Polyvinylpyrrolidone of up to 1.500.000 MW, having aqueous viscosity of NMT 700 mPAs (10%, 20C) D) polyethylene oxide (PEO), of up to 300.000 MW, having aqueous viscosity of NMT 1200 mPAs (5%, 25C) and E) Cyclodextrines and their derivatives. The second category of Non-Amphiphilic solubility enhancers type (II): A) with majority of hydrophilic constituents: examples are not limited to Glycerol, Propylene glycol, and PEGs. Said PEGs of up to 6600 MW and of viscosity of Not More Than (NMT) 390 mPas ( at 98.98C + / - 0.3C) B) With majority of hydrophobic constituents examples are not limited to oily surfactant of lower Hydrophilic Lipophilic Balance (HLB) below 3 and oily solubility enhancer: Medium chain triglycerides (MCT) and Glycerol monolinoleate (Maisin CC TM), soybean oil, Olive oil, Sorbitan trioleate, Sorbitan tristearate.

[0073] The term “solubilizing system” for oral films refers to a combination of ingredients or components within the formulation of the film that enhances the solubility and dissolution of hydrophobic or poorly water-soluble substances, such as active pharmaceutical ingredients (APIs) or bioactive agents. The solubilizing system is designed to improve the dispersion of these substances within the film matrix, ensuring their effective release and bioavailability when the film is administered orally. In the context of oral films for pets or humans, a solubilizing system may include various excipients, surfactants, co-solvents, and other additives that interact with the hydrophobic components, breaking down their structure and enabling them to mix more readily with the surrounding aqueous environment. This results in a homogenous and stable formulation that allows for efficient absorption of the active ingredients upon administration.

[0074] The purpose of a solubilizing system in oral films is to overcome the challenge of delivering poorly water-soluble compounds, which can otherwise lead to uneven distribution, reduced bioavailability, and compromised therapeutic effects. By using an effective solubilizing system, the oral film can enhance the solubility and dissolution of the bioactive agents, thereby optimizing their absorption and ensuring consistent and reliable therapeutic outcomes.

[0075] The “surface pH” is the pH measured on a surface of the film, such as the top or bottom surface of a monolayer film or on an exposed surface of the layer containing the active in a multilayer oral film. The film is prepared for pH testing by slightly wetting the film (adding water as needed for a pH test - e.g. one to three drops). The pH is then measured by bringing the electrode in contact with the surface of the oral film. This measurement of the surface pH is preferably performed on several films of the same formulation.

[0076] The “blend pH” is the pH measure of the blend including all the excipients and API prior to casting. In this case, the electrode is placed in contact with the blend to perform the test.

[0077] The term “surfactant” is intended to mean an amphiphilic compound that lowers the surface tension of a liquid, the interfacial tension between two liquids, or the interfacial tension between a liquid and a solid. Surfactants are also distinguishable based on their HLB “Hydrophilic-lipophilic balance”, a measure of the degree to which it is hydrophilic or lipophilic. Common examples of surfactants include but not limited to polysorbates, sorbitan ester, polyoxylglycerides and propylene glycol laurates.

[0078] The term “stabilizer” refers to a substance which prevents degradation of the product. An example of stabilizer is an “antioxidant”, which prevents or inhibits oxidation of molecules by terminating free radical reactions, and may delay or prevent some types of cellular damage. Antioxidants may be naturally occurring including those found in foods and botanical materials or synthetic. Non-limiting examples of antioxidants include citric acid, Vitamin E, vit E-D-o-tocopheryl polyethylene glycol succinate or a derivative thereof, a tocopherol, and combinations thereof. In some embodiments, the antioxidant is Vitamin E or a derivative thereof, a flavonoid, a polyphenol, a carotenoid, or a combination thereof. Other stabilizer examples includes but are not limited to butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), tertiary butylhydroquinone (TBHQ), phenolic acids, Ethylenediaminetetraacetic acid (EDTA), sodium metabisulfite, cupper, guthathion, vitamin C and derivation like ascorbic palmitate or a combination thereof.

[0079] The term “sweetener” and variations thereof generally refers to a solid or liquid ingredient that is used to impart a sweet taste to food or drug product. Sweeteners are often classified as either nutritive (caloric) or non-nutritive (non-caloric), natural or synthetic. Examples of sweeteners include but are not limited to sucrose, dextrose, lactose, glucose, advantame, sorbitol, mannitol, liquid glucose, honey molasses, saccharin, sucralose, rebaudioside A stevia, rebaudioside M stevia, stevioside, mogroside IV, mogroside V, alitame, saccharin, neohesperidin dihydrochalcone, cyclamate, neotame, N- [3_ (3- hydroxy-4-methoxybenzylyl) propyl] -L-a- aspartyl] -L-phenylalanine 1-methyl ester, N- [3- (3- hydroxy-4-methoxyphenyl) -3-methylbutanyl] -La - aspartyl] -L- phenylalanine 1-methyl ester, N- [3- (3- methoxy-4-hydroxyphenyl) propyl] -L- a - aspartyl] -L- phenylalanine 1-methyl ester, curculin, cyclamate, aspartame, acesulfame potassium and others or mixtures thereof.

[0080] The term “viscosity enhancer” refers to a substance or ingredient added to the formulation to increase the thickness or viscosity of the film-forming solution. These substances help in improving the rheological properties of the solution, making it more manageable during the film manufacturing process. By enhancing viscosity, these agents contribute to control spreading and uniformity of the solution over the substrate, aiding in the formation of a consistent and cohesive film. Viscosity enhancers play a crucial role in controlling the flow properties of the film-forming solution, thereby influencing the final characteristics of the oral film, such as its thickness, flexibility, and dissolution behavior.

[0081] Preferred film dosage forms include sublingual and buccal film oral dosage forms. Buccal and / or sublingual mucosa absorption allows the drug to be absorbed directly into the blood stream skipping the hepatic metabolism. From a pharmaceutical formulation perspective this is particularly challenging, as the process of transmucosal permeation needs to be carefully optimized to obtain an acceptable pharmacokinetic profile. The use of a long residence time oral film allowing the dissolving film to direct the active agent through the mucosa directly to the blood stream may be desired to improve the absorption profile of the API and consequently improve bioavailability.

[0082] The buccal or sublingual film dosage form can comprise a single film layer, or multiple layers. In some embodiments, a bilayer or multilayer film would include a mucoadhesive layer containing the API which is placed against the oral mucosa and a second layer directed outwards from the mucosa serving as a protective barrier against abrasion from the tongue or mastication or simply against constant washing of the saliva. This protective layer also serves to favor the directed absorption of the API within the oral mucosa rather than enteric uptake in the gastrointestinal (Gl) tract.

[0083] The present disclosure relates to providing a film forming matrix carrying a high loading of a drug substance where a considerable portion is intended to be released and absorbed buccally to avoid hepatic first pass or gastric degradation and resulting in better API bioavailability.

[0084] In film manufacturing, unwinding of the master roll and slitting are essential processes used to prepare large rolls of film into smaller, more manageable widths to proceed with packaging. Unwinding is the initial step of the slitting process after completion of coating. It involves taking a large roll of film, known as a master or parent roll, and feeding it into a machine or system designed to unwind it. This master roll can be made of various materials like plastic films, paper, or laminates. Unwinding allows the continuous cutting of the material, which is then directed to subsequent processing stages. The unwinding process must maintain tension control to prevent any irregularities or distortions in the film. Slitting occurs after unwinding and involves cutting the wide web of film into narrower strips or rolls, commonly referred to as slit rolls, slit reels or narrow rolls. Slitting machines have sharp circular blades or rotary knives that precisely cut the material to the desired width. The number of slits depends on the side of the master roll, and machines can perform single or multiple slits simultaneously. Slitting allows manufacturers to create multiple rolls of film with different widths, accommodating various product specifications or production needs. Both unwinding and slitting processes require precision and control to ensure uniformity and consistency in the resulting film rolls. They are critical steps in film manufacturing, enabling customization, optimizing material usage, and facilitating downstream processing in various industries.

[0085] “Delamination” refers to a critical issue where layers or portions of the film separate or peel away from their support, causing the film to be unsupported. Delamination can occur between different layers within a multilayer film or within a single-layer film with the support on which the product was coated, leading to a lack of cohesion between the film components.

[0086] Several factors can contribute to delamination in oral films such as inadequate adhesion, inadequate residual moisture, excessive stiffness of the product, incompatibility of ingredients, nature of the support liner or manufacturing conditions. Delamination in oral films is a concern as it can compromise the final dimensions of the product and its quality, efficacy, and safety of the medication. It can lead to dose variability, and inconsistent drug release, impacting the intended therapeutic effect for patients.

[0087] Adhesion of the bottom side of the film to the support liner on which the liquid blend is casted is critical to ensure that the following steps, slitting and packaging, can be performed. However, if the top side of the casted film is dry yet sticky it will cause issues when unwinding for slitting.

[0088] Once delamination has happened, as illustrated in Figure 1, the following step can no longer be completed and the delaminated section need to discarded impacting directly on the production yield. In addition, lack of stiffness in a product results also in packaging difficulties as transfer from liner to packaging material is difficult. A certain equilibrium between level of stiffness and adhesion is required to ensure efficient transfer from liner to packaging material. Lacking on one or both of them results in unpackageable product. In the context of oral films, achieving a delicate equilibrium between stiffness and adhesion is crucial for the efficient transfer of the film from its liner (carrier material) to the intended packaging material. Stiffness refers to the rigidity or resistance to deformation of the oral film, while adhesion denotes the ability of the film to stick to the packaging material upon transfer. When the oral film possesses an optimal balance between stiffness and adhesion, it detach adequately from the liner and adheres appropriately to the packaging material during the transfer process. Adequate stiffness ensures that the film retains its structural integrity and doesn't excessively deform or break during the transfer. At the same time, sufficient adhesion guarantees that the film sticks firmly to the packaging material, preventing any detachment or displacement.

[0089] However, if the oral film lacks the necessary stiffness, it might bend excessively or become too pliable during the transfer process. This could lead to difficulties in handling or transferring the film from the liner to the packaging material, resulting in an inability to package the product efficiently. Conversely, if the film lacks proper adhesion, it might fail to stick firmly to the packaging material, leading to detachment or incomplete transfer. This scenario results in an unpackageable product as the film does not adhere securely, causing issues with packaging integrity or compromising the protection of the product.

[0090] Liquids, water and solvents, are known to act as a plasticizer and are also used as such in film manufacturing. When the blend is coated, a residual portion of the liquid from the blend is intentionally left in to improve flexibility and adhesion of the film to the liner. In the case of low melting point APIs, the API itself acts as a plasticizer reducing the requirement for residual liquid. The foregoing implies that if the product absorbs moisture after coating, during packaging, or is exposed to high humidity before packaging or being taken by a subject, the film will become sticky, soft and lose strength. The film matrix must provide the appropriate mechanical properties to ensure the film retains acceptable mechanical properties at all times. Mechanical properties of a film are mainly defined by elongation, tensile strength and folding resistance, a film formulation developed with inadequate level of plasticizer vs polymers will show excessive elongation which would impact on manufacturability of the product, as illustrated in the exemplary films of Figure 2.

[0091] Melting point is a known value for molecules, and formulation strategy is usually adjusted based on it. For example, lower levels of plasticizer and lower residual levels of water can be applied during manufacturing - but the real impact is usually observed once the product is completed and its physical characteristics can be evaluated. After evaluation, the formulation is adjusted based on the observed impact or effectiveness of the API to act as a plasticizer as well as its stability under different conditions, i.e. humidity and temperature. Then, depending on the intensity of the effect of the presence of the API, adjustments are made. Such adjustments can be made after qualitative evaluation based on stickiness and softness.

[0092] In this disclosure, melting point can vary from a molecule’s inherent number to describe the moment at which melting occurs during different points of a film formulation. Products with melting points above 90 degrees Celsius are generally not impacted by blending or stability in terms of melting point or processes to manufacture a film. However, anything with a melting point below 80 degrees Celsius will be melted during coding, or could alternatively melt during stability and cool down afterwards. During this transition, the product may stay amorphous or recrystallize based on processes.

[0093] As defined above, plasticizers are a low-volatility liquid or solid substance that can be added to a raw polymer like a type of plastic or rubber to improve its flexibility, making it easier to shape and mold, and reducing friction on its surface. Plasticizers increase the free volume between polymer chains, spacing them apart. The polymer chains slide past each other at lower temperatures resulting in a decrease in Tg.

[0094] The glass transition temperature (Tg) is a critical concept when formulating oral films, especially those containing amorphous polymers. In the context of pharmaceuticals, the Tg is the temperature at which an amorphous polymer transitions from a glassy, brittle state to a rubbery, more flexible state. This transition influences the physical properties and stability of the polymer and, consequently, the characteristics of the oral film.

[0095] In oral film formulation, polymers are fundamental components that contribute to the film's mechanical strength, flexibility, and drug release profile. Amorphous polymers, due to their disordered molecular structure, offer advantages such as enhanced solubility, improved bioavailability, and ease of processing compared to crystalline polymers. However, their physical behavior, especially concerning Tg, is crucial for their successful application in oral films.

[0096] Tg is an important feature of polymer behavior. It marks a region of dramatic changes in the physical and mechanical properties. Below Tg - due to lack of mobility, the 5 polymers are hard and brittle like glass. Above Tg - due to some mobility, the polymers are soft and flexible like rubber.

[0097] Factors affecting the Glass Transition Temperature: Molecular weight In straight-chain polymers, increasing molecular weight decreases chain end concentration. This results in the decrease of free volume at the end group region and an increase in Tg. Molecular structure Insertion of bulky, inflexible side group increases Tg of material due to a decrease in mobility. Chemical crosslinking An increase in cross-linking decreases the mobility of the polymer. This leads to a decrease in free volume and an increase in Tg. Polar groups The presence of polar groups increases intermolecular forces, interchain attraction, and cohesion. This leads to a decrease in free volume resulting in an increase in Tg.

[0098] As such, to properly formulate low melting point APIs into stable and io manufactureable films, the right combination of plasticizer and polymer systems must be selected. Polymer Tg (oC) HPC 150 HPMC 162 PEG -50 PEG -52 Pullulan       121 EC         130 HEC        150 PVP         161 Maltodextrin 150 CMC       600 Maltitol        62 Pullulan      242

[0099] Such an approach can enable the development of stable formulations with high loading of low melting point API.

[0100] Nowadays, a significantly high number of molecules have low bioavailabilty and / or low solubility. The buccal route provides systemic bioavailability due to the high total blood circulation through the cheek and it also advantageously avoids first-pass hepatic metabolism and gastrointestinal drug degradation. Moreover, it is suitable for selfmedication and easy for dose control and has a removable formulation form. Solubilizing and stabilizing the drug in an amorphous state is the best way to improve the absorption of the drug and increase its efficacy in the subject.

[0101] In some embodiments, a film containing 20 milligrams to 100 milligrams or more of an API could be considered as having high loading, depending on the specific drug, its potency, therapeutic dosage, and the intended use of the oral film.

[0102] In some embodiments, the oral film formulation is contemplated for placing the strip on or under the tongue (sublingual).

[0103] In some embodiments, the oral film formulation is contemplated for placing the strip or along the inside of the cheek (buccal).

[0104] In some embodiments, an oral film formulation contains at least one API with a low melting point, which would mean below 80oC in concentration above 20%.

[0105] In some embodiments, melting point is assessed based on the stage of formulation.

[0106] In some embodiments, an oral film formulation contains at least two polymers that act as matrix formers, representing more that 20% of the formulation by weight.

[0107] In some embodiments, an oral film formulation contains at least one polymer that acts as a viscosity enhancer.

[0108] In some embodiments, an oral film formulation contains at least one polymer that acts as a matrix stiffener with a Tg above 120oC.

[0109] In some embodiments, an oral film formulation contains at least one polymer that acts to reduce stickiness and reduce softness with a Tg at least three times higher than the melting point of the API.

[0110] In some embodiments, an oral film formulation contains at least one polymer that is a crystal inhibitor.

[0111] In some embodiments, an oral film formulation contain a plasticizer.

[0112] In some embodiments, an oral film formulation contains less than 5% of plasticiser by weight.

[0113] In some embodiments, an oral film formulation contains less than 5% residual solvent by weight.

[0114] In some embodiments the API liquefies or melts at temperatures below 80 degrees Celsius.

[0115] In some embodiments, the oral film formulation has an API which liquefies or melts at temperatures below 60 degrees Celsius.

[0116] In some embodiments, the oral film formulation comprises an API in a concentration of at least 30% of the dry formulation.

[0117] In some embodiments, the oral film formulation comprises an API in a concentration of at least 40% of the dry formulation.

[0118] In some embodiments, the oral film formulation the API which liquefies or melts at temperatures below 70 degrees Celsius.

[0119] In some embodiments, the oral film formulation the API which liquefies or melts at temperatures between 20 and 55 degrees Celsius.

[0120] In some embodiments, the oral film formulation comprises less than 5% plasticizer.

[0121] In some embodiments, the crystal inhibitor is Hydroxypropyl Methylcellulose.

[0122] In some embodiments, the viscosity enhancing polymer is Hydroxypropyl Cellulose.

[0123] In some embodiments, the oral formulation further comprises an pH modifier.

[0124] In some embodiments, the oral formulation further comprises a stabilizer.

[0125] In some embodiments, the oral film formulation further comprises a stabilizer selected from the group consisting of ascorbic acid, Vitamin E TPGS, Sodium metabisulfite, and BHT.

[0126] In certain embodiments, the oral film formulation further comprises a flavoring agent.

[0127] In certain embodiments, the oral film formulation further comprises a flavor enhancer.

[0128] In certain embodiments, the oral film formulation further comprises a pore former.

[0129] In certain aspects of this disclosure, the disclosed formulations further comprise flavors and flavor enhancers to improve palatability for humans and animals.

[0130] According to some aspects of the disclosure, content of the API per oral film is at least 50 mg representing at least 25% of the total dry weight of the oral film and not more than 60% of the said total dry weight.

[0131] In some aspects of the disclosure, to properly formulate low melting point APIs into stable and manufactureable films, the right combination of plasticizer and polymer systems is be selected, with a view to glass transition temperature. A number of different ratios are contemplated in this disclosure.

[0132] According to some aspects of the disclosure, the oral film further comprises a sweetener.

[0133] According to some aspects of the disclosure, the oral film further comprises a plasticizer.

[0134] According to some aspects of the disclosure, the oral film further comprises a preservative.

[0135] In other embodiments, the blend includes a high percentage of alcohol (methanol) which overcomes the need for a preservative.

[0136] According to some aspects of the disclosure, the oral film further comprises a colorant.

[0137] In specific embodiments, the oral dissolvable film is palatable to humans.

[0138] In specific embodiments, the oral dissolvable film is palatable to animals.

[0139] In specific embodiments, the external surfaces of the oral dissolvable film have a smooth texture.

[0140] In specific embodiments, the oral dissolvable film has a high tensile strength.

[0141] In specific embodiments, the oral dissolvable film is pliable.

[0142] In specific embodiments, the oral dissolvable film is non-sticky to touch.

[0143] In specific embodiments, the oral dissolvable film does not readily stick to another oral dissolvable film.

[0144] In specific embodiments, the oral dissolvable film is relatively soft to touch.

[0145] In specific embodiments, some of the excipients used in the oral dissolvable films of the present disclosure may have one or more functions. Hence, a skilled person should not construe the limit of an excipient stated or illustrated in any aspect or embodiment or an example of an oral film in the present disclosure to a single function.

[0146] In specific embodiments, the oral dissolvable film has a resilient configuration.

[0147] According to certain aspects of this disclosure, the film forming matrix comprises not more than 60% of the dry weight of the oral film, and preferably ranging from 20% to 50% of total dry weight of the oral film.

[0148] According to certain aspects of this disclosure, the film forming matrix comprises preferably 25% to 45% of total dry weight of the oral film.

[0149] In certain embodiments, it is advantageous to have a single layer film strip. However, in certain other embodiments, a multi-layer film strip is advantageous.

[0150] In some embodiments, the oral film formulation demonstrates enhanced stability against factors such as light, heat, and moisture, ensuring prolonged shelf life and consistent drug efficacy.

[0151] In some embodiments, the formulation allows for customizable drug release kinetics, presenting options for immediate, sustained, or targeted release profiles based on therapeutic requirements.

[0152] In some embodiments, variations in the thickness of the oral film are achievable, providing flexibility to tailor films of different thicknesses suitable for diverse applications or dosages.

[0153] In some embodiments, the formulation displays compatibility with a broad spectrum of active pharmaceutical ingredients (APIs) from various therapeutic classes, showcasing its versatility.

[0154] In some embodiments, the oral film components demonstrate biodegradability or eco-friendly attributes, aligning with sustainable practices and environmental consciousness.

[0155] In some embodiments, the formulation exhibits bioadhesive properties, promoting improved adhesion to mucosal surfaces within the oral cavity for prolonged drug contact.

[0156] In some embodiments, the formulation is designed to enhance the bioavailability of poorly soluble drugs or APIs with low systemic absorption, potentially improving therapeutic outcomes.

[0157] In some embodiments, a range of flavors, taste-masking agents, or sweeteners is available within the formulation, catering to varied palatability preferences and enhancing patient compliance.

[0158] In some embodiments, the formulation is tailored for specific populations, such as pediatric or geriatric patients, focusing on ease of administration and safety considerations.

[0159] In some embodiments, the formulation is designed to facilitate co-administration of multiple drugs or compatibility with combination therapies within a single oral film, offering treatment convenience for complex medical needs.

[0160] In some embodiments, the oral film is tailored to provide prolonged drug release, ensuring sustained therapeutic concentrations for chronic conditions, optimizing patient outcomes.

[0161] In some embodiments, the formulation demonstrates superior taste-masking capabilities, especially beneficial for pediatric patients, enhancing their willingness to adhere to the prescribed treatment regimen.

[0162] In some embodiments, the oral film is adaptable for personalized medicine applications, facilitating tailored dosing or drug combinations to meet individual patient needs and treatment responses.

[0163] In some embodiments, the formulation is optimized for patients with gastrointestinal sensitivities or malabsorption issues, ensuring efficient drug absorption via the oral mucosa.

[0164] In some embodiments, the oral film is designed for targeted drug delivery to specific regions within the oral cavity or systemic circulation, optimizing therapeutic outcomes while minimizing side effects.

[0165] In certain aspects of this disclosure, the oral film formulation enables rapid onset of action, providing quick relief for acute conditions or immediate therapeutic effects.

[0166] In certain aspects of this disclosure, the oral film formulation is designed to cater to patients with dysphagia or swallowing difficulties, offering a user-friendly alternative to conventional dosage forms.

[0167] In some aspects of this disclosure, the oral film formulation accommodates high loading of low melting point APIs, addressing challenges associated with their physical state changes during formulation and ensuring stability while maintaining desired drug concentrations.

[0168] In some aspects of this disclosure, specialized formulation strategies are employed to optimize the incorporation of low melting point APIs at high concentrations into oral films, focusing on maintaining uniform distribution and preventing phase separation or recrystallization.

[0169] In some aspects of this disclosure, the formulation process is tailored to address the specific characteristics of low melting point APIs, enabling their efficient incorporation into high loading films without compromising film integrity or drug potency.

[0170] In some aspects of this disclosure, innovative methods are employed to enhance the solubility and dispersion of low melting point APIs at high loadings within the oral film matrix, ensuring consistent drug delivery and therapeutic efficacy.

[0171] In some aspects of this disclosure, the oral film formulation utilizes synergistic combinations of excipients and stabilizers to mitigate the challenges posed by low melting point APIs at higher concentrations, promoting formulation homogeneity and shelf-life stability.

[0172] In some aspects of this disclosure, innovative approaches are explored to modify the crystalline structure or phase transitions of low melting point APIs within the film matrix, addressing challenges associated with their temperature-dependent behavior during processing and storage.

[0173] In some aspects of this disclosure, the formulation process is designed to achieve superior bioavailability and controlled release of low melting point APIs at high loadings, enhancing therapeutic outcomes and patient compliance.

[0174] The technical problem addressed by the present disclosure is how to create stable oral film formulations containing high loadings of low melting point APIs while maintaining both physical stability and suitable mechanical properties. This problem is particularly challenging because such APIs tend to act as plasticizers within the film matrix, potentially compromising the film's structural integrity and stability. Additionally, these APIs often have a tendency to recrystallize during storage, especially when present in high concentrations, which can lead to non-uniform drug distribution and altered dissolution properties.

[0175] The solution to this technical problem involves the careful selection and combination of specific polymer types with particular glass transition temperature characteristics. It has been surprisingly found that by selecting at least one polymer with a glass transition temperature (Tg) at least three times higher than the melting point of the API, stable films can be produced even with API loadings of 30% or higher by weight of the dry film. This represents an unexpected technical effect, as conventional wisdom in the field would suggest that such high loadings of low melting point APIs would inevitably lead to unstable, overly plasticized films.

[0176] The inventors have discovered that the key to achieving this stability lies in creating a polymer matrix that provides sufficient molecular mobility restriction to prevent API recrystallization while maintaining appropriate mechanical properties. This is achieved through a specific combination of at least two polymers, wherein the film forming matrix comprises at least 20% by weight of the dry film. The technical effect of this combination is particularly pronounced when the formulation contains less than 5% plasticizer by weight, as the low melting point API itself contributes to the plasticization of the film.

[0177] In particular embodiments, the film forming matrix comprises three functionally distinct polymer types: (a) at least one polymer that acts as a crystal inhibitor; (b) at least one polymer that acts as a viscosity enhancer; and (c) at least one polymer that acts as a matrix stiffener with a Tg above 120°C.

[0178] This specific combination provides several unexpected technical advantages. The crystal inhibitor, which may comprise hydroxypropyl methylcellulose (HPMC), helps maintain the API in an amorphous state. The viscosity enhancer, which may comprise hydroxypropyl cellulose (HPC), helps ensure uniform drug distribution during manufacturing and provides appropriate mechanical properties to the final film. The matrix stiffener counteracts the plasticizing effect of the low melting point API, maintaining suitable film rigidity.

[0179] The inventors have found that controlling the residual solvent content to less than 5% by weight in the final film product provides an additional technical effect in terms of stability. This is because excess residual solvent can act as an additional plasticizer and may promote API recrystallization during storage. The combination of controlled residual solvent content and specific polymer selection results in films that maintain physical stability without recrystallization when exposed to accelerated stability conditions (40°C / 75% RH) for at least one month.

[0180] The manufacturing process for these films has been specifically developed to address the technical challenges posed by high loadings of low melting point APIs. The process involves: (1) Dissolving the API in a suitable solvent system; (2) Combining the dissolved API with the selected polymers in specific order and under controlled mixing conditions; (3) Forming a uniform blend; and (4) Continuously casting the blend under conditions that achieve the target residual solvent content.

[0181] The order of addition and mixing conditions have been found to be critical for achieving uniform drug distribution and preventing premature API crystallization. This represents a non-obvious technical solution to the problem of manufacturing high-loaded films with low melting point APIs.

[0182] The inventors have further discovered that films prepared according to the invention can achieve API loadings of at least 40% by weight while maintaining stability. This is particularly surprising for APIs having melting points below 60°C, and even more surprisingly, for APIs with melting points between 20°C and 55°C. Such high loadings would typically be expected to result in significant stability and mechanical property issues, but the specific polymer combination and manufacturing process of the invention overcome these challenges.

[0183] The technical effect of the invention is particularly evident in the case of APIs requiring sublingual or buccal administration. The stable amorphous state of the API in these high-loaded films, combined with the rapid disintegration properties achieved through the specific polymer matrix composition, results in improved bioavailability compared to conventional formulations. This is demonstrated by permeability studies using pig mucosa, which show enhanced API absorption compared to traditional oral dosage forms.

[0184] The stability of these formulations is achieved through several complementary technical effects: (1) The high Tg polymer(s) provide a rigid matrix structure that restricts molecular mobility; (2) The crystal inhibitor polymer prevents API recrystallization; (3) The viscosity enhancer maintains uniform drug distribution; and (4) The controlled residual solvent content prevents additional plasticization effects.

[0185] These effects work synergistically to maintain the API in a stable amorphous state, even at high loadings and under stressed storage conditions.

[0186] The mechanical properties of the films represent another unexpected technical effect of the invention. Despite the high loading of low melting point APIs, which would typically result in overly soft or sticky films, the specific polymer combination provides appropriate tensile strength and flexibility. This is achieved without the need for traditional plasticizers, as demonstrated by mechanical testing of films containing various API loadings and polymer combinations.

[0187] For example, films prepared according to the disclosure typically exhibit the following mechanical properties: tensile strength sufficient for handling and administration, appropriate flexibility without cracking, non-sticky surface characteristics, uniform thickness distribution

[0188] These properties are maintained even with API loadings up to 40% by weight, which represents a significant advance over conventional film formulations.

[0189] The disclosure also provides a solution to the technical problem of content uniformity in high-loaded films. The specific combination of polymers, particularly the inclusion of a viscosity enhancer, helps maintain uniform API distribution during manufacturing and storage. This is demonstrated by content uniformity testing of films cut from different areas of the same batch, which show consistent API content within accepted pharmacopeial limits.

[0190] The inventors have further discovered that the formulations of the invention can accommodate various functional additives without compromising stability or mechanical properties. These may include: (i) pH modifiers for optimizing API stability, (ii) stabilizers selected from ascorbic acid, Vitamin E TPGS, sodium metabisulfite, and BHT, (iii) flavoring agents and sweeteners for palatability or (iv) other functional excipients as needed for specific applications.

[0191] The ability to incorporate these additives while maintaining stability represents another technical advantage of the invention, as high-loaded films are typically sensitive to changes in composition that might affect the polymer matrix properties.

[0192] In specific embodiments, the film forming matrix comprises between 25% and 45% by weight of the dry film. This range has been found to provide optimal balance between API loading capacity and film properties. Below 25%, the films may lack sufficient structural integrity, while above 45%, the API loading capacity becomes limited. This represents a non-obvious optimization of the formulation parameters to achieve the desired technical effects.

[0193] The following examples are provided to further clarify the present disclosure and are not to be interpreted as limitations of the present disclosure, as several variations of the present disclosure are possible without deviation from its spirit or scope. EXAMPLE 1

[0194] The following table demonstrates the formulation for example 1. Formulation 1 Function % wet (w / w) % dry (w / w) Water Solvent 37.628 3.850 methanol solvent 25.085 0 Low melting point API API 15.678 40.429 citric acid pH modifier 2.200 5.673 Ascorbic acid stabilizer 0.921 2.374 Advantame sweetener 0.052 0.135 Sucralose sweetener 0.657 1.694 Suppresseur amertume Flavor enhancer 1.359 3.504 Citrus flavor Flavoring agent 0.697 1.797 HPC-mid viscosity Stiffness / crystal inhibitor polymer 2.489 6.417 HPC-high viscosity Viscosity enhancer 0.498 1.283 PVP 30 Matrix polymer 1.140 2.939 HPC-mid viscosity Matrix polymer 10.104 26.054 CMC low viscosity Reduce stickiness and      softness polymer 1.493 3.850 Total Wet 100.000 Total Dry 100.000 % solid

[0195] There are a variety of approaches to the blending process which are possible. In some embodiments, the blending process of this disclosure is as follows: 1. Add citric acid, stabilizer, sweeteners and flavors in a beaker 2. Add water, put the beaker under homogenizer 3. Set homogenizer speed to 10K rpm, add HPC-high viscosity, homogenize for at least 5 min until all excipients are well-dispersed or dissolved. 4. Put the above beaker under mix (400 rpm), add methanol, add API, cover the beaker, mix until API dissolved 5. Add mix of the 4 polymers (HPC-low and mid viscosity, PVP and CMC), increasing mixing speed to 700-800 rpm, mix for 2 minutes. 6. Reduce speed of mixing to 600-700 rpm, mix for at least 2 hours, until the blend is uniform. 7. Reduce mixing speed to 20 rpm, de-gas overnight EXAMPLE 2

[0196] A good film formulation is usually the result a using more than one polymer to balance the final properties of the film. In the case of a low melting point product the 5 resulting matrix must be sufficiently strong to prevent agglomeration, recrystallization of the amorphous API and should provide sufficient mechanical property preventing stickiness and softness of the film.

[0197] The following table demonstrates the formulation for example 2. Formulation 2 Function % wet (w / w) % dry (w / w) Water Solvent 44.999 3.144 Low melting point API API 18.749 33.017 vitamin E TPGS Stabilizer 1.101 1.939 acesulfame K Sweetener 0.062 0.110 Sucralose Sweetener 0.786 1.384 Suppresseur amertume Flavor enhancer 1.625 2.861 Citrus flavor Flavoring agent 0.833 1.467 Stiffness and crystal HPC-mid viscosity inhibitor, increase viscosity and matrix polymer 2.976 5.241 PVP K90 Reduce stickiness and softness polymer 16.071 28.300 HPC-low viscosity Matrix polymer 12.083 21.278 PEG 300 Plasticizer 0.714 1.258 Total Wet 100.000 Total Dry 100.000 % solid EXAMPLE 3

[0198] The following uses glass transition temperatures to demonstrate how the two above formulations exhibit good softness and stiffness and have not shown any 5 recrystallization.

[0199] The glass transition temperature, Tg1, of a polymer can be changed via an additive with Tg2. The effect is calculated from the weight fractions of the two components, w1 and w1, via the Fox Equation: 1 / Tg=w1 / Tg1+w2 / Tg2, where w is the faction of the polymer in the system and the Tg is expressed in degree Kelvin. The resulting Tg of the product io must be above the melting point of the API or above temperature the product is expected to be exposed. This provides an environment where movement is restricted resulting in stiffness and low softness. Formulation      1 Polymer fraction present in dry product Tg (K) fraction / Tg HPC mid viscosity 15.8 423 0.00037 HPC-high viscosity 3.2 425 0.00007 PVP 30 7.2 436 0.00017 HPC-mid viscosity 64.3 423 0.00152 CMC low viscosity 9.5 873 0.00011 Total 100.0 0.00224 Tg of the final product 172.9°C Formulation     2 Polymer fraction present in Tg (K) fraction / Tg dry product HPC-mid viscosity 9.3 423 0.0002209 PVP K90 50.5 434 0.0011628 H PC-low viscosity 37.9 423 0.000897 PEG 300 2.2 221 0.0001015 Total 100.0 0.00238 Tg of the final product 146.8 °C

[0200] The above two formulations exhibit good softness and stiffness and have not shown any recrystallization over time when exposed to aggressive conditions like 50oC. 5 EXAMPLE 4

[0201] The following is a formulation as well as glass transition temperature data to demonstrate a weaker result. Formulation 3 Function % wet (w / w) % dry (w / w) Water Solvent 17.662 - methanol Solvent 41.212 - Low melting point API API 14.723 35.800 Citric acid pH modifier 2.066 5.023 Sodium metabisulfite Stabilizer 1.472 3.579 BHT Stabilizer 0.864 2.102 Neotame Sweetener 0.098 0.239 Sucralose Sweetener 0.615 1.495 Menthol Flavoring agent 1.93 1.591 FD&C Yellow Colorant 0.016 0.040 PEG 200,000 Matrix polymer 9.345 22.723 Plasdone S-630 Matrix polymer 1.068 2.596 HPC-mid viscosity Reduce stickiness and softness and increase viscosity polymer 2.388 5.806 HPMC mid-viscosity Crystal inhibitor and increase stiffness polymer 1.962 4.772 D-Maltitol Pore former 4.579 11.134 Total Wet 100.000 100.000 Total Dry % solid Formulation 3 Polymer fraction present in dry product Tg (K) fraction / Tg polyethylene oxide 63.3 225 0.002813385 Plasdone S-630 7.2 385 0.000187848 HPC mid viscosity 16.2 425 0.000380552 HPMC low viscosity 13.3 435 0.000305592 Total 100.0 0.00369 Tg of the final product -1.80 °C

[0202] Formulation 3 has all of the required components but the calculation of the final Tg 5 indicates a poor result meaning that the product is above the Tg hence has a lot of freedom of movement. When this product was placed in stability, recrystallization was observed after one week.

[0203] The above description is considered that of the preferred embodiment(s) only. Modifications of these embodiments will occur by those skilled in the art and by those io who make or use the illustrated embodiments. Therefore, it is understood that the embodiment(s) described above are merely exemplary and not intended to limit the scope of this disclosure, which is defined by the following claims as interpreted according to the principles of patent law, including the doctrine of equivalents. EXAMPLE 5 5

[0204] The following example uses cannabidoil which has a low melting point at about 67oC and is also a resin which needs to be melted to be added during blend preparation. Formulation 5 Function % wet (w / w) % dry (w / w) Water Solvent 74 - cannabidiol API 6 23 l-menthol Flavoring agent 1.5 6 Sodium citrate pH modifier 0.5 2 Advantame sweetener 1 4 Eucaliptol Flavoring agent 1 4 Peppermint oil Flavoring agent 1 4 Maltitol Pore former 5 19 Stiffness / HPMC E15 crystal inhibitor polymer 3 12 Stiffness / CMC high viscosity Viscosity enhancer 3 12 CMC low viscosity Reduce stickiness and      softness polymer 4 15 Total Wet 100 Total Dry 100 % solid 26

[0205] Since CBD is a resin it needs to be melted first before added to the blend. In some embodiments, the blending process of this disclosure is as follows: 1. Melt CBD at 70 oC and add the liquid flavors in a beaker 2. In a second beaker add water and warm up to at least 60oC 3. Set homogenizer speed to 10K rpm, add the warm CBD and flavors to the warm water, homogenize for at least 5 min until all excipients are well-dispersed and an homogeneous solution is obtained. 4. under mixing lower the temperature back to normal. 5. Set homogenizer speed to 10K rpm, add HPC and CMC, homogenize for at least 5 min until all excipients are well-dispersed or dissolved 6. Stop the homogenization and switch a a regular mixer set to 600-700 rpm, mix for at least 2 hours, until the blend is uniform. 7. Reduce mixing speed to 20 rpm, de-gas overnight EXAMPLE 6

[0206] Example 6 is a variation of the Example 5 which is manufactured using the same process. Formulation 6 Function % wet (w / w) % dry (w / w) Water Solvent 72 - cannabidiol API 7 25 l-menthol Flavoring agent 1 4 Sodium citrate pH modifier 1 4 Advantame sweetener 0.3 1 Eucaliptol Flavoring agent 0.2 1 Peppermint oil Flavoring agent 2 7 Xanthan gum Gum, adhesion 3 11 Soy Lecithin surfactant 1.5 5 HPMC E4M Stiffness / crystal inhibitor polymer 11 HPMC E15 Stiffness / crystal inhibitor polymer 11 CMC high viscosity Stiffness / Viscosity                   $ enhancer 11 CMC low viscosity Reduce stickiness and      softness polymer 11 Total Wet 100 100 Total Dry % solid 28 EXAMPLE 7

[0207] Lidocaine, melting point 60oC, belongs to the family of medicines called local anesthetics. This medicine prevents pain by blocking the signals at the nerve endings in 5 the skin or the buccal mucosa. When formulated a buccal film it can act on the buccal mucosa nerves and enable procedures in the mouth. Formulation 7 Function % wet (w / w) % dry (w / w) Water Solvent 72 - Lidocaine API 7 25 Strawberry flavor Flavoring agent 1 3.6 Citric acid pH modifier 1 3.6 Sucralose sweetener 0.3 1.1 Arome type suppressor ammertume Bitterness masking agent 0.2 0.7 Polysorbate 80 surfactant 4 14.3 Soy Lecithin surfactant 2.5 8.9 HPMC E4M Stiffness / crystal inhibitor polymer 10.7 HPMC E15 Stiffness / crystal inhibitor polymer 10.7 PEO 200,000 Stiffness / Viscosity                   $ enhancer 10.7 CMC low viscosity Reduce stickiness and      softness polymer 10.7 Total Wet 100 Total Dry 100 % solid 28

[0208] There are a variety of approaches to the blending process which are possible. In some embodiments, the blending process of this disclosure is as follows: 1. Add citric acid, bitter masker, sweeteners and flavors in a beaker 2. Add water, put the beaker under homogenizer 3. Put the above beaker under mix (400 rpm), add the surfactant to the beaker and mix until a homogenous solution is obtained 4. Add API, cover the beaker, mix until API dissolved 5. Add mix of the 4 polymers (HPCs, PEO and CMC), increasing mixing speed to 700-800 rpm, mix for 2 minutes. 6. Reduce speed of mixing to 600-700 rpm, mix for at least 2 hours, until the blend is uniform. 7. Reduce mixing speed to 20 rpm, de-gas overnight EXAMPLE 8

[0209] Example 8 is a variation of the Example 7, which is manufactured using the same 5 process. Formulation 8 Function % wet (w / w) % dry (w / w) Water Solvent 70 - Lidocaine API 10 33.3 Strawberry flavor Flavoring agent 1 3.3 Citric acid pH modifier 1 3.3 Sucralose sweetener 0.3 1.0 Arome type Bitterness suppressor masking agent ammertume 0.4 1.3 Polysorbate 80 surfactant 5 16.7 Soy Lecithin surfactant 2.5 8.3 Stiffness / HPMC E4M crystal inhibitor polymer 2 6.7 Stiffness / HPMC E15 crystal inhibitor polymer 3 10.0 PEG 200,000 Stiffness / Viscosity enhancer 2 6.7 CMC low viscosity Reduce stickiness and      softness polymer 2.8 9.3 Total Wet 100 Total Dry 100 % solid 30 EXAMPLE 9

[0210] Example 9 presents a formulation using pullulan and the main polymer. The formulation generates films that have good mechanical properties and are capable of 5 sustaining the manufacturing process. Formulation 9 Function % wet (w / w) % dry (w / w) Water Solvent 72 - methylphenidate API 9 33.3 maltodextrin Pore former 1 3.7 EDTA Stabilizer 1 3.7 Sucralose Sweetener 0.3 1.1 L-menthol Flavoring agent 0.2 0.7 Antimicrobial propylparaben agent 2 7.4 Methanol Solvent 1 - PEG Surfactant 1.5 5.6 Stiffness / Pullulan crystal inhibitor polymer 3 22.2 Stiffness / HPM-LF crystal inhibitor polymer 3 11.1 HPM-JF Stiffness / Viscosity enhancer 3 11.1 Total Wet 100 Total Dry 100 % solid 28

[0211] There are a variety of approaches to the blending process which are possible. In some embodiments, the blending process of this disclosure is as follows: 1. Add maltodextrin, stabilizer, sweeteners and flavors in a beaker 2. Add water, put the beaker under homogenizer 3. Set homogenizer speed to 10K rpm, add HPC-J viscosity, homogenize for at least 5 min until all excipients are well-dispersed or dissolved. 4. Put the above beaker under mix (400 rpm), add methanol, add API, cover the beaker, mix until API dissolved 5. Add mix of the 2 remaining polymers (HPC-L and pullulan), increasing mixing speed to 700-800 rpm, mix for 2 minutes. 6. Reduce speed of mixing to 600-700 rpm, mix for at least 2 hours, until the blend is uniform. 7. Reduce mixing speed to 20 rpm, de-gas overnight EXAMPLE 10

[0212] Example 10 is a variation of the Example 5 which is manufactured using the same process. Formulation 10 Function % wet (w / w) % dry (w / w) Water Solvent 72 - cannabidiol API 7 25 l-menthol Flavoring agent 1 4 Sodium citrate pH modifier 1 4 Advantame sweetener 0.3 1 Eucaliptol Flavoring agent 0.2 1 Peppermint oil Flavoring agent 2 7 Xanthan gum Gum, adhesion 3 11 Soy Lecithin surfactant 1.5 5 Stiffness / HPMC E4M crystal inhibitor polymer 3 11 Stiffness / HPMC E15 crystal inhibitor polymer 3 11 Stiffness / CMC high viscosity Viscosity enhancer 3 11 CMC low viscosity Reduce stickiness and      softness polymer 3 11 Total Wet 100 Total Dry 100 % solid 26

Claims

1. An oral film formulation comprising:a. at least one active pharmaceutical ingredient (API) having a melting point below 80°C, wherein the API comprises at least 20% by weight of the dry film;b. a film forming matrix comprising at least two polymers, wherein the film forming matrix comprises at least 20% by weight of the dry film; andc. wherein at least one polymer has a glass transition temperature (Tg) at least three times higher than the melting point of the API.

2. The oral film formulation of claim 1, wherein the API comprises at least 30% by weight of the dry film.

3. The oral film formulation of claim 1, wherein the API comprises at least 40% by weight of the dry film.

4. The oral film formulation of claim 1, wherein the API has a melting point below 60°C.

5. The oral film formulation of claim 1, wherein the film forming matrix comprises:a. at least one polymer that acts as a crystal inhibitor;b. at least one polymer that acts as a viscosity enhancer; andc. at least one polymer that acts as a matrix stiffener with a Tg above 120°C.

6. The oral film formulation of claim 5, wherein the crystal inhibitor compriseshydroxypropyl methylcellulose (HPMC).

7. The oral film formulation of claim 5, wherein the viscosity enhancer comprises hydroxypropyl cellulose (HPC).

8. The oral film formulation of claim 1, further comprising less than 5% plasticizer by weight.

9. The oral film formulation of claim 1, further comprising less than 5% residual solvent by weight.

10. The oral film formulation of claim 1, further comprising at least one component selected from the group consisting of: pH modifiers, stabilizers, flavoring agents, flavor enhancers, sweeteners, and colorants.

11. The oral film formulation of claim 10, wherein the stabilizer is selected from the group consisting of: ascorbic acid, Vitamin E TPGS, sodium metabisulfite, and BHT.

12. The oral film formulation of claim 1, wherein the film forming matrix comprises 25% to 45% by weight of the dry film.

13. The oral film formulation of claim 1, wherein the formulation is configured for sublingual or buccal administration.

14. A method of preparing an oral film formulation comprising:a. providing at least one API having a melting point below 80°C;b. combining the API with a film forming matrix comprising at least two polymers, wherein at least one polymer has a glass transition temperature at least three times higher than the melting point of the API;c. forming a blend comprising the API and film forming matrix; andd. casting the blend to form an oral film.

15. The method of claim 14, wherein the API comprises at least 30% by weight of the dry film.

16. The method of claim 14, further comprising selecting polymers for the film forming matrix to achieve a final glass transition temperature above the melting point of the API.

17. The method of claim 14, wherein forming the blend comprises:a. dissolving the API in a solvent;b. combining the dissolved API with the polymers; andc. mixing until uniform.

18. The method of claim 14, wherein casting the blend comprises maintaining the residual solvent content below 5% by weight in the final oral film.

19. The method of claim 14, wherein the API has a melting point between 20°C and 55°C.

20. A stable oral film formulation comprising:a. at least one API having a melting point below 80°C in an amount of at least 30% by weight of the dry film;b. a film forming matrix comprising 25% to 45% by weight of the dry film;c. wherein the film forming matrix comprises at least two polymers including a crystal inhibitor and a matrix stiffener;d. wherein the formulation maintains physical stability without recrystallization when exposed to 40°C / 75% RH for at least one month.

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