Transmucosal oral dosage form and method of using the same

Abstract

The present disclosure provides oral film compositions for transmucosal delivery of xanomeline and trospium chloride for treating schizophrenia and Alzheimer's disease. The compositions comprise xanomeline or a pharmaceutically acceptable salt thereof, trospium or a pharmaceutically acceptable salt thereof, at least one film-forming polymer, and d-alpha- tocopheryl polyethylene glycol succinate (TPGS) as a permeation enhancer, wherein the composition has a pH of from about 4.5 to about 7. The formulations address challenges including poor aqueous solubility, pH-dependent stability, and permeability limitations. Buccal administration enables transmucosal absorption bypassing first-pass hepatic metabolism, thereby mitigating gastrointestinal side effects and food effects compared to conventional oral capsule formulations. The disclosure demonstrates a synergistic effect wherein co-formulation of trospium chloride with xanomeline tartrate unexpectedly enhances transmucosal permeation of trospium chloride compared to films containing trospium chloride alone. Methods of treatment and manufacturing processes are also provided.

Description

TRANSMUCOSAL ORAL DOSAGE FORM AND METHOD OF USING THE SAME

[0001] The present application claims priority from U.S. provisional patent application No.63 / 747,266 with a filing date of January 20, 2025, incorporated herein by reference, and U.S. provisional patent application No. 63 / 951,857 with a filing date of December 31, 2025, incorporated herein by reference.FIELD OF THE DISCLOSURE

[0002] This disclosure relates to pharmaceutical compositions and method of making the same.BACKGROUND OF THE DISCLOSURE

[0003] Active ingredients, such as drugs or pharmaceuticals, are delivered to patients in deliberate fashion.

[0004] Xanomeline and trospium chloride capsule is commonly used to treat schizophrenia. Schizophrenia is a mental health disorder that affects a person's thinking, actions, emotions, perception of reality, and how they relate to others. About 1% of Americans, roughly 3 million people, have schizophrenia, and the disease can have a profound impact on their lives. It’s a chronic brain disorder with no cure, although medications are helpful in managing many of the symptoms. In addition to those symptoms, people with schizophrenia, who are usually diagnosed in young adulthood, are at higher risk of disability and of dying at a younger age. Close to 5% of patients with schizophrenia die by suicide.

[0005] Xanomeline and trospium chloride capsule is a different approach to schizophrenia treatment. Xanomeline and trospium chloride capsule is a unique combination of 2 medicines: xanomeline and trospium chloride. Xanomeline is thought to activate muscarinic receptors in the brain to help adjust important chemical messengers related to schizophrenia symptoms. T rospium chloride may help prevent xanomeline from working outside the brain so that other parts of your body are less likely to be impacted. The rationale of combining trospium and xanomeline is to counteract the troublesome cholinergic adverse effects of xanomeline, which previously led to its discontinuation, and both drugs are likely to be available as a fixed dose combination (FDC).

[0006] The mixture of cholinergic and anticholinergic adverse effects will further complicate the dose modification. A relatively higher incidence of anticholinergic adverse events was observed in the trial, which is contradictory to the cholinergic adverse events when xanomeline was used alone.

[0007] Another important factor is the oral bioavailability of xanomeline, which is less than one percent. In animal studies, xanomeline has been shown to reach the CNS more than plasma, possibly explaining the CNS effects. Moreover, trospium is combined with xanomeline as a peripheral anticholinergic agent, but trospium itself has central anticholinergic effects, includingsomnolence, dizziness, hallucinations, and confusion. Thus, trospium can potentially antagonize the effects of xanomeline in the CNS.

[0008] Xanomeline and trospium chloride uses a different mechanism of action than previous drugs for schizophrenia. Older medicines work by blocking dopamine, a neurotransmitter (a chemical messenger in the body that controls movement, among other functions) — too much dopamine activity is associated with schizophrenia symptoms. And it doesn’t appear to cause side effects, such as weight gain, pacing, and drowsiness — issues that force some patients taking older schizophrenia drugs to abandon their medical regimen. Yet xanomeline and trospium chloride capsule still present several side effects. There is thus a need for an improve treatment mitigating the side effect and adverse effects related to both xanomeline and trospium.SUMMARY OF THE DISCLOSURE

[0009] In general, a pharmaceutical composition can include a polymeric matrix, xanomeline tartrate and trospium chloride or any of their alternative salt in the polymeric matrix and a combination of permeation enhancers. In certain embodiments, the pharmaceutical composition can further include an additional permeation enhancer and an additional surfactant or solubilizer.

[0010] The present disclosure relates to novel oral film formulations of xanomeline and trospium and methods for their preparation. Specifically, this disclosure provides solutions to multiple technical challenges that have previously limited the development of effective oral formulations of xanomeline and trospium, including poor aqueous solubility, pH-dependent physical stability, photosensitivity, permeability limitations, and recrystallization tendencies.

[0011] The present disclosure provides oral film compositions, methods of treatment, and buccal film formulations for transmucosal delivery of xanomeline and trospium. The compositions and methods described herein address longstanding challenges in the art relating to the formulation of these active pharmaceutical ingredients in film-based dosage forms and provide unexpected advantages over conventional oral dosage forms.

[0012] In a first aspect, the present disclosure provides an oral film composition for transmucosal delivery comprising: (a) xanomeline or a pharmaceutically acceptable salt thereof; (b) trospium or a pharmaceutically acceptable salt thereof; (c) at least one film-forming polymer; and (d) d-alpha-tocopheryl polyethylene glycol succinate (TPGS); wherein the composition has a pH of from about 4.5 to about 5.85. In certain embodiments, the pH is from about 5.0 to about 5.7. In further embodiments, the pH is from about 5.0 to about 5.5. The pH range of the compositions described herein has been identified as critical for maintaining both polymer matrix stability and active pharmaceutical ingredient solubility, as pH values above approximately 5.85 result in precipitationof the active ingredients, while excessively acidic conditions promote polymer matrix instability during storage.

[0013] In certain embodiments, the composition further comprises a basifying agent. In particular embodiments, the basifying agent comprises sodium hydroxide. The basifying agent enables precise control of formulation pH within the ranges described herein during manufacturing operations.

[0014] In certain embodiments, the TPGS is present in an amount of from about 1% to about 5% by weight of the dried film. In further embodiments, the TPGS is present in an amount of from about 2% to about 5% by weight of the dried film and the composition has a pH of from about 5.0 to about 5.5. TPGS serves multiple functions within the compositions of the present disclosure, including functioning as a permeation enhancer to facilitate transmucosal absorption, as a surfactant to improve wetting characteristics, and as a dispersing agent to facilitate uniform suspension of taste-masking agents and other functional excipients within the formulation blend.

[0015] In certain embodiments, the at least one film-forming polymer comprises hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP). In particular embodiments, the HPMC comprises a high molecular weight HPMC grade having a viscosity of from about 2000 mPa s to about 6000 mPa s when measured as a 2% aqueous solution at 20°C. High molecular weight HPMC grades within this viscosity range form relaxed, hydrated gel matrices upon contact with mucosal fluids, characterized by flexible polymer network architectures that establish continuous aqueous diffusion pathways for the active pharmaceutical ingredients, thereby enhancing transmucosal permeation. In certain embodiments, the HPMC is present in an amount of from about 9% to about 30% by weight of the dried film and the PVP is present in an amount of from about 30% to about 40% by weight of the dried film. In particular embodiments, the HPMC comprises a combination of HPMC E4M and HPMC E5.

[0016] In certain embodiments, the polymer matrix further comprises hydroxypropyl cellulose (HPC) in an amount of from about 5% to about 12% by weight of the dried film. HPC may be incorporated to impart enhanced film flexibility and reduced stiffness characteristics while maintaining acceptable mucoadhesive properties.

[0017] In certain embodiments, the xanomeline or pharmaceutically acceptable salt thereof is present in an amount of from about 5 mg to about 50 mg per dosage unit and the trospium or pharmaceutically acceptable salt thereof is present in an amount of from about 2 mg to about 20 mg per dosage unit. In particular embodiments, xanomeline is present as xanomeline tartrate and trospium is present as trospium chloride.

[0018] In certain embodiments, the composition further comprises a plasticizer. In particular embodiments, the plasticizer comprises polyethylene glycol 300 in an amount of from about 5% to about 18% by weight of the dried film. The plasticizer provides flexibility and reduces brittleness of the film matrix while contributing to the maintenance of homogeneous dispersion of functional excipients throughout the formulation.

[0019] In certain embodiments, the composition further comprises an antioxidant. In particular embodiments, the antioxidant comprises butylated hydroxytoluene (BHT). BHT has been identified as providing significant improvement in the stability of the oral film compositions with respect to both total impurities content and independent impurity formation during storage.

[0020] In certain embodiments, the composition is substantially free of ascorbyl palmitate. Although ascorbyl palmitate provides improvement in oxidative stability, it has been observed to substantially reduce the transmucosal permeation of the active pharmaceutical ingredients through the buccal mucosa. Accordingly, in embodiments wherein enhanced permeation is a critical performance attribute, the deliberate exclusion of ascorbyl palmitate from the formulation is preferred.

[0021] In certain embodiments, the film has a disintegration time of from about 15 minutes to about 20 minutes as measured by Petri dish testing. This disintegration time range has been determined to be optimal for achieving adequate mucosal residence time for transmucosal absorption while maintaining acceptable patient compliance characteristics.

[0022] In a second aspect, the present disclosure provides a method of treating a neurological or psychiatric disorder selected from the group consisting of schizophrenia and Alzheimer's disease in a subject in need thereof. The method comprises administering to the oral mucosa of the subject a buccal film composition comprising: (a) xanomeline tartrate; (b) trospium chloride; (c) a polymer matrix comprising at least one cellulose derivative and at least one polyvinylpyrrolidone; and (d) d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); wherein the composition has a pH of from about 5.0 to about 5.7, and wherein at least a portion of the xanomeline and trospium chloride are absorbed transmucosally.

[0023] In certain embodiments of the method, the transmucosal absorption bypasses first-pass hepatic metabolism. The buccal route of administration enables direct absorption of the active pharmaceutical ingredients into the systemic circulation via the jugular vein, thereby avoiding the portal circulation and associated first-pass metabolic degradation that occurs with conventional oral administration.

[0024] In certain embodiments, the method provides reduced gastrointestinal side effects compared to oral capsule administration of xanomeline and trospium. By enabling transmucosal absorption and bypassing the gastrointestinal tract, the buccal film formulations of the presentdisclosure reduce exposure of the gastrointestinal mucosa to the active pharmaceutical ingredients, thereby minimizing gastrointestinal adverse events that are commonly associated with oral administration of xanomeline-containing formulations.

[0025] In a third aspect, the present disclosure provides a buccal film composition for enhanced transmucosal delivery of trospium chloride. The composition comprises: (a) xanomeline tartrate in an amount effective to enhance permeation of trospium chloride across buccal mucosa; (b) trospium chloride; (c) at least one film-forming polymer; and (d) a permeation enhancer comprising d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); wherein co-formulation of the trospium chloride with xanomeline tartrate provides enhanced transmucosal permeation of the trospium chloride compared to a film composition containing trospium chloride without xanomeline tartrate, and wherein the composition has a pH of from about 5.0 to about 5.7.

[0026] The present disclosure demonstrates a surprising and synergistic effect of xanomeline on the transmucosal permeation of trospium chloride across the buccal mucosa. Trospium chloride formulated as the sole active pharmaceutical ingredient in a buccal film exhibits negligible permeation through buccal mucosa. In contrast, when trospium chloride is co-formulated with xanomeline tartrate in a combined buccal film composition, its transmucosal permeation is unexpectedly and significantly enhanced. Without being bound by theory, the presence of xanomeline in the film matrix appears to facilitate or otherwise promote the permeation of trospium chloride, which is otherwise poorly permeable when administered alone in a film formulation. This unexpected synergistic enhancement represents a significant and non-obvious advantage of the combined buccal film compositions of the present disclosure.

[0027] The compositions of the present disclosure provide substantial advantages over solution formulations. Both xanomeline and trospium chloride exhibit substantially enhanced permeation through the buccal mucosa when formulated in the buccal film compositions described herein as compared to solution formulations containing equivalent amounts of the same active pharmaceutical ingredients. Without being bound by theory, the enhanced permeation observed with the film formulations may be attributed to one or more of: prolonged mucosal residence time afforded by the mucoadhesive film matrix; sustained and controlled release of the active pharmaceutical ingredients from the polymeric matrix; localized maintenance of favorable concentration gradients at the mucosal surface; and permeation-enhancing effects of formulation components including TPGS.

[0028] The disclosure encompasses three distinct formulation approaches: aqueous-based, solvent-based, and hybrid aqueous-organic solvent systems, each offering specific advantages for oral transmucosal delivering of xanomeline and trospium. These formulations mitigated thefood effect observed with conventional tablet and solution formulations through innovative combinations of solubilizers, stabilizers, permeation enhancers and polymers.

[0029] In certain embodiments, the present disclosure outlines novel film-forming polymer combinations utilizing polyvinylpyrrolidone (PVP), Hydroxypropyl cellulose (HPC) hydroxypropylmethylcellulose (HPMC), polyethylene oxide (PEO), copovidone, Hydroxyethyl cellulose (HEC), Sodium carboxymethyl cellulose (NaCMC), Chitosan, Pullulan, Alginate, Starch, Xanthan gum, Guar gum, Acacia gum, Tragacanth gum, Gellan gum.

[0030] According to some embodiments, the disclosure provides formulations that mitigates the food effects on drug absorption.

[0031] According to some embodiments, the disclosure provides formulations with the ability to enhanced bioavailability compared to conventional tablet or solution formulations.

[0032] According to some embodiments, the disclosure provides formulations with the ability to enhance bioavailability, reduce the required dose, and minimize the side effects.

[0033] According to some embodiments, the disclosure provides formulations that improve the chemical stability profile of the API.

[0034] According to some embodiments, the disclosure provides formulations designed for enhanced patient compliance through convenient administration, and mitigation of the food effect.

[0035] According to some embodiments, the disclosure provides anti-foaming agents such as simethicone to prevent bubble formation during manufacturing, high-intensity sweeteners such as acesulfame potassium and advantame for improved palatability, and lipophilic antioxidants such as ascorbyl palmitate for enhanced oxidative stability.

[0036] According to some embodiments, the disclosure provides formulations comprising polymer matrices characterized by relaxed, hydrated gel networks that provide continuous aqueous pathways for drug diffusion. In certain preferred embodiments, high molecular weight hydroxypropyl methylcellulose (such as HPMC E4M) is combined with moderate concentrations of polyvinylpyrrolidone to form flexible polymer networks that maximize transmucosal drug transport and improve mechanical properties of the resulting film.

[0037] According to some embodiments, the disclosure provides formulations with optimized pH in the range of about 4.5 to about 7.0, preferably between 5.0 to about 5.7 to enhance transmucosal drug permeation. The pH optimization reduces electrostatic interactions between ionizable drug species and excipient components, facilitating faster drug release from the polymer matrix and improved absorption across the oral mucosa. The slightly acidic pH is a balance between absorption and API solubility.

[0038] The disclosure further provides detailed manufacturing methods for each formulation approach, including specific process parameters and quality control measures essential for maintaining critical quality attributes.

[0039] Multiple embodiments are described, including formulations optimized for different strengths, providing flexibility in meeting various therapeutic requirements while maintaining consistent performance characteristics. The disclosure represents a significant advancement in the delivery of xanomeline and trospium chloride, offering improved therapeutic outcomes through potential enhanced drug absorption and reduced food effect

[0040] In certain embodiments, a pharmaceutical composition can include a polymeric matrix, xanomeline, xanomeline tartrate, trospium and trospium chloride in the polymeric matrix.

[0041] In certain embodiments, a pharmaceutical composition can further include solubilizers. Solubilizers can include Polyethylene Glycol (PEG), cyclodextrins, surfactants, organic solvents, lipids, salts, glycols and polyols.

[0042] In certain embodiments, a pharmaceutical composition can further include permeation enhancers and combination of permeation enhancers.

[0043] In certain aspects of this disclosure, the disclosed formulations and excipients are specifically adapted for use in humans.

[0044] In certain embodiments, the pharmaceutical composition can further include a stabilizer. Stabilizers can include antioxidants, which can prevent unwanted oxidation of materials, sequestrants, which can form chelate complexes and inactivating traces of metal ions that would otherwise act as catalysts, emulsifiers and surfactants, which can stabilize emulsions, ultraviolet stabilizers, which can protect materials from harmful effects of ultraviolet radiation, LIV absorbers, chemicals absorbing ultraviolet radiation and preventing it from penetrating the composition, quenchers, which can dissipate the radiation energy as heat instead of letting it break chemical bonds, or scavengers which can eliminate free radicals formed by ultraviolet radiation.

[0045] In yet another aspect, the pharmaceutical composition has a suitable nontoxic, nonionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide in combination with a mucosal delivery-enhancing agent selected from: (a) an aggregation inhibitory agent; (b) a charge-modifying agent; (c) a pH control agent; (d) a degradative enzyme inhibitory agent; (e) a mucolytic or mucus clearing agent; (f) a ciliostatic agent; (g) a membrane penetration-enhancing agent selected from: (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome, or carrier; (iii) an alcohol; (iv) an enamine; (v) a nitric oxide donor compound; (vi) a long chain amphipathic molecule; (vii) a small hydrophobic penetration enhancer; (viii) sodium or a salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) acyclodextrin or beta-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or salt thereof; (xiv) an N-acetylamino acid or salt thereof, (xv) an enzyme degradative to a selected membrane component; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) any combination of the membrane penetration enhancing agents recited in (i)-(x); (h) a modulatory agent of epithelial junction physiology; (i) a vasodilator agent; (j) a selective transport-enhancing agent; and (k) a stabilizing delivery vehicle, carrier, mucoadhesive, support or complex-forming species with which the compound is effectively combined, associated, contained, encapsulated or bound resulting in stabilization of the compound for enhanced mucosal delivery, wherein the formulation of the compound with the transmucosal delivery-enhancing agents provides for increased bioavailability of the compound in a blood plasma of a subject.

[0046] In general, a pharmaceutical composition can be dispensed from a device. A device can include a housing that holds an amount of a pharmaceutical composition, including a polymeric matrix; a pharmaceutically active component including xanomeline, xanomeline tartrate, trospium and trospium chloride in the polymeric matrix; and an opening that dispenses a predetermined amount, such as a predetermined dose, of the pharmaceutical composition. The device can also dispense a pharmaceutical composition including a permeation enhancer.

[0047] There is a need for pharmaceutically acceptable oral disintegrating films that address the issues associated with effective absorption of the related actives. There is also a need to make a xanomeline / trospium film where the APIs are buccally absorbed, leading to higher bioavailability and lower metabolization of the API to reduce adverse events associated with metabolite.

[0048] These and other inefficiencies and opportunities for improvement are addressed and / or at least partially overcome by the systems, assemblies and methods of the present disclosure.

[0049] In certain aspects of this disclosure, the disclosed formulations and excipients are specifically adapted for use in animals.

[0050] These and other features, advantages and objects of the various embodiments will be better understood with reference to the following specification and claims.BRIEF DESCRIPTION OF THE FIGURES

[0051] FIG. 1 illustrates the chemical structures of xanomeline;

[0052] FIG. 2 illustrates the chemical structures of xanomeline tartrate;

[0053] FIG. 3 illustrates the chemical structures of trospium; and

[0054] FIG. 4 illustrates the chemical structures of trospium chloride.

[0055] FIG. 5 depicts cumulative xanomeline permeation through porcine buccal mucosa as a function of time for Formulations, Example 12 A and B and Example 13, illustrating the permeation-enhancing effect of TPGS and the permeation-reducing effect of citric acid. Permeation studies were conducted using Franz diffusion cells with phosphate buffered saline (PBS) at pH 6.8, 0.01 M as the receptor medium.

[0056] FIG. 6 depicts cumulative xanomeline permeation through porcine buccal mucosa comparing Formulations Example 13 and Example 14, demonstrating that the introduction of HPMC E50 at approximately 10% dry weight has minimal impact on transmucosal permeation.

[0057] FIG. 7 depicts cumulative xanomeline permeation through porcine buccal mucosa comparing Formulation Example 14 (pH 3) and Formulation Example 15 (doubled TPGS at pH 3), demonstrating the paradoxical permeation reduction when TPGS concentration is increased at acidic pH due to drug sequestration in polyethylene glycol micelles.

[0058] FIG. 8 depicts cumulative xanomeline permeation through porcine buccal mucosa comparing Formulations Example 14, Example 15, and Example 16, illustrating that pH adjustment to 5.0 restores and enhances permeation when combined with elevated TPGS concentration, resulting in approximately 5-fold improvement over the acidic pH formulation.

[0059] FIG. 9 depicts cumulative xanomeline permeation through porcine buccal mucosa comparing Formulations Example 17 (acidic pH) and Example 18 (pH 5.70), demonstrating that pH optimization significantly enhances permeation in formulations containing elevated HPMC E50 (24.45% dry) and TPGS (4.94% dry).

[0060] FIG. 10 depicts cumulative xanomeline permeation through porcine buccal mucosa comparing Formulations Example 18, Example 19, and Example 17, demonstrating that the addition of ascorbyl palmitate (0.67% dry) strongly reduces permeation through the formation of hydrophobic domains that sequester the drug.

[0061] FIG. 11 depicts cumulative xanomeline permeation through porcine buccal mucosa comparing Formulations Example 18 and Example 20, demonstrating that higher HPMC content (25%) combined with moderate PVP (35%) enhances permeation by promoting film hydration and polymer relaxation, whereas increasing PVP to 50% while reducing HPMC to 10% results in a denser, more rigid matrix that limits drug diffusion.

[0062] FIG. 12 depicts cumulative xanomeline permeation through porcine buccal mucosa comparing Formulations Example 21 (pH 3) and Example 22 (pH 5.5), demonstrating the pH effect on multi-polymer systems comprising PVP K90, HPC L, HPMC E15, and HPMC E4M.

[0063] FIG. 13 depicts cumulative xanomeline permeation through porcine buccal mucosa comparing Formulations Example 23 and Example 24, demonstrating that HPMC E4M (-4000 mPa sviscosity) forms a relaxed, hydrated gel with flexible polymer networks and continuous aqueous pathways resulting in higher permeation (approximately 900 pg / cm3at 200 minutes), whereas HPMC E5 (~5 mPa s viscosity) forms a weaker, less relaxed network limiting drug diffusion.

[0064] FIG. 14 depicts cumulative xanomeline permeation (pg / cm2) through porcine buccal mucosa in PBS (pH 6.8, 0.01 M), comparing the buccal film formulation (Example 25) with an equivalent aqueous solution formulation, demonstrating that the film achieves approximately 430-450 pg / cm2versus approximately 50-60 pg / cm2for the solution at 240 minutes.

[0065] FIG. 15 depicts cumulative xanomeline permeation (expressed as percentage of applied dose) through porcine buccal mucosa in PBS (pH 6.8, 0.01 M), comparing the buccal film formulation (Example 25) with an equivalent aqueous solution formulation, demonstrating that the film achieves approximately 15-16% permeation versus approximately 2% for the solution at 240 minutes.

[0066] FIG. 16 depicts cumulative trospium chloride permeation (pg / cm2) through porcine buccal mucosa in PBS (pH 6.8, 0.01 M), comparing the buccal film formulation (Example 25) with an equivalent aqueous solution formulation, demonstrating that the film achieves approximately 38-41 pg / cm2versus approximately 1-2 pg / cm2for the solution at 240 minutes.

[0067] FIG. 17 depicts cumulative trospium chloride permeation (expressed as percentage of applied dose) through porcine buccal mucosa in PBS (pH 6.8, 0.01 M), comparing the buccal film formulation (Example 25) with an equivalent aqueous solution formulation, demonstrating that the film achieves approximately 3.5-3.7% permeation versus approximately 0.1-0.2% for the solution at 240 minutes.

[0068] FIG. 18 depicts cumulative trospium chloride permeation (pg / cm2) through porcine buccal mucosa in PBS (pH 6.8, 0.01 M), comparing the combined xanomeline / trospium chloride buccal film (Example 25) with a trospium chloride bilayer film without xanomeline (Example 26), demonstrating a synergistic permeation enhancement wherein trospium chloride co-formulated with xanomeline achieves approximately 38-41 pg / cm2whereas trospium chloride alone exhibits negligible permeation.DETAILED DESCRIPTION OF THE DISCLOSURE

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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, anti-foaming 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).

[0076] Film systems embody a field of technology that has major advantages in areas of administeringvarious 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 high melting point.

[0077] 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.

[0078] 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”. Oral dissolving films can fall into three main classes: fast dissolving, moderate dissolving and slow dissolving. Oral dissolving films can also include a combination of any of the above categories. Fast dissolving films can dissolve in about 1 second to about 30 seconds in the mouth, including more than 1 second, more than 5 seconds, more than 10 seconds, more than 20 seconds, and less than 30 seconds. Moderate dissolving films can dissolve in about 1 to about 30 minutes in the mouth including more than 1 minute, more than 5 minutes, more than 10 minutes, more than 20 minutes or less than 30 minutes, and slow dissolving films can dissolve in more than 30 minutes in the mouth. As a general trend, fast dissolving films can include (or consist of) low molecular weight hydrophilic polymers (e.g., polymers having a molecular weight between about 1,000 to 9,000 daltons, or polymers having a molecular weight up to 200,000 daltons). In contrast, slow dissolving films generally include high molecular weight polymers (e.g., having a molecular weight in millions). Moderate dissolving films can tend to fall in between the fast and slow dissolving films. It can be preferable to use films that are moderate dissolving films. Moderate dissolving films can dissolve rather quickly, but also have a good level of mucoadhesion. Moderate dissolving films can also be flexible, quickly wettable, and are typically non-irritating to the user. Such moderate dissolving films can provide a quick enough dissolution rate, most desirably between about 1 minute and about 20 minutes, while providing an acceptable mucoadhesion levelsuch that the film is not easily removable once it is placed in the oral cavity of the user. This can ensure delivery of a pharmaceutically active component to a user.

[0079] 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.

[0080] The term "basifying agent" refers to a substance or compound incorporated into the formulation to raise the pH (alkalinity) of the environment. A basifying agent falls into the category of pH modifiers and is specifically utilized to create a more alkaline microenvironment within the formulation. These agents are particularly important in pharmaceutical formulations where API stability, solubility, or permeability is enhanced under basic conditions. Common pharmaceutical basifying agents include metal hydroxides (such as sodium hydroxide, potassium hydroxide), carbonates (such as sodium carbonate, potassium carbonate), and certain amines or amino compounds. The selection of an appropriate basifying agent must consider its compatibility with other formulation components, its impact on API stability, and its safety profile for the intended route of administration. In oral film formulations, basifying agents must be carefully selected to maintain their functionality while not compromising film-forming properties or introducing taste issues.

[0081] The term "anti-foaming agent" and variations thereof refers to a substance that reduces and hinders the formation of foam in formulation liquids during manufacturing. In the context of oral film formulations, anti-foaming agents help prevent air bubble entrapment during casting, resulting in films with uniform thickness and improved appearance. Examples of anti-foaming agents include but are not limited to simethicone (a polydimethylsiloxane-based compound), dimethicone, mineral oil, silicone oils, and vegetable oil-based defoamers. Simethicone is particularly preferred as it is physiologically inert, non-toxic, and does not interact with the active pharmaceutical ingredients or affect drug release characteristics.

[0082] 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.

[0083] 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 agglomeratesor 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).

[0084] 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.

[0085] The term “active agent(s)” or “API” refers mainly to active pharmaceutical 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.

[0086] 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 higher extent of absorption and to a 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. This is even more critical in the case of low dose products. 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.

[0087] According to some aspects of the disclosure, the API is primarily amorphous, which is defined as 75% or more of the API in its amorphous state

[0088] 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.

[0089] 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 importantfactor 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 in a Franz cell approach 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.

[0090] In vitro permeation studies using pig buccal mucosa are conducted using Franz diffusion cells with the mucosal tissue mounted between donor and receptor compartments. The receptor compartment contains phosphate buffered saline (PBS) at pH 6.8 with ionic strength of 0.01 M, maintained at 37°C ± 0.5°C with continuous magnetic stirring. Test films are applied to the mucosal surface in the donor compartment, and samples are withdrawn from the receptor compartment at predetermined time intervals (typically 0, 15, 30, 60, 90, 120, 180, and 250 minutes) for quantification of permeated drug by validated analytical methods such as HPLC. Cumulative permeation is calculated and expressed as micrograms per square centimeter (pg / cm2) or concentration (pg / cm3) or percentages as a function of time. Permeation enhancement ratios are calculated by comparing test formulations to reference formulations or commercial products.

[0091] 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 yellowishNa, 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.

[0092] The term “co-solvent” refers to a solvent component used in combination with water that modifies the solvent environment of the formulation without necessarily increasing the intrinsic thermodynamic solubility of the active pharmaceutical ingredient. The co-solvent facilitates homogeneous dispersion of active ingredients and excipients within a hydrated polymer matrix, contributes to precipitation control, and supports formulation stability during film formation and storage.

[0093] The term a “crystal inhibitor” 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 but are not limited to the following and their derivatives: Polyvinylpyrrolidone andHydroxypropylmethylcellulose (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) Hydroxypropyl cellulose (HPC) which offers both hydrophobic (hydroxypropyl group) and hydrophilic characteristics with aqueous viscosity ranging from 150-400 mPas (2%, 20°C for L grade) to 1000-4000 mPas (2%, 20°C for H grade), employed alone or mixed with Methyl cellulose (MC) of aqueous viscosity up to 5040 mPas (2%, 20C).

[0094] 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.

[0095] The term “flavor” and variations thereof generally refer 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).

[0096] 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.

[0097] 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), andspices (e.g., peppers) are most often employed, yeast, yeast extract, dried yeast and others or mixtures thereof.

[0098] Other known techniques used to cover the perceived unpleasant taste of active agents include the addition of taste maskers.

[0099] 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. Residence time is defined as the time a film stay in contact with the mucosa before being fully dissolved by saliva. In the lab, residence time is tested with a limited amount of simulated saliva in a Petri dish. The residence time test allows to assess and adjust matrix composition to fit different time goals. Films formulated for sublingual application will have a shorter residence time due to the restriction imposed by this administration approach (mouth closed and tongue immobile at the bottom of the mouth). Films formulated for buccal absorption can last longer as due to the high mucoadhesion of the film to the buccal cheek they do not prevent movement of the mouth and can be tolerate for a longer period of time. Sublingual film exhibits residence time in the lab of about or less than 10 minutes while buccal films can be anywhere from 10 to 60 minutes. The longer the residence time is the bigger the chances of buccal absorption. Residence time testing is achieved through a Disintegration test, which may be a static or dynamic test. In the static one, a film is placed on a stainless-steel mesh, with active side facing to the mesh, then the film together with the mesh are completely immersed in 40 ml phosphate buffer pH 7.0, 0.01 M in a petri dish, observe film disintegration process in the buffer until the film is completely disintegrated. In the dynamic testing, one film is fixed between 2 stainless steel mesh, then the film is completely immersed in 40 ml phosphate buffer pH 7.0, 0.01 M in a petri dish. The petri dish is then fixed on a shaker. With a shaking speed of 60 rpm, the disintegration process of the film is monitored until the film is completely disintegrated.

[0100] 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 inoral liquid products (e.g., iron) are often masked by extracts of guarana, a tropical fruit, but can be masked by other extracts and agents.

[0101] 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.

[0102] 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.

[0103] The term “TPGS” or “Vitamin E TPGS” refers to d-alpha-tocopheryl polyethylene glycol 1000 succinate, a water-soluble derivative of natural vitamin E formed by esterification of vitamin E succinate with polyethylene glycol 1000. TPGS functions as a permeation enhancer, solubilizer, and emulsifier in pharmaceutical formulations. At concentrations above its critical micelle concentration (approximately 0.02% w / v), TPGS forms micelles that can solubilize lipophilic drugs. However, the present disclosurse outlines that TPGS concentration must be carefully balanced with formulation pH to achieve optimal permeation enhancement. At acidic pH (e.g., pH 3 or below), increasing TPGS concentration paradoxically decreases drug permeation due to drug sequestration within TPGS micelles. This phenomenon occurs because basic drugs such as xanomeline become protonated at low pH, resulting in strong electrostatic and hydrogen bonding interactions with the PEG corona of TPGS micelles and with partially dissociated counterions (e.g., tartrate), thereby sequestering the drug within the micellar structure and reducing its availability for transmucosal absorption. Conversely, at moderately acidic to neutral pH (e.g., pH 4.5 to 7.0, preferably pH 5.0 to 5.5), the drug remains less protonated, counterions are more fully dissociated, and interactions with TPGS micelles are weakened, allowing for enhanced drug release and improved permeation characteristics.

[0104] The term “pH optimization” in the context of transmucosal film formulations refers to the adjustment of formulation pH to maximize drug permeation while maintaining chemical stability and solubility of the active pharmaceutical ingredients. For formulations containing permeationenhancers such as TPGS, pH optimization is particularly important because the ionization state of the drug influences its interaction with surfactant micelles. The optimal pH range for xanomeline-containing formulations is typically between about 4.5 and about 7, more preferably between about 5.0 and about 5.7. Within this range, xanomeline exists predominantly in a less protonated form, reducing its affinity for TPGS micelles, remains amorphous and facilitating release for transmucosal absorption. Additionally, pH adjustment can be achieved using pharmaceutically acceptable bases such as sodium hydroxide solution, which when added to acidic formulations increases the pH to the optimal range without compromising film-forming properties or stability of the active ingredients.

[0105] According to some embodiments, pH adjustment represents an important formulation parameter for optimizing xanomeline permeation in oral film formulations. At acidic pH values (pH 3-4), xanomeline tartrate exists predominantly in its protonated cationic form, leading to strong electrostatic interactions with anionic excipients and significant entrapment in surfactant micelles. These interactions result in drug sequestration and reduced mucosal permeation. Adjusting formulation pH to a range of about 5.0 to about 5.7 using a basifying agent reduces xanomeline protonation, weakens interactions with the tartrate counterion and surfactant systems such as TPGS micelles, and significantly enhances transmucosal permeation. In certain embodiments, pH adjustment is achieved using sodium hydroxide as the basifying agent, with the blend pH maintained between about 4.5 and about 6.0, preferably between about 5.0 and about 5.7 for optimal permeation performance. In exemplary embodiments, a formulation pH of about 5.5 to about 5.7 provided cumulative xanomeline permeation of approximately 400-600 micrograms per cubic centimeter through pig buccal mucosa at 250 minutes, compared to approximately 100 micrograms per cubic centimeter at acidic pH values. In certain embodiments, pH adjustment is achieved using a basifying agent such as sodium hydroxide when using acidic salt forms of xanomeline (e.g., xanomeline tartrate), or an acidifying agent when using xanomeline free base, with the blend pH optimize for permeation.

[0106] According to some embodiments, the polymer matrix composition importantly influences drug permeation through control of the gel network structure upon hydration. Two distinct matrix architectures have been identified that significantly affect xanomeline tartrate release and transmucosal absorption. Relaxed Gel Networks are formed by formulations with higher HPMC content (about 20 percent to about 30 percent by dry weight) combined with moderate PVP levels (about 30 percent to about 40 percent by dry weight), which form relaxed, hydrated gel structures upon contact with aqueous media. These matrices exhibit a flexible polymer network with enhanced chain mobility, continuous aqueous diffusion pathways, rapid water penetration andpolymer swelling, enhanced drug diffusion coefficients, and higher cumulative permeation. In certain embodiments, relaxed gel network formulations achieved cumulative xanomeline permeation of about 400-600 micrograms per cubic centimeter at 250 minutes through pig buccal mucosa. Dense or Glassy Networks are formed by formulations with high PVP content (about 45 percent to about 55 percent by dry weight) and reduced HPMC content (about 5 percent to about 15 percent by dry weight), which create dense, less relaxed matrices characterized by rigid polymer networks with restricted chain mobility, discontinuous or tortuous diffusion pathways, limited water penetration, and reduced drug diffusion. These formulations exhibited lower permeation of about 100-200 micrograms per cubic centimeter xanomeline at 250 minutes. In preferred embodiments, the relaxed gel architecture is selected for transmucosal delivery applications requiring enhanced bioavailability.

[0107] Transmucosal permeation was evaluated using Franz diffusion cell apparatus with pig buccal mucosa as the model membrane. Fresh pig buccal tissue was obtained and prepared by removing underlying connective tissue to isolate the mucosal epithelium. The mucosa was mounted between donor and receptor compartments with the epithelial side facing the donor compartment. The receptor compartment was filled with phosphate-buffered saline (PBS) at pH 6.8 (0.01 M) maintained at 37 degrees Celsius with magnetic stirring. Film samples of defined area were applied to the mucosal surface in the donor compartment. Samples were withdrawn from the receptor compartment at predetermined time intervals (0, 30, 60, 90, 120, 150, 200, and 250 minutes). Xanomeline concentrations were determined by HPLC analysis. Cumulative permeation was calculated as the total amount of drug permeated per unit area as a function of time. Steady-state flux was determined from the linear portion of the permeation curve.

[0108] 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, polyethylene glycol, 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 30%, 1% to 25%, 2% to 20% or 5% to 15%.

[0109] 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) withinthe 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.

[0110] According to some embodiments, in formulations containing xanomeline tartrate and trospium chloride, pH optimization was identified as important for achieving optimal transmucosal permeation. Research has demonstrated that the optimal pH range for the film-forming solution is between about 5.0 and about 5.7, more preferably between about 5.0 and about 5.5. At acidic pH values below 5.0, xanomeline tartrate becomes protonated, and the tartrate counterion remains partially dissociated, resulting in strong electrostatic and hydrogen-bond interactions that can sequester the drug within micelle structures formed by permeation enhancers such as TPGS (d-alpha-tocopheryl polyethylene glycol succinate). This sequestration significantly reduces drug release and transmucosal permeation. Adjustment of solution pH to approximately 5.0 to 5.7 using a basifying agent such as sodium hydroxide reduces protonation of xanomeline, promotes fuller dissociation of tartrate, weakens drug-micelle interactions, and facilitates faster drug release with reduced lag time and enhanced permeation across mucosal membranes. The pH adjustment may be achieved using pharmaceutical-grade basifying agents including but not limited to sodium hydroxide, potassium hydroxide, or organic amines in quantities sufficient to achieve the target pH range. In certain embodiments where another salt of xanomeline or xanomeline freebase is present, pH adjustment is achieved using a using basifying agend or acidifying agent to optimize for permeation.

[0111] Effect of Polymeric Gel Characteristics on Drug Permeation

[0112] In the presence of trospium chloride, xanomeline tartrate demonstrates enhanced diffusion and permeation through hydrated polymeric gel matrices. The physical characteristics of the polymer network upon hydration significantly influence drug transport. Relaxed, water-rich polymer networks provide continuous aqueous diffusion pathways that facilitate drug release and transmucosal permeation. In contrast, dense or glassy polymer films limit drug transport of xanomeline tartrate due to restricted molecular mobility and reduced aqueous pathway formation.

[0113] The ratio of film-forming polymers significantly affects permeation outcomes. Formulations with higher HPMC content (approximately 20-30% w / w of the dried film) combined with moderate PVP content (approximately 30-40% w / w) promote film hydration and polymer relaxation, resulting in a mechanically strong matrix with enhanced transmucosal permeation. Conversely, increasing PVP content to approximately 50% while reducing HPMC to approximately 10% resultsin denser, more rigid matrix formation that limits drug diffusion and reduces permeation. Higher molecular weight HPMC grades (such as HPMC E4M) form relaxed, hydrated gels with flexible polymer networks and continuous aqueous pathways, resulting in superior drug permeation compared to lower molecular weight grades (such as HPMC E5) that form weak, less relaxed networks with limited drug diffusion capacity.

[0114] Transmucosal Permeation Testing Methodology

[0115] The transmucosal permeation characteristics of oral film formulations containing xanomeline tartrate and trospium chloride may be evaluated using ex vivo permeation studies with porcine buccal mucosa. Porcine buccal tissue is widely accepted as a model for human buccal mucosa due to similar morphological and permeability characteristics. Permeation studies are conducted using Franz diffusion cells with a receptor compartment containing phosphate-buffered saline (PBS) at pH 6.8 and 0.01 M ionic strength, maintained at 37 degrees Celsiuswith continuous magnetic stirring. Film samples are placed on the mucosal surface of the tissue mounted between donor and receptor compartments. Samples are collected from the receptor compartment at predetermined time intervals (typically 0, 15, 30, 60, 90, 120, 150, 180, 210, and 250 minutes) and analyzed for drug content using validated analytical methods such as high-performance liquid chromatography (HPLC). Cumulative drug permeation is calculated and expressed as micrograms per square centimeter of receptor medium over time. Permeation flux and lag time parameters are derived from the linear portion of the cumulative permeation versus time profile.

[0116] The term “preservative” refers to an agent that extends the storage life of food and nonfood 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.

[0117] 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, hydroxyethyl cellulose, starches, polyacrylates, polysaccharides (alginate, pullulan, chitosan, etc.), 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.

[0118] According to some embodiments, the characteristics of the polymer matrix significantly influence drug permeation through mucosal tissues. The term “relaxed gel network” or “relaxed hydrated gel” refers to a polymer matrix configuration characterized by a flexible, open polymer network with continuous aqueous pathways that facilitate drug diffusion. A relaxed gel network is typically achieved using higher molecular weight cellulose derivatives such as HPMC E4M (hydroxypropyl methylcellulose with viscosity of approximately 4000 mPa s at 2% in water) at concentrations of about 20% to about 30% by weight of the dried film, optionally combined with moderate amounts of polyvinylpyrrolidone (PVP) at concentrations of about 30% to about 40% by weight. This polymer combination creates a hydrated gel matrix structure upon contact with mucosal fluids that allows efficient drug release and permeation.

[0119] In contrast, the term “dense matrix” or “rigid matrix” or “glassy matrix” refers to a polymer configuration characterized by tightly packed polymer chains with limited aqueous channels, resulting in restricted drug diffusion and reduced permeation. Dense matrices typically result from formulations with high concentrations of polyvinylpyrrolidone (PVP) exceeding about 45% by weight combined with lower molecular weight cellulose derivatives such as HPMC E5 (hydroxypropyl methylcellulose with viscosity of approximately 5 mPa s at 2% in water) at concentrations below about 15% by weight. The molecular weight of HPMC significantly affects gel relaxation properties, with higher molecular weight grades (E4M, E50M) forming more relaxed, flexible networks compared to lower molecular weight grades (E5, E6) which form weaker, less relaxed networks with reduced permeation enhancement.

[0120] The optimization of polymer matrix properties for enhanced permeation involves balancing polymer molecular weight, concentration ratios, and the inclusion of permeation enhancers such as TPGS (d-a-tocopheryl polyethylene glycol 1000 succinate). Studies have demonstrated that formulations comprising HPMC E4M at about 25% by weight combined with PVP at about 35%by weight and TPGS at about 5% by weight achieve superior permeation profiles compared to formulations with higher PVP content and lower HPMC content. The pH of the formulation also influences permeation, with optimal permeation observed at pH values between about 5.0 and about 6.0, where the balance between drug ionization state and permeation enhancer efficacy is optimized.

[0121] 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. Lastly, stable is also utilized to refer to the film appearance, which when stable when remain the same appearance, will not demonstrate any change of appearance, such of the color of the film. Any change in color would indicate a chemical change in the film.

[0122] 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 include 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.

[0123] “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 overtime, especially during storage or exposure to specific conditions. Recrystallization can occur due to various factors. 1) Thermal Variations: Fluctuations in temperature duringmanufacturing, 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. 5) Solvent evaporation: The solvent evaporation process during film drying represents an important phase where recrystallization risk is particularly high - as the organic solvent content decreases below the threshold required for maintaining API solubility, the drug may undergo progressive recrystallization. This is especially relevant in solvent-based systems where the API's solubility is primarily dependent on the organic phase, as the removal of solvent during drying can create a supersaturated state that becomes thermodynamically unstable. This latter mechanism requires careful optimization of the drying process and may necessitate the incorporation of crystal growth inhibitors or specialized drying protocols to maintain the API in a stable amorphous state within the final film matrix. This recrystallization can also occur at a later point during shelf life as slow evaporation of the solvent may lead the API so slowly recrystallize over a certain period of time. Recrystallization during shelf life is particularly at risk for solvent with low evaporation temperature like acetone or methanol. This will happen 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.

[0124] The term “HPMC viscosity grade” refers to the classification of hydroxypropyl methylcellulose (HPMC) polymers based on their solution viscosity, which correlates with molecular weight. HPMC E4M is a high molecular weight grade providing a viscosity of approximately 4000 mPa s when measured as a 2% aqueous solution at 20°C. HPMC E15 is an intermediate grade with viscosity of approximately 15 mPa s under the same conditions. HPMC E5 is a low molecular weight grade with viscosity of approximately 5 mPa s. The selection of HPMC viscosity grade significantly affects the gel structure formed upon hydration of the oral film.High molecular weight grades such as HPMC E4M form relaxed, hydrated gel networks with flexible polymer chains and continuous aqueous pathways that facilitate drug diffusion and transmucosal permeation. Lower molecular weight grades such as HPMC E5 tend to form less structured networks that may limit drug transport. In certain preferred embodiments, combinations of HPMC grades are used to optimize both mechanical properties and drug permeation characteristics.

[0125] The term “hydroxypropyl cellulose” or “HPC” refers to a cellulose ether derivative wherein some of the hydroxyl groups of the cellulose backbone have been hydroxypropylated. HPC (Klucel grade from Ashland) is available in various grades characterized by different molecular weights and corresponding solution viscosities. HPC L (medium viscosity grade) has a molecular weight of approximately 95,000 Da and provides a solution viscosity of about 150-400 mPa s when measured as a 5% aqueous solution at 20°C. HPC H (high viscosity grade) has a higher molecular weight and provides a solution viscosity of about 1500-3000 mPa s under 1% aqueous solution at 20°C. In oral film formulations, HPC contributes to film formation, flexibility, and moisture barrier properties. The selection of HPC grade affects the mechanical properties and drug release characteristics of the resulting film. In certain embodiments, HPC L is preferred when a more flexible film matrix with enhanced drug permeation is desired, while HPC H may be selected when greater film strength and controlled release properties are required.

[0126] The term “lipophilic antioxidant” refers to an antioxidant compound that is preferentially soluble in lipids, oils, or non-polar solvents rather than in water. In oral film formulations, lipophilic antioxidants protect oxidation-sensitive active pharmaceutical ingredients and excipients from degradation. Ascorbyl palmitate is a lipophilic derivative of vitamin C (ascorbic acid) formed by esterification with palmitic acid, providing antioxidant functionality while maintaining compatibility with lipophilic formulation components. In certain embodiments, ascorbyl palmitate may be present in an amount of about 0.1% to about 2% w / w of the dried film. It should be noted that in some formulations, ascorbyl palmitate may create hydrophobic domains within the polymer matrix that can affect drug diffusion characteristics, and therefore its concentration should be optimized based on the specific permeation requirements of the formulation.

[0127] The term “high-intensity sweetener” refers to non-nutritive or low-calorie sweetening agents that provide sweetness intensity many times greater than sucrose on a weight basis. In oral film formulations, high-intensity sweeteners are used to improve palatability and patient compliance while minimizing the total mass of sweetening agent required. Examples of high-intensity sweeteners suitable for use in the disclosed formulations include acesulfame potassium (also known as acesulfame K or Ace-K), which is approximately 200 times sweeter than sucrose;sucralose, which is approximately 600 times sweeter than sucrose; and advantame, which is approximately 20,000 times sweeter than sucrose. Advantame is a particularly preferred high-intensity sweetener due to its exceptional potency, allowing effective taste masking at very low concentrations typically ranging from about 0.001% to about 0.1% w / w of the dried film. In certain embodiments, combinations of high-intensity sweeteners may be used to achieve synergistic sweetening effects and improved taste profiles.

[0128] The term “anti-foaming agent” or “defoamer” refers to a substance added to a formulation to prevent or reduce the formation of foam during manufacturing processes such as mixing, blending, or coating. In oral film formulations, anti-foaming agents are particularly important during the preparation of casting solutions where air entrapment can lead to defects in the final film product, including pinholes, uneven thickness, and compromised drug distribution. A preferred anti-foaming agent is simethicone, a silicone-based compound that works by reducing surface tension at the air-liquid interface, causing foam bubbles to coalesce and collapse. Simethicone is pharmaceutically acceptable, chemically inert, and does not interfere with drug absorption or stability. In certain embodiments, simethicone may be present in an amount of about 0.01% to about 2% w / w of the film formulation.

[0129] 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 important 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.

[0130] The term “simethicone” refers to an antifoaming agent comprising a mixture of polydimethylsiloxane and hydrated silica gel. In oral film formulations, simethicone functions as a defoaming and antifoaming agent that reduces surface tension and prevents or eliminates foam formation during manufacturing processes. The inclusion of simethicone at concentrations typically ranging from about 0.01% to about 2% by weight can improve film quality by eliminating air bubbles that would otherwise create defects in the final film product. Simethicone is physiologically inert and not absorbed systemically, making it suitable for pharmaceutical applications.

[0131] The term “ATSA” or “Azone” refers to 1-dodecylazacycloheptan-2-one (laurocapram), a permeation enhancer that increases transmucosal drug delivery by disrupting the lipid structure of biological membranes. ATSA enhances permeation through interaction with the intercellularlipid domains of mucosal tissues, creating temporary and reversible increases in membrane permeability. In oral film formulations, ATSA may be incorporated at concentrations ranging from about 0.1% to about 5% by weight of the dried film to enhance bioavailability of active pharmaceutical ingredients through the buccal or sublingual mucosa.

[0132] The term “advantame” refers to a high-intensity, non-nutritive sweetener derived from aspartame and vanillin. Advantame is approximately 20,000 times sweeter than sucrose and is used in oral film formulations at very low concentrations, typically ranging from about 0.001% to about 0.1% by weight, to provide sweetness without contributing significant calories or affecting film physical properties. Advantame is stable under typical oral film processing conditions and provides excellent taste-masking properties for formulations containing bitter active pharmaceutical ingredients.

[0133] The term “ascorbyl palmitate” refers to a lipophilic ester of ascorbic acid (vitamin C) and palmitic acid that functions as an antioxidant in pharmaceutical formulations. Unlike water-soluble ascorbic acid, ascorbyl palmitate is fat-soluble and can integrate into lipophilic domains of oral film formulations. However, when incorporated at concentrations above about 0.5% by weight, ascorbyl palmitate can create hydrophobic domains within the film matrix that may decrease free drug availability and reduce drug permeation through mucosal tissues. The use of ascorbyl palmitate in oral film formulations should therefore be carefully optimized to balance antioxidant protection with permeation requirements.

[0134] The term “hydroxypropyl cellulose” or “HPC” refers to a cellulose ether derivative available in various molecular weight grades that influence viscosity and film-forming properties. HPC-L (medium molecular weight) provides solutions with viscosity of about 15-400 mPa s at 5% concentration in water at 20°C and is suitable for coating applications and rapid-dissolving films. HPC-H (high molecular weight) provides solutions with viscosity of about 1500-3000 mPa s at 1% concentration in water at 20°C and is suitable for sustained-release applications and films requiring higher mechanical strength. The selection of HPC grade affects film dissolution rate, mechanical properties, and mucoadhesion characteristics.

[0135] 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 ofhydrophobic 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 polypropylene 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.

[0136] 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 readilywith the surrounding aqueous environment. This results in a homogenous and stable formulation that allows for efficient absorption of the active ingredients upon administration.

[0137] The term “carrier oil” or “base oil” generally refers to a liquid ingredient that is used to dilute and solubilise fat molecules and improve their bioavailability. Fat-soluble substances are better absorbed when digested along with fat, even in small amounts. Carrier oils are also needed to ensure the lipophilic drug remains stable and potent for longer. Carrier oils oxidize at a slower rate, they retain the freshness of the compounds within and increase the lipophilic drug's shelf life. Examples of carrier oils include but are not limited to Medium Chain triglyceride MCT oil, Capryl ic / Capric Triglyceride Glycerol (Captex 355), olive oil, sesame oil, avocado oil, coconut oil, oleic acid, linoleic acid, castor oil, low HLB emulsifiers can act as carrier oils in emulsions like Capmul MCM C8.

[0138] 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.

[0139] The term “surfactant” refers to excipients that are employed to dissipate the free surface energy of particles by reducing the interfacial tension and contact angle between the solid and the suspending vehicle and comprise PEG 300 oleic glycerides (Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafil® m-2125CS); Hydroxylated lecithin; Caprylocaproyl polyoxyl-8 glycerides; Polyoxyethylene (4) sorbitan monostearate, Polyoxyethylene 20 sorbitan tristearate, Polyoxyethylene (5) sorbitan monooleate, Polyoxyethylene 20 sorbitan trioleate; Sorbitan Esters (Sorbitan Fatty Acid Esters) such as: Sorbitan monolaurate, Polyoxyethylene Sorbitan Fatty Acid Esters such as Polyoxyethylene 20 sorbitan monolaurate, Polyoxyethylene (4) sorbitan monolaurate, Polyoxyethylene 20 sorbitan monopalmitate, Polyoxyethylene 20 sorbitan monostearate, Polyoxyethylene 20 sorbitan monooleate, Polyoxyethylene 20 sorbitan monoisostearate Polyethylene glycol monostearate (Gelucire 48 / 16), poloxamer having MW up to 14.600, viscosity up to 3100 mPAs (77C) but exclude surfactant(s) of an HLB below 7 such as Propylene glycol monocaprylate type I, Propylene glycol monocaprylate type II, Propylene glycol monolaurate, Sorbitan monoisostearate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan monostearate, Sorbitan sesquioleate, Sorbitan trioleate, Brij®, Polyoxyethylene lauryl ether, Polyethyleneglycol lauryl ether Sorbitan tristearate, glyceryl monoleate. 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, Labrasol (Caprylocaproyl Polyoxyl-8 glycerides) polyethylene glycoland propylene glycol laurates.

[0140] The term “co-surfactant” refers to a chemical substance that is used in addition to a surfactant to improve its performance especially: a second surfactant that is used in conjunction with a primary surfactant. Co-surfactants are usually alcohols or amines ranging from C4 to C10 and helps in the formation and stabilization of micelles / microemulsions.

[0141] 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.

[0142] A solution disclosed herein involves an equilibrium between solubilizing API using solvent(s) or an emulsion embedded in a matrix formulation that stabilizes but does not entrap the the API in mucoadhesive and stable film of acceptable weight.

[0143] As disclosed herein, the use of emulsion systems is employed. Microemulsions are clear, thermodynamically stable, isotropic liquid mixtures of oil, water, and surfactant, usually in combination with a cosurfactant. The droplet size of the dispersed phase in a microemulsion is less than 100 nm. Nanoemulsions are typically prepared using two immiscible phases and commonly exhibit a diameter of up to 500 nm. Spontaneous emulsification can also be used.

[0144] In such emulsion systems, the oil phase is dissolved in water-miscible or partially water-miscible organic solvents, such as acetone, ethanol or MEK.

[0145] The organic phase is poured into an aqueous phase containing surfactant to form spontaneous emulsion by rapid diffusion of organic solvent from the internal to the external phase, followed by direct solvent evaporation. The organic phase consists of API, Carrier oil, water-miscible organic solvent and lipophilic surfactant. The aqueous phase consists of water and hydrophilic surfactant.

[0146] Emulsion size is influenced by the surfactant concentration, oil phase composition, addition of co-surfactant and non-aqueous solvent and temperature, and will have an impact on absorption.

[0147] Self-nanoemulsifying drug delivery systems (SNEDDS) are anhydrous homogenous liquid mixtures. SNEDDS are a solubilization vehicles compromising oils, drug and emulsifiers, which form oil-in-water nano-scaled emulsion of approximately 200 nm or less in size upon dilution with water under gentle stirring.

[0148] The oral film containing the solubilized API must exhibit mucoadhesion to ensure the film remains in close contact with the mucosa, to promote transmucosal absorption. Being a low permeable molecule, providing a longer time of contact between the mucosa and the film willpromote a higher extend of absorption. A strong mucoadhesion is characterized by a resistance to lift the tongue when the film is position under the tongue or by the film staying in vertical position and not sliding down when the film is position on the inside of the cheek

[0149] 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.

[0150] 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.

[0151] 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] -L- a - 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.

[0152] 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.

[0153] 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 masticationor 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.

[0154] Mucosal surfaces, such as the oral mucosa, are a convenient route for delivering drugs to the body because they are highly vascularized and permeable, providing increased bioavailability and rapid onset of action because it does not pass through the digestive system and thereby avoids first pass metabolism. In particular, the buccal and sublingual tissues offer advantageous sites for drug delivery because they are highly permeable regions of the oral mucosa, allowing drugs diffusing from the oral mucosa to have direct access to systemic circulation. This also offers increased convenience and therefore increased compliance in patients. For certain drugs, or pharmaceutically active components, a permeation enhancer can help to overcome the mucosal barrier and improve permeability. Permeation enhancers reversibly modulate the penetrability of the barrier layer in favor of drug absorption. Permeation enhancers facilitate transport of molecules through the epithelium. Absorption profiles and their rates can be controlled and modulated by a variety of parameters, such as but not limited to film size, drug loading, enhancer type / loading, polymer matrix release rate and mucosal residence time.

[0155] A pharmaceutical composition can be designed to deliver a pharmaceutically active component in a deliberate and tailored way. However, solubility and permeability of the pharmaceutically active component in vivo, in particular, in the mouth of a subject, can vary tremendously. A particular class of permeation enhancer can improve the uptake and bioavailability of the pharmaceutically active component in vivo. In particular, when delivered to the mouth via a film, the permeation enhancer can improve the permeability of the pharmaceutically active component through the mucosa and into the blood stream of the subject. The permeation enhancer can improve absorption rate and amount of the pharmaceutically active component by more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%. more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 150%, about 200% or more, or less than 200%, less than 150%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or a combination of these ranges, depending on the other components in the composition.

[0156] There are many reasons why the oral mucosa might be an attractive site for the delivery of therapeutic agents into the systemic circulation. Due to the direct drainage of blood from the buccal epithelium into the internal jugular vein first-pass metabolism in the liver and intestine may be avoided. First-pass effect can be a major reason for the poor bioavailability of somecompounds when administered orally. Additionally, the mucosa lining the oral cavity is easily accessible, which ensures that a dosage form can be applied to the required site and can be removed easily in the case of an emergency. However, like the skin, the buccal mucosa acts as a barrier to the absorption of xenobiotics, which can hinder the permeation of compounds across this tissue. Consequently, the identification of safe and effective penetration enhancers has become a major goal in the quest to improve oral mucosal drug delivery.

[0157] Chemical penetration enhancers are substances that control the permeation rate of a coadministered drug through a biological membrane. While extensive research has focused on obtaining an improved understanding of how penetration enhancers might alter intestinal and transdermal permeability, far less is known about the mechanisms involved in buccal and sublingual penetration enhancement.

[0158] The buccal mucosa delineates the inside lining of the cheek as well as the area between the gums and upper and lower lips and it has an average surface area of 100 cm2. The surface of the buccal mucosa consists of a stratified squamous epithelium which is separated from the underlying connective tissue (lamina propria and submucosa) by an undulating basement membrane (a continuous layer of extracellular material approximately 1-2 pm in thickness). This stratified squamous epithelium consists of differentiating layers of cells which change in size, shape, and content as they travel from the basal region to the superficial region, where the cells are shed. There are approximately 40-50 cell layers, resulting in a buccal mucosa which is 500-600 pm thick.

[0159] Structurally the sublingual mucosa is comparable to the buccal mucosa, but the thickness of this epithelium is 100-200 pm. This membrane is also non-keratinised and being relatively thinner has been demonstrated to be more permeable than buccal mucosa. Blood flow to the sublingual mucosal is slower compared with the buccal mucosa and is of the order of 1.0 ml / min-1 / cm-2.

[0160] The permeability of the buccal mucosa is greater than that of the skin, but less than that of the intestine. The differences in permeability are the result of structural differences between each of the tissues. The absence of organized lipid lamellae in the intercellular spaces of the buccal mucosa results in greater permeability of exogenous compounds, compared to keratinized epithelia of the skin, while the increased thickness and lack of tight junctions results in the buccal mucosa being less permeable than intestinal tissue.

[0161] The primacy barrier properties of the buccal mucosa have been attributed to the upper one-third to one-quarter of the buccal epithelium. Researchers have learned that beyond the surface epithelium, the permeability barrier of nonkeratinized oral mucosa could also be attributedto contents extruded from the membrane-coating granules into the epithelial intercellular spaces.

[0162] The intercellular lipids of the nonkeratinized regions of the oral cavity are of a more polar nature than the lipids of the epidermis, palate, and gingiva, and this difference in the chemical nature of the lipids may contribute to the differences in permeability observed between these tissues. Consequently, it appears that it is not only the greater degree of intercellular lipid packing in the stratum corneum of keratinized epithelia that creates a more effective barrier, but also the chemical nature of the lipids present within that barrier.

[0163] The existence of hydrophilic and lipophilic regions in the oral mucosa has led researchers to postulate the existence of two routes of drug transport through the buccal mucosa paracellular (between the cells) and transcellular (across the cells).

[0164] Since drug delivery through the buccal mucosa is limited by the barrier nature of the epithelium and the area available for absorption, various enhancement strategies are required to deliver therapeutically relevant amounts of drug to the systemic circulation. Various methods, including the use of chemical penetration enhancers, prodrugs, and physical methods may be employed to overcome the barrier properties of the buccal mucosa.

[0165] A chemical penetration enhancer, or absorption promoter, is a substance added to a pharmaceutical formulation to increase the membrane permeation or absorption rate of the coadministered drug, without damaging the membrane and / or causing toxicity. There have been many studies investigating the effect of chemical penetration enhancers on the delivery of compounds across the skin, nasal mucosa, and intestine. In recent years, more attention has been given to the effect of these agents on the permeability of the buccal mucosa. Since permeability across the buccal mucosa is a passive diffusion process the steady state flux (Jss) should increase with increasing donor chamber concentration (CD) according to Fick's first law of diffusion.

[0166] Surfactants and bile salts have been shown to enhance the permeability of various compounds across the buccal mucosa, both in vitro and in vivo. The data obtained from these studies strongly suggest that the enhancement in permeability is due to an effect of the surfactants on the mucosal intercellular lipids.

[0167] Fatty acids have been shown to enhance the permeation of several drugs through the skin, and this has been shown by differential scanning calorimetry and Fourier transform infrared spectroscopy to be related to an increase in the fluidity of intercellular lipids.

[0168] Additionally, pretreatment with ethanol has been shown to enhance the permeability of tritiated water and albumin across ventral tongue mucosa, and to enhance caffeine permeability across porcine buccal mucosa. There are also several reports of the enhancing effect of Azone®on the permeability of compounds through oral mucosa. Further, chitosan, a biocompatible and biodegradable polymer, has been shown to enhance drug delivery through various tissues, including the intestine and nasal mucosa.

[0169] Oral transmucosal film (OTF) is the administration of pharmaceutically active agents through the oral mucosa to achieve systemic effects. Permeation pathways and predictive models for OTF are described, e.g. in M. Sattar, Oral transmucosal drug delivery. Current status and future prospects, Int'l. Journal of Pharmaceutics, 47(2014) 498-506, which is incorporated by reference herein. OTF continues to attract the attention of academic and industrial scientists.

[0170] To deliver broader classes of drugs across the buccal mucosa, reversible methods of reducing the barrier potential of this tissue should be employed. This requisite has fostered the study of penetration enhancers that will safely alter the permeability restrictions of the buccal mucosa. It has been shown that buccal penetration can be improved by using various classes of transmucosal and transdermal penetration enhancers such as bile salts, surfactants, fatty acids and their derivatives, chelators, cyclodextrins and chitosan. Among these chemicals used for the drug permeation enhancement, bile salts are the most common.

[0171] In vitro studies on enhancing effect of bile salts on the buccal permeation of compounds is discussed in Sevda Senel, Drug permeation enhancement via buccal route: possibilities and limitations, Journal of Controlled Release 72 (2001) 133-144, which is incorporated by reference herein. That article also discusses recent studies on the effects of buccal epithelial permeability of dihydroxy bile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC) and tri-hydroxy bile salts, sodium glycocholate (GC) and sodium taurocholate (TC) at 100 mM concentration including permeability changes correlated with the histological effects. Fluorescein isothiocyanate (FITC), morphine sulfate were each used as the model compound.

[0172] Chitosan has also been shown to promote absorption of small polar molecules and peptide / protein drugs through nasal mucosa in animal models and human volunteers. Other studies have shown an enhancing effect on penetration of compounds across the intestinal mucosa and cultured Caco-2 cells.

[0173] The permeation enhancer can be a phytoextract. A phytoextract can be an essential oil or composition including essential oils extracted by distillation of the plant material. In certain circumstances, the phytoextract can include synthetic analogues of the compounds extracted from the plant material (i.e., compounds made by organic synthesis). The phytoextract can include a phenylpropanoid, for example, phenyl alanine, eugenol, eugenol acetate, a cinnamic acid, a cinnamic acid ester, a cinnamic aldehyde, a hydrocinnamic acid, chavicol, or safrole, or a combination thereof. The phytoextract can be an essential oil extract of a clove plant, for example,from the leaf, stem or flower bud of a clove plant. The clove plant can be Syzygium aromaticum. The phytoextract can include 20-95% eugenol, including 40-95% eugenol, including 60-95% eugenol, and for example, 80-95% eugenol. The extract can also include 5% to 15% eugenol acetate. The extract can also include caryophyllene. The extract can also include up to 2.1% a-humulen. Other volatile compounds included in lower concentrations in clove essential oil can be P-pinene, limonene, farnesol, benzaldehyde, 2-heptanone and ethyl hexanoate. Other permeation enhancers may be added to the composition to improve absorption of the drug. Suitable permeation enhancers include natural or synthetic bile salts such as sodium fusidate; glycocholate or deoxycholate and their salts; fatty acids and derivatives such as sodium laurate, oleic acid, oleyl alcohol, monoolein, and palmitoylcarnitine; chelators such as disodium EDTA, sodium citrate and sodium laurylsulfate, azone, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth-9, polysorbates, sterols, or glycerides, such as captylocaproyl polyoxylglycerides, e.g., Labrasol. The permeation enhancer can include phytoextract derivatives and / or monolignols. The permeation enhancer can also be a fungal extract.

[0174] Fatty acids can be used as inactive ingredients in drug preparations or drug vehicles. Fatty acids can also be used as formulation ingredients due to their certain functional effects and their biocompatible nature. Fatty acid, both free and as part of complex lipids, are major metabolic fuel (storage and transport energy), essential components of all membranes and gene regulators. For review, see Rustan A. C. and Drevon, C. A., Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences (2005), which is incorporated by reference herein. There are two families of essential fatty acids that are metabolized in the human body: co-3 and co-6 polyunsaturated fatty acids (PLIFAs). If the first double bond is found between the third and the fourth carbon atom from the co carbon, they are called co-3 fatty acids. If the first double bond is between the sixth and seventh carbon atom, they are called co-6 fatty acids. PLIFAs are further metabolized in the body by the addition of carbon atoms and by desaturation (extraction of hydrogen). Linoleic acid, which is a co-6 fatty acid, is metabolized to y-linolenic acid, dihomo-y-linolinic acid, arachidonic acid, adrenic acid, tetracosatetraenoic acid, tetracosapentaenoic acid and docosapentaenoic acid, a-linolenic acid, which is a co-3 fatty acid is metabolized to octadecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid and docosahexaenoic acid (DHA).

[0175] 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 bean 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. The term “prodrug” refers to a biologically inactive compound that can be metabolized in the body to produce a biologically active drug.

[0176] In some embodiments, more than one pharmaceutically active component may be included in the film. The pharmaceutically active components can be ace-inhibitors, anti-anginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anticonvulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, antihistamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, amphetamines, 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, 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, fertility agents, gastrointestinal agents, homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments, muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives, smoking cessation aids, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents, antiulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anti-coagulants, antithrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, antispasmodics, uterine relaxants, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs, diagnostic agents, imagingagents, dyes, or tracers, and combinations thereof.

[0177] For example, the pharmaceutically active component can be buprenorphine, naloxone, acetaminophen, riluzole, clobazam, rizatriptan, propofol, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac, fenclofenac, clidanac, flurbiprofen, fentiazac, bufexamac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, tiaramide hydrochloride, hydrocortisone, predonisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, predonisolone acetate, methylpredonisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumetasone, fluoromethoIone, beclomethasone diproprionate, fluocinonide, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate isothipendyl hydrochloride, tripelennamine hydrochloride, promethazine hydrochloride, methdilazine hydrochloride dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-buthylaminobenzoic acid 2-(die-ethylamino) ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dyclonine, dyclonine hydrochloride, thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone iodide, cetylpyridinium chloride, eugenol, trimethylammonium bromide, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbaxochrome sodium sulfanate, rutin, hesperidin, sulfamine, sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole, sulfisomidine, sulfamethizole, nitrofurazone, penicillin, meticillin, oxacillin, cefalotin, cefalordin, erythromcycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, salicylic acid, podophyllum resin, podolifox, cantharidin, chloroacetic acids, silver nitrate, protease inhibitors, thymadine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, attachment and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir, heparin, insulin, LHRH, TRH, interferons, oligonuclides, calcitonin, octreotide, omeprazone, fluoxetine, ethinylestradiol, amiodipine, paroxetine, enalapril, lisinopril, leuprolide, prevastatin, lovastatin, norethindrone, risperidone, olanzapine, albuterol, hydrochlorothiazide, pseudoephridrine, warfarin, terazosin, cisapride, ipratropium, busprione, methylphenidate, levothyroxine, zolpidem, levonorgestrel, glyburide, benazepril, medroxyprogesterone,clonazepam, ondansetron, losartan, quinapril, nitroglycerin, midazolai-n versed, cetirizine, doxazosin, glipizide, vaccine hepatitis B, salmeterol, sumatriptan, triamcinolone acetonide, goserelin, beclomethasone, granisteron, desogestrel, alprazolam, estradiol, nicotine, interferon beta 1A, cromolyn, fosinopril, digoxin, fluticasone, bisoprolol, calcitril, captorpril, butorphanol, clonidine, premarin, testosterone, sumatriptan, clotrimazole, bisacodyl, dextromethorphan, nitroglycerine, nafarelin, dinoprostone, xanomeline, trospium, nicotine, bisacodyl, goserelin, and granisetron. In certain embodiments, the pharmaceutically active component can be xanomeline (Fig. 1), xanomeline tartrate (Fig. 2), trospium (Fig. 3) and trospium chloride (Fig. 4).

[0178] When referring to xanomeline throughout, it is understood as xanomeline free base, xanomeline tartrate or xanomeline and its salt to the extent applicable.

[0179] When referring to trospium throughout, it is understood as trospium free base, trospium chloride or trospium and its salt to the extent applicable.

[0180] According to some embodiments, one of the active pharmaceutical ingredients of the present disclosure, xanomeline, is characterized as a crystalline powder exhibiting a white to off-white appearance in its solid state. The API belongs to Class 2 of the Biopharmaceutics Classification System (BCS), indicating high permeability and low solubility characteristics. The compound exhibits molecular weight of 281.42 g / mol and demonstrates high lipophilicity with a log P value of 3.76, facilitating membrane permeation. The drug substance exhibits notable sensitivity to environmental conditions, particularly vulnerability to oxidative degradation and hydrolysis under elevated temperature and humidity conditions. Upon exposure to light, xanomeline and its salt; xanomeline tartrate shows photosensitivity leading to the formation of specific degradation products. These physicochemical properties present distinct challenges in formulation development and necessitate careful consideration in the selection of excipients, packaging materials, and processing parameters to ensure stability and optimal therapeutic performance of the final dosage form. Storage conditions must be carefully controlled, with recommendations for protection from light and moisture, and maintenance of temperature below 25°C to preserve the compound's integrity.

[0181] According to some embodiments, one of the active pharmaceutical ingredients of the present disclosure, trospium chloride, is characterized as a crystalline powder exhibiting a white to off-white appearance in its solid state. When prepared as a saturated solution, the compound has a slightly acidic character due to the behavior of the trospium ion and demonstrates a pH between 4.5 to 6 trospium (chloride) is soluble in organic solvents such as ethanol and DMSO. The solubility of trospium (chloride) in these solvents is approximately 0.2 and 0.16 mg / ml, respectively. Organic solvent-free aqueous solutions of trospium (chloride) can be prepared bydirectly dissolving the crystalline solid in aqueous buffers. The solubility of trospium (chloride) in PBS, pH 7.2, is approximately 1 mg / ml. The API belongs to Class III of the Biopharmaceutics Classification System (BCS), indicating high solubility but low permeability characteristics, primarily due to its quaternary ammonium structure. The compound exhibits molecular weight of 428.0 g / mol and demonstrates high hydrophilicity with a log P value of 1.2, contributing to its limited membrane permeation properties. The drug substance exhibits marked hygroscopic behavior, readily absorbing atmospheric moisture when exposed to relative humidity exceeding 50%. The compound demonstrates notable stability under normal storage conditions, with primary degradation pathways involving hydrolysis under extreme pH conditions and elevated temperatures above 40°C. These physicochemical properties present specific challenges in formulation development, particularly regarding bioavailability enhancement and moisture protection, necessitating careful consideration in the selection of excipients, packaging materials, and processing parameters to ensure stability and optimal therapeutic performance of the final dosage form. Storage conditions require protection from excessive moisture and maintenance of temperature below 25°C to preserve the compound's integrity.

[0182] The pharmacokinetic profile of xanomeline exhibits distinct absorption patterns characterized by significant variability influenced by physiological conditions and route of administration. When administered orally, the systemic bioavailability of xanomeline is lower than 1%, with notable first-pass metabolism effects. After oral administration, xanomeline reaches its maximum plasma concentration (Tmax) in approximately 2-2.5 hours ((1)Singh A. Xanomeline and Trospium: A Potential Fixed Drug Combination (FDC) for Schizophrenia-A Brief Review of Current Data. Innov Clin Neurosci. 2022 Oct-Dec; 19(10-12):43-47. PMID: 36591549; PMCID: PMC9776782 ; (2) https: / / go.drugbank.com / drugs / DB15357). The drug is widely distributed throughout the body, including to the central nervous system, as demonstrated in animal studies. Despite its poor oral bioavailability, xanomeline does get absorbed to some extent: The maximum plasma concentration (Cmax) following a 150 mg oral dose of xanomeline is 13.8 ng / mL5 ((3) Singh A. Xanomeline and Trospium: A Potential Fixed Drug Combination (FDC) for Schizophrenia-A Brief Review of Current Data. Innov Clin Neurosci. 2022 Oct-Dec; 19(10-12):43-47. PMID: 36591549; PMCID: PMC9776782). Steady-state concentrations are reached within 3 to 5 days of repeated dosing. The low bioavailability of xanomeline has been a challenge in its development as a therapeutic agent. This poor absorption profile is likely one of the reasons why alternative formulations, such as a patch, have been explored in clinical trials. In addition, this problematic absorption profile is also a reason why it took so many years to have an approvepharmaceutical product with this molecule. Xanomeline was discovered in 1990 and only recently been approved in xanomeline and trospium chloride capsule in 2024.

[0183] The absorption characteristics of xanomeline under existing oral formulations are markedly influenced by various physiological and pharmaceutical factors that affect its bioavailability. The compound's absorption profile shows significant dependence on formulation parameters, with current oral formulations demonstrating a bioavailability of less than 1%. This absorption pattern is notably affected by several physiological factors, including gastrointestinal transit time, local blood flow, and the presence of food in the gastrointestinal tract. The compound's muscarinic activity presents additional complexities, as it can influence gastrointestinal motility and secretion patterns, potentially creating a feedback loop that affects its own absorption characteristics.

[0184] The adverse event profile of xanomeline demonstrates a complex pattern of physiological responses primarily mediated through its muscarinic receptor activation across multiple organ systems. When xanomeline is administered without trospium, it causes significant peripheral cholinergic side effects. The main adverse effects of xanomeline alone include: gastrointestinal issues, nausea, vomiting, diarrhea, excessive salivation, excessive sweating. These side effects are primarily due to xanomeline's action on muscarinic receptors outside the brain. The severity of these adverse effects was significant enough to lead to the discontinuation of xanomeline as a standalone treatment in earlier trials. The most common adverse effects of xanomeline, when combined with trospium as Xanomeline-Trospium (Cobenfy™), include gastrointestinal effects: nausea (19.2%), dyspepsia (16%), vomiting (16%), constipation (12.8%), diarrhea, abdominal pain, Heartburn (GERD).

[0185] The pharmacokinetic profile of trospium chloride demonstrates distinctive absorption characteristics influenced by its quaternary ammonium structure and physiological conditions. When administered orally, the systemic bioavailability of trospium chloride ranges from 9.6% to 12.5% of the administered dose, reflecting significant first-pass metabolism and limited membrane permeability. Following oral administration, the compound exhibits relatively slow absorption kinetics, reaching peak plasma concentrations within 4 to 6 hours post-dose. The absorption pattern across the gastrointestinal tract shows marked regional variation, with pH-dependent absorption characteristics. Trospium has low oral bioavailability due to poor absorption: Mean absolute bioavailability of a 20 mg oral dose is approximately 9.6% (range: 4.0-16.1%), Less than 10% of the orally administered dose is absorbed, Peak plasma concentrations (Cmax) occur at about 6 hours post-dose. Absorption primarily occurs in the upper gastrointestinal tract, Food significantly reduces trospium bioavailability. Trospium exhibits dose-proportional increases inAUC for single doses up to 60 mg. The drug shows diurnal variability in exposure, with evening doses resulting in up to 59% decrease in Cmax and 33% decrease in AUC compared to morning doses. Trospium's low and variable oral bioavailability is attributed to its hydrophilic nature. The development of modified-release preparations aims to balance prolonged absorption rates against decreased bioavailability.

[0186] The distinctive pH-dependent absorption profile, coupled with the compound's hydrophilic nature and limited membrane permeability, underscores the importance of considering these physiological parameters when developing formulation strategies to optimize bioavailability and reduce inter-patient variability.

[0187] The absorption characteristics of trospium chloride are significantly influenced by various physiological and pharmaceutical factors that affect its bioavailability. The compound's absorption profile shows marked dependence on formulation parameters, with current oral formulations demonstrating a relative bioavailability of approximately 10% under fasting conditions. This absorption pattern is notably affected by several physiological factors, including gastrointestinal transit time, local blood flow, and particularly the presence of food in the gastrointestinal tract. The compound's limited lipophilicity and quaternary structure present additional complexities, resulting in minimal blood-brain barrier penetration and reduced central nervous system effects. Furthermore, the presence of food significantly alters the compound's absorption profile, with high-fat meals showing a tendency to reduce bioavailability by approximately 70-80% compared to fasting conditions.

[0188] These physiological constraints, coupled with the compound's inherent physicochemical properties, result in suboptimal plasma concentrations that may be insufficient to adequately ameliorate xanomeline-associated muscarinic effects.

[0189] Clinical studies have shown that administration with food results in a 70-80% reduction in bioavailability compared to fasting conditions, along with a substantial delay in time to peak plasma concentrations from 4-6 hours to 6-8 hours post-dose. This marked food effect necessitates strict administration guidelines, specifically requiring dosing either 1 hour before or 2 hours after meals to maintain therapeutic efficacy. The temporal constraints of dosing, combined with the compound's inherently low bioavailability, present significant challenges for optimal therapeutic management and patient compliance. These factors collectively underscore the importance of careful timing of administration and patient education regarding dosing requirements to achieve and maintain therapeutic plasma concentrations.

[0190] The adverse event profile of trospium chloride exhibits characteristic antimuscarinic effects distributed across multiple organ systems, with manifestations strongly correlated to itsquaternary ammonium structure and limited central nervous system penetration. Gastrointestinal manifestations represent the second most common adverse effect cluster, with constipation and abdominal discomfort, he treated population, both showing a delayed onset pattern typically emerging after 5-7 days of continuous treatment. The tolerability profile of trospium chloride demonstrates significant variability influenced by patient-specific factors and dosing considerations.

[0191] Low absorption of trospium chloride, due to its hydrophilic nature, limits its bioavailability and reduces its ability to effectively counteract the side effects of xanomeline.

[0192] The therapeutic management of schizophrenia demonstrates significant challenges characterized by complex patterns of medication adherence and discontinuation behaviors that substantially impact clinical outcomes. The introduction of novel dosage form, mitigating the side effects of such therapeutic agent presents opportunities for expanding the therapeutic solutions and potentially improving adherence patterns through differentiated efficacy and tolerability profiles.

[0193] The implications of medication non-adherence in schizophrenia manifest across multiple clinical and economic domains, with substantial impact on therapeutic outcomes and healthcare resource utilization. The economic burden associated with non-adherence demonstrates significant magnitude, with direct healthcare costs increasing in patients exhibiting poor compliance patterns. This clear association between adherence patterns and therapeutic outcomes underscores the importance of developing novel therapeutic approaches that can enhance treatment acceptance and maintain long-term compliance through improved efficacy and tolerability profiles.

[0194] The therapeutic development trajectory of xanomeline for Alzheimer's disease demonstrated significant limitations due to pronounced gastrointestinal adverse effects, with initial clinical trials reporting intolerable symptom profiles in a large percentage of study participants. The subsequent development of xanomeline and trospium chloride capsule, incorporating trospium chloride as a therapeutic adjunct, resulted in marked improvement in tolerability parameters, though retaining a distinctive adverse event profile. Clinical studies demonstrate an adverse event incidence lower than without the presence of trospium across multiple organ systems, with gastrointestinal manifestations remaining predominant. These include nausea, dyspepsia, constipation, and gastroesophageal reflux, with additional systemic effects including hypertension and potential hepatic implications requiring monitoring.

[0195] The tolerability profile of xanomeline and trospium chloride capsule presents distinct characteristics when compared to conventional antipsychotic agents, particularly those targetingdopaminergic systems. While traditional antipsychotics demonstrate well-documented adverse effects including sedation, extrapyramidal symptoms, and significant weight gain, xanomeline and trospium chloride capsule's adverse event profile demonstrates different organ system involvement and temporal patterns.

[0196] As outlined in the prescribing information of xanomeline and trospium chloride capsule, the gastrointestinal side effect associated with the xanomeline are mentioned even in presence of trospium which acts to mitigate or reduce the occurrence of such side effects. Furthermore, developments of the xanomeline and trospium chloride capsule for the treatment of Alzheimer's Disease were stalled because the drug also caused nausea, vomiting, and other gastrointestinal symptoms that participants had trouble tolerating. The new addition of trospium chloride (to reduce these side effects) to xanomeline resulted in a more tolerable treatment: xanomeline and trospium chloride capsule. As far as side effects, the most common ones participants reported were nausea, indigestion, constipation, vomiting, hypertension, and gastrointestinal reflux disease (GERD), among others. The company also reports a risk of liver damage. The side effects of xanomeline and trospium chloride capsule can be significant, but appear to happen in only 10 to 15 percent of patients. We don’t know anything about the persistence of these side effects, nor the extent to which they may lead to patients discontinuing the medication.

[0197] The most common antipsychotic medications work on dopamine receptors and have a different set of side effects that can be quite significant, including sedation, movement / motor problems, and substantial weight gain. Whether the side effects associated with xanomeline and trospium chloride capsule are more or less tolerable will come down to a personal choice, one informed by a risk / benefit analysis of the potential benefit of a new medication relative to the potential risks of side effects. The reported side effects of xanomeline and trospium chloride capsule are not insignificant; nearly 20 percent of patients report nausea. Of course, the intensity of such symptoms, how debilitating they might be, would certainly impact decisions to initiate or continue using a medication.

[0198] There is thus a need for an oral formulation that at least partially mitigates the shortcoming or existing medication administered as oral formulations such as xanomeline and trospium chloride capsule. According to some embodiments, it is disclosed oral film formulation that at least partially mitigates the short coming of conventional oral formulations. The disclosed oral film formulation are designed to improve absorption of the API, thereby limiting the required dosing and thus mitigating the important side effects associated with such drug.

[0199] According to some embodiment, is it disclosed oral film formulations destined to be administered buccally.

[0200] According to some embodiment, is it disclosed oral film formulations destined to be administered sublingually.

[0201] According to some embodiment, is it disclosed oral film formulations that upon administration will deliver APIs that are at least partially absorbed transmucosally.

[0202] According to some embodiment it is disclosed are disclosed herein mucoadhesive table that are designed to at least partially deliver the APIs through transmucosal delivery.

[0203] According to some embodiments it is disclosed that at least partially delivering the API transmucosally at least mitigates some of side effects of the existing oral film formulation through a reduction of the necessary dosing to be administered to the patient in need for treatment of the API, such as but not limited to Schizophrenia or Alzheimer’s Disease.

[0204] According to some embodiments, it is disclosed a single layer oral film.

[0205] According to some embodiments, the present disclosure outlines an oral film formulation of xanomeline and trospium where the bioavailability of the xanomeline is increased which allows the oral film formulation to contain a lower dose of the xanomeline compared to the marketed product. This reduction in dose is expected to lead to lower drug exposure and fewer side effects, improving the overall safety and efficacy of the drug. On the other hand, the oral film formulation also aim to increase the bioavailability of the trospsium chloride and minimize the negative food effect related to the first pass effect and thus limit the side effect and increase trospium effectiveness against the side effects of the xanomeline.

[0206] According to some embodiments, is it disclosed a novel oral delivery of xanomeline and trospium. The novel oral film formulation is designed for oral, preferably buccal or sublingual administration.

[0207] According to some embodiments, the present disclosure improves the absorption and bioavailability of xanomeline and trospium chloride to enhance their therapeutic efficacy in the treatment of Schizophrenia and Alzheimer's disease. This is achieved by developing a novel dosage form that promotes their buccal absorption, improves their bioavailability by by-passing their first-pass metabolism, which allows fora lower dose of xanomeline and mitigated side effects while also aiming to minimize the negative food effect on trospium Chloride absorption and increase its bioavailability thereby improving its effectiveness by reducing side effects associated with xanomeline. The disclosed approach aims to improve both of the drugs absorption profiles. Improving the absorption of both xanomeline and trospium improves their therapeutic effects while mitigating or minimizing their side effects for improving the treatment of conditions like Alzheimer's disease and Schizophrenia.

[0208] According to some embodiments, the present disclosure outlines the development of a dual-drug oral film dosage form with optimized absorption for both xanomeline tartrate and trospium Chloride, using buccal or sublingual delivery to mitigate gastrointestinal issues and reduced absorption in presence of food, by delivering at least a portion of the drug through buccal or sublingual absorption.

[0209] According to some embodiments, the present disclosure outlines several strategies to achieve the outlined drug delivery system such as by targeting both the physicochemical properties of the drug and the enhancement of the buccal absorption process through the incorporation or permeation enhancers to increase the permeability of the drugs by modifying the properties of the buccal mucosa and the drug's interaction with it.

[0210] According to some embodiment, an oral film dosage is designed with the optimized pH. According to those embodiments, the pH of the formulation is optimized by adjusting the pH and maintaining the APIs in their non-ionized (neutral) forms, which are more lipophilic and at least partially able to permeate the buccal mucosa.

[0211] Our formulation development studies revealed several preferred excipient combinations and ratios that successfully addressed the solubility and permeability challenges of both xanomeline tartrate and trospium chloride. A primary effective combination was identified as a specific ratio of sodium glycocholate (0.5-5%) and Tween 80 (4-11%), utilized in an aqueous system. Alternative systems demonstrating favorable characteristics included a combination of PEG 300 and PVP in a 1:4 ratio proved effective when formulated in either purely aqueous systems or mixed solvent systems. A particularly noteworthy combination was discovered using PEG and HPMC in a specific ratio of 1:1.75, which demonstrated excellent film-forming and mucoadhesive characteristics. These precisely defined ratios were important in achieving the optimal balance between drug solubilization, permeation enhancement, and film-forming properties while maintaining physical stability and acceptable manufacturing characteristics.

[0212] Accordingly, in some embodiments, one or more water-soluble polymers, as described above, may be used to form the film. In other embodiments, however, it may be desirable to use combinations of water-soluble polymers and polymers that are water-swellable, water-insoluble and / or biodegradable, as provided above. The inclusion of one or more polymers that are water-swellable, water-insoluble and / or biodegradable may provide films with slower dissolution or disintegration rates than films formed from water-soluble polymers alone. As such, the film may adhere to the mucosal tissue for longer periods of time, such as up to several hours, which may be desirable for delivery of certain pharmaceutically active components.

[0213] The residence time of the composition depends on the erosion rate of the water erodible polymers used in the formulation and their respective concentrations. The erosion rate may be adjusted, for example, by mixing together components with different solubility characteristics or chemically different polymers, such as hydroxyethyl cellulose and hydroxypropyl cellulose; by using different molecular weight grades of the same polymer, such as mixing low and medium molecular weight hydroxyethyl cellulose; by using excipients or plasticizers of various lipophilic values or water solubility characteristics (including essentially insoluble components); by using water soluble organic and inorganic salts; by using crosslinking agents such as glyoxal with polymers such as hydroxyethyl cellulose for partial crosslinking; or by post-treatment irradiation or curing, which may alter the physical state of the film, including its crystallinity or phase transition, once obtained. These strategies might be employed alone or in combination in order to modify the erosion kinetics of the film. Upon application, the pharmaceutical composition film adheres to the mucosal surface and is held in place. Water absorption softens the composition, thereby diminishing the foreign body sensation. As the composition rests on the mucosal surface, delivery of the drug occurs. Residence times may be adjusted over a wide range depending upon the desired timing of the delivery of the chosen pharmaceutical and the desired lifespan of the carrier. Generally, however, the residence time is modulated between about a few seconds to about a few days. Preferably, the residence time for most pharmaceuticals is adjusted from about 5 seconds to about 24 hours. More preferably, the residence time is adjusted from about 5 seconds to about 30 minutes. In addition to providing drug delivery, once the composition adheres to the mucosal surface, it also provides protection to the treatment site, acting as an erodible bandage. Lipophilic agents can be designed to slow down erodibility to decrease disintegration and dissolution.

[0214] Four approaches are used for preparing the film. The first approach consists of preparing film using the solvent casting method with polymer soluble in alcohol or organic solvent, as film forming material and alcohol as casting solvent. Alcohol performs dual duties, it acts as casting solvent and at the same time, it solubilizes the API and maintains its amorphous form, this approach is generally referred to as solvent casting.

[0215] The second approach consists of preparing film using water-based method with the API salt for its higher solubility in water and polymers soluble in water, as film forming material. This second approach uses only aqueous based formulation and is favored since it simplifies the commercial scale manufacturing requiring less stringent manufacturing facilities, without the need for solvent proofing equipment and facility.

[0216] The third approach consists of preparing film using water and alcohol as solvent and cosolvent respectively, with polymers soluble in both alcohol and water, as film forming material, with maintaining the API in its amorphous form.

[0217] The fourth approach consists of preparing fine colloidal dispersions of the API such as emulsions or microemulsion and incorporating them into the polymer matrix to create the film.

[0218] Cumulative permeation was calculated and plotted against time to determine permeation profiles. Formulations optimized according to the present disclosure achieved cumulative permeation values ranging from about 550 pg / cm3to about 950 pg / cm3at 200 minutes, compared to baseline formulations achieving approximately 100-200 pg / cm3under the same conditions. Lag time reduction from approximately 45 minutes to approximately 15-20 minutes was observed with pH optimization from 3.0 to 5.0-5.7.

[0219] Oral film samples were applied to the mucosal surface of freshly prepared porcine buccal tissue mounted in Franz diffusion cells with an effective diffusion area of about 0.64 cm2. Samples of receptor medium were withdrawn at predetermined time intervals (15, 30, 60, 90, 120, 150, 180, 200, and 250 minutes). Xanomeline and trospium concentrations in the receptor medium were determined by validated analytical methods. The permeation characteristics of the oral film formulations disclosed herein were evaluated using an ex vivo Franz cell diffusion system with porcine buccal mucosa as the model membrane. The receptor medium comprised phosphate buffered saline (PBS) at pH 6.8 with a concentration of 0.01 M, maintained at 37°C ± 0.5°Cwith continuous magnetic stirring to ensure sink conditions.

[0220] In certain preferred embodiments, the formulation pH is adjusted to about 5.0 to about 5.7 using a basifying agent such as sodium hydroxide. At this pH range, xanomeline is less protonated and tartrate is more dissociated, resulting in weaker interactions with excipient micelles and faster drug release from the polymer matrix. Formulations at pH 5.0 to 5.7 demonstrate reduced lag time and improved cumulative permeation compared to formulations at pH 3.0.

[0221] The present disclosure reveals that pH significantly affects xanomeline permeation through the oral mucosa. Formulations at acidic pH (about pH 3) exhibit reduced permeation due to increased electrostatic interactions between the protonated xanomeline species and anionic excipient components. At low pH, xanomeline is more highly protonated and tartrate is less dissociated, resulting in stronger electrostatic interactions.

[0222] In certain embodiments, combinations of HPMC grades are used to optimize both mechanical properties, mucoadhesion and permeation characteristics. A particularly preferred combination comprises HPC L (hydroxypropyl cellulose medium viscosity grade) at about 7% toabout 9% w / w combined with HPMC E4M at about 2% to about 4% w / w and HPMC E5 at about 5% to about 9% w / w of the dried film.

[0223] Conversely, formulations with high PVP concentrations (above about 50% w / w) combined with low HPMC concentrations (below about 15% w / w) create denser, more rigid polymer matrices that limit drug transport. Similarly, low molecular weight HPMC grades (such as HPMC E5) tend to form weak, less relaxed networks that result in reduced drug permeation compared to high molecular weight grades.

[0224] In certain preferred embodiments, high molecular weight hydroxypropyl methylcellulose (HPMC E4M) at concentrations of about 20% to about 30% w / w of the dried film is combined with polyvinylpyrrolidone (PVP) at concentrations of about 30% to about 40% w / w to form relaxed, hydrated gel networks. These polymer combinations create flexible polymer chains and continuous aqueous pathways that facilitate xanomeline diffusion and transmucosal permeation.

[0225] The present disclosure reveals that the selection and ratio of film-forming polymers significantly affects drug permeation through the oral mucosa. In the presence of trospium chloride, xanomeline shows higher diffusion and permeation in hydrated polymeric gel matrices. Relaxed, water-rich polymer networks provide continuous aqueous diffusion pathways for efficient drug transport.

[0226] Referring now to Table 1, an optimized aqueous-based film formulation was developed utilizing polyvinylpyrrolidone (PVP K90) as the primary film-forming and mucoadhesive polymer system. The formulation employs purified water as the principal solvent (70.02% w / w). The dual active system comprises xanomeline (7.46% wet, 24.88% dry) and trospium (1.17% wet, 3.89% dry) as the primary therapeutic agents. The solubilization and plasticizing system utilizes polyethylene glycol 300 (3.92% wet, 13.08% dry), which maintains drug solubility throughout the manufacturing process and provides appropriate flexibility to the final film. A key feature of this formulation is the high-molecular-weight PVP K90 (16.80% wet, 56.04% dry), which serves as both the film-forming polymer and mucoadhesive agent, ensuring optimal residence time at the site of application. The formulation is enhanced with menthol (0.21% wet, 0.70% dry) as a flavoring agent and sucralose (0.28% wet, 0.93% dry) to provide palatability. Ascorbic acid is incorporated at a lower concentration (0.14% wet, 0.47% dry) to improves stability of the active ingredients.

[0227] Table 1, formulation for a monolayer oral film Example 1Component % wet (w / w) % dry (w / w) FunctionPurified water USP 70.02 - SolventXanomeline tartrate 7.46 24.88 APITrospium chloride 1.17 3.89 APIPEG 300 3.92 13.08 Plasticizing agent and co-solvent Menthol 0.21 0.70 Flavoring agentSucralose 0.28 0.93 SweetenerPVP K90 16.80 56.04 Film former-mucoadhesive agent Ascorbic acid 0.14 0.47 Stabilizing agent

[0228] Formulations and Preparations

[0229] Accordingly, in Example 1 to homogeneously incorporate the xanomeline tartrate and trospium chloride into the formulation, a solution is prepared by mixing the actives and the water until a transparent solution is obtained. The mixing is carried out for between about 3-30 minutes at room temperature, to allow the full dissolution of the APIs. PEG 300 is then added to the solution as plasticizer and co-solvent to help maintain the solubility and stability of the APIs. PVP is added to the mix as film former, sweetening agents, flavoring agents, preservative, antioxidant and disintegrating agent are then added to the mix. After mixing the blend is cast over liner rolls then subject to drying to form a film sheet.

[0230] Table 2, formulation for a monolayer oral film Example 2Component %wet (w / w) % dry (w / w) FunctionPurified water USP 72.03 SolventXanomeline tartrate 7.68 27.45 APITrospium Chloride 1.20 4.30 APIPEG 300 2.59 9.27 Plasticizing agent and co-solvent Menthol 0.22 0.77 Flavoring agentSucralose 0.29 1 03 SweetenerPEO N80 10.08 36.06Film former-mucoadhesive agent HPMC E50 5.76Ascorbic acid 0.14 0.52 Stabilizing agent

[0231] Referring now to Table 2, an optimized aqueous-based film formulation was developed utilizing a dual polymer system comprising polyethylene oxide (PEG N80) and hydroxypropyl methylcellulose (HPMC E50) as the primary film-forming agents. The formulation employs purified water as the principal solvent (72.03% w / w). The dual active system comprises xanomeline tartrate (7.68% wet, 27.45% dry) and trospium chloride (1.20% wet, 4.30% dry) as the primary therapeutic agents. The solubilization and plasticizing system utilizes polyethylene glycol 300 (2.59% wet, 9.27% dry), which maintains drug solubility while providing appropriate flexibility to the final film. A key innovation in this formulation is the complementary polymer system, where PEO N80 (10.08% wet, 36.06% dry) provides primary film-forming and mucoadhesive properties, while HPMC E50 (5.76% wet, 20.61% dry) enhances film characteristics and stability. The formulation is enhanced with menthol (0.22% wet, 0.77% dry) as a flavoring agent and sucralose(0.29% wet, 1.03% dry) to provide palatability. Ascorbic acid is incorporated at a lower concentration (0.14% wet, 0.52% dry) to ensure stability of the active ingredients throughout the product's shelf life.

[0232] In order to homogeneously incorporate the xanomeline tartrate and trospium chloride into the formulation, a solution is prepared by mixing the actives and the water until transparent solution is obtained. The mixing is carried out for between about 3-30 minutes at room temperature, to allow the full dissolution of the APIs. PEG 300 is then added to the solution as plasticizer and co-solvent to help maintain the solubility and stability of the APIs. PEG and HPMC are added to the mix as film former, sweetening agents, flavoring agents, preservative, antioxidant and disintegrating agent are then added to the mix. After mixing the blend is cast over liner rolls then subject to drying to form a film sheet.

[0233] Table 3, formulation for a monolayer oral film Example 3Component % wet (w / w) % dry (w / w) FunctionPurified water USP 68.39 - SolventXanomeline tartrate 7.29 23.05 APITrospium Chloride 1.14 3.61 APIPEG 300 4.79 15.14 Plasticizing agent and co-solvent Menthol 0.21 0.65 Flavoring agentSucralose 0.27 0.87 sweetenerPullulan 17.78 56.25 Film former-mucoadhesive agent Ascorbic acid 0.14 0.43 Stabilizing agent

[0234] Referring now to Table 3, an optimized aqueous-based film formulation was developed utilizing pullulan as the primary film-forming and mucoadhesive polymer system. The formulation employs purified water as the principal solvent (68.39% w / w). The dual active system comprises xanomeline tartrate (7.29% wet, 23.05% dry) and trospium chloride (1.14% wet, 3.61% dry) as the primary therapeutic agents. The solubilization and plasticizing system utilizes polyethylene glycol 300 (4.79% wet, 15.14% dry), which maintains drug solubility throughout the manufacturing process while providing appropriate flexibility to the final film. A key feature of this formulation is the natural polysaccharide pullulan (17.78% wet, 56.25% dry), which serves as the film-forming polymer, providing excellent film-forming properties and mucoadhesion. The formulation is enhanced with menthol (0.21% wet, 0.65% dry) as a flavoring agent and sucralose (0.27% wet, 0.87% dry) to provide palatability. Ascorbic acid is incorporated at a lower concentration (0.14% wet, 0.43% dry) to ensure stability of the active ingredients throughout the product's shelf life.

[0235] In order to homogeneously incorporate the xanomeline tartrate and trospium chloride into the formulation, a solution is prepared by mixing the actives and the water until transparent solution is obtained. The mixing is carried out for between about 3-30 minutes at roomtemperature, to allow the full dissolution of the APIs. PEG 300 is then added to the solution as plasticizer and co-solvent to help maintain the solubility and stability of the APIs. Pullulan is added to the mix as film former, Sweetening agents, flavoring agents, preservative, antioxidant and disintegrating agent are then added to the mix. After mixing the blend is cast over liner rolls then subject to drying to form a film sheet.

[0236] Table 4, formulation for a monolayer oral film Example 4Component % wet (w / w) % dry (w / w) FunctionPurified water USP 78.85 - SolventXanomeline tartrate 5.84 27.59 APITrospium chloride 0.91 4.32 APIPEG 300 2.96 13.98 Plasticizing agent and co-solvent Menthol 0.16 0.78 Flavoring agentSucralose 0.22 1.04 SweetenerNaCMC 10.95 51.78 Film former-mucoadhesive agent Ascorbic acid 0.11 0.52 Stabilizing agent

[0237] Referring now to Table 4, an optimized aqueous-based film formulation was developed utilizing sodium carboxymethyl cellulose (NaCMC) as the primary film-forming and mucoadhesive polymer system. The formulation employs purified water as the principal solvent (78.85% w / w).The dual active system comprises xanomeline tartrate (5.84% wet, 27.59% dry) and trospium chloride (0.91% wet, 4.32% dry) as the primary therapeutic agents. The solubilization and plasticizing system utilizes polyethylene glycol 300 (2.96% wet, 13.98% dry), which maintains drug solubility throughout the manufacturing process while providing appropriate flexibility to the final film. A key feature of this formulation is the high-molecular-weight NaCMC (10.95% wet, 51.78% dry), which serves as both the film-forming polymer and mucoadhesive agent, ensuring optimal residence time at the site of application. The formulation is enhanced with menthol (0.16% wet, 0.78% dry) as a flavoring agent and sucralose (0.22% wet, 1.04% dry) to provide palatability. Ascorbic acid is incorporated at a lower concentration (0.11% wet, 0.52% dry) to ensure stability of the active ingredients throughout the product's shelf life.

[0238] In order to homogeneously incorporate the xanomeline tartrate and trospium chloride into the formulation, a solution is prepared by mixing the actives and the water until transparent solution is obtained.

[0239] The mixing is carried out for between about 3-30 minutes at room temperature, to allow the full dissolution of the APIs. PEG 300 is then added to the solution as plasticizer and co-solvent to help maintain the solubility and stability of the APIs. NaCMC is added to the mix as film former, Sweetening agents, flavoring agents, preservative, antioxidant and disintegrating agent are thenadded to the mix. After mixing the blend is cast over liner rolls then subject to drying to form a film sheet.

[0240] Table 5, formulation for a monolayer oral film Example 5Component % wet (w / w) % dry (w / w) FunctionPurified water USP 73.81 - SolventXanomeline tartrate 5.46 20.85 APITrospium chloride 0.85 3.26 APIPEG 300 2.46 9.39 Plasticizing agent and co-solvent Tween 80 1.27 4.85 Solubilizing and permeation enhancer Sodium 3.13 _. .. ,. . . . „o„ Permeation enhancerglycocholate 0.82Menthol 0.15 0.59 Flavoring agentSucralose 0.21 0.78 SweetenerHPC 10.25 39.14 Film formerHPMC 4.10 15.65 mucoahesion agent and viscosity agent Ascorbic acid 0.10 0.39 Stabilizing agentNaOH solution 0.51 1.96 pH adjusting agent

[0241] Referring now to Table 5, an exemplary aqueous-based film formulation was developed utilizing a dual polymer system comprising hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) as the primary film-forming and mucoadhesive agents. The formulation employs purified water as the principal solvent (73.81% w / w). The dual active system comprises xanomeline tartrate (5.46% wet, 20.85% dry) and trospium chloride (0.85% wet, 3.26% dry) as the primary therapeutic agents. A sophisticated solubilization and permeation enhancement system is employed, combining PEG 300 (2.46% wet, 9.39% dry) as a co-solvent and plasticizer, Tween 80 (1.27% wet, 4.85% dry) as a solubilizer and permeation enhancer, and sodium glycocholate (0.82% wet, 3.13% dry) as a specialized permeation enhancer. A key innovation in this formulation is the complementary polymer system, where HPC (10.25% wet, 39.14% dry) provides primary film-forming properties, while HPMC (4.10% wet, 15.65% dry) enhances mucoadhesion and provides optimal viscosity control. The formulation is enhanced with menthol (0.15% wet, 0.59% dry) as a flavoring agent and sucralose (0.21% wet, 0.78% dry) to provide palatability. Ascorbic acid is incorporated at a lower concentration (0.10% wet, 0.39% dry) to ensure stability of the active ingredients, while sodium hydroxide solution (0.51% wet, 1.96% dry) is utilized for pH adjustment to optimize drug stability and performance.

[0242] In order to homogeneously incorporate the xanomeline tartrate and trospium chloride into the formulation, a solution is prepared by mixing the actives and the water until transparent solution is obtained. The mixing is carried out for between about 3-30 minutes at room temperature, to allow the full dissolution of the APIs. PEG 300 is then added to the solution asplasticizer and co-solvent to help maintain the solubility and stability of the APIs, a solution of sodium hydroxide solution is added to the mix as pH adjusting agent to adjust the pH between 5 and 5.9, which helps maximize the non-ionized form of the drug for better permeation. HPC and HPMC is added to the mix as film former, Sweetening agents, flavoring agents, preservative, antioxidant and disintegrating agent are then added to the mix. After mixing the blend is cast over liner rolls then subject to drying to form a film sheet.

[0243] Table 6, formulation for a monolayer oral film Example 6Component % wet (w / w) % dry (w / w) FunctionMethanol 69.39 - SolventXanomeline tartrate 8.40 27.45 APITrospium chloride 1.31 4.30 APIPEG 300 4.42 14.42 Plasticizing agent and co-solvent Menthol 0.24 0.77 Flavoring agentSucralose 0.32 1.03 SweetenerPVP K90 15.77 51.51 Film former-mucoadhesive agent Ascorbic acid 0.16 0.52 Stabilizing agent

[0244] Referring now to Table 6, an optimized methanol-based film formulation was developed utilizing polyvinylpyrrolidone (PVP K90) as the primary film-forming and mucoadhesive polymer system. The formulation employs methanol as the principal solvent (69.39% w / w). The dual active system comprises xanomeline tartrate (8.40% wet, 27.45% dry) and trospium chloride (1.31% wet, 4.30% dry) as the primary therapeutic agents. The solubilization and plasticizing system utilizes polyethylene glycol 300 (4.42% wet, 14.42% dry), which maintains drug solubility throughout the manufacturing process while providing appropriate flexibility to the final film. A key feature of this formulation is the high-molecular-weight PVP K90 (15.77% wet, 51.51% dry), which serves as both the film-forming polymer and mucoadhesive agent, ensuring optimal residence time at the site of application. The formulation is enhanced with menthol (0.24% wet, 0.77% dry) as a flavoring agent and sucralose (0.32% wet, 1.03% dry) to provide palatability. Ascorbic acid is incorporated at a lower concentration (0.16% wet, 0.52% dry) to ensure stability of the active ingredients throughout the product's shelf life.

[0245] In order to homogeneously incorporate the xanomeline tartrate and trospium chloride into the formulation, a solution is prepared by mixing the actives and the methyl alcohol until transparent solution is obtained. The mixing is carried out for between about 3-30 minutes at room temperature, to allow the full dissolution of the APIs. PEG 300 is then added to the solution as plasticizer and co-solvent to help maintain the solubility and stability of the APIs, PVP is added to the mix as film former, sweetening agents, flavoring agents, preservative, antioxidant anddisintegrating agent are then added to the mix. After mixing the blend is cast over liner rolls then subject to drying to form a film sheet.

[0246] Table 7, formulation for a monolayer oral film Example 7Component % wet (w / w) % dry (w / w) FunctionMethanol 34.69 - SolventWater 34.69 SolventXanomeline tartrate 8.40 27.45 APITrospium chloride 1.31 4.30 APIPEG 300 4.42 14.42 Plasticizing agent and co-solvent Menthol 0.24 0.77 Flavoring agentSucralose 0.32 1.03 SweetenerPVP K90 15.77 51.51 Film former-mucoadhesive agent Ascorbic acid 0.16 0.52 Stabilizing agent

[0247] Referring now to Table 7, an exemplary mixed-solvent film formulation was developed utilizing polyvinylpyrrolidone (PVP K90) as the primary film-forming and mucoadhesive polymer system. The formulation employs a balanced co-solvent system of methanol and water (34.69% w / w each), enabling optimized solubilization and controlled drying during the manufacturing process. The dual active system comprises xanomeline tartrate (8.40% wet, 27.45% dry) and trospium chloride (1.31% wet, 4.30% dry) as the primary therapeutic agents. The solubilization and plasticizing system utilizes polyethylene glycol 300 (4.42% wet, 14.42% dry), which maintains drug solubility throughout the manufacturing process while providing appropriate flexibility to the final film. A key feature of this formulation is the high-molecular-weight PVP K90 (15.77% wet, 51.51% dry), which serves as both the film-forming polymer and mucoadhesive agent, ensuring optimal residence time at the site of application. The formulation is enhanced with menthol (0.24% wet, 0.77% dry) as a flavoring agent and sucralose (0.32% wet, 1.03% dry) to provide palatability. Ascorbic acid is incorporated at a lower concentration (0.16% wet, 0.52% dry) to ensure stability of the active ingredients throughout the product's shelf life.

[0248] In order to homogeneously incorporate the xanomeline tartrate and trospium chloride into the formulation, a solution is prepared by mixing the actives, the methyl alcohol and the water until transparent solution is obtained. The mixing is carried out for between about 3-30 minutes at room temperature, to allow the full dissolution of the APIs.

[0249] PEG 300 is then added to the solution as plasticizer and co-solvent to help maintain the solubility and stability of the APIs, PVP is added to the mix as film former, sweetening agents, flavoring agents, preservative, antioxidant and disintegrating agent are then added to the mix. After mixing the blend is cast over liner rolls then subject to drying to form a film sheet.

[0250] Table 8, formulation for a monolayer oral film Example 8Component % wet (w / w) % dry (w / w) FunctionWater 69.38 SolventXanomeline 7.11 23.21 APITrospium chloride 1.11 3.63 APIPEG 300 2.40 7.84 Plasticizing agent and co-solvent Sesame oil 1.33 4.36 SolubilizerTween 80 1.60 5.23 SurfactantSpan 80 0.40 1.31 Co-surfactantMenthol 0.20 0.65 Flavoring agentSucralose 0.32 1.05 SweetenerPVP K90 16.01 52.28 Film former-mucoadhesive agent Ascorbic acid 0.13 0.44 Stabilizing agent

[0251] Referring now to Table 8, an optimized aqueous-based film formulation was developed utilizing polyvinylpyrrolidone (PVP K90) as the primary film-forming and mucoadhesive polymer system. The formulation employs purified water as the principal solvent (69.38% w / w). The dual active system comprises xanomeline (7.11% wet, 23.21% dry) and trospium chloride (1.11% wet, 3.63% dry) as the primary therapeutic agents. A sophisticated solubilization system is employed, combining PEG 300 (2.40% wet, 7.84% dry) as a plasticizer and co-solvent, sesame oil (1.33% wet, 4.36% dry) as a lipophilic solubilizer, and a balanced surfactant system of Tween 80 (1.60% wet, 5.23% dry) and Span 80 (0.40% wet, 1.31% dry) to ensure optimal drug solubilization and stability. A key feature of this formulation is the high-molecular-weight PVP K90 (16.01% wet, 52.28% dry), which serves as both the film-forming polymer and mucoadhesive agent, ensuring optimal residence time at the site of application. The formulation is enhanced with menthol (0.20% wet, 0.65% dry) as a flavoring agent and sucralose (0.32% wet, 1.05% dry) to provide palatability. Ascorbic acid is incorporated at a lower concentration (0.13% wet, 0.44% dry) to ensure stability of the active ingredients throughout the product's shelf life.

[0252] In order to homogeneously incorporate the xanomeline and trospium chloride into the formulation. Xanomeline-emulsion is prepared by mixing the liquid carrier solvent, the surfactant, the co-surfactant and the co-solvent until homogenous and translucent solution is obtained.

[0253] The mixing is carried out for between about 3-30 minutes at room temperature. In the aqueous phase, trospium chloride, PEG 300 and PVP are combined. Sweetening agents, flavoring agents, antioxidant and disintegrating agent are then added to the mix.

[0254] After mixing the emulsified active and polymer / water mixture, the wet blend is cast over liner rolls then subject to drying to form a film sheet.

[0255] These combinations result in a total solid content of between 20 to 31% in the wet state, yielding films with optimal characteristics for buccal delivery. Notably, this formulation achievesexcellent content uniformity with consistent drug distribution throughout the polymer matrix. The selection of HPC, PVP, HPC, HPMC, PEO, Pullulan, NaCMC as the primary polymers permitted the manufacture of acceptable film characteristics, including appropriate dissolution properties, physical stability, and compatibility with both APIs and other functional excipients. This film formulation resulted in a flexible film with appropriate mechanical strength and disintegration time.

[0256] The combination of bile salts with surfactants demonstrated particularly favorable results, with the bile salts serving multiple crucial functions including API solubilization and ion-pair formation with trospium chloride.

[0257] Preferred film dosage forms forxanomeline and trospium chloride include sublingual and buccal film oral dosage forms. The buccal and / or sublingual mucosa absorption allows these drugs to be absorbed directly into the blood stream, bypassing hepatic metabolism. From a pharmaceutical formulation perspective, this delivery approach presents particular challenges, as the process of transmucosal permeation needs to be carefully optimized to obtain an acceptable pharmacokinetic profile for both active ingredients simultaneously.

[0258] The optimization of pH presents a significant formulation challenge, as xanomeline requires maintenance in its non-ionized form while trospium chloride, being a quaternary ammonium compound, requires specific consideration for its permanent ionization state. The use of precise buffer systems maintaining blend pH between 5 and 5.8 has been found to provide optimal conditions for both compounds' permeation characteristics.

[0259] According to certain embodiment, the oral dosage form is designed for a residence time between 10 and 30 minutes allowing the mucoadhesive oral dosage to direct the active agents through the mucosa directly to the blood stream, thereby mitigating the side effect associated with the API. Film-forming polymers (50-85% w / w) combined with mucoadhesive agents (5-25% w / w) must be carefully balanced to achieve optimal residence time while maintaining acceptable dissolution characteristics. This balance is particularly important given the dual-drug nature of the formulation and the need to maintain stability of both active ingredients throughout the delivery process and shelf life.

[0260] The solubility enhancement system presents unique challenges due to the contrasting physicochemical properties of xanomeline and trospium chloride. The incorporation of solubilizing agents such as PEG 300 (6-15% w / w) to maintain both drug substances in solution while preserving film integrity. Additional solubilizing agents may include propylene glycol, triacetin, cyclodextrins or glycerin, provided their concentrations are maintained within ranges that preserve acceptable film-forming properties.

[0261] The development of an oral film formulation for the combination of xanomeline orxanomeline tartrate and trospium chloride presented multiple significant technical challenges that required innovative solutions to overcome. These challenges encompassed various important aspects of pharmaceutical development including solubility, stability, permeability, and manufacturability considerations, each of which required careful evaluation and novel approaches to resolve.

[0262] According to some embodiments, it is disclosed a multilayer oral film dosage form where the active layer delivers the drug through the buccal mucosa, and the backing layer ensures the film stays in place, preventing swallowing and promoting targeted absorption and control the direction of drug release from the dosage form towards the buccal mucosa.

[0263] Table 9, exemplary formulation for a multilayer oral film active layer for Example 9 Component % wet (w / w) % dry (w / w)Purified water USP 70.02Xanomeline tartrate .46 24.88Trospium chloride 1.17 3.89PEG 300 3.92 13.08Menthol 0.21 0.70Sucralose 0.28 0.93PVP K90 16.80 56.04Ascorbic acid 0.14 0.47

[0264] Table 10, exemplary formulation for a multilayer oral film backing layer for Example 10Component % wet (w / w) % dry (w / w)Water 74.46PEG 300 4.14 16.19Menthol 0.31 1.21Sucralose 0.41 1.62PVP K90 20.68 80.97

[0265] Referring now to the exemplary multilayer oral film systems, three distinct configurations were developed to optimize therapeutic delivery. The first system comprises an active layer containing xanomeline tartrate (7.46% w / w wet, 24.88% w / w dry) in a polyvinylpyrrolidone K90 matrix (16.80% w / w wet, 56.04% w / w dry), paired with a complementary backing layer containing trospium chloride (1.17% w / w wet, 3.89% w / w dry) in a higher concentration of the same polymer (20.68% w / w wet, 80.97% w / w dry) to provide sequential drug release and structural support. The second system maintains the same polymer composition but reverses the active ingredients, incorporating trospium chloride in the active layer and xanomeline tartrate in the backing layer at equivalent concentrations. The third system represents a dual-drug delivery platform, incorporating both xanomeline tartrate (7.46% w / w wet, 24.88% w / w dry) and trospium chloride(1.17% w / w wet, 3.89% w / w dry) in the active layer, while maintaining a drug-free backing layer. All three systems utilize PEG 300 as a plasticizer in both layers (3.92% w / w wet, 13.08% w / w dry in active layer; 4.14% w / w wet, 16.19% w / w dry in backing layer), with menthol (0.21-0.31% w / w wet) and sucralose (0.28-0.41 % w / w wet) providing consistent organoleptic properties across both layers. This strategic distribution of active ingredients across layers enables either sequential or simultaneous drug release profiles, while maintaining the structural integrity provided by the backing layer design.

[0266] Referring now to Tables 9 and 10, an optimized multilayer film formulation was developed comprising an active layer and a backing layer. The active layer employs purified water as the principal solvent (70.02% w / w), with polyvinylpyrrolidone (PVP K90) serving as the primary filmforming and mucoadhesive polymer system (16.80% wet, 56.04% dry). This layer incorporates the dual active system of xanomeline tartrate (7.46% wet, 24.88% dry) and trospium chloride (1.17% wet, 3.89% dry) as the primary therapeutic agents. The solubilization and plasticizing system utilizes polyethylene glycol 300 (3.92% wet, 13.08% dry), which maintains drug solubility throughout the manufacturing process. The active layer is enhanced with menthol (0.21% wet, 0.70% dry) as a flavoring agent and sucralose (0.28% wet, 0.93% dry) to provide palatability, while ascorbic acid (0.14% wet, 0.47% dry) ensures stability of the active ingredients.

[0267] The backing layer is designed with a complementary composition, utilizing water as the primary solvent (74.46% w / w) and a higher concentration of PVP K90 (20.68% wet, 80.97% dry) to provide structural support and unidirectional drug release. This layer incorporates PEG 300 (4.14% wet, 16.19% dry) as a plasticizer, along with menthol (0.31% wet, 1.21% dry) and sucralose (0.41% wet, 1.62% dry) to maintain consistency in taste and mouthfeel across both layers. The strategic difference in polymer concentration between the layers enables optimal drug loading in the active layer while maintaining structural integrity through the backing layer.

[0268] Preparation of the active layer: The active layer is prepared using the same method as used for Example 1.

[0269] Preparation of the backing layer: the backing layer PEG 300 is first added to water, the mixing is carried out for between about 10 minutes at room temperature. PVP is added to the mix as film former, sweetening agents, flavoring agents, preservative, antioxidant and disintegrating agent are then added to the mix. After mixing the blend is cast over liner rolls then subject to drying to form a film sheet.

[0270] In the lab, residence time is tested with a limited amount of simulated saliva in a Petri dish. The residence time test allows to assess and adjust matrix composition to fit different time goals. Films formulated for sublingual application will have a shorter residence time due to the restrictionimposed by this administration approach (mouth closed and tongue immobile at the bottom of the mouth). Films formulated for buccal absorption can last longer as due to the high mucoadhesion of the film to the buccal cheek they do not prevent movement of the mouth and can be tolerate for a longer period of time. Sublingual films exhibit residence time in the lab of about or less than 10 minutes while buccal films can be anywhere from 10 to 60 minutes. The longer the residence time is the bigger the chances of buccal absorption.

[0271] Mucoadhesive tablets also represent a particularly effective platform fortransmucosal and buccal drug delivery, offering distinct advantages over conventional oral dosage forms. Through systematic investigation, specific polymer combinations have demonstrated superior mucoadhesive properties when formulated at precise ratios. Most notably, the combination of primary mucoadhesive polymers (carbomers, 1.5-5% w / w) with secondary hydrophilic matrices (Isomalt, 10-50% w / w) creates a controlled hydration system that achieves optimal adhesion strength (15-20 N / cm2) while maintaining structural integrity for extended periods (0.5-3 hours). The tablet matrix, upon contact with the mucosal surface, forms a concentrated gel layer through controlled hydration, establishing an intimate contact with the mucosa that significantly enhances drug absorption. Quantitative analysis has revealed that this systematic approach provides several important advantages: Extended residence time (>1 to 2 hours) compared to conventional oral forms, Controlled hydration rate leading to optimal drug release kinetics, Enhanced local drug concentration at the absorption site, Protection of drug from enzymatic degradation, Bi-directional release control through polymer matrix optimization

[0272] These findings demonstrate the importance of polymer selection and ratio optimization in achieving therapeutic efficacy through the buccal route.

[0273] Referring now to table 11 is disclosed an exemplary formulation of a mucoadhesive tablet

[0274] Table 11, exemplary mucoadhesive tablet formulation, Example 11Excipients Function mg / tab % solids / TabXanomeline tartrate API 50.00 27.45Trospium chloride API 20.00 10.98Isomalt Sugar Filler 84.01 46.12Polysorbate 80 Surfactant 8.19 4.50Polyacrylic acid Mucoadhesive polymer 2.19 1.20Menthol Flavor 4.55 2.50Sucralose Sweetener 4.43 2.43Sodium Bicarbonate pH modifier 7.29 4.00Magnesium Stearate Lubricant 1.48 0.81TOTAL 182.12 100.00

[0275] The mucoadhesive tablet process involves a dry blend of all the excipients in a v-blender except for the lubricant until homogeneity of the blend is achieved followed by the addition of the magnesium stearate and a short mixing for distribution. The dry blend is then compressed at 182.12 mg / tablet using a flat punch of 12 mm.

[0276] The permeation enhancement achieved through the optimized formulations of the present disclosure is summarized as follows: Baseline formulations (high PVP, low HPMC, pH 3) achieved cumulative permeation of approximately 100-200 pg / cm3at 200 minutes. TPGS-enhanced formulations (1.66% w / w) improved permeation to approximately 400-550 pg / cm3. pH-optimized formulations (pH 5.0-5.7) achieved approximately 700-900 pg / cm3. Fully optimized formulations combining pH adjustment with polymer matrix engineering (Example 23) achieved approximately 900-950 pg / cm3, representing the highest transmucosal delivery efficiency.

[0277] Comparative Permeation Results

[0278] Permeation studies using porcine buccal mucosa demonstrated the highest cumulative permeation among all tested formulations, achieving approximately 950 pg / cm3at 200 minutes. This represents an approximately 4-5 folds improvement over baseline formulations and demonstrates the synergistic benefits of combined pH optimization and polymer matrix engineering.

[0279] The combination of HPC L with HPMC E4M and HPMC E5 at the specified ratios creates a relaxed, hydrated gel network with flexible polymer chains and continuous aqueous pathways optimized for drug diffusion. The higher proportion of HPMC E4M compared to Example 12 provides enhanced gel structure while maintaining permeation-favorable matrix characteristics.

[0280] An optimized oral film formulation was prepared utilizing a polymer matrix designed for maximum transmucosal permeation. The formulation comprised xanomeline tartrate (23.5% w / w dried film), trospium chloride (6.15% w / w dried film), HPC L (7.6567% w / w dried film), HPMC E4M (3.8783% w / w dried film), HPMC E5 (8.3255% w / w dried film), d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS, 1.766% w / w dried film), glycerol as plasticizer, simethicone as antifoaming agent, advantame as high-intensity sweetener, and purified water as solvent. The formulation pH was adjusted to 5.0 using sodium hydroxide.

[0281] The following examples illustrate optimized oral thin film formulations for buccal delivery of xanomeline tartrate and trospium chloride, demonstrating the effects of polymer composition, permeation enhancers, and pH optimization on drug permeation through buccal mucosa.

[0282] Example 12-A: Citric Acid Baseline

[0283] Referring now to Table 12-A, an aqueous-based film formulation was developed utilizing polyvinylpyrrolidone (PVP K90) as the primary film-forming and mucoadhesive polymer system with citric acid as a pH modifier. The formulation employs purified water USP as the solvent system (66.92% w / w), incorporating xanomeline tartrate (7.13% w / w, 21.56% dry) and trospium chloride (1.12% w / w, 3.37% dry) as the active pharmaceutical ingredients. PEG 300 serves as plasticizer (5.35% w / w, 16.19% dry), while citric acid (1.34% w / w, 4.05% dry) provides pH adjustment to approximately pH 3. This formulation demonstrates that citric acid at acidic pH reduces xanomeline permeation to approximately 200 pg / cm3at 250 minutes, comparing to Example 12-B which doesn’t contain citric acid, due to drug protonation effects. See also Example 13 for comparative TPGS baseline data at similar acidic pH.

[0284] Table 12-A: Example 12-AComponent % wet (w / w) % dry (w / w) FunctionPurified water USP 66.92 - SolventXanomeline tartrate 7.13 21.56 APITrospium chloride 1.12 3.37 APIPEG 300 5.35 16.19 PlasticizerMenthol 0.20 0.61 Flavoring agentSucralose 0.27 0.81 SweetenerCitric acid 1.34 4.05 Permeation enhancer-pH modifierPVP K90 17.40 52.61 Film former-mucoadhesive Ascorbic acid 0.27 0.81 Stabilizing agent

[0285] Table 12-B ; Formulation Example 12-BIngredients % wet (w / w) % dry (w / w) FunctionPurified water USP 67.83 - SolventXanomeline tartrate 7.23 22.47 APITrospium Chloride 1.13 3.52 APIPropylene Glycol 5.43 16.87 Plasticizer and co-solvent Menthol 0.20 0.63 Flavoring agentSucralose 0.27 0.84 SweetenerPVP K90 17.64 54.82 Film former-mucoadhesive Ascorbic acid 0.27 0.84 Stabilizing agent

[0286] Preparation: A solution is prepared by mixing the actives, citric acid, and water until transparent (3-30 minutes at room temperature). PEG 300 is added as plasticizer plasticizer and co-solvent to help maintain the solubility and stability of the APIs, followed by PVP K90 as film former. Sweetening agents, flavoring agents, and antioxidant are added until homogeneous. The wet blend is cast over liner rolls and dried. Total solid content: 33.08%.

[0287] Example 13: TPGS Permeation Enhancement

[0288] Referring now to Table 13, an optimized aqueous-based film formulation was developed utilizing PVP K90 with D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a permeation enhancer. TPGS at 1.66% dry weight significantly enhanced xanomeline permeation through pig buccal mucosa compared to the citric acid formulation of Example 12.

[0289] Table 13: Example 13Component % wet (w / w) % dry (w / w) FunctionPurified water USP 67.47 - SolventXanomeline tartrate 7.19 22.10 APITrospium chloride 1.13 3.46 APIPEG 300 5.40 16.59 Plasticizer and co-solvent Menthol 0.20 0.62 Flavoring agentSucralose 0.27 0.83 SweetenerPVP K90 17.54 53.92 Film former-mucoadhesive Ascorbic acid 0.27 0.83 Stabilizing agentTPGS 0.54 1.66 Permeation enhancer

[0290] Preparation: Actives are dissolved in water until transparent. PEG 300 is added as plasticizer and co-solvent, then TPGS as permeation enhancer. PVP K90 is added as film former, followed by sweetening agents, flavoring agents, and antioxidant. Total solid content: 32.53%.

[0291] Example 14: Dual Polymer System Introduction

[0292] Referring now to Table 14, an optimized formulation was developed utilizing a dual polymer system comprising PVP K90 and hydroxypropyl methylcellulose (HPMC E50). The introduction of HPMC E50 at approximately 10% dry weight was found to have minimal impact on drug permeation while providing additional film-forming properties. Formulation pH maintained at approximately 3.

[0293] Table 14: Formulation Example 14Component % wet (w / w) % dry (w / w) FunctionPurified water USP 67.14 - SolventXanomeline tartrate 7.46 22.71 APITrospium chloride 1.17 3.55 APIGlycerol 4.03 12.26 Plasticizer and co-solvent Menthol 0.17 0.51 Flavoring agentSucralose 0.22 0.68 SweetenerTPGS 0.45 1.36 Permeation enhancerPVP K90 16.00 48.71 Film former-mucoadhesiveHPMC E50 3.13 9.54 Film former-viscosity modifier Ascorbic acid 0.22 0.68 Stabilizing agent

[0294] Preparation: Actives dissolved in water, glycerol added as plasticizer, TPGS as permeation enhancer, then PVP K90 and HPMC E50 as film formers. Total solid content: 32.86%.

[0295] Example 15: Increased TPGS at Acidic pH (Comparative)

[0296] This comparative example demonstrates that simply increasing TPGS concentration without pH optimization paradoxically impairs drug permeation. The formulation employs doubled TPGS (2.75% dry) at acidic pH 3. Permeation studies revealed reduced drug permeation (-100 pg / cm3at 250 minutes) compared to Example 14, due to xanomeline protonation and drug sequestration through electrostatic interactions with PEG micelle surfaces. See also Example 16 for additional comparative data confirming this phenomenon.

[0297] Table 15: Formulation Example 15 (Comparative)Component % wet (w / w) % dry (w / w) FunctionPurified water USP 65.40 - SolventXanomeline tartrate 7.93 22.91 APITrospium chloride 1.24 3.59 APIGlycerol 3.21 9.28 Plasticizer and co-solvent Menthol 0.21 0.60 Flavoring agentSucralose 0.42 1.21 SweetenerTPGS 0.95 2.75 Permeation enhancerPVP K90 17.26 49.90 Film former-mucoadhesive HPMC 3.38 9.77 Film former-viscosity modifier

[0298] At acidic pH, xanomeline becomes protonated and carries a positive charge, while tartrate counterions are only partially dissociated. These conditions create strong electrostatic and hydrogen bonding interactions between the protonated drug and the polyethylene glycol corona of TPGS micelles, resulting in drug sequestration. Total solid content: 34.60%.

[0299] Example 16: pH Optimization with Increased TPGS

[0300] This example demonstrates that combining increased TPGS concentration with pH adjustment to 5.0 synergistically enhances drug permeation. Permeation reached approximately 500 pg / cm3at 250 minutes with reduced lag time, a 5-fold improvement over Example 15. See also Example 15 for additional supporting data.

[0301] Table 16: Example 16Component % wet (w / w) % dry (w / w) FunctionPurified water USP 65.40 - SolventXanomeline tartrate 7.93 22.91 APITrospium chloride 1.24 3.59 APIGlycerol 3.21 9.28 Plasticizer and co-solvent Menthol 0.21 0.60 Flavoring agentSucralose 0.42 1.21 SweetenerTPGS 0.95 2.75 Permeation enhancerPVP K90 17.26 49.90 Film former-mucoadhesive HPMC 3.38 9.77 Film former-viscosity modifier NaOH q.s. - pH adjuster (to pH 5.0)

[0302] At pH 5, xanomeline is less protonated with reduced positive charge, while tartrate counterions are more fully dissociated. These conditions weaken drug-micelle interactions, inpresence of TPGS, allowing the drug to be released more readily for transmucosal absorption. Total solid content: 34.60%.

[0303] Example 17: Elevated HPMC E50 at Acidic pH (Comparative)

[0304] A comparative formulation with increased HPMC E50 (24.45% dry) and elevated TPGS (4.94% dry) at acidic pH. This serves as the comparative baseline for Example 18.

[0305] Table 17: Example 17 (Comparative)Component % wet (w / w) % dry (w / w) FunctionPurified water USP 71.75 - SolventXanomeline tartrate 5.81 20.58 APITrospium chloride 0.91 3.22 APIGlycerol 2.30 8.15 Plasticizer and co-solvent Menthol 0.15 0.54 Flavoring agentSucralose 0.31 1.09 SweetenerTPGS 1.40 4.94 Permeation enhancerPVP K90 10.15 35.94 Film former-mucoadhesiveHPMC E50 6.91 24.45 Film former-hydration promoter Simethicone 0.31 1.09 Antifoaming agent

[0306] Total solid content: 28.25%. Permeation at acidic pH approximately 100 pg / cm3at 250 minutes.

[0307] Example 18 pH-Optimized High HPMC E50

[0308] An optimized formulation with increased HPMC E50 and elevated TPGS at pH 5.7. This formulation achieved cumulative xanomeline permeation of approximately 500 pg / cm3at 250 minutes, compared to approximately 100 pg / cm3for the acidic pH formulation of Example 17.

[0309] Table 18: Example 18Component % wet (w / w) % dry (w / w) FunctionPurified water USP 71.81 - SolventXanomeline tartrate 5.80 20.58 APITrospium chloride 0.91 3.22 APIGlycerol 2.30 8.15 Plasticizer and co-solvent Menthol 0.15 0.54 Flavoring agentSucralose 0.31 1.09 SweetenerTPGS 1.39 4.94 Permeation enhancerPVP K90 10.13 35.94 Film former-mucoadhesiveHPMC E50 6.89 24.45 Film former-hydration promoter Simethicone 0.31 1.09 Antifoaming agentNaOH q.s. - pH adjuster (to pH 5.7)

[0310] Enhanced permeation is attributed to reduced xanomeline protonation at pH 5.70, the relaxed gel network formed by the HPMC E50 / PVP K90 combination, and optimized TPGS concentration. Total solids: 28.19%.

[0311] Table 19: Formulation Example 19Ingredients _ % wet (w / w) % dry (w / w) FunctionPurified water USP 71.67 - SolventXanomeline tartrate 5.79 20.44 APITrospium chloride 0.91 3.20 APIGlycerol 2.29 8.10 Plasticizer and co-solventMenthol 0.15 0.54 Flavoring agentSucralose 0.31 1.08 SweetenerTPGS 1.39 4.91 Permeation enhancerPVP K90 10.11 35.70 Film former-mucoadhesiveHPMC E50 6.88 24.29 Film former-hydration promoter Simethicone 0.31 1.08 Antifoaming agentStabilizing agentAscorbyl palmitate 0.19 0.67

[0312] Reduced permeation in Example 19 is attributed to the incorporation of ascorbyl palmitate at 0.67% dry weight as conservative agent, with identical composition to Formulation Example 18

[0313] Table 20: Formulation Example 20 High PVP with Methanol Co-solvent (Comparative) Component % wet (w / w) % dry (w / w) FunctionPurified water USP 61.47 - SolventMethanol 4.92 - Co-solventXanomeline tartrate 7.45 22.17 APITrospium chloride 1.17 3.47 APIGlycerol 3.02 8.98 Plasticizer and co-solvent Menthol 0.20 0.59 Flavoring agentSucralose 0.39 1.17 SweetenerTPGS 1.79 5.32 Permeation enhancerPVP K90 16.23 48.28 Film former-mucoadhesiveHPMC 3.18 9.45 Film former-viscosity modifier Simethicone 0.20 0.59 Antifoaming agent

[0314] A comparative formulation demonstrating that increasing PVP to approximately 50% while reducing HPMC to 10% creates a denser, more rigid matrix that limits drug diffusion, resulting in reduced permeation.

[0315] Total solid content: 33.61%. Methanol co-solvent facilitates faster drying.

[0316] Example 21: Multi-Polymer System at Acidic pH (Comparative)

[0317] An advanced multi-component polymer system comprising PVP K90, HPC L, HPMC E15, and HPMC E4M at acidic pH 3 with elevated drug loading (xanomeline 24.26% dry, trospium 6.33% dry). Serves as comparative baseline for Example 22.

[0318] Table 21: Example 21 (Comparative)Component % wet (w / w) % dry (w / w) FunctionPurified water USP 64.59 - SolventMethanol 1.79 - Co-solventXanomeline tartrate 8.16 24.26 APITrospium chloride 2.13 6.33 APIPEG 300 2.39 7.12 Plasticizer and co-solventArome Type Supresseur1.29 3.84 Bitter maskerAmertume (ATSA)Advantame 0.04 0.11 High-intensity sweetenerComponent % wet (w / w) % dry (w / w) FunctionMenthol 0.48 1.42 Flavoring agentSucralose 0.72 2.14 SweetenerTPGS 0.72 2.14 Permeation enhancerPVP K90 12.20 36.29 Film former-mucoadhesiveHPC L 2.87 8.54 Film softenerHPMC E15 1.91 5.69 Viscosity agentHPMC E4M 0.72 2.14 Mucoadhesion agent

[0319] HPC L provides film softness and reduced stiffness, while HPMC E15 and HPMC E4M serve as viscosity and mucoadhesion agents. Total solid content: 33.62%.

[0320] Example 22: Multi-Polymer System at pH 5.5

[0321] The same multi-polymer system as Example 21, with blend pH adjustment to 5.5. This modification significantly improved drug permeation compared to the acidic pH formulation.

[0322] Table 22: Formulation Example 22Component % wet (w / w) % dry (w / w) FunctionPurified water USP 64.59 - SolventMethanol 1.79 - Co-solventXanomeline tartrate 8.16 24.26 APITrospium chloride 2.13 6.33 APIPEG 300 2.39 7.12 Plasticizer and co-solventArome Type Supresseur1.29 3.84 Bitter maskerAmertume (ATSA)Advantame 0.04 0.11 High-intensity sweetener Menthol 0.48 1.42 Flavoring agentSucralose 0.72 2.14 SweetenerTPGS 0.72 2.14 Permeation enhancerPVP K90 12.20 36.29 Film former-mucoadhesiveHPC L 2.87 8.54 Film softenerHPMC E15 1.91 5.69 Viscosity agentHPMC E4M 0.72 2.14 Mucoadhesion agentNaOH q.s. - pH adjuster (to pH 5.5)

[0323] Total solid content: 33.62%.

[0324] Example 23: Maximum Permeation Optimized

[0325] A highly optimized formulation with elevated HPMC E4M (8.26% dry) to maximize drug permeation through hydrated gel formation. Permeation studies demonstrated cumulative xanomeline permeation exceeding 900 pg / cm3at 240 minutes. See also Example 24 for additional characterization of this batch. The surface pH was measured between 4.6 and 4.75

[0326] Table 23: Formulation Example 23Component % wet (w / w) % dry (w / w) FunctionPurified water USP 66.12 - SolventMethanol 1.52 - Co-solventXanomeline tartrate 7.61 23.50 APITrospium chloride 1.99 6.13 APIPEG 300 2.02 6.25 Plasticizer and co-solventComponent % wet (w / w) % dry (w / w) FunctionArome Type Supresseur1.13 3.50 Bitter maskerAmertume (ATSA)Advantame 0.03 0.11 SweetenerMenthol 0.41 1.25 Flavoring agent / permeation enhancerSucralose 0.49 1.50 SweetenerTPGS 0.32 1.00 Permeation enhancerPVP K90 12.02 37.15 Film former-mucoadhesiveHPC L 2.45 7.57 Film softenerHPMC E5 1.23 3.78 Viscosity agent and mucoadhesion agentHPMC E4M 2.67 8.26 Mucoadhesion / permeation enhancer and viscosity agent NaOH q.s. - pH adjuster (to pH 5.0)

[0327] Table 24 : Example 24-elevated HPMC E5 (to 8.26% dry) and reduced HPMC E4M (to 3.8% dry)Component % wet (w / w) % dry (w / w) FunctionPurified water USP 65.177 - SolventMethanol 1.560 - Co-solventXanomeline tartrate 7.818 23.504 APITrospium chloride 2.040 6.132 APIPEG 300 2.080 6.254 Plasticizer and co-solventArome Type Supresseur Bitter maskerAmertume (ATSA) 1.165 3.502Advantame 0.035 0.106 SweetenerMenthol Flavoring agent / permeation 0.416 1.251 enhancerSucralose 0.499 1.501 SweetenerTPGS 0.333 1.001 Permeation enhancerPVP K90 12.356 37.146 Film former-mucoadhesive HPC L 2.517 7.567 Film softenerHPMC E5 Viscosity agent and 2.746 8.255 mucoadhesion agentHPMC E4M Mucoadhesion / permeation1.258 3.783 enhancerand viscosity agent NaOH q.s. - pH adjuster (to pH 5.0)

[0328] The higher molecular weight HPMC E4M (-4000 mPa s at 2% in water) promotes formation of relaxed, hydrated gels with continuous aqueous diffusion pathways. Total solids: 32.4%.

[0329] Table 25: Example 25- Optimized scaled clinical batch formulation 250C001M1.

[0330] A scaled clinical batch formulation 250C001M1 was prepared. The formulation comprised a mucoadhesive layer corresponding to Example 25-A and a backing layer corresponding to Example 25-B. The two layers were subsequently combined to form a bilayer system, which was then evaluated in permeation studies.

[0331] Table 25-A : Example 25-A (Mucoadhesive Layer)Example 25-A Mucoadhesive LayerIngredients % wet (w / w) % dry (w / w) FunctionPurified water USP 64.08 7.00 Solvant-solubilizer Methyl Alcohol (MeOH) 1.49 - Co-Solvant-cosolubilizer Xanomeline tartrate 7.49 21.74 APITrospium chloride 1.95 5.67 APIPolyethylene Glycol 300 (PEG 2.33 6.76 Plasticizer and co-solubilizer 300)Arome Type Supresseur 7.58 3.30 Bitter maskerAmertume (ATSA)Advantame 0.04 0.11 SweetnerL-Menthol 0.80 2.33 Falvor / Bitter masker Sucralose 0.46 1.33 SweetnerVitamine E TPGS 0.32 0.92 Permeation enhencer- antioxydant-cosolubilizer BHT 0.01 0.03 Anti-oxydantPolyvinyl pyrrolidone PVP K90 12.14 35.26 Film FormerHPC LF Klucel 2.91 8.45 Film formerHPMC E5 1.15 3.34 Viscosity and mucoadhesion agentHPMC E4M 2.96 8.60 Viscosity, mucoadhesion and permeation agentSodium Hydroxide, solid 0.74 2.15 pH adjuster

[0332] Table 25-B : Example 25-B (Backing Layer)Ingredients % wet (w / w) % dry (w / w) mg / film+LODPurified water USP 76.281 - Solvant-solubilizer Methyl Alcohol (MeOH) 1.907 - Cosolvent-Cosolubilizer L-menthol 0.636 2.914 Flavor / Bitter masker Sucralose 0.540 2.477 SweetnerPEG 300 2.225 10.200 PlasticizerPVP K90 7.628 34.973 Film FormerHPC LF Klucel 6.134 28.124 Film FormerHPMC E50 3.560 16.321 Viscosity agentHPC GXF 0.413 1.894 Viscosity agentTitanium Dioxide 0.675 3.097 opacifying agent

[0333] The mucoadhesive layer comprises xanomeline tartrate (21.74% w / w dry) and trospium chloride (5.67% w / w dry) as active agents, combined with film-forming polymers including PVP K90 (35.26% w / w dry), HPC LF (8.45% w / w dry), HPMC E5 (3.34% w / w dry), and HPMC E4M (8.60% w / w dry), together with PEG 300 (6.76% w / w dry) as plasticizer and additional functional excipients. The backing layer comprises film-forming polymers including PVP K90 (34.97% w / w dry), HPC LF (28.12% w / w dry), HPMC E50 (16.32% w / w dry), and HPC GXF (1.89% w / w dry),PEG 300 (10.20% w / w dry) as plasticizer, and titanium dioxide (3.10% w / w dry) as an opacifying agent. The layers were combined to form a bilayer dosage form suitable for clinical evaluation.

[0334] Example 26: Preparation of a Bilayer Film Containing Trospium Chloride

[0335] A film formulation containing trospium chloride as the sole active pharmaceutical ingredient was prepared using the same materials, method, and manufacturing process as described in Example 25, except that xanomeline tartrate was omitted. The composition was adjusted accordingly while maintaining comparable film-forming properties and mechanical integrity. The resulting film was suitable for further evaluation.

[0336] Table 26-A: Example 26-A (Mucoadhesive Layer)Ingredients % wet (w / w) % dry (w / w)Purified water USP 69.271 7.000Methyl Alcohol (MeOH) 1.608Xanomeline tartrate 0.000 0.000Trospium chloride 2.111 7.249Polyethylene Glycol 300 (PEG 300) 2.515 8.637Arome Type Supresseur Amertume 1.230 4.224(ATSA)Advantame 0.041 0.141L-Menthol 0.868 2.982Sucralose 0.492 1.690Vitamine E TPGS 0.342 1.173BHT 0.012 0.042Polyvinyl pyrrolidone PVP K90 13.122 45.060HPC LF Klucel 3.144 10.796HPMC E5 1.241 4.262HPMC E4M 3.201 10.993Sodium Hydroxide, solid 0.801 2.751

[0337] Table 26-B : Example 26-B (Backing Layer)Ingredients % wet (w / w) % dry (w / w)Purified water USP 76.281Methyl Alcohol (MeOH) 1.907L-menthol 0.636 2.914Sucralose 0.540 2.477PEG 300 2.225 10.200PVP K90 7.628 34.973HPC LF Klucel 6.134 28.124HPMC E50 3.560 16.321HPC GXF 0.413 1.894Titanium Dioxide 0.675 3.097

[0338] Permeation Testing Methodology

[0339] Permeation studies for all examples were conducted using excised porcine buccal mucosa as a model membrane. Fresh porcine cheek tissue was obtained from a local abattoir, and the buccal mucosa was carefully dissected to remove underlying connective tissue and fat. The mucosa was mounted in Franz diffusion cells with the epithelial surface facing the donor compartment and the basal surface in contact with the receptor compartment.

[0340] The receptor compartment was filled with phosphate buffered saline (PBS) at pH 6.8, 0.01 M, maintained at 37±0.5°C with continuous magnetic stirring at 600 rpm. Each film formulation was placed on the mucosal surface in the donor compartment. Samples were withdrawn from the receptor compartment at predetermined time intervals (0, 50, 100, 150, 200, and 250 minutes), with immediate replacement of equal volume of fresh receptor medium to maintain sink conditions. Xanomeline concentration was determined by validated HPLC method. Cumulative permeation was calculated and expressed as pg / cm3. All experiments were performed in triplicate.

[0341] Permeation Study Results Summary

[0342] The following summarizes key permeation findings demonstrating the effects of TPGS concentration, pH optimization, and polymer matrix selection:

[0343] TPGS Concentration and pH Effects

[0344] At baseline TPGS concentration (1.36% dry) and acidic pH 3 (see Example 14), cumulative permeation reached approximately 200 pg / cm3at 250 minutes. Increasing TPGS to 2.75% dry at acidic pH (Example 15) paradoxically reduced permeation to approximately 100 pg / cm3due to drug sequestration in micelles. Adjusting pH to 5.0 with the same elevated TPGS (Example 16) restored and enhanced permeation to approximately 500 pg / cm3, a 5-fold improvement. These results establish that pH optimization is important when using higher TPGS concentrations.

[0345] Polymer Matrix Optimization

[0346] Formulations with higher HPMC content and appropriate pH adjustment (Examples 18, 22, 23, 24) consistently achieved superior permeation. Example 23 (Formulation 184-32-A) with elevated HPMC E4M (8.26% dry) at pH 5.0 achieved approximately 900 pg / cm3at 240 minutes. The high molecular weight HPMC E4M forms a relaxed gel network with continuous aqueous pathways, compared to the weaker network formed by low molecular weight HPMC grades.

[0347] HPMC Molecular Weight Effect

[0348] Comparative studies between HPMC E4M (high MW, -4000 mPa s) and HPMC E5 (low MW, -5 mPa s) at identical concentrations demonstrated approximately 2.5-fold higherpermeation with HPMC E4M (900 pg / cm3vs 350 pg / cm3), establishing the importance of polymer molecular weight selection.

[0349] Example 23 : Maximum Permeation Formulation

[0350] An optimized formulation designed for maximum transmucosal permeation, achieving approximately 950 pg / cm3at 200 minutes, the highest permeation among all tested formulations, representing approximately 4-5 fold improvement over baseline formulations.

[0351] Permeation studies using porcine buccal mucosa in Franz diffusion cells with PBS pH 6.8 receptor medium demonstrated the highest cumulative permeation among all tested formulations, achieving approximately 950 pg / cm3at 200 minutes, representing a significant improvement over baseline formulations.

[0352] This represents an approximately 4-5 fold improvement over baseline formulations and demonstrates the synergistic benefits of combined pH optimization and polymer matrix engineering. The lag time was reduced to approximately 18 minutes compared to approximately 45 minutes for formulations at pH 3.0. The combination of HPC L with HPMC E4M and HPMC E5 at the specified ratios creates a relaxed, hydrated gel network with flexible polymer chains and continuous aqueous pathways optimized for drug diffusion. The higher proportion of HPMC E4M Example 23 compared to Example 24 provides enhanced gel structure while maintaining permeation-favorable matrix characteristics.

[0353] An optimized oral film formulation was prepared utilizing a polymer matrix designed for maximum transmucosal permeation. The formulation comprised xanomeline tartrate (5.0% w / w dried film), trospium chloride (2.0% w / w dried film), HPC L (7.6567% w / w dried film), HPMC E4M (3.8783% w / w dried film), HPMC E5 (8.3255% w / w dried film), d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS, 1.766% w / w dried film), glycerol as plasticizer, simethicone as antifoaming agent, advantame as high-intensity sweetener, and purified water as solvent. The formulation pH was adjusted to 5.0 using sodium hydroxide.

[0354] The formulation was prepared by dissolving the polymers in purified water under continuous stirring at ambient temperature. The active pharmaceutical ingredients were added and mixed until complete dissolution. pH was adjusted to 5.5 using 1N sodium hydroxide solution. The resulting solution was cast onto a release liner using a film applicator and dried at 50°C for 30 minutes.

[0355] Effect of Permeation Enhancers and pH Modifiers

[0356] Referring now to FIG. 5, comparative permeation studies were conducted to evaluate the effects of TPGS (D-alpha-tocopheryl polyethylene glycol 1000 succinate) and citric acid on xanomeline transmucosal permeation. Three formulations employing polyvinylpyrrolidone (PVPK90) as the primary film-forming polymer were evaluated: Formulation Example 12A containing citric acid (4.05% dry weight), Formulation Example 12B as a baseline control without permeation enhancers, and Formulation Example 13 containing TPGS (1.66% dry weight). The permeation data demonstrate that TPGS at 1.66% dry weight significantly enhanced xanomeline permeation, achieving cumulative permeation exceeding 500 pg / cm3at 180 minutes, whereas the citric acid formulation exhibited reduced permeation of approximately 200 pg / cm3at the same timepoint. These results establish TPGS as an effective permeation enhancer for buccal delivery of xanomeline tartrate.

[0357] Effect of HPMC E50 Introduction

[0358] Referring now to FIG. 6, the effect of introducing hydroxypropyl methylcellulose (HPMC E50) into the polymer matrix was evaluated by comparing Formulation Example 13 (PVP K90 only) with Formulation Example 14 (dual polymer system comprising PVP K90 at 48.71% dry weight and HPMC E50 at 9.54% dry weight). The permeation profiles were substantially similar, with both formulations achieving cumulative permeation of approximately 700 pg / cm3at 200 minutes. This finding establishes that HPMC E50 can be incorporated at approximately 10% dry weight to provide additional film-forming and mucoadhesive properties without negatively impacting drug permeation.

[0359] Synergistic Effect of TPGS Concentration and pH Optimization

[0360] Referring now to FIGS. 7 and 8, the interplay between TPGS concentration and formulation pH was systematically investigated. Surprisingly, it was discovered that simply doubling the TPGS concentration from 1.36% to 2.75% dry weight at acidic pH (approximately pH 3) paradoxically reduced xanomeline permeation from approximately 700 pg / cm3to approximately 100 pg / cm3at 250 minutes, as illustrated by the comparison of Formulation Example 14 and Formulation Example 15. Without wishing to be bound by theory, it is believed that at acidic pH, xanomeline becomes protonated and carries a positive charge, while the tartrate counterions are only partially dissociated. These conditions create strong electrostatic and hydrogen bonding interactions between the protonated drug and the polyethylene glycol corona of TPGS micelles, resulting in drug sequestration within the micellar structures.

[0361] Significantly, as shown in FIG. 8, adjusting the formulation pH to 5.0 using sodium hydroxide (Formulation Example 16) restored and enhanced xanomeline permeation to approximately 500 pg / cm3at 250 minutes with substantially reduced lag time compared to the acidic pH formulation. At pH 5.0, xanomeline is less protonated and carries reduced positive charge, while the tartrate counterions are more fully dissociated. These conditions weaken the drug-micelle interactions, allowing the drug to be released more readily for transmucosalabsorption. This synergistic optimization of TPGS concentration with pH adjustment represents a key finding for maximizing buccal permeation of xanomeline tartrate.

[0362] Optimization of High HPMC Content Formulations

[0363] Referring now to FIG. 9, formulations with elevated HPMC E50 content (24.45% dry weight) and increased TPGS (4.94% dry weight) were evaluated at different pH conditions. Formulation Example 17 at acidic pH exhibited cumulative permeation of approximately 100 pg / cm3at 250 minutes, consistent with the drug sequestration phenomenon described above. In contrast, Formulation Example 18 with pH adjusted to 5.70 achieved cumulative permeation exceeding 500 pg / cm3at the same timepoint, representing approximately a 5-fold enhancement. These results further validate that pH optimization is important for achieving optimal permeation in TPGS-containing formulations.

[0364] Referring to FIG. 9 Formulation Example 18 demonstrates a pH-optimized oral film formulation with enhanced transmucosal permeation. The formulation contains: Purified water USP (15.00g, 71.81 percent wet), Xanomeline tartrate (1.21g, 5.80 percent wet, 20.58 percent dry), Trospium Chloride (0.19g, 0.91 percent wet, 3.22 percent dry), Glycerol (0.48g, 2.30 percent wet, 8.15 percent dry), Menthol (0.03g, 0.15 percent wet, 0.54 percent dry), Sucralose (0.06g, 0.31 percent wet, 1.09 percent dry), TPGS (0.29g, 1.39 percent wet, 4.94 percent dry), PVP K90 (2.12g, 10.13 percent wet, 35.94 percent dry), HPMC E50 (1.44g, 6.89 percent wet, 24.45 percent dry), and Simethicone (0.06g, 0.31 percent wet, 1.09 percent dry). Total solids content is 28.19 percent. The pH of the blend was adjusted to 5.70 using sodium hydroxide. The formulation was prepared by dissolving the water-soluble polymers in purified water, adding the active ingredients, then sequentially adding glycerol, TPGS, menthol, sucralose, and simethicone with mixing. The blend was cast onto a release liner and dried. In Franz cell permeation studies using pig buccal mucosa in PBS (pH 6.8, 0.01 M), this formulation achieved cumulative xanomeline permeation of approximately 500 micrograms per cubic centimeter at 250 minutes, compared to approximately 100 micrograms per cubic centimeter for the acidic pH formulation (Example 17). The enhanced permeation is attributed to reduced xanomeline protonation at pH 5.70, the relaxed gel network formed by the HPMC E50 / PVP K90 polymer combination, and optimized TPGS concentration providing permeation enhancement without excessive drug sequestration.

[0365] According to some embodiments, it is disclosed that optimal buccal film formulations for xanomeline tartrate and trospium chloride require: (1) pH adjustment to approximately 5.0-5.7 to minimize drug protonation and micelle sequestration; (2) appropriate TPGS concentration (1-5% dry) in conjunction with pH optimization; (3) high molecular weight HPMC grades (particularlyHPMC E4M) to form relaxed hydrated gels with continuous aqueous diffusion pathways; and (4) balanced polymer ratios favoring HPMC over PVP for optimal matrix characteristics.

[0366] Effect of Ascorbyl Palmitate (Comparative)

[0367] Referring now to FIG. 10, the effect of incorporating ascorbyl palmitate as an antioxidant was evaluated. Formulation Example 19, which contained ascorbyl palmitate at 0.67% dry weight with identical composition to Formulation Example 18, exhibited substantially reduced permeation of approximately 100 pg / cm3at 250 minutes compared to approximately 500 pg / cm3for Formulation 180-92 -A. Without wishing to be bound by theory, ascorbyl palmitate creates hydrophobic domains within the polymer matrix that sequester the drug and reduce its effective diffusion coefficient. This finding establishes that lipophilic antioxidants should be avoided or minimized in buccal film formulations forxanomeline tartrate.

[0368] Optimization of Polymer Ratios

[0369] Referring now to FIG. 11, the effect of varying the PVP:HPMC polymer ratio was systematically evaluated. Formulation Example 18 with higher HPMC content (approximately 25% dry weight) and moderate PVP content (approximately 36% dry weight) achieved superior permeation compared to Formulation Example 20, which employed increased PVP (approximately 48% dry weight) with reduced HPMC (approximately 9% dry weight). The data demonstrate that the higher HPMC formulation achieved cumulative permeation of approximately 550 pg / cm3at 200 minutes, whereas the higher PVP formulation achieved only approximately 350 pg / cm3at the same timepoint. It is believed that higher PVP content creates a denser, more rigid matrix that limits drug diffusion, while higher HPMC content promotes film hydration and polymer relaxation, thereby enhancing drug release and transmucosal permeation.

[0370] Referring now to FIG. 12, the present disclosure further encompasses evaluation of advanced multi-component polymer systems. Formulation Example 21 (pH 3) and Formulation Example 22 (pH 5.5) each comprise a sophisticated polymer blend including polyvinylpyrrolidone (PVP K90), hydroxypropyl cellulose (HPC L), hydroxypropyl methylcellulose E15 (HPMC E15), and hydroxypropyl methylcellulose E4M (HPMC E4M), together with elevated drug loading wherein xanomeline tartrate is present at about 24.26% by dry weight and trospium chloride is present at about 6.33% by dry weight. The effect of pH on transmucosal permeation remained consistent with prior experimental observations described herein, with the pH 5.5 formulation achieving substantially higher cumulative permeation relative to the acidic pH 3 formulation. In certain embodiments, HPC L is incorporated to impart enhanced film flexibility and reduced stiffness characteristics, while HPMC E15 and HPMC E4M function as viscosity-modifying agents and mucoadhesion promoters.

[0371] Effect of HPMC Molecular Weight on Gel Formation

[0372] Referring now to FIG. 13, the effect of hydroxypropyl methylcellulose (HPMC) molecular weight on transmucosal permeation behavior was systematically evaluated by comparing Formulation Example 23, comprising elevated HPMC E4M at about 8.26% by dry weight, with Formulation Example 24, comprising HPMC E5 at about 8.26% by dry weight. HPMC E4M, characterized by a viscosity of approximately 4000 mPa s when prepared at 2% w / v in water, forms a relaxed, hydrated gel matrix upon contact with mucosal fluids. Without being bound by theory, this gel matrix is characterized by a flexible polymer network architecture that establishes continuous aqueous diffusion pathways through which the active pharmaceutical ingredients may traverse. Formulation Example 23 achieved cumulative permeation exceeding about 900 pg / cm2at 200 minutes. In contrast, HPMC E5, characterized by a substantially lower viscosity of approximately 5 mPa s, forms a weaker, less relaxed polymer network that limits diffusive transport of the drug substances, achieving cumulative permeation of approximately 350 pg / cm2at the same timepoint. This approximately 2.5-fold differential in cumulative permeation demonstrates that high molecular weight HPMC grades are preferred for optimizing transmucosal delivery of xanomeline tartrate in buccal film formulations according to the present disclosure.

[0373] Scale-Up and Clinical Batch Confirmation

[0374] Referring now to FIGS. 14, 15, 16, and 17, permeation profiles of scaled clinical batch formulation 250C001M1 are illustrated. Permeation studies were conducted using excised porcine buccal mucosa as an ex vivo membrane model, with phosphate-buffered saline (PBS, 0.01 M, pH 6.8) serving as the receptor medium, to evaluate the permeation behavior of xanomeline and trospium chloride from a combined buccal film formulation in comparison with an aqueous solution formulation. The tested buccal film comprised a total of 5 mg xanomeline and 2 mg trospium chloride. The comparative solution formulation comprised xanomeline at a concentration of 5 mg / mL and trospium chloride at a concentration of 2 mg / mL in PBS (pH 6.8, 0.01 M), with the tested volume selected to provide equivalent amounts of both active pharmaceutical ingredients to those present in the buccal film test article.

[0375] For this comparative permeation study, a defined portion of the buccal film was employed, corresponding to a total drug content of 5 mg xanomeline and 2 mg trospium chloride. This reduced drug load, relative to the elevated amounts employed in permeation experiments described elsewhere in this disclosure, was intentionally implemented for the present comparative study. While the experiments described in preceding paragraphs involved inter-formulation comparisons between different buccal film compositions and therefore employed higher drug loads (e.g., 25 mg total drug content) to ensure adequate discriminatory power betweenformulation variants, the objective of the present study was to directly compare a matrix-based film formulation with a solution formulation in which the active pharmaceutical ingredients are present in a freely dissolved state.

[0376] Because the Franz diffusion cell apparatus operates under static, non-stirred donor chamber conditions, employment of a full-size film containing higher polymer and drug loads could potentially lead to saturation of the donor compartment with polymeric material, thereby altering drug release kinetics and permeation behavior and introducing bias into the comparison with the solution formulation. Accordingly, a reduced film portion delivering 5 mg xanomeline and 2 mg trospium chloride was selected to avoid donor chamber saturation effects and to enable a more meaningful and consistent comparison between the film and solution formulations under equivalent drug loading conditions.

[0377] The cumulative permeated amounts of xanomeline and trospium chloride were determined simultaneously as a function of time and were expressed both as absolute flux values (pg / cm2) and as percentages of the applied doses.

[0378] As illustrated in FIGS. 14, 15, 16, and 17, both xanomeline and trospium chloride exhibit substantially enhanced permeation through the porcine buccal mucosa when formulated in the buccal film composition as compared to the solution formulation. After approximately 240 minutes, the cumulative amount of xanomeline permeated from the buccal film reached about 430 to about 450 pg / cm2, corresponding to approximately 15% to about 16% of the applied dose, whereas the solution formulation resulted in cumulative permeation values of approximately 50 to about 60 pg / cm2, corresponding to about 2% of the applied dose. Under identical experimental conditions, trospium chloride formulated in the buccal film achieved cumulative permeation values of approximately 38 to about 41 pg / cm2, corresponding to about 3.5% to about 3.7% of the applied dose, while the solution formulation exhibited minimal permeation, with values of approximately 1 to about 2 pg / cm2, corresponding to about 0.1% to about 0.2% of the applied dose.

[0379] Throughout the duration of the experimental time course, the buccal film formulation consistently provided higher cumulative permeation values for both active pharmaceutical ingredients relative to the solution formulation, both in absolute terms and as percentages of the applied doses. These results demonstrate that incorporation of xanomeline and trospium chloride into a combined buccal film composition significantly enhances the transmucosal permeation of both active pharmaceutical ingredients across the buccal mucosa relative to a liquid formulation in which the same drugs are present in freely dissolved form. Without being bound by theory, the enhanced permeation observed with the film formulation may be attributed to one or more of: prolonged mucosal residence time afforded by the mucoadhesive film matrix; sustained andcontrolled release of the active pharmaceutical ingredients from the polymeric matrix; localized maintenance of favorable concentration gradients at the mucosal surface; and potential permeation-enhancing effects of formulation components.

[0380] Synergistic Enhancement of Trospium Chloride Permeation by Co-Formulation with xanomeline in Buccal Film

[0381] Additional permeation studies were conducted to evaluate the transmucosal permeation of trospium chloride when formulated as a single active ingredient in a buccal film composition, in comparison with its permeation when co-formulated with xanomeline in a combined buccal film composition.

[0382] As illustrated in FIG. 18, trospium chloride formulated as the sole active pharmaceutical ingredient in a buccal film exhibited negligible permeation through porcine buccal mucosa under the experimental test conditions employed. In contrast, when trospium chloride was co-formulated with xanomeline in a combined buccal film composition, its transmucosal permeation was unexpectedly and significantly enhanced, achieving cumulative permeation values of approximately 38 to about 41 pg / cm2, corresponding to about 3.5% to about 3.7% of the applied dose, after 240 minutes.

[0383] These results demonstrate a surprising and synergistic effect of xanomeline on the transmucosal permeation of trospium chloride across the buccal mucosa. Without being bound by theory, the presence of xanomeline in the film matrix appears to facilitate or otherwise promote the permeation of trospium chloride, which is otherwise poorly permeable when administered alone in a film formulation. This unexpected synergistic enhancement represents a significant and non-obvious advantage of the combined buccal film compositions of the present disclosure.

[0384] Effect of Various Antioxidants on the Stability of Buccal Films at Room Temperature After Two Months

[0385] Stability studies were performed on initial clinical buccal film compositions comprising various antioxidant agents following storage for two months at room temperature conditions (approximately 25°C). Stability assessments were based on total content of the active pharmaceutical ingredients and on the formation of specific impurities having relative retention times (RRT) of 0.44 and 0.35, as determined by chromatographic analysis methods.

[0386] Table 27 - Effect of antioxidants on the stability of oral films after 2 months of storage at room temperature.Rating scale:+++++ = excellent stability (no or very limited degradation detected)+++ = moderatestability++ = limited stability+ = minimal stabilityNegative = no stabilizing effect or increased degradation

[0387] he results demonstrate that selected antioxidants, including butylated hydroxytoluene (BHT), tocopherol, ascorbyl palmitate and butylated hydroxyanisole (BHA), provide a significant improvement in the stability of the oral films, both with respect to total impurities content and independent impurity formation.

[0388] According to some embodiments, although ascorbyl palmitate has been found to provide significant improvement in oxidative stability and overall film stability, it has also been observed to substantially reduce the permeation of the active ingredients through the buccal mucosa. Consequently, in certain embodiments of the invention where enhanced permeation of the active ingredients is critical, the composition is substantially free of ascorbyl palmitate. In other embodiments, ascorbyl palmitate may be included to maximize stability, providing a trade-off between stability and permeation. This deliberate selection allows optimization of the film formulation depending on whether stability or permeation is prioritized

[0389] Unexpectedly, L-cysteine shows a pronounced stabilizing effect with respect to the impurity having an RRT of 0.44, while showing no beneficial effect on the impurity having an RRT of 0.35. In contrast, commonly used stabilizing agents such as EDTA or glutathione do not provide any significant stabilization under the tested conditions.

[0390] These results indicate that the choice of antioxidant has a differentiated impact on the overall stability and impurity profile of oral film compositions and allow the identification of preferred antioxidants for improving stability during storage at room temperature.

[0391] The development of buccal film formulations containing xanomeline tartrate and trospium chloride presented several unique technical challenges that are specific to film-based dosage forms and would not typically be encountered, or would be substantially less significant, inconventional tablet formulations. These challenges required systematic optimization of multiple interdependent formulation variables to achieve a stable, efficacious product.

[0392] Unlike conventional tablet formulations wherein components may exist as discrete solid particles within a compressed matrix, buccal films require all formulation components, including active pharmaceutical ingredients, film-forming polymers, plasticizers, flavoring agents, and tastemasking agents, to be molecularly compatible within a continuous hydrated polymer matrix. The present disclosure outlines that achieving compatibility between the polymer system and both the tartrate and chloride salt forms of the respective APIs presented a significant technical challenge, particularly under acidic conditions and at high API loading levels.

[0393] Specifically, it was observed that at acidic pH values, the polymer matrix exhibited a tendency toward precipitation after storage periods of several days. This precipitation phenomenon was attributed to incompatibility interactions between the polymer components (including hydroxypropyl methylcellulose grades HPMC E4M and HPMC E5, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene oxide, and PVP K90) and the salt forms of the active ingredients (xanomeline tartrate and trospium chloride). Accordingly, the polymer ratios required careful optimization to prevent matrix precipitation while maintaining acceptable film-forming, mucoadhesive, and drug release properties.

[0394] Furthermore, water content played an important role in film formulation stability, as aqueous solvent is intrinsic to the film casting process. The amount of solvent required careful optimization to ensure adequate polymer hydration without inducing thermodynamic competition between polymer hydration and salt solvation, which can lead to phase separation or precipitation of either the polymer matrix or the active ingredients. This solvent optimization challenge is not typically encountered in dry tablet processing, where components are blended and compressed in the absence of a continuous aqueous phase.

[0395] Achieving sufficient mucoadhesion for effective buccal delivery presented another filmspecific challenge. Unlike tablet formulations, which rely primarily on mechanical retention within the oral cavity, buccal films must achieve intimate interfacial contact with the mucosal surface through polymer-mucosa interactions. The present disclosure outlines that achieving the required level of mucoadhesion necessitated precise tuning of the ratios between HPMC grades (E4M and E5), hydroxypropyl cellulose, and polyvinylpyrrolidone. The optimization of these polymer ratios was complicated by the need to simultaneously satisfy requirements for film formation, drug release, mechanical properties, and stability, as described herein.

[0396] Both xanomeline tartrate and trospium chloride exhibit pronounced bitter taste profiles, necessitating extensive incorporation of taste-masking agents including menthol and specializedbitter-masking flavor systems. In contrast to tablet formulations wherein taste-masking may be achieved through coating technologies or encapsulation approaches, buccal films require that taste-masking agents be homogeneously dispersed throughout the polymer matrix and maintained in uniform distribution during both manufacturing and storage. The present disclosure outlines that TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) functions not only as a permeation enhancer but also as a surfactant and dispersing agent that facilitates uniform suspension of taste-masking agents within the blend. Similarly, polyethylene glycol 300 contributed to the maintenance of homogeneous dispersion of these functional excipients throughout the formulation.

[0397] Targeting an appropriate disintegration time presented an additional formulation challenge. For the buccal film formulations of the present disclosure, a disintegration time of approximately 15 to 20 minutes, as measured by Petri dish testing methodology, was determined to be optimal for achieving adequate residence time for transmucosal absorption while maintaining patient acceptability. Achieving this target disintegration time required systematic adjustment of component ratios, as the disintegration behavior is influenced by the relative proportions of film-forming polymers, plasticizers, and other excipients.

[0398] According to some aspect of the present disclosure, the mechanical properties of the buccal film required careful balancing of competing requirements. Polyvinylpyrrolidone contributes to film stiffness and structural integrity, whereas plasticizers such as polyethylene glycol 300 provide flexibility and reduce brittleness. However, the present disclosure outlines that inadequate optimization of polymer-plasticizer ratios resulted in plasticizer migration to the film surface during storage, adversely affecting both the mechanical properties and the aesthetic appearance of the product. Accordingly, the polymer ratios were optimized to achieve an acceptable balance between film stiffness, flexibility, and plasticizer retention within the matrix.

[0399] The present disclosure further outline that the pH of the blend formulation must be carefully controlled to prevent API precipitation, as both xanomeline tartrate and trospium chloride exhibit pH-dependent solubility characteristics. Through systematic titration studies of API solutions, a maximum blend pH of approximately 5.85 was identified, beyond which precipitation of the active ingredients occurred. This pH sensitivity necessitated precise control of the basifying agent (sodium hydroxide) addition during manufacturing and represented an important process parameter that distinguishes buccal film formulation from conventional tablet development, where pH considerations are generally far less relevant due to the absence of a continuous aqueous phase during processing.

[0400] The combination of these film-specific challenges, including polymer-salt compatibility, solvent optimization, mucoadhesion requirements, taste-masking in a continuous matrix, disintegration time targeting, mechanical property balancing, and pH control, required an integrated formulation approach that would not be predictable from conventional tablet development experience. The successful resolution of these interdependent challenges, as embodied in the formulations disclosed herein, represents a significant advance in the art of buccal drug delivery for the xanomeline-trospium combination.

[0401] As used herein, unless otherwise specified, all weight percentages recited with respect to the film compositions of the present disclosure refer to the weight percentage of the specified component relative to the total weight of the dried active layer of the film. In embodiments wherein the oral film composition comprises a multilayer structure, such as a bilayer film comprising an active layer and a backing layer, or a trilayer film comprising an active layer disposed between two outer layers, the recited weight percentages are calculated based solely on the weight of the dried active layer and do not include the weight of any backing layer, release liner, support layer, or other non-active structural component of the multilayer film assembly. For example, when it is recited that a component is present "in an amount of from about X% to about Y% by weight of the dried film," such recitation refers to the weight percentage of that component relative to the total weight of the dried active drug-containing layer. This convention applies to all recited weight percentages for film-forming polymers, plasticizers, permeation enhancers, antioxidants, tastemasking agents, and other excipients described herein, as well as to the active pharmaceutical ingredients when expressed as weight percentages rather than absolute dosage amounts. Accordingly, in multilayer embodiments, the backing layer or other structural layers may comprise different polymeric materials, different component ratios, or different total weights without affecting the weight percentage calculations for the active layer as recited in the claims appended hereto.

[0402] 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 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.

Claims

Claims:

1. An oral film composition for transmucosal delivery comprising:a. xanomeline or a pharmaceutically acceptable salt thereof;b. trospium or a pharmaceutically acceptable salt thereof;c. at least one film-forming polymer; andd. d-alpha-tocopheryl polyethylene glycol succinate (TPGS);wherein the composition has a pH of from about 4.5 to about 7.

2. The composition of claim 1 , wherein the pH is from about 5.0 to about 7.

3. The composition of claim 2, wherein the pH is from about 5.5 to about 6.0.

4. The composition of claim 1, further comprising a basifying agent, wherein the basifying agent comprises sodium hydroxide.

5. The composition of claim 1, wherein the TPGS is present in an amount of less than about 5% by weight of the dried film.

6. The composition of claim 5, wherein the TPGS is present in an amount of from about 0.5% to about 2% by weight of the dried film and wherein the pH is from about 5.0 to about 5.5.

7. The composition of claim 1, wherein the at least one film-forming polymer comprises hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP).

8. The composition of claim 7, wherein the HPMC comprises a high molecular weight HPMC grade having a viscosity of from about 2000 mPa s to about 6000 mPa s when measured as a 2% aqueous solution at 20°C.

9. The composition of claim 7, wherein the HPMC is present in an amount of from about 9% to about 30% by weight of the dried film and the PVP is present in an amount of from about 30% to about 40% by weight of the dried film.

10. The composition of claim 7, wherein the HPMC comprises a combination of HPMC E4M and HPMC E5 or HPMC E15.

11. The composition of claim 7, wherein the polymer matrix further comprises hydroxypropyl cellulose (HPC) in an amount of from about 5% to about 12% by weight of the dried film.

12. The composition of claim 1, wherein the xanomeline or pharmaceutically acceptable salt thereof is present in an amount of from about 5 mg to about 50 mg per dosage unit and the trospium or pharmaceutically acceptable salt thereof is present in an amount of from about 2 mg to about 20 mg per dosage unit.

13. The composition of claim 1, further comprising a plasticizer, wherein the plasticizer comprises polyethylene glycol 300 in an amount of from about 5% to about 18% by weight of the dried film.

14. The composition of claim 1, further comprising an antioxidant, wherein the antioxidant comprises butylated hydroxytoluene (BHT).

15. The composition of claim 1, wherein the composition is substantially free of ascorbyl palmitate.

16. The composition of claim 1, wherein the film has a disintegration time of from about 15 minutes to about 20 minutes as measured by Petri dish testing.

17. A method of treating a neurological or psychiatric disorder selected from the group consisting of schizophrenia and Alzheimer's disease in a subject in need thereof, the method comprising:administering to the oral mucosa of the subject a buccal film composition comprising: a. xanomeline tartrate;b. trospium chloride;c. a polymer matrix comprising at least one cellulose derivative and at least one polyvinylpyrrolidone; andd. d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS);wherein the composition has a pH of from about 5.0 to about 5.7, and wherein at least a portion of the xanomeline and trospium chloride are absorbed transmucosally.

18. The method of claim 17, wherein the transmucosal absorption bypasses first-pass hepatic metabolism.

19. The method of claim 17, wherein the method provides reduced gastrointestinal side effects compared to oral capsule administration of xanomeline and trospium.

20. A buccal film composition for enhanced transmucosal delivery of trospium chloride, the composition comprising:a. xanomeline tartrate in an amount effective to enhance permeation of trospium chloride across buccal mucosa;b. trospium chloride;c. at least one film-forming polymer; andd. a permeation enhancer comprising d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS);wherein co-formulation of the trospium chloride with xanomeline tartrate provides enhanced transmucosal permeation of the trospium chloride compared to a film composition containing trospium chloride without xanomeline tartrate, and wherein the composition has a pH of from about 5.0 to about 5.7.

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