Pharmaceutical compositions having enhanced stability profiles

Abstract

The soluble drug delivery films may exhibit enhanced stability.

Description

[Technical field]

[0001] (Priority Claim) This application claims priority to U.S. Provisional Patent Application No. 63 / 271,001, filed October 22, 2021, which is incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION The present invention relates to pharmaceutical methods and compositions that are particularly suitable for oral delivery. The film product may include a film-forming polymer, an active ingredient, and a desiccant. The composition may also include excipients, including one or more of a stabilizer, an antioxidant, a permeation enhancer, or an adrenergic receptor interactor. Background of the invention

[0003] (background) Although active pharmaceutical ingredients can be administered in various forms, film delivery can provide products with superior organoleptic properties and improve the physical and chemical stability of alternative dosage forms. However, this delivery method can be associated with slow drug release and permeability, film brittleness and poor stability profiles. There is a need for improved formulations that deliver effective amounts of active pharmaceutical ingredients while exhibiting improved dissolution rates and improved stability. Summary of the Invention

[0004] (Summary of the invention) In general, pharmaceutical compositions with enhanced dissolution may include an active ingredient, a film-forming polymer, including a starch ether, and a desiccant.

[0005] In certain embodiments, the starch ether may be a hydroxyalkyl ether of starch.

[0006] In certain embodiments, the hydroxyalkyl ether of starch can be a hydroxypropyl ether of starch.

[0007] In some embodiments, the film-forming polymer may be pea starch.

[0008] In some embodiments, the desiccant may include silica. In some embodiments, the desiccant may include fumed silica or mesoporous silica. In some embodiments, the film-forming polymer and the desiccant may have a ratio of 10:1 to 2:1 by weight.

[0009] In some embodiments, the active ingredient may comprise from 0.1% to 80% by weight of the composition.

[0010] In some embodiments, the pharmaceutical composition may include a stabilizer. In some embodiments, the stabilizer may include a chelating agent. In some embodiments, the pharmaceutical composition further includes an antioxidant. In some embodiments, the stabilizer may include an ion exchange resin. The resin may be a cation exchange resin.

[0011] In some embodiments, the pharmaceutical composition may include a permeation enhancer. In some embodiments, the pharmaceutical composition that includes a permeation enhancer may include an adrenergic receptor interactor.

[0012] In some embodiments, the permeation enhancer may include eugenol.

[0013] In certain embodiments, the pharmaceutical composition may include a processing solvent. The processing solvent may be an organic processing solvent.

[0014] In certain embodiments, the process solvent may include one or more of ethanol, acetone, acetonitrile, t-butanol, methanol, 1-propanol, isopropanol, tetrahydrofuran, acetaldehyde, dioxane, or methyl isocyanide.

[0015] In some embodiments, the processing solvent may comprise at least 20% ethanol. In some embodiments, the processing solvent may comprise at least 30% ethanol. In some embodiments, the processing solvent may comprise at least 40% ethanol. In some embodiments, the processing solvent may comprise at least 50% ethanol.

[0016] In some embodiments, the pharmaceutical composition may include a plasticizer. In some embodiments, the plasticizer may include a polyol. In some embodiments, the plasticizer may include pentatol. In some embodiments, the plasticizer may include sucralose; sugar alcohol such as sorbitol, mannitol, or xylitol.

[0017] In certain embodiments, the pharmaceutical composition may include a viscosity enhancing agent.

[0018] In some embodiments, the viscosity enhancing agent may include gelatin, xantham gum, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, microcrystalline cellulose, chitosan, natural gum, polyvinyl, cross-linked polymers, or other synthetic polymers. In some embodiments, the pharmaceutical composition may include a surfactant. In some embodiments, the surfactant may include Labrasol®. In some embodiments, the surfactant may include GMO.

[0019] In some embodiments, the pharmaceutical composition may include an esterase inhibitor. In some embodiments, the esterase inhibitor may include NaF. In some embodiments, the pharmaceutical composition may include a sweetener. In some embodiments, the sweetener may include sucralose. In some embodiments, the sweetener may include Magnasweet.

[0020] In certain embodiments, the pharmaceutical composition may include a flavoring agent.

[0021] In certain embodiments, the pharmaceutical composition may include a colorant.

[0022] In general, a pharmaceutical composition for delivering a pharmaceutical composition with increased stability may include an active ingredient, a pH adjusting agent comprising HCl, and a plasticizer comprising a non-reducing sugar.

[0023] In some embodiments, the non-reducing sugar can be a polyol. In some embodiments, the non-reducing sugar can be pentitol. In some embodiments, the non-reducing sugar can be xylitol.

[0024] In certain embodiments, the pH adjusting agent can produce a formulation pH of 2.5 to 3.5 and the plasticizer has a ratio of 1:20 to 1:8 by weight.

[0025] In general, the pharmaceutical film product may include an active ingredient, a stabilizer, a plasticizer, and the film product may have a small volume disintegration value in the range of about 1 to about 240 seconds, as measured according to a small volume disintegration assay.

[0026] In some embodiments, the film product may have a small volume collapse time ranging from about 2 to about 30 seconds. In some embodiments, the film product may have a small volume collapse time ranging from about 2 to about 10 seconds.

[0027] Generally, methods of producing a pharmaceutical composition with enhanced stability can include forming a composition having a dissolution profile in the range of about 1 to about 60 seconds as measured according to a small volume disintegration assay.

[0028] In some embodiments, the film product may have a partial immersion dissolution value in the range of about 2 to about 30 seconds as measured according to the small volume disintegration assay. In some embodiments, the film product may have a partial immersion dissolution value in the range of about 2 to about 10 seconds as measured according to the small volume disintegration assay.

[0029] In general, a method of producing a pharmaceutical formulation with an enhanced dissolution rate may include providing an active ingredient incorporating a desiccant comprising mesoporous silica and applying a film-forming polymer comprising pea starch.

[0030] In general, methods of producing pharmaceutical formulations with increased stability may include providing the active ingredient with a pH adjusting agent that results in a formulation pH of 2.5 to 3.5 and incorporating a plasticizer, including xylitol.

[0031] In general, a method of stabilizing epinephrine for transmucosal delivery can include administering a pharmaceutical composition comprising an active ingredient, a pH adjusting agent that provides a formulation pH of 2.5 to 3.5, a desiccant comprising mesoporous silica, and a plasticizer comprising xylitol; and achieving an effective plasma concentration of the pharma- ceutical active form of epinephrine in less than one hour. In certain embodiments, the pH adjusting agent can be HCl.

[0032] In some embodiments, the active ingredient may include a prodrug of epinephrine.

[0033] In some embodiments, the composition can include a degradant. The degradant can be a hydrolysis product of a prodrug of epinephrine.

[0034] In some embodiments, the degradation product may be part of the delivered active ingredient that is delivered to a subject.

[0035] In certain embodiments, degradant levels may be present at about 3.5% or greater at the end of six months.

[0036] In certain embodiments, degradant levels may be present at about 2.3% or greater at the end of 12 months.

[0037] In certain embodiments, degradant levels may be present at about 2.4% or greater at the end of 24 months.

[0038] In one embodiment, the degradant is about 2.2×10 -3 % decomposition rate.

[0039] In certain embodiments, the degradants may maintain a shelf life for at least 3 years of storage at 25°C.

[0040] In certain embodiments, the degradants may maintain a shelf life for at least 4 years of storage at 25°C.

[0041] In certain embodiments, the degradants may maintain a shelf life for at least 5 years of storage at 25°C.

[0042] In certain embodiments, the rate of degradant growth may remain substantially unchanged for at least three months.

[0043] In certain embodiments, the rate of degradant growth may remain substantially unchanged for at least five months.

[0044] Other aspects, embodiments, and features will become apparent from the following description, the drawings, and the claims. [Brief description of the drawings]

[0045] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] The disintegration data for DSF and DESF formulations are depicted.

[0046] [Diagram 2] The average percent DSF and DESF transmitted through the film are shown.

[0047] [Diagram 3] Figures 3A and 3B show the hydrolysis data across formulations.

[0048] [Figure 4] 4A and 4B show the drug release of dipivefrin.

[0049] [Diagram 5] 5A and 5B show tissue penetration as a function of SVD and PID.

[0050] [Figure 6] 4 shows the effect of pH on formulation stability.

[0051] [Figure 7] Ex vivo tissue penetration data is shown.

[0052] [Figure 8] 1 shows epinephrine concentrations over time following administration of the formulations.

[0053] [Figure 9] Median epinephrine Tmax from formulations is shown.

[0054] [Figure 10] The mean change in systolic blood pressure is shown.

[0055] [Figure 11] 1 shows the hydrolysis product reaction rate as a function of temperature. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] Detailed Description of the Invention In general, the soluble drug delivery film may exhibit increased stability. Stability of 24 months or more has been achieved according to the present formulations and methods. For example, the drug may include a prodrug of an active agent, such as an ester of epinephrine, an acidifier, a solvent system, a drying agent, an antioxidant, a polymer system, and an ion exchange resin. Exemplary compositions include epinephrine soluble film, dipivefrin soluble film (DSF), and diisobutyryl epinephrine soluble film (DESF). Administering a medicamentously active ingredient may include administering a prodrug. Transdermal or transmucosal delivery of a drug or medicament may require that the prodrug, drug, active agent, or medicament, alone or in combination, partially or completely penetrate or otherwise cross at least one biological membrane in an effective and efficient manner. For example, a method of treating a medical condition in a human subject can include administering a composition comprising a prodrug and a permeation enhancer from a matrix, the permeation enhancer facilitating the permeation of the prodrug through mucosal tissue to achieve an effective plasma concentration of the medicamentously active form of the prodrug in the human subject in less than one hour. An acidifier can be selected to provide an optimal pH and promote formulation stability without leading to mucosal irritation. The solvent system used to prepare the film can be optimized to reduce the overall water loading of the liquid intermediate and the residual moisture in the film. Desiccants and antioxidants can be provided to reduce moisture damage and oxidative damage. The polymer system can be designed to minimize polymer-induced oxidative degradants and reduce disintegration time. The formulations herein can reduce the thickness of the film and film coating by up to 50%, thereby reducing disintegration time and hastening drug release. Resins can be incorporated to increase stability, for example, by selectively sequestering free sodium.

[0057] The amount of medicament active used will depend on the desired therapeutic strength and the composition of the layer, but preferably the medicament comprises from about 0.001% to about 99%, more preferably from about 0.003 to about 75%, and most preferably from about 0.005% to about 50% by weight of the composition, including greater than 0.005%, greater than 0.05%, greater than 0.5%, greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 30%, about 50%, greater than 50%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.05%, or less than 0.005%. The amount of other ingredients may vary depending on the drug or other ingredients, but typically these ingredients comprise 90% or less, 50% or less, preferably 30% or less, and most preferably 15% or less of the total weight of the composition.

[0058] The thickness of the film may vary depending on the thickness of each layer and the number of layers. As mentioned above, both the thickness and the amount of layers may be adjusted to change the erosion kinetics. Preferably, when the composition has only two layers, the thickness is in the range of 0.005 mm to 2 mm, preferably 0.01 to 1 mm, more preferably 0.1 to 0.5 mm, including greater than 0.1 mm, greater than 0.2 mm, about 0.5 mm, greater than 0.5 mm, less than 0.5 mm, less than 0.2 mm, or less than 0.1 mm. The thickness of each layer may vary from 10 to 90% of the total thickness of the layered composition, but preferably varies from 30 to 60%, including greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 70%, greater than 90%, about 90%, less than 90%, less than 70%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%. Thus, the preferred thickness of each layer may vary from 0.01 mm to 0.9 mm, or from 0.03 mm to 0.5 mm.

[0059] As one skilled in the art will appreciate, when systemic delivery, such as transmucosal or transdermal delivery, is desired, the treatment site may include any area where the film is capable of delivering and / or maintaining a desired level of medication in the blood, lymph, or other bodily fluids. Typically, such treatment sites include the mucosal tissues of the mouth, esophagus, ear, eye, anus, nose, and vagina, as well as the skin. When skin is utilized as the treatment site, relatively large areas of skin, such as the upper arms or thighs, where movement does not interfere with the attachment of the film, are typically preferred.

[0060] While the pharmaceutical composition can be applied to mucosal tissues, which are naturally moist tissues, it can also be used on other surfaces, such as skin or wounds. The pharmaceutical film can be applied to skin when the skin is moistened prior to application by aqueous-based fluids, such as water, saliva, wound drainage, or sweat. The film can be applied to the skin until it is eroded due to contact with water, for example, by washing, showering, bathing, or washing.

[0061] (Film-forming polymers) The film-forming polymer or polymers may be water-soluble, water-swellable, water-miscible, water-dispersible, or a combination of any one or more of water-soluble, water-swellable, water-miscible, or water-dispersible polymers. The film-forming polymer may include cellulose or a cellulose derivative or starch. It may also include a hydroxyalky ether of starch, or a hydroalkyl ether of starch, or a hydroxypropyl ether of starch. The starch may be pea starch. An example of a film-forming polymer may include PVP K90. It may also include Lycoat® RS. The film-forming polymer may be a water-soluble polymer, including, but not limited to, polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), carboxymethyl cellulose (CMC), polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymers, carboxyvinyl copolymers, starch, gelatin, and combinations thereof. Specific examples of useful water-miscible or water-dispersible polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate ("HPMCAS"), or combinations thereof.

[0062] Polymer systems can be constructed to minimize polymer-induced oxidative degradation and decrease disintegration time. Decreasing the thickness of the film coating can decrease disintegration time and therefore hasten drug release.

[0063] The film-forming polymer or combination of film-forming polymers may be about 5% to about 50% by weight of the pharmaceutical composition. For example, a single film-forming polymer may be about 5% to about 50% w / w of the pharmaceutical composition. A second or additional film-forming polymer may be about 5% to about 50% w / w of the pharmaceutical composition by weight. In some embodiments, a combination of two or more film-forming polymers may be about 5% to about 50% w / w of the pharmaceutical composition. For example, a film-forming polymer or combination of film-forming polymers may be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% w / w of the pharmaceutical composition.

[0064] Additives may be included in the film. Examples of classes of additives include preservatives, antimicrobials, excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, bulking agents, sweeteners, flavorings, flavorings, release modifiers, adjuvants, plasticizers, flow accelerators, release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, anti-adhesives, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, anti-blocking agents, antistatic agents, and mixtures thereof. These additives may be added together with the pharmacoactive ingredient. As used herein, the term "stabilizer" refers to an excipient that can prevent aggregation or other physical and chemical degradation of the pharmacoactive ingredient, another excipient, or combinations thereof.

[0065] Stabilization of the composition can help protect the components of the composition from several degradation pathways, including, for example, transesterification and hydrolysis. The compositions and methods described herein can address any of these pathways or a combination of pathways by blocking these mechanisms. For example, a prodrug can form a degradation product by hydrolysis or transesterification to form an intermediate prodrug, a variant or derivative of the first prodrug, or an active pharmaceutical ingredient.

[0066] Prodrugs are compounds of formula (I), [ka] R 1a , R 1b , R 2 and R 3 Each of may independently be H, C1-C16 acyl, alkylaminocarbonyl, alkyloxycarbonyl, phenacyl, sulfate, or phosphate, or R 1a and R 1b Both are R 1a and R 2 Both are R 1a and R 3 Both are R 1b and R 2 Both are R 1b and R 3 Both are or R 2 and R 3 together form a cyclic structure containing a dicarbonyl, disulfate, or diphosphate moiety, with the proviso that R 1a , R 1b , R 2 and R 3 provided that one of is not H) or a pharma- ceutically acceptable salt thereof.

[0067] In one embodiment, R 2 and R 3 is H, and each R 1a and R 1b may independently be ethanoyl, n-propanoyl, isopropanoyl, n-butanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl, n-pentanoyl, isopentanoyl, sec-pentanoyl, tert-pentanoyl, or neopentanoyl.

[0068] For example, a diester of epinephrine may undergo hydrolysis to a mono-ester or non-ester form, or a combination thereof. In another example, a triester may undergo hydrolysis to a di-ester, mono-ester, or non-ester form, or a combination thereof. Transesterification may result in a mixed ester prodrug.

[0069] Useful additives are, for example, vegetable proteins such as gelatin, sunflower protein, soy protein, cottonseed protein, peanut protein, grapeseed protein, whey protein, whey protein isolate, blood proteins, egg proteins, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragacanth), synthetic gums, lecithin, pectin, locust bean, starch, water-soluble derivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses such as cellulose esters and hydroxyalkylcellulose esters, for example, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC), and the like; carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such as carboxymethylcellulose and the alkali metal salts thereof; These may include water-soluble synthetic polymers, such as polyacrylic acid and polyacrylic acid esters, polymethacrylic acid and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVA / vinyl acetate copolymers, and polycrotonic acid; also suitable are phthalated gelatin, succinic gelatin, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates having tertiary or quaternary amino groups, such as diethylaminoethyl groups, which may be quaternized if desired; or other similar polymers.

[0070] The additional components may range from about 80% based on the weight of the total composition components, including greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, about 80%, greater than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, about 3%, or less than 1%, preferably in the range of about 0.005%-50% and more preferably 1%-20%. Other additives may include antiblocking agents, flow agents, and opacifiers such as oxides of magnesium aluminum, silicon, titanium, and the like, desirably in a concentration range of from about 0.005% to about 15% by weight, and desirably from about 0.02% to about 2%, including greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, greater than 1.5%, greater than 2%, greater than 4%, about 5%, greater than 5%, less than 4%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.02%, based on the weight of the total film components. In certain embodiments, the composition comprises a polyalkylene oxide, such as polyethylene glycol, polypropylene glycol, polyethylene-propylene glycol, or an organic solvent having a low molecular weight, added at a concentration ranging from about 0.1% to about 40%, including greater than 0.5%, greater than 1%, greater than 1.5%, greater than 2%, greater than 4%, greater than 5%, greater than 10%, greater than 15%, about 20%, greater than 20%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 2%, less than 1%, and less than 0.5%, by weight of the composition. Plasticizers may be included, which may include, for example, glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbates, cetyl alcohol, propylene glycol, sugar alcohols, erythritol, threitol, xylitol, mannitol, sorbitol, galactitol, fucitol, isomalt, maltitol, lactitol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, plant extracts, fatty acid esters, fatty acids, oils, etc. Compounds that improve the textural properties of the film material, such as animal or vegetable fats, may also be added, preferably in their hydrogenated form. The composition may also include compounds that improve the textural properties of the product.Other ingredients may include binders that contribute to the ease of formation and overall quality of the film, non-limiting examples of binders include starch, maltodextrin, natural gums, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxoazolidone, or polyvinyl alcohol.

[0071] Further possible additives include solubility enhancers, such as substances that form inclusion compounds with active ingredients. Such substances may be useful for improving the properties of very insoluble and / or unstable active ingredients. Generally, these substances are doughnut-shaped molecules with a hydrophobic interior cavity and a hydrophilic exterior. Insoluble and / or unstable medicament active ingredients fit into the hydrophobic cavity, which creates an inclusion complex that is soluble in water. Thus, the formation of an inclusion complex allows the very insoluble and / or unstable medicament active ingredient to dissolve in water. A particularly desirable example of such an agent is cyclodextrin, which is a cyclic carbohydrate derived from starch. However, other similar substances are considered to fall within the scope of the present invention.

[0072] Surface tension reducing agents, antifoaming agents and / or defoaming agents may also be used with the film. These agents aid in the removal of air, such as trapped air, from the film-forming composition. Such trapped air may lead to an uneven film. Simethicone is one particularly useful antifoaming agent and / or defoaming agent. However, the invention is not so limited and other suitable antifoaming agents and / or defoaming agents may be used. Simethicone and related agents may be utilized for densification purposes. More specifically, such agents may facilitate the removal of voids, air, moisture, and similar undesirable components, thereby providing a denser and therefore more uniform film. Agents or ingredients that perform this function are referred to as densification agents or densifying agents. As mentioned above, trapped air or undesirable components may lead to an uneven film. Any other optional components described in the above-referenced commonly assigned US Pat. Nos. 7,425,292 and 8,765,167 may also be included in the films described herein.

[0073] The pharmaceutical films described herein can be formed by any desired process. Suitable processes are described in U.S. Patent Nos. 8,652,378, 7,425,292 and 7,357,891, which are incorporated herein by reference. In one embodiment, a film dosage composition is formed by first preparing a wet composition, which includes a polymeric carrier matrix and a therapeutically effective amount of a medicament active ingredient. The wet composition is cast into a film and then sufficiently dried to form a self-supporting film composition. The wet composition is cast into individual doses, or it is cast into a sheet, which is then cut into individual doses.

[0074] The pharmaceutical composition can be applied to a mucosal surface, such as the mouth, vagina, organs, or other types of mucosal surfaces. The composition carries the drug and upon application and application to the mucosal surface, provides a protective layer and delivers the drug to the treatment site, surrounding tissues, and other body fluids. Given the controlled erosion in body fluids, such as aqueous solutions or saliva, and the slow, natural erosion of the film during or after delivery, the composition provides a suitable residence time for effective drug delivery at the treatment site.

[0075] In one embodiment, the pharmaceutical composition comprises: (a) an aggregation inhibitor; (b) a charge-modifying agent; (c) a pH control agent; (d) a degradative enzyme inhibitor; (e) a mucolytic or mucus-clearing agent; (f) a ciliostatic agent; agent); (g) a membrane permeation enhancer 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) an NO donor compound; (vi) a long chain amphipathic molecule; (vii) a small hydrophobic permeation enhancer; (viii) a sodium or salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or a β-cyclodextrin derivative; (xi) a medium chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) an N-acetyl amino acid or a salt thereof; (xv) an enzyme degradable to selected membrane components; (ix) an inhibitor of fatty acid synthesis; (x) a cholestyryl group. Inhibitors of terol synthesis; and (xi) any combination of membrane permeation enhancers listed in (i)-(x); (h) modulators of epithelial junction physiology; (i) vasodilators; (j) selective transport enhancers; and (k) suitable non-toxic, non-ionic alkyl glycosides having hydrophobic alkyl groups attached by alpha-linkages to hydrophilic sugars in combination with a mucosal delivery enhancer selected from stabilizing delivery vehicles, carriers, mucoadhesives, carriers or complexing species with which the compound is effectively formulated, associated, contained, encapsulated or bound to provide stabilization of the compound for enhanced mucosal delivery, where formulation of the compound with the mucosal delivery enhancer provides increased bioavailability of the compound in the plasma of a subject. Permeation enhancers are described in J. Nicolazzo et al., J. of Controlled Disease, 105(2005)1-15, incorporated herein by reference.

[0076] (Erosive dynamics and erosion time) 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 can be adjusted, for example, by mixing together components with different solubility properties or chemically different polymers such as hydroxyethylcellulose and hydroxypropylcellulose; by using different molecular weight grades of the same polymer, such as mixing low molecular weight hydroxyethylcellulose with medium molecular weight hydroxyethylcellulose; by using excipients or plasticizers (including essentially insoluble components) with different lipophilicity values ​​or water solubility properties; by using water-soluble organic and inorganic salts; by using crosslinking agents such as glyoxal for partial crosslinking with polymers such as hydroxyethylcellulose; or by post-treatment irradiation or curing, which can change the physical state of the film, including the crystallinity or phase transition of the film, once obtained. These strategies can be utilized alone or in combination to adjust the erosion kinetics of the film. Upon application, the pharmaceutical composition film adheres to the mucosal surface and remains in place. Water absorption softens the composition, thereby gradually reducing the foreign body sensation. As the composition sits on the mucosal surface, drug delivery occurs. The residence time can be adjusted over a wide range depending on the desired timing of delivery of the selected drug and the desired lifespan of the carrier. In general, however, the residence time is adjusted between about a few seconds and about several days. Preferably, the residence time for most drugs is adjusted between about 5 seconds and about 24 hours. More preferably, the residence time is adjusted between about 5 seconds and about 30 minutes. In addition to providing drug delivery, once the composition is attached to the mucosal surface, it also provides protection for the treatment site and acts as an erodible dressing. The lipophilic agent can be designed to slow erosion and reduce disintegration and dissolution.

[0077] It is also possible to adjust the erosion kinetics of the composition by adding highly water-soluble excipients, such as water-soluble organic and inorganic salts, that are sensitive to enzymes such as amylase. Suitable excipients may include sodium and potassium salts of chlorides, carbonates, bicarbonates, citrates, trifluoroacetates, benzoates, phosphates, fluorides, sulfates, or tartrates. The amount added may vary depending on the extent to which the erosion kinetics is to be modified, as well as the amount and nature of other ingredients in the composition.

[0078] In some embodiments, the film dose may be capable of dispersing and dissolving at a rate of about 1 to about 30 minutes, such as about 1 to about 20 minutes, or greater than 1 minute, greater than 5 minutes, greater than 7 minutes, greater than 10 minutes, greater than 12 minutes, greater than 15 minutes, greater than 20 minutes, greater than 30 minutes, about 30 minutes, or less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, or less than 1 minute. The sublingual dispersion rate may be shorter than the buccal dispersion rate.

[0079] For example, in some embodiments, the film may contain polyethylene oxide, alone or in combination with a second polymer component. The second polymer may be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer, or any combination thereof. Suitable water-soluble polymers include, but are not limited to, any of those provided above. In some embodiments, the water-soluble polymer comprises a hydrophilic cellulosic polymer, such as hydroxypropyl cellulose and / or hydroxypropyl methylcellulose. In some embodiments, one or more water-swellable, water-insoluble, and / or biodegradable polymers may also be included in the polyethylene oxide-based film. Any of the water-swellable, water-insoluble, or biodegradable polymers provided above may be utilized. The second polymer component may be utilized in an amount of about 0% to about 80% by weight of the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight, including greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, and greater than 70%, about 70%, 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% by weight.

[0080] (Small Volume Disintegration (SVD)) Dissolution testing is a central performance test in pharmaceutical development and quality control. Dissolution testing has been increasingly developed to establish a relationship with in vivo performance or with manufacturing critical quality attributes (CQAs) within the scope of quality by design (QbD). The overall goal is to better control product performance within the product life cycle. To this end, the use of classical USP dissolution working conditions using 1 liter vessels with baskets (USP1, respectively) and paddles (USP2, respectively) is well established and is used as the first choice for the development of new dissolution methods. However, limitations arising from the amount of available material, analytical sensitivity, discrimination or lack of biorelevance may justify the use of non-commendatory methods. Especially in early development, during screening of drug candidates, formulations are often developed for testing in animals, and dissolution should ideally be performed using a medium that mimics the gastrointestinal environment as well as in volumes consistent with animal physiology. Other cases where classical methods are not suitable are for low dose drugs or when analytical methods are not sensitive enough to precisely detect the amount of dissolved drug due to low concentrations of drug in the formulation. To overcome these problems, the concept of small volume disintegration has recently arisen, which offers various advantages in terms of substances and material consumption due to the possibility of using smaller sample sizes and lower volumes of media, and can act as a valuable tool for dosage form screening or formulation selection.

[0081] The disintegration / retention time of a dose administered sublingually is an important design factor for the dose to remain within the sublingual space. <701> is utilized to determine disintegration time, but results are obtained for dose disintegration following exposure to mechanically agitated aqueous media, with the understanding that the end point is the formation of an "impalpable mass." To better understand and predict in vivo dose disintegration, a volume-limited, non-agitated method (referred to as small volume disintegration or "SVD") can be applied to create a more discriminatory disintegration method that emphasizes solvation of the dose from a single side and edges. In this case, SVD utilizes the dose applied to the surface of a volume of aqueous media within a Petri dish.

[0082] The SVD time is described as the time (in seconds) it takes for the film to disperse when it comes into contact with water or saliva. A film strip is immersed in a Petri dish containing 20 mL water or saliva. The film absorbs water and begins to swell. After a period of time, the film bursts and disperses. The time it takes for the film to disperse or disintegrate is noted as the small volume disintegration time.

[0083] For example, the volume may be 20 mL, medium: sterile water or simulated saliva. SVD can also highlight the visualization and time to dose expansion, burst (considered the end point), and disintegration. SVD time has been used as a variable in the product design driven by DOE for novel and generic film products as well as in predictive models of in vivo film disintegration time.

[0084] (fatty acid) Fatty acids can be used as inactive ingredients in drug preparations or drug vehicles. Fatty acids can also be used as formulation components due to their specific functional effects and their biocompatible properties. Fatty acids, both free lipids and part of complex lipids, are essential components of the main metabolic fuel (storage and transport energy), all membranes and gene regulators. For a review, see Rustan AC and Drevon, CA, Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences (2005), incorporated herein by reference. There are two families of essential fatty acids metabolized in the human body: ω-3 and ω-6 polyunsaturated fatty acids (PUFAs). When the first double bond is found between the third and fourth carbon atoms from the ω carbon, they are referred to as ω-3 fatty acids. When the first double bond is found between the sixth and seventh carbon atoms, they are referred to as ω-6 fatty acids. PUFAs are further metabolized in the body by the addition of carbon atoms and desaturation (removal of hydrogen). Linoleic acid is an omega-6 fatty acid and is metabolized to gamma-linolenic acid, dihomo-gamma-linolinic acid, arachidonic acid, adrenic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, and docosapentaenoic acid. Alpha-linolenic acid is an omega-3 fatty acid and is metabolized to octadecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and docosahexaenoic acid (DHA).

[0085] Fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid contain sodium + K +It has been reported that fatty acids induced relaxation and hyperpolarization of porcine coronary artery smooth muscle cells through a mechanism involving activation of the -APTase pump, and that the greater the degree of cis-desaturation, the more potent the fatty acid was. See Pomposiello, SI et al., Hypertension 31:615-20 (1998), incorporated herein by reference. Interestingly, the pulmonary vascular response to arachidonic acid, a metabolite of linoleic acid, can be either vasoconstrictive or vasodilatory, depending on the dose, animal species, mode of arachidonic acid administration, and tone of the pulmonary circulation. For example, it has been reported that arachidonic acid causes cyclooxygenase-dependent and -independent pulmonary vasodilation. See Feddersen, CO et al., J. Appl. Physiol. 68(5):1799-808 (1990); and Spannhake, EW et al., J. Appl. Physiol. 44:397-495 (1978); and Wicks, TC et al., Circ. Res. 38:167-71 (1976), each of which is incorporated herein by reference.

[0086] Many studies have reported the effects of EPA and DHA on vascular reactivity after administration in ingestible forms. Some studies have found that EPA-DHA or EPA alone inhibited the vasoconstrictor action of norepinephrine or enhanced the vasodilator response to acetylcholine in the forearm microcirculation. See Chin, JPF et al., Hypertension 21:22-8 (1993), and Tagawa, H. et al., J Cardiovasc Pharmacol 33:633-40 (1999), each of which is incorporated herein by reference. Another study found that both EPA and DHA tended to increase systemic arterial compliance and reduce pulse pressure and total vascular resistance. See Nestel, P. et al., Am J. Clin. Nutr. 76:326-30 (2002), incorporated herein by reference. Meanwhile, a study found that DHA, but not EPA, enhanced vasodilatory mechanisms and attenuated constrictor responses in the forearm microcirculation of hyperlipidemic overweight men. See Mori, TA et al., Circulation 102:1264-69 (2000), incorporated herein by reference. Another study found the vasodilatory effect of DHA on rhythmic contractions of isolated human coronary arteries in vitro. See Wu, K.-T. et al., Chinese J. Physiol. 50(4):164-70 (2007), incorporated herein by reference.

[0087] (Adrenergic receptor interactor) Adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of catecholamines, particularly norepinephrine (noradrenaline) and epinephrine (adrenaline). Epinephrine (adrenaline) interacts with both α- and β-adrenoreceptors, causing vasoconstriction and vasodilation, respectively. α-receptors are less sensitive to epinephrine, but peripheral α1 receptors are more numerous than β-adrenoreceptors, so that when activated, α-receptors abolish vasodilation mediated by β-adrenoreceptors. As a result, high levels of circulating epinephrine cause vasoconstriction. At lower levels of circulating epinephrine, β-adrenoreceptor stimulation dominates, resulting in vasodilation and subsequent reduction in peripheral vascular resistance. α1-adrenoreceptors are known for smooth muscle contraction, mydriasis, vasoconstriction in the skin, mucous membranes and abdominal viscera, and sphincter contraction in the gastrointestinal (GI) tract and bladder. q It is a member of the protein-coupled receptor superfamily. Upon activation, it binds heterotrimeric G proteins, G q Activates phospholipase C (PLC). Its mechanism of action involves interaction with calcium channels, altering intracellular calcium content. For review, see Smith RS et al., Journal of Neurophysiology 102(2):1103-14 (2009), incorporated herein by reference. Many cells have these receptors.

[0088] Alpha 1-adrenergic receptors may be the main receptors for fatty acids. For example, saw palmetto extract (SPE), which is widely used to treat benign prostatic hyperplasia (BPH), has been reported to bind to alpha 1-adrenergic, muscarinic, and 1,4-dihydropyridine (1,4-DHP) calcium channel agonist receptors. See Abe M. et al., Biol. Pharm. Bull. 32(4)646-650 (2009), and Suzuki M. et al., Acta Pharmacologica Sinica 30:271-81 (2009), each of which is incorporated herein by reference. SPE contains a variety of fatty acids, including lauric acid, oleic acid, myristic acid, palmitic acid, and linoleic acid. Lauric acid and oleic acid can bind noncompetitively to α1-adrenergic, muscarinic, and 1,4-DHP calcium channel agonist receptors.

[0089] In some embodiments, the permeation enhancer can be an adrenergic receptor interactor. An adrenergic receptor interactor refers to a compound or substance that modifies and / or otherwise changes the action of an adrenergic receptor. For example, an adrenergic receptor interactor can prevent the stimulation of the receptor by increasing or decreasing their binding ability. Such interactors can be provided in short-acting or long-acting forms. Some short-acting interactors can act quickly, but their action lasts only a few hours. Some long-acting interactors can take a long time to act, but their action can last longer. The interactor can be selected and / or designed based on, for example, one or more of the desired delivery and dosage, active pharmaceutical ingredient, permeation modifier, permeation enhancer, matrix, and condition to be treated. The adrenergic receptor interactor can be an adrenergic receptor blocker. The adrenoceptor interactor may be a terpene (e.g., a volatile unsaturated hydrocarbon derived from an isoprene unit and found in plant essential oils), or a C3-C22 alcohol or acid, preferably a C7-C18 alcohol or acid. In some embodiments, the adrenoceptor interactor may include farnesol, linoleic acid, arachidonic acid, docosahexanoic acid, eicosapentanoic acid, and / or docosapentanoic acid. The acid may be a carboxylic acid, a phosphoric acid, a sulfuric acid, a hydroxamic acid, or a derivative thereof. The derivative may be an ester or an amide. For example, the adrenoceptor interactor may be a fatty acid or a fatty alcohol.

[0090] The C3-C22 alcohol or acid may be an alcohol or acid having a linear C3-C22 hydrocarbon chain, for example, a C3-C22 hydrocarbon chain, optionally including at least one double bond, at least one triple bond, or at least one double bond and one triple bond; 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, hydroxyl, halo, amino, nitro, cyano, C 3-5Cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4 Alkylcarbonyloxy, C 1-4 Alkyloxycarbonyl, C 1-4 Optionally substituted with alkylcarbonyl, or formyl; and optionally further substituted with -O-, -N(R a )-, -N(R a )-C(O)-O-, -OC(O)-N(R a )-, -N(R a )-C(O)-N(R b )- or -OC(O)-O- is sandwiched between them. a and R b Each of is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.

[0091] Fatty acids with higher degrees of unsaturation are effective candidates for enhancing drug permeation. Unsaturated fatty acids showed higher enhancement than saturated fatty acids, and enhancement increased with the number of double bonds. See A. Mittal et al., "Status of Fatty Acids as Skin Penetration Enhancers - A Review," Current Drug Delivery, 2009, 6, pp. 274-279, incorporated herein by reference. The position of the double bond also affects the enhancing activity of fatty acids. The difference in the physicochemical properties of fatty acids due to the difference in the position of the double bond most likely determines the efficacy of these compounds as skin penetration enhancers. As the position of the double bond is shifted toward the hydrophilic end, the skin distribution increases. It has also been reported that fatty acids with double bonds in even positions act more rapidly to disrupt the structure of both the stratum corneum and dermis than fatty acids with double bonds in odd positions. Cis-unsaturation within the chain may tend to increase activity.

[0092] The adrenergic receptor interactor may be a terpene. The antihypertensive activity of terpenes in essential oils has been reported. See Menezes IA et al., Z. Naturforsch. 65c:652-66 (2010), incorporated herein by reference. In some embodiments, the permeation enhancer may be a sesquiterpene. Sesquiterpenes are composed of three isoprene units and have the empirical formula C 15 H 24 Sesquiterpenes are a class of terpenes having the general formula: ##STR1## Like monoterpenes, sesquiterpenes can be acyclic or contain rings, and include many unique combinations. Biochemical modifications such as oxidation or rearrangement produce related sesquiterpenoids.

[0093] The adrenergic receptor interactor may be an unsaturated fatty acid such as linoleic acid. In some embodiments, the permeation enhancer may be farnesol. Farnesol is a 15-carbon organic compound that is an acyclic sesquiterpene alcohol, which is the natural dephosphorylated form of farnesyl pyrophosphate. Under standard conditions, it is a colorless liquid. It is hydrophobic and therefore insoluble in water, but miscible with oils. Farnesol can be extracted from the oils of plants such as citronella, neroli, cyclamen, and moonflower. It is an intermediate step in the biosynthesis of cholesterol from mevalonic acid in vertebrates. It has a delicate floral or weak citrus-lime scent and is used in perfumes and fragrances. It has been reported that farnesol selectively kills acute myeloid leukemia blasts and leukemia cell lines rather than primary hematopoietic cells. See Rioja A. et al., FEBS Lett 467(2-3):291-5 (2000), incorporated herein by reference. Vasoactive properties of farnesyl analogs have been reported. See Roullet, J.-B. et al., J. Clin. Invest., 1996, 97:2384-2390, incorporated herein by reference. Both farnesol and N-acetyl-S-trans, trans-farnesyl-L-cysteine ​​(AFC), a synthetic mimetic of the carboxyl terminus of farnesylated proteins, inhibited vasoconstriction in rat aortic rings.

[0094] In some embodiments, the interactor can be an aporphine alkaloid, for example, the interactor can be dicentrine.

[0095] Generally, the interacting substance can also be a vasodilator or a therapeutic vasodilator. A vasodilator is a drug that opens or widens blood vessels. Vasodilators are usually used to treat hypertension, heart failure, and angina, but can also be used to treat other conditions, including glaucoma. Some vasodilators (arterial dilators) that act primarily on resistance vessels are used for hypertension, heart failure, and angina; however, reflex cardiac stimulation makes some arterial dilators unsuitable for angina. Venodilators are very effective for angina and are sometimes used for heart failure, but are not used as primary therapy for hypertension. Vasodilators can be mixed (or balanced) vasodilators in that they dilate both arteries and veins, and therefore have broad application in hypertension, heart failure, and angina. Some vasodilators, due to their mechanism of action, also have other important actions that can in some cases enhance their therapeutic utility or provide some additional therapeutic benefits. For example, some calcium channel blockers not only dilate blood vessels but also reduce the mechanical and electrical function of the heart, thereby enhancing their antihypertensive effects and conferring additional therapeutic benefits such as blocking arrhythmias.

[0096] Vasodilators can be classified based on their site of action (arterial vs. venous) or by mechanism of action. Some drugs primarily dilate resistance vessels (arterial dilators; e.g., hydralazine), while others primarily affect venous capacitance vessels (venous dilators; e.g., nitroglycerin). Many vasodilators, such as phentolamine, have mixed arterial and venous dilation properties (mixed dilators; e.g., α-adrenergic receptor antagonists, angiotensin-converting enzyme inhibitors).

[0097] However, it is more common to classify vasodilators based on their primary mechanism of action. These classes of drugs, as well as others that produce vasodilation, include: α-adrenergic receptor antagonists (α-blockers); angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); β2-adrenergic receptor agonists (β2-agonists); calcium channel blockers (CCBs); centrally acting sympatholytic agents; direct acting vasodilators; endothelin receptor antagonists; ganglion blockers; nitrodilators; phosphodiesterase inhibitors; potassium channel openers; and renin inhibitors.

[0098] In general, the active or inactive ingredient or material may be a substance or compound that produces increased blood flow or tissue flushing, allowing for a modification or difference (increase or decrease) in the transmucosal uptake of the API, and / or a substance or compound that has a positive or negative heat of solution and is used as an adjuvant to modify (increase or decrease) the transmucosal uptake.

[0099] (Desiccant) Desiccants are compounds designed to protect pharmaceuticals from moisture damage by absorbing moisture through physical adsorption or by chemical reaction, thereby improving product stability. Suitable desiccants may include silica, fumed silica, or mesoporous silica. Examples of desiccants include silicon dioxide variants such as Cab-o-Sil and Syloid 244FP. The desiccant may be 1-15% by weight of the pharmaceutical composition. For example, it may be 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% w / w of the pharmaceutical composition.

[0100] (Stabilizer) Stabilizers are materials designed to help maintain the desired properties of a product or pharmaceutical composition until the active pharmaceutical ingredient (API) is consumed by the patient or otherwise takes effect. For example, gelling agents can stabilize liquid dosage forms such as suspensions and emulsions. Examples include methacrylic acid copolymers, cellulose acetate, alginates, and polystyrene sulfonates. Stabilizers can also be used in conjunction with pH adjusters and plasticizers to prevent or reduce degradation or hydrolysis of pharmaceutical compositions. Stabilizers can also be classified as antioxidants, ion scavengers, sequestering agents, pH adjusters, emulsifiers and / or surfactants, and UV stabilizers. Stabilizers can protect the composition or components of the composition from degradation pathways, such as transesterification and / or hydrolysis, by preventing any of these mechanisms or a combination of these mechanisms. An example is polystyrene sulfonates.

[0101] The stabilizer can be an ion exchange resin. It can be a cation exchange resin. It can be constructed to trap ions. It can trap basic ions. It can be an Amberlite® resin, such as AmberLite® HPR1100 Na Ion, Amberlite® IR-120(H) or Amberlite® IRP64. It can be a chelating agent. It can be egtazic acid (EGTA), ethylenediaminetetraacetic acid (EDTA), or citric acid, tartaric acid, ethylenediaminetetra(methylenephosphonic acid), 2-[bis(carboxymethyl)amino]acetic acid, or (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid). A single stabilizer can be about 0.1% to about 50% w / w of the pharmaceutical composition, preferably about 0.1% to about 100% w / w of the pharmaceutical composition. For example, it may be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w / w of the pharmaceutical composition.

[0102] In certain embodiments, stabilizers may include antioxidants that can prevent unwanted oxidation of materials, sequestering agents that can form chelate complexes and inactivate trace metal ions that would otherwise act as catalysts, emulsifiers and surfactants that can stabilize emulsions, UV stabilizers that can protect materials from the harmful effects of UV light, UV absorbers, which are chemicals that absorb UV light and prevent it from entering the composition, quenchers that can dissipate radiant energy as heat rather than allowing it to break chemical bonds, or scavengers that can remove free radicals formed by UV light.

[0103] Examples of UV stabilizers include UV absorbers (e.g., benzophenone), UV quenchers (i.e., any compound that dissipates UV energy as heat rather than having a decomposing effect on the energy), scavengers (i.e., any compound that removes free radicals resulting from exposure to UV radiation), and combinations thereof.

[0104] In other embodiments, the stabilizer comprises ascorbyl palmitate, ascorbic acid, alpha tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, cysteine ​​HC1, citric acid, ethylenediaminetetraacetic acid (EDTA), methionine, sodium citrate, sodium ascorbate, sodium thiosulfate, sodium metabisulfite, sodium bisulfite, propyl gallate, glutathione, thioglycerol, singlet oxygen quenchers, hydroxyl radical scavengers, hydroperoxide scavengers, reducing agents, metal chelators, detergents, chaotropes, and combinations thereof. "Singlet oxygen quenchers" include, but are not limited to, alkylimidazoles (e.g., histidine, L-camocine, histamine, imidazole 4-acetic acid), indoles (e.g., tryptophan and its derivatives, such as N-acetyl-5-methoxytryptamine, N-acetylserotonin, 6-methoxy-1,2,3,4-tetrahydro-beta-carboline), sulfur-containing amino acids (e.g., methionine, ethionine, dienkholic acid, lanthionine, N-formylmethionine, felinine, S-allylcysteine, S-aminoethyl-L-cysteine), phenolic compounds (e.g., tyrosine and its derivatives), aromatic acids (e.g., ascorbate, salicylic acid, and their derivatives), azides (e.g., sodium azide), tocopherol and related vitamin E derivatives, and carotene and related vitamin A derivatives. "Hydroxyl radical scavengers" include, but are not limited to, azide, dimethylsulfoxide, histidine, mannitol, sucrose, glucose, salicylate, and L-cysteine. "Hydroperoxide scavengers" include, but are not limited to, catalase, pyruvate, glutathione, and glutathione peroxidase. "Reducing agents" include, but are not limited to, cysteine ​​and mercaptoethylene. "Metal chelators" include, but are not limited to, EDTA, EGTA, o-phenanthroline, and citrate. "Detergents" include, but are not limited to, SDS and sodium lauroyl sarcosine. "Chaotropes" include, but are not limited to, guanidinium hydrochloride, isothiocyanate, urea, and formamide.As discussed herein, the stabilizer can be present from 0.0001% to 50% by weight, including greater than 0.0001%, greater than 0.001%, greater than 0.01%, greater than 0.1%, greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% by weight.

[0105] (Antioxidants) Antioxidants are molecules capable of reducing or preventing the oxidation of other molecules or otherwise improving the shelf life of pharmaceuticals. Antioxidants are efficient excipients that retard or inhibit the oxidation of organic and inorganic molecules and prevent their degradation. Antioxidants (i.e., pharma- ceutically compatible compound(s) or composition(s) that slow down, inhibit, interrupt and / or stop the oxidation process) include, in particular, the following substances: tocopherol and their esters, sesamol from sesame oil, coniferyl benzoate from benzoin resin, nordihydroguaietic resin, benzoyl peroxide, benzoic acid from benzoin resin, benzoyl peroxide ... Resin) and nordihydroguaiaretic acid (NDGA), gallic acid esters (especially methyl, ethyl, propyl, amyl, butyl, lauryl gallate), butylated hydroxyanisole (BHA / BHT, also butyl-p-cresol); ascorbic acid and its salts and esters (e.g. ascorbyl palmitate), erythorbic acid (isoascorbic acid) and its salts and esters, monothioglycerol, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium hydrogen sulfite, sodium sulfite, potassium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT), propionic acid. Typical antioxidants are tocopherols, e.g. α-tocopherol and its esters, butylated hydroxytoluene and butylated hydroxyanisole. The term "tocopherol" also includes esters of tocopherol. A known tocopherol is α-tocopherol. The term "α-tocopherol" includes esters of α-tocopherol (eg, α-tocopherol acetate).

[0106] Sequestering agents (i.e., any compound that can participate in host-guest complexation with another compound, such as an active ingredient or another excipient; also referred to as sequestrants) include calcium chloride, calcium disodium ethylenediaminetetraacetate, glucono delta-lactone, sodium gluconate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate, and combinations thereof. Sequestering agents also include cyclic oligosaccharides such as cyclodextrins, cyclomannines (five or more α-D-mannopyranose units linked by α-linkages at the 1,4 positions), cyclogalactins (five or more β-D-galactopyranose units linked by β-linkages at the 1,4 positions), cycloalturins (five or more α-D-altropyranose units linked by α-linkages at the 1,4 positions), and combinations thereof. pH adjusters include acids (e.g., tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, ascorbic acid, acetic acid, succinic acid, adipic acid, maleic acid, ethylenediaminetetra(methylenephosphonic acid), 2-[bis(carboxymethyl)amino]acetic acid, (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid), acidic amino acids (e.g., glutamic acid, aspartic acid, and the like), inorganic salts of such acidic substances (alkali metal salts, alkaline earth metal salts, ammonium salts, and the like), salts of such acidic substances with organic bases (e.g., basic amino acids such as lysine, arginine, and the like, meglumine and the like), and solvates (e.g., hydrates) thereof.Other examples of pH adjusting agents include silicified microcrystalline cellulose, magnesium aluminometasilicate, calcium salts of phosphoric acid (e.g., calcium hydrogen phosphate anhydrous or hydrated, calcium carbonate or bicarbonate, sodium or potassium, and calcium lactate or mixtures thereof), sodium and / or calcium salts of carboxymethylcellulose, crosslinked carboxymethylcellulose (e.g., croscarmellose sodium and / or calcium), polacrilin potassium, sodium and / or calcium alginate, docusate sodium, magnesium, calcium, aluminum, or zinc stearate, magnesium palmitate, and magnesium oleate, sodium stearyl fumarate, and combinations thereof.

[0107] In an exemplary pharmaceutical formulation, the antioxidant may be about 0.1% to about 20% by weight of the pharmaceutical composition. For example, it may be about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18% or 20% w / w of the pharmaceutical composition. Examples of antioxidants include EGTA, EDTA, citric acid, L-cysteine, and caffeic acid.

[0108] (pH adjuster) pH adjusting excipients are used in the pharmaceutical industry for their antioxidant properties and ability to help maintain pharmaceutical stability, and can also be used as preservatives. For pH adjustment, the addition of a base or acid is often preferred over the use of a buffer. The pH adjusting agent can result in a formulation with a pH of 2.5-6, preferably 2.5-4.0, and more preferably 2.5-3.5. The pH of the formulation balances the permeability of the active agent through the mucosal surface without leading to mucosal irritation and promotes formulation stability. The pH adjusting agent can be a straight chain acid. Examples of pH adjusting agents include hydrochloric acid, phosphoric acid, hydrofluoric acid, and citric acid. In some embodiments, the pH adjusting agent can be an antacid.

[0109] In some circumstances, the film composition may further comprise a buffering agent to control the pH of the film composition.Any desired level of buffering agent may be incorporated into the film composition to provide a desired pH level that the pharmacoactive ingredient encounters when released from the composition.Preferably, the buffering agent is provided in an amount sufficient to control the release of the pharmacoactive ingredient from the film and / or its absorption into the body.In some embodiments, the buffering agent may comprise sodium citrate, citric acid, bitartrate, and combinations thereof.

[0110] (Processing Solvent) The processing solvent incorporates an organic / aqueous solvent system to displace and reduce bound water, thereby reducing the overall water loading of the liquid intermediate. The solvent can be aqueous-organic or aqueous-alcoholic, for example, a mixture including at least an alcohol or organic solvent and water. In some embodiments, it can be an ethanol / water mixture. The processing solvent can include an organic solvent that is more volatile than water. In some circumstances, the organic solvent can form an azeotrope with water. The processing solvent can include 2%-70% water, 5%-60% water, or 10%-50% water. For example, the processing solvent can be a 50:50 ethanol / water w / w mixture. In other embodiments, the processing solvent can include acetone or acetonitrile. In other embodiments, the processing solvent can include one or more of t-butanol, methanol, 1-propanol, isopropanol, tetrahydrofuran, acetaldehyde, dioxane, dichloromethane, or methyl isocyanide. The processing solvent can also be a mixture of one or more of the above solvents.

[0111] (API addition amount) The active pharmaceutical ingredients (APIs) can be provided at sufficiently high API loadings to optimize the dosage of each API while limiting dosage form size. In one example, the API loading can be greater than 8%, greater than 10%, greater than 12%, greater than 14%, greater than 16%, greater than 18%, greater than 20%, greater than 22%, or greater than 24% w / w. The API loading can be between 2% and 40% w / w, or between 5% and 30% w / w.

[0112] (Permeation Enhancer) The permeation enhancer may be provided to improve the permeation of the drug or API through a surface, such as a mucosal surface. One example is eugenol. The permeation enhancer may be provided at a concentration of more than 1%, more than 2%, more than 5%, more than 10%, more than 12%, more than 14%, more than 16%, more than 18%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% w / w.

[0113] Certain classes of permeation enhancers can improve the in vivo uptake and bioavailability of pharmacoactive ingredients. In particular, when delivered to the mouth via a film, permeation enhancers can improve the permeability of pharmacoactive ingredients through the mucous membrane of a subject and into the bloodstream. Permeation enhancers can improve the rate and amount of absorption of pharmacoactive ingredients 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 combinations of these ranges, depending on the other ingredients in the composition.

[0114] Chemical permeation enhancers are substances that control the permeation rate of co-administered drugs across biological membranes. Although extensive research has focused on gaining a better understanding of how permeation enhancers can alter intestinal and transdermal permeability, little is known about the mechanisms involved in buccal and sublingual permeation enhancement.

[0115] The buccal mucosa outlines the inner lining of the cheek and the area between the gums and the upper and lower lips, and it extends beyond 100 cm 2The buccal mucosa has an average surface area of ​​1000 μm. The surface of the buccal mucosa consists of stratified squamous epithelium separated from the underlying connective tissue (lamina propria and submucosa) by an undulating basement membrane (a continuous layer of extracellular material approximately 1-2 μm thick). This stratified squamous epithelium consists of differentiated layers of cells that change in size, shape, and content as they move from the basal region to the superficial region, where cells are shed. There are approximately 40-50 cell layers, giving rise to the buccal mucosa that is 500-600 μm thick.

[0116] Structurally, the sublingual mucosa is similar to the buccal mucosa, but the epithelium is 100-200 μm thick. This membrane is also non-keratinized and relatively thin, which has been shown to make it more permeable than the buccal mucosa. Blood flow to the sublingual mucosa is slower than that of the buccal mucosa, on the order of 1.0 ml / min-1 / cm-2.

[0117] The permeability of the buccal mucosa is greater than that of the skin, but less than that of the intestine. The difference in permeability is the result of structural differences between each tissue. The absence of organized lipid lamellae in the intercellular spaces of the buccal mucosa results in a higher permeability of foreign compounds compared to the keratinized epithelium of the skin; on the other hand, due to the increased thickness and lack of tight junctions, the buccal mucosa is less permeable than intestinal tissue.

[0118] The primary barrier properties of the buccal mucosa have been attributed to the upper one-third to one-quarter of the buccal epithelium. Researchers have noted that the permeability barrier of the non-keratinized oral mucosa beyond the surface epithelium is also attributable to contents extruded from membrane-coated granules into the intercellular spaces of the epithelium.

[0119] The intercellular lipids of the non-keratinized regions of the oral cavity are more polar in nature than those of the epidermis, palate, and gingiva, and this difference in lipid chemistry 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 epithelium that creates a more effective barrier, but also the chemical nature of the lipids present within that barrier.

[0120] The presence of hydrophilic and lipophilic regions in the oral mucosa has led researchers to hypothesize the existence of two drug transport pathways through the buccal mucosa: paracellular (between cells) and transcellular (across cells).

[0121] Drug delivery through the buccal mucosa is limited by the barrier properties of the epithelium and the area available for absorption, so various enhancement strategies are required to deliver therapeutically relevant amounts of drugs to the systemic circulation. Various methods can be utilized to overcome the barrier properties of the buccal mucosa, including the use of chemical penetration enhancers, prodrugs, and physical methods.

[0122] Chemical permeation enhancers, or absorption promoters, are substances added to pharmaceutical formulations to increase the rate of membrane permeation or absorption of co-administered drugs without causing membrane damage and / or toxicity. There have been many studies investigating the effect of chemical permeation enhancers on the delivery of compounds across the skin, nasal mucosa, and intestine. In recent years, more attention has been paid to the effect of these agents on the permeability of the buccal mucosa. Since the permeability across the buccal mucosa is considered to be 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.

[0123] Surfactants and bile salts have been shown to enhance the permeability of a variety of compounds across the buccal mucosa both in vitro and in vivo. The data from these studies strongly suggest that the enhanced permeability is due to the action of the surfactants on the intercellular lipids of the mucosa.

[0124] Fatty acids have been shown to enhance the permeation of some drugs through the skin, and this has been shown to be associated with increased intercellular lipid fluidity by differential scanning calorimetry and Fourier transform infrared spectroscopy.In addition, pretreatment with ethanol has been shown to enhance the permeability of tritiated water and albumin across the ventral tongue mucosa, and caffeine across the buccal mucosa of pigs.There are also some reports of the enhancing effect of Azone® on the permeability of compounds through the oral mucosa.Furthermore, chitosan, a biocompatible and biodegradable polymer, has been shown to enhance drug delivery through various tissues, including the intestinal and nasal mucosa.

[0125] Oral transmucosal drug delivery (OTDD) is the administration of pharmacologic active substances through the oral mucosa to achieve a systemic effect. OTDD permeation pathways and predictive models are described, for example, in M. Sattar, "Oral transmucosal drug delivery-Current status and future prospects," Int'l. Journal of Pharmaceutics, 47(2014)498-506, which is incorporated herein by reference. OTDD continues to attract the attention of scientists in academia and industry. Despite limited characterization of permeation pathways in the oral cavity compared to dermal and nasal delivery pathways, the outlook is bright due to recent advances in our understanding of the extent to which ionized molecules permeate the buccal epithelium, as well as the emergence of new analytical techniques to study the oral cavity, and the ongoing development of in silico models predicting buccal and sublingual permeation.

[0126] In order to deliver a broader class of drugs across the buccal mucosa, a reversible method should be utilized to reduce the barrier capacity of this tissue. This requirement has prompted the search for permeation enhancers that safely modify the permeability constraints of the buccal mucosa. It has been shown that buccal permeation can be improved by using various classes of transmucosal and transdermal permeation enhancers, such as bile salts, surfactants, fatty acids and their derivatives, chelating agents, cyclodextrins, and chitosan. Among these chemicals used for drug permeation enhancement, bile salts are the most common.

[0127] In vitro studies on the enhancing effect of bile salts on buccal permeation of compounds are discussed in Sevda Senel's article "Drug permeation enhancement via buccal route: possibilities and limitations," Journal of Controlled Release 72 (2001) 133-144, which is incorporated herein by reference. The article also discusses recent studies on the effect of dihydroxy bile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC), and tri-hydroxy bile salts, sodium glycocholate (GC) and sodium taurocholate (TC), at a concentration of 100 mM, on the permeability of the buccal epithelium, including permeability changes related to histological effects. Fluorescein isothiocyanate (FITC), morphine sulfate, respectively, were used as model compounds.

[0128] Chitosan has also been shown to enhance the absorption of polar small molecule and peptide / protein drugs across the nasal mucosa in animal models and human volunteers. Other studies have shown an enhancing effect on the permeation of compounds across the intestinal mucosa and cultured Caco-2 cells.

[0129] The permeation enhancer can be a plant extract. The plant extract can be an essential oil extracted by distillation of the plant material or a composition that includes the essential oil. In some circumstances, the plant extract can include synthetic analogs of compounds extracted from the plant material (i.e., compounds produced by organic synthesis). The plant extract can include a phenylpropanoid, such as phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid esters, cinnamaldehyde, hydrocinnamic acid, chavicol, or safrole, or a combination thereof. The plant extract can be an essential oil extract of a clove plant, such as the leaves, stems, or flower buds of a clove plant. The clove plant can be Syzygium aromaticum. The plant extract can include 20-95% eugenol, such as 40-95% eugenol, such as 60-95% eugenol, such as 80-95% eugenol. The extract may also contain 5% to 15% eugenol acetate. The extract may also contain caryophyllene. The extract may also contain up to 2.1% α-humulene. Other volatile compounds found in lower concentrations in clove essential oil may be β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone, and ethyl hexanoate. Other permeation enhancers may be added to the composition to improve drug absorption.Suitable penetration 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 palmitoyl carnitine; chelating agents, such as citric acid, tartaric acid, ethylenediaminetetra(methylenephosphonic acid), 2-[bis(carboxymethyl)amino]acetic acid, (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid), disodium EDTA, sodium citrate and sodium lauryl sulfate, azone, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth-9, polysorbates, sterols, or glycerides, such as caprylocaproyl polyoxylglycerides, such as Labrasol®. The penetration enhancer may include a derivative of a plant extract and / or a monolignol. The penetration enhancer may also be a fungal extract.

[0130] (Plasticizer) Plasticizers can be added to polymers used as film formers to make them pliable and soft, increasing the flexibility and plasticity of the film. Plasticizers are often used in solid dosage forms, especially oral solid dosage forms. Examples are glycerin, propylene glycol, polyethylene glycol (PEG), organic esters such as diethyl ester, dibutyl ester, dibutyl sebacete, citrate ester, triacetin. Other examples are oils or glycerides such as castor oil, acetylated monoglycerides, or fractionated coconut oil. It can be a carbohydrate, polyalcohol or sugar alcohol, such as mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, and hydrogenated starch hydrolysates (HSH). Plasticizers can be provided at more than 2%, more than 4%, more than 6%, more than 8%, or more than 10% w / w.

[0131] (Viscosity modifier) Viscosity modifiers are designed to modify the thickness or texture of pharmaceutical ingredients. Viscosity modifiers may include such products as thickeners, texturizers, gelling agents, and hardeners. Many viscosity modifiers can transform liquids into gels, pastes, or powders, helping formulators create the ideal product for the end consumer. Viscosity modifiers can reduce the thickness of a liquid, improving its flowability and ultimately making it more palatable. Particular examples are natural or synthetic gums, which can be derived from sugars. Viscosity modifiers can be provided at greater than 0.2%, greater than 0.4%, greater than 0.6%, greater than 0.8%, greater than 1%, greater than 1.2%, greater than 1.4%, or greater than 1.6%. Examples are gelatin, xantham gum, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, microcrystalline cellulose, chitosan, natural gums, and other synthetic polymers.

[0132] (Surfactant) Surfactants are agents that adsorb to surfaces, interfaces and reduce surface or interfacial tension, or are used to reduce surface tension between liquids. Surfactants aid in the wetting and dispersion of hydrophobic active pharmaceutical ingredients, and usually act by reducing the interfacial tension between solids and liquids in suspension. Surfactants can be nonionic, anionic, cationic, or amphoteric. These surfactants vary in composition and polarity. Examples of suitable surfactants include ethoxylates, Labrasol®, or Transcutol®, and PEG derivatives such as PEG-fatty acid esters, PEG amine ethers. Examples may also include structure-forming lipids and fatty alcohols, i.e. monoglycerides such as glyceryl monooleate (GMO) and phytantriol (PHT).

[0133] Examples of emulsifiers and / or surfactants include poloxamers or pluronics, polyethylene glycol, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oils, alkyl polyosides, water-soluble proteins grafted onto a hydrophobic backbone, lecithin, glyceryl stearate, glyceryl stearate / polyoxyethylene stearate, ketostearyl alcohol / sodium lauryl sulfate, carbomers, phospholipids, (C 10 -C 20 )-alkyl and alkylene carboxylates, alkyl ether carboxylates, fatty alcohol sulfates, fatty alcohol ether sulfates, alkylamide sulfates and sulfonates, fatty acid alkylamide polyglycol ether sulfates, alkane sulfonates and hydroxyalkane sulfonates, olefin sulfonates, acyl esters of isethionates, α-sulfofatty acid esters, alkylbenzene sulfonates, alkylphenol glycol ether sulfonates, sulfosuccinates, mono- and diesters of sulfosuccinic acid, fatty alcohol ether phosphates, protein / fatty acid condensation products, alkyl monoglyceride sulfates and sulfonates, alkyl glyceride ether sulfonates, fatty acid methyl taurides, fatty acid sarcosinates, sulforicinolates, and acyl glutamates, quaternary ammonium salts (e.g., di-(C 10 -C 24 )-alkyl-dimethylammonium chloride or bromide), (C 10 -C 24 )-Alkyl-dimethylethyl ammonium chloride or bromide, (C 10 -C 24 )-alkyl-trimethylammonium chloride or bromide (e.g., cetyltrimethylammonium chloride or bromide), (C 10 -C 24 )-Alkyl-dimethylbenzyl ammonium chloride or bromide (e.g., (C 12 -C 18 )-Alkyl-dimethylbenzyl ammonium chloride), N-(C10 -C 18 )-alkyl-pyridinium chloride or bromide (e.g., N-(C 12 -C 16 )-alkyl-pyridinium chloride or bromide), N-(C 10 -C 18 )-Alkyl-isoquinolinium chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 )-Alkyl-polyoylaminoformylmethylpyridinium chloride, N-(C 12 -C 18 )-Alkyl-N-methylmorpholinium chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 )-Alkyl-N-ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C 16 -C 18 )-alkyl-pentaoxethylammonium chloride, diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride, N,N-di-ethylaminoethylstearylamide and -oleylamide salts with hydrochloric acid, acetic acid, lactic acid, citric acid, phosphoric acid, N-acylaminoethyl-N,N-diethyl-N-methylammonium chloride, bromide or monoalkyl sulfate, and N-acylaminoethyl-N,N-diethyl-N-benzylammonium chloride, bromide or monoalkyl sulfate (wherein "acyl" means, for example, stearyl or oleyl), as well as combinations thereof.

[0134] The emulsifiers typically used in the water-based emulsions described above are either obtained in situ, preferably when selected from linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid, cetoleic acid or oleic acid and sodium or potassium hydroxide, or are selected from sorbitol and sorbitol anhydrides, lauric acid, palmitic acid, stearic acid or oleic acid esters, polyoxyethylene derivatives including monooleates, monostearates, monopalmitates, monolaurates, fatty alcohols, alkylphenols, allyl ethers, alkylaryl ethers, sorbitan monostearate, sorbitan monooleate and / or sorbitan monopalmitate.

[0135] (Esterase inhibitors) Esterase inhibitors prevent chemical or enzymatic hydrolysis of drugs such as esters, amides and carbamates during analytical procedures where it is desired to achieve the desired pharmacokinetics of the drug. Such hydrolysis occurs due to the action of non-specific esterases present in blood, plasma and tissues. Examples of such esterase inhibitors include sodium fluoride (NaF), diisopropyl-fluorophosphate (DFP) and 1,5,bis(4-allyldimethylammoniumphenyl)-pentan-3-one dibromide (ADAPP), H2NSO3 - , I - , SCN - , NO3 - , NO2 - , N3 - , I - , Br - , Cl - , SO4 2- , S -2 , PO4 3- , HPO4 2- , H2PO 4- , HSO 4- , SO3 2- , CO 3- , or C2O4 2 There is.

[0136] (Sweetener) Sweeteners may be selected from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts, such as the sodium salt; dipeptide-based sweeteners, such as aspartame, neotame, advantame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (stevioside); chlorine derivatives of sucrose, such as sucralose; sugar alcohols, such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and synthetic sweeteners 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide, especially the potassium salt (acesulfame-K), as well as the sodium and calcium salts thereof, and natural high-intensity sweeteners, such as Lo Han Kuo. Other sweeteners may also be used.

[0137] Sweeteners can be broadly classified into two categories - nutritive and non-nutritive. Nutritive sweeteners deliver calories and, as the name suggests, non-nutritive do not. Non-nutritive sweeteners can be further characterized as bulk (sugar alcohols) and high intensity (artificial). Some examples include aspartame, saccharin, sucralose, acesulfame K, Magnasweet, stevia, and sugar alcohols.

[0138] (Fragrances and colors) Flavoring agents may be selected from natural and synthetic flavoring liquids. An exemplary list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. A non-limiting representative list of examples includes mint oil, cocoa, and citrus oils such as lemon, orange, lime, and grapefruit, as well as fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or other fruit flavors. Other useful flavoring agents include aldehydes and esters such as benzaldehyde (cherry, almond), citral, i.e., alpha citral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), toluylaldehyde (cherry, almond), 2,6-dimethyloctanol (green fruits), or 2-dodecenal (citrus, mandarin), combinations thereof, and the like.

[0139] Flavoring agents may be added to a formulation to enhance its organoleptic properties or to mask its bitter or other unpleasant tastes. Reduction of bitterness can be achieved by balancing complementary tastes-sweet, sour, and salty through taste / taste interaction mechanisms-basic principles of taste and aroma masking. Once bitterness is reduced, pharmaceutical flavors such as orange, grape, or mint can be selected based on compatibility with the active drug and excipients, patient demographics, and dosing frequency and other quality of life factors. A suitable drug formulation requires a robust and balanced base to achieve palatability.

[0140] (Coloring agent) Colorants or coloring agents are primarily used to impart a distinctive appearance to pharmaceutical dosage forms. Suitable colorants enhance the aesthetic appearance of the dosage form, especially for oral pharmaceutical preparations. The Food Drug and Cosmetic Act of 1938 created three classifications of dyes: (1) FD&C dyes-colorants that can be certified for use in food, drugs, and cosmetics; (2) D&C dyes-dyes and pigments that are considered safe for use in drugs and cosmetics when in contact with mucous membranes or when ingested; and (3) topical D&C dyes-colorants that cannot be certified for use in products intended for ingestion because of their oral toxicity, but are considered safe for use in products applied topically. Some examples of colorants commonly used in medicines include FD&C Blue No. 1 - Brilliant Blue, (a shade of blue), FD&C Blue No. 2 - Indigotine, (a shade of indigo), FD&C Red No. 3 - Erythrosine, (a shade of pink), FD&C Red No. 40 - Allura Red, (a shade of red), FD&C Yellow No. 5 - Tartrazine, (a shade of yellow), and FD&C Yellow No. 6 - Sunset Yellow, (a shade of orange).

[0141] Other examples of colorants include known azo dyes, organic or inorganic pigments, or naturally derived colorants. Inorganic pigments, such as oxides of iron or titanium, are preferred, and these oxides are added at concentrations ranging from about 0.001 to about 10%, preferably from about 0.5 to about 3%, based on the weight of the total components, including greater than 0.001%, greater than 0.01%, greater than 0.1%, greater than 0.5%, greater than 1%, greater than 2%, greater than 5%, about 10%, greater than 10%, less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001%.

[0142] (Sequence of permeation enhancer and active pharmaceutical ingredient) The placement, order, or sequence of the permeation enhancer and active pharmaceutical ingredient (API) delivered to the desired mucosal surface can be varied to achieve the desired pharmacokinetic profile. For example, the permeation enhancer can be applied first by a film, swab, spray, gel, rinse, or by the first layer of film, and then the API can be applied by a single film, swab, or by the second layer of film. This sequence can be reversed or changed, for example, by applying the API first by a film, swab, or by the first layer of film, and then applying the permeation enhancer by a film, swab, spray, gel, rinse, or by the second layer of film. In another embodiment, the permeation enhancer can be applied by a film and the drug can be applied by another film. For example, a permeation enhancer film located under a film containing the API, or a film containing the API located under a film containing the permeation enhancer, depending on the desired pharmacokinetic profile.

[0143] For example, a permeation enhancer can be used as a pretreatment alone or in combination with at least one API to precondition the mucosa for further absorption of the API. This treatment can be followed by another treatment with neat permeation enhancer, followed by application of said at least one API to the mucosa. The pretreatment can be applied as a separate treatment (film, gel, solution, swab, etc.) or as a layer within a multi-layer film structure of one or more layers. Similarly, the pretreatment can be included within a separate domain of a single film designed to dissolve and release into the mucosa prior to the release of the second domain with or without the permeation enhancer or API. The active ingredient can then be delivered from the second treatment, alone or in combination with additional permeation enhancers. There can be a third treatment or domain that delivers additional permeation enhancers and / or at least one API or prodrug, either in different ratios relative to each other or to the total loading of the other treatments. This allows for a desired pharmacokinetic profile to be obtained. Thus, the product may have single or multiple domains containing API and permeation enhancers that can modify the sequence, composition, concentration, or total loading onto the mucosa leading to a desired amount and / or rate of absorption that achieves an intended pharmacokinetic profile and / or pharmacodynamic effect.

[0144] The film formats can be oriented so that there are no distinct faces, or the films have at least one face of the multilayer film that share an edge boundary (have or meet at a shared border or limit).

[0145] The pharmaceutical composition may be a chewable or gelatin-based dosage form, a spray, a gum, a gel, a cream, a tablet, a liquid, a powder inhalation, or a film. The composition may include textures, such as surface microneedles or microprojections. Recently, the use of micron-scale needles in increasing skin permeability has been shown to significantly increase transdermal delivery, especially for macromolecules. Most drug delivery studies have focused on solid microneedles, which have been shown to increase skin permeability to a wide range of molecules and nanoparticles in vitro. In vivo studies have demonstrated delivery of oligonucleotides, reduction of blood glucose levels with insulin, and induction of immune responses from protein and DNA vaccines. For such studies, needle arrays have been used to puncture the skin to increase transport by diffusion or iontophoresis, or as drug carriers to release drugs into the skin from a microneedle surface coating. Hollow microneedles have also been developed and shown to microinject insulin into diabetic rats. To address practical applications of microneedles, the ratio of microneedle crushing strength to skin insertion force (i.e., safety margin) was found to be optimal for needles with small tip radius and large wall thickness. Microneedles inserted into the skin of human subjects were reported to be painless. Taken together, these results suggest that microneedles are a promising technology to deliver therapeutic compounds to the skin for a wide range of potential applications. Using tools from the microelectronics industry, microneedles have been made in a wide range of sizes, shapes, and materials. Microneedles can be, for example, polymeric microscopic needles that deliver encapsulated drugs in a minimally invasive manner, although other suitable materials can be used.

[0146] Applicants have found that microneedles can be used to enhance the delivery of drugs through the oral mucosa, especially with the claimed compositions. Microneedles create micron-sized holes in the oral mucosa, which can enhance the delivery of drugs across the mucosa. Solid, hollow, or dissolvable microneedles can be made from suitable materials, including but not limited to metals, polymers, glasses, and ceramics. Microfabrication processes can include photolithography, silicon etching, laser cutting, metal electroplating, metal electropolishing, and molding. Microneedles can be solid, which is used to pretreat tissue and is removed before application of the film. Drug-loaded polymer films described in this application can be used as the matrix material for the microneedles themselves. These films can have microneedles or microprojections created on their surface, which dissolve after forming microchannels in the mucosa through which drugs can permeate.

[0147] The term "film" may include films and sheets of any shape, including rectangular, square, or other desired shapes. The film may be of any desired thickness and size. In a preferred embodiment, the film may have a thickness and size such that it can be administered to a user, for example, placed in the user's oral cavity. The film may have a relatively thin thickness of about 0.0025 mm to about 0.250 mm, or the film may have a somewhat thicker thickness of about 0.250 mm to about 1.0 mm. For some films, the thickness may be even relatively large, i.e., greater than about 1.0 mm, or may be relatively thin, i.e., less than about 0.0025 mm. For example, the film may have dimensions from 10 mm x 10 mm to 30 mm x 30 mm. The film may be monolayer, or the film may be multilayer, including laminated films or multiple cast films. The permeation enhancer and the pharmacoactive ingredient can be combined in a single layer, each contained in a separate layer, or each otherwise contained in separate regions of the same dosage form. In some embodiments, the pharmacoactive ingredient contained in the polymer matrix can be dispersed in the matrix. In some embodiments, the permeation enhancer contained in the polymer matrix can be dispersed in the matrix.

[0148] Oral dissolving films can be classified into three main classes: immediate dissolving, moderate dissolving and slow dissolving. Oral dissolving films can also include any combination of the above categories. Immediately dissolving films can dissolve in the mouth in about 1 second to about 30 seconds, including more than 1 second, more than 5 seconds, more than 10 seconds, more than 20 seconds, and less than 30 seconds. Moderately dissolving films can dissolve in the mouth in about 1 to about 30 minutes, 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 the mouth over more than 30 minutes. As a general trend, immediate dissolving films can include (or consist of) low molecular weight hydrophilic polymers (e.g., polymers having a molecular weight of about 1,000 to 9,000 Daltons, or polymers having a molecular weight of up to 200,000 Daltons). In contrast, slow dissolving films generally include high molecular weight polymers (e.g., having a molecular weight of several million). Moderately dissolving films may tend to fall between the quickly dissolving and slowly dissolving films.

[0149] It may be preferable to use a film that is a moderately soluble film. A moderately soluble film can dissolve fairly quickly, but also has a good level of mucoadhesion. A moderately soluble film is also soft, quickly wettable, and typically non-irritating to the user. Such a moderately soluble film can provide a sufficiently rapid dissolution rate, most desirably about 1 minute to about 20 minutes, while providing an acceptable level of mucoadhesion such that the film is not easily removed once placed in the user's oral cavity. This can ensure delivery of the medicament active ingredient to the user.

[0150] A pharmaceutical composition may contain one or more pharmacoactive ingredients. The pharmacoactive ingredient may be a single pharmaceutical ingredient or a combination of pharmaceutical ingredients. The pharmacoactive ingredient may be an anti-inflammatory analgesic, a steroidal anti-inflammatory, an antihistamine, a local anesthetic, a bactericide, an antiseptic, a vasoconstrictor, a hemostatic, a chemotherapeutic, an antibiotic, a keratolytic, a cauterizing agent, an antiviral, an antirheumatic, a hypertensive, a bronchodilator, an anticholinergic, an anxiolytic, an antiemetic compound, a hormone, a peptide, a protein, or a vaccine. The pharmacoactive ingredient may be a compound, a pharmacoactive salt of a drug, a prodrug, a derivative, a drug conjugate, or an 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. For example, the pharmacoactive ingredient may be an ester of epinephrine, such as dipivefrin. See, for example, J. Anderson et al., "Site of ocular hydrolysis of a prodrug, dipivefrin, and a comparison of its ocular metabolism with that of the parent compounds, epinephrine," Invest., Ophthalmol. Vis. Sci. July 1980. In some embodiments, administering the prodrug stimulates one or more adrenergic receptors. In some embodiments, administering the prodrug may not activate alpha 1 adrenergic receptors for epinephrine. In some embodiments, the pharma- ceutically active form of the prodrug has a Tmax of less than 60 minutes. In some embodiments, the prodrug has a Tmax of less than 30 minutes. In some embodiments, the prodrug has a Tmax of less than 15 minutes.

[0151] In some embodiments, two or more pharmacoactive ingredients may be included in the film, including ACE inhibitors, antianginal drugs, antiarrhythmic drugs, antiasthmatic drugs, anticholesterolemic drugs, analgesics, anesthetics, anticonvulsants, antidepressants, antidiabetic drugs, antidiarrheal preparations, detoxifying drugs, antihistamines, antihypertensive drugs, anti-inflammatory drugs, antilipid drugs, antimanic drugs, antinausea drugs, anti-stroke drugs, antithyroid preparations, amphetamines, antitumor drugs, antiviral drugs, acne drugs, alkaloids, amino acid preparations, antitussives, antiuricemic drugs, antiviral drugs, and the like. Metabolic preparations, Systemic and non-systemic infectious disease treatments, Anti-neoplastic agents, Anti-Parkinson's agents, Anti-rheumatic agents, Appetite stimulants, Blood modifiers, Bone metabolism regulators, Cardiovascular agents, Central nervous system stimulants, Cholinesterase inhibitors, Contraceptives, Decongestants, Dietary supplements, Dopamine receptor agonists, Endometriosis management agents, Enzymes, Erectile dysfunction treatments, Infertility drugs, Gastrointestinal agents, Homeopathic remedies, Hormones, Hypercalcemia and hypocalcemia management agents, Immunomodulators quality, immunosuppressants, migraine preparations, motion sickness medicines, muscle relaxants, obesity management drugs, osteoporosis preparations, uterotonics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic drugs, respiratory system drugs, sedatives, smoking cessation aids, sympatholytics, tremor treatment preparations, urinary system drugs, vasodilators, laxatives, antacids, ion exchange resins, laxatives, appetite suppressants, expectorants, anti-anxiety drugs, anti-ulcer drugs, anti-inflammatory substances, coronary artery dilators, cerebral vasodilators, peripheral vasodilators, psychotropic drugs, The agent may be a stimulant, an antihypertensive, a vasoconstrictor, an antimigraine agent, an antibiotic, a tranquilizer, an antipsychotic, an anti-tumor agent, an anticoagulant, an antithrombotic agent, a hypnotic, an antiemetic, an anti-nausea agent, an anticonvulsant, a neuromuscular agent, an hyperglycemic and hypoglycemic agent, a thyroid and anti-thyroid preparation, a diuretic, an anticonvulsant, a uterine relaxant, an anti-obesity agent, an erythropoietic agent, an anti-asthmatic agent, a cough suppressant, a mucolytic agent, a DNA and gene modifying agent, a diagnostic agent, a contrast agent, a dye, or a tracer, and combinations thereof.

[0152] For example, the active pharmaceutical ingredient may 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, phenylbufen ... acetazon, oxyphenbutazone, clofezone, pentazocine, mepirizole, tiaramide hydrochloride, hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumethasone, fluorometholone, beclomethasone dipropionate, fluocinonide, edaravone, lurasidone, esomeprazole, lumateperone, naldemedine, doxylamine, pyridoxine, diphen Hydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate, isothipendyl hydrochloride, tripelennamine hydrochloride, promethazine hydrochloride, methdilazine hydrochloride, dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoic acid 2-(diethylamino)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 iodine, cetylpyridinium chloride, eugenol, trimethylammonium bromide, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbazochrome sodium sulfonate, rutin, hesperidin, sulfamine,Sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole, sulfisomidine, sulfamethizole, nitrofurazone, penicillin, methicillin, oxacillin, cephalothin, cefalordin, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, methacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, salicylic acid, podophyllum resin, podophyllum fox ifox, cantharidin, chloroacetic acid, silver nitrate, protease inhibitors, thymadine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, adhesion and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir, heparin, insulin, LHRH, TRH, interferons, oligonucleides, calcitonin, octreotide, omeprazone, fluoxetine, ethinyl estradiol, amiodipine iodipine), paroxetine, enalapril, lisinopril, leuprolide, prevastatin, lovastatin, norethindrone, risperidone, olanzapine, albuterol, hydrochlorothiazide, pseudoephedrine, warfarin, terazosin, cisapride, ipratropium, busprione, methylphenidate, levothyroxine, zolpidem, levonorgestrel, glyburide, benazepril, medroxyprogesterone, clonazepam, ondansetron, losartan, quinap rilonitrile, nitroglycerin, midazolam versed, cetirizine, doxazosin, glipizide, hepatitis B vaccine, salmeterol, sumatriptan, triamcinolone acetonide, goserelin, beclomethasone, granisteron, desogestrel, alprazolam, estradiol, nicotine, interferon beta 1A, cromolyn, fosinopril, digoxin, fluticasone, bisoprolol, calcitril, captopril, butorphanol, clonidine, premarin, testosterone, sumatriptan, clotrimazole,It can be bisacodyl, dextromethorphan, nitroglycerin, nafarelin, dinoprostone, nicotine, bisacodyl, goserelin, and granisetron. In some embodiments, the pharmaceutical active ingredient is epinephrine, a prodrug of epinephrine, a benzodiazepine, such as diazepam or lorazepam or alprazolam.

[0153] (Example: epinephrine / dipivefrin) In one example, a composition containing epinephrine or a salt or ester thereof (such as dipivefrin) can have a biodelivery profile similar to that of epinephrine administered by injection, for example, using an EpiPen®. Epinephrine or a prodrug thereof may be present in an amount of about 0.01 mg to about 100 mg per dose, for example, 0.1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg doses, including greater than 0.1 mg, greater than 5 mg, greater than 20 mg, greater than 30 mg, greater than 40 mg, greater than 50 mg, greater than 60 mg, greater than 70 mg, greater than 80 mg, greater than 90 mg, less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, or less than 5 mg, or any combination thereof. In another example, a composition containing diazepam may have a biodelivery profile similar to or better than the biodelivery profile of a diazepam tablet or gel.

[0154] Dipivefrin can be present in an amount of about 0.5 mg to about 100 mg per dose, for example, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg doses, including greater than 1 mg, greater than 5 mg, greater than 20 mg, greater than 30 mg, greater than 40 mg, greater than 50 mg, greater than 60 mg, greater than 70 mg, greater than 80 mg, greater than 90 mg, or less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, or less than 5 mg, or any combination thereof.

[0155] In another example, the composition (e.g., comprising epinephrine) comprises: (a) an aggregation inhibitor; (b) a charge modifier; (c) a pH control agent; (d) a degradative enzyme inhibitor; (e) a mucolytic or mucus-clearing agent; (f) a ciliostatic agent; (g) a membrane permeability enhancer 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) an NO donor compound; (vi) a long chain amphipathic molecule; (vii) a hydrophobic permeability enhancer; (viii) a sodium or salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or a β-cyclodextrin derivative; (xi) a medium chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) an N-acetyl amino acid or a salt thereof; (xv) enzymes degrading selected membrane components; (ix) inhibitors of fatty acid synthesis; (x) inhibitors of cholesterol synthesis; and (xi) any combination of the membrane permeability enhancers described in (i)-(x); (h) regulators of epithelial junction physiology; (i) vasodilators; (j) selective transport enhancers; or (k) a suitable non-toxic non-ionic alkyl glycoside having a hydrophobic alkyl group attached by an alpha linkage to a hydrophilic sugar in combination with a mucosal delivery enhancer selected from a stabilizing delivery vehicle, carrier, mucoadhesive, carrier or complexing species with which the compound is effectively formulated, associated, contained, encapsulated or bound to provide stabilization of the compound for enhanced mucosal delivery, where formulation of the compound with the mucosal delivery enhancer provides increased bioavailability of the compound in the plasma of a subject. This formulation may include approximately the same active pharmaceutical ingredient (API):enhancer ratio as in the other example for epinephrine.

[0156] Administering epinephrine as a prodrug, such as dipivefrin, offers certain advantages. For one thing, dipivefrin is lipophilic and therefore has higher permeability through mucous membranes. It also has a longer plasma half-life due to higher protein binding. It allows for sustained blood levels and does not interact with alpha receptors, thus minimizing or eliminating unwanted or harmful vasoconstriction. [ka]

[0157] Dipivefrin can be provided as a sublingual film in a manner similar to epinephrine.

[0158] The film and / or its components may be water-soluble, water-swellable or water-insoluble. The term "water-soluble" may refer to a material that is at least partially soluble in an aqueous solvent, including but not limited to water. The term "water-soluble" may not necessarily mean that the material is 100% soluble in an aqueous solvent. The term "water-insoluble" refers to a material that does not dissolve in an aqueous solvent, including but not limited to water. The solvent may include water or may include other solvents, preferably polar solvents, alone or in combination with water. The composition may include a polymer matrix. Any desired polymer matrix may be used, provided that it is orally dissolvable or erodible. The dosage must have sufficient bioadhesiveness to not be easily removed and must form a gel-like structure when administered. These are moderately soluble in the oral cavity and are particularly suitable for the delivery of pharmaceutical active ingredients, although immediate release, delayed release, controlled release and sustained release compositions are all also within the various contemplated embodiments.

[0159] (Branched Polymer) The pharmaceutical composition films may include dendritic polymers, which may include highly branched macromolecules with a variety of structural architectures. Dendritic polymers may include dendrimers, dendritic polymers (dendritic grafted polymers), linear dendritic hybrids, multi-arm star polymers, or hyperbranched polymers.

[0160] Hyperbranched polymers are highly branched polymers that have imperfections in their structure. However, they can be synthesized in a single-step reaction, which is an advantage over other dendritic structures, and therefore suitable for large-scale use. Apart from their globular structure, the properties of these polymers are abundant functional groups, intramolecular cavities, low viscosity, and high solubility. Dendritic polymers are used in several drug delivery applications. See, for example, "Dendrimers as Drug Carriers: Applications in Different Routes of Drug Administration," J Pharm Sci, VOL. 97, 2008, 123-143, incorporated herein by reference.

[0161] Dendritic polymers may have internal cavities that can encapsulate drugs. Steric hindrance caused by dense polymer chains may prevent drug crystallization. Thus, branched polymers may offer additional advantages in formulating crystalline drugs in polymer matrices.

[0162] Examples of suitable dendritic polymers include poly(ether)-based dendrons, dendrimers, and hyperbranched polymers, poly(ester)-based dendrons, dendrimers, and hyperbranched polymers, poly(thioether)-based dendrons, dendrimers, and hyperbranched polymers, poly(amino acid)-based dendrons, dendrimers, and hyperbranched polymers, poly(aryl alkylene ether)-based dendrons, dendrimers, and hyperbranched polymers, poly(alkylene imine)-based dendrons, dendrimers, and hyperbranched polymers, poly(amido amine)-based dendrons, dendrimers, or hyperbranched polymers.

[0163] Other examples of hyperbranched polymers include poly(amines), polycarbonates, poly(ether ketones), polyurethanes, polycarbosilanes, polysiloxanes, poly(ester amines), poly(sulfone amines), poly(urethane ureas) and polyether polyols, such as polyglycerol.

[0164] The film can be made by combining at least one polymer and a solvent, optionally including other ingredients. The solvent can be water, a polar organic solvent, including but not limited to ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent can be a non-polar organic solvent, such as methylene chloride. The film can be prepared by utilizing a selected casting or deposition method and a controlled drying process. For example, the film can be prepared through a controlled drying process, including application of heat and / or radiation energy to a wet film matrix to form a viscoelastic structure, thereby controlling the content uniformity of the film. The controlled drying process can include air only, heat only, or heat and air together, contacting the top side of the film or the bottom side of the film, or a substrate supporting the cast or deposited or extruded film, or contacting two or more surfaces at the same time or at different times during the drying process. Some of such processes are described in detail in U.S. Pat. No. 8,765,167 and U.S. Pat. No. 8,652,378, which are incorporated herein by reference. Alternatively, the film may be extruded as described in US Patent Publication No. 2005 / 0037055A1, which is incorporated herein by reference.

[0165] The polymers contained in the film may be water-soluble, water-swellable, water-insoluble, or a combination of any one or more of water-soluble, water-swellable, and water-insoluble polymers. The polymers may include cellulose, cellulose derivatives, or gums. Examples of useful water-soluble polymers include, but are not limited to, polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, and combinations thereof. Examples of useful water-insoluble polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and combinations thereof. At higher doses, it may be desirable to incorporate a polymer that provides a higher level of viscosity compared to lower doses.

[0166] The phrase "water-soluble polymer" and its variations as used herein refer to a polymer that is at least partially soluble in water, and desirably completely or mostly soluble in water or absorbs water. Polymers that absorb water are often referred to as water-swellable polymers. Materials useful in the present invention can be water-soluble or water-swellable at room temperature and other temperatures, such as temperatures above room temperature. Furthermore, these materials can be water-soluble or water-swellable at pressures below atmospheric pressure. In some embodiments, films formed from such water-soluble polymers can be sufficiently water-soluble to be dissolvable upon contact with bodily fluids.

[0167] Other polymers useful for incorporation into the film include biodegradable polymers, copolymers, block polymers, or combinations thereof. It is understood that the term "biodegradable" is intended to include materials that degrade chemically as opposed to materials that physically break down into pieces (i.e., bioerodible materials). The polymers incorporated into the film can also include combinations of biodegradable or bioerodible materials. Known useful polymers or classes of polymers that meet the above criteria include: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanes, polyoxalates, poly(α-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymers thereof. Additional useful polymers include stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propanoic acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymers, copolymers of polyurethane and (poly(lactic acid)), copolymers of α-amino acids, copolymers of α-amino acids and caproic acid, copolymers of α-benzyl glutamate and polyethylene glycol, copolymers of succinic acid esters and poly(glycols), polyphosphazenes, polyhydroxy-alkanoates, or mixtures thereof. The polymer matrix can include one, two, three, four or more components.

[0168] A variety of different polymers may be used, but it is desirable to select a polymer that provides the film with mucoadhesive properties and the desired dissolution and / or disintegration rate. In particular, the time that it is desirable to maintain the film in contact with the mucosal tissue depends on the type of pharmacoactive ingredient contained in the composition. Some pharmacoactive ingredients may only require a few minutes for delivery through the mucosal tissue, whereas other pharmacoactive ingredients may require up to several hours or even longer. Thus, in some embodiments, one or more water-soluble polymers as described above may be used to form the film. However, in other embodiments, it may be desirable to use a combination of a water-soluble polymer and a water-swellable, water-insoluble and / or biodegradable polymer as provided above. The inclusion of one or more water-swellable, water-insoluble and / or biodegradable polymers may provide a film with a slower dissolution or disintegration rate than a film formed with only a water-soluble polymer. Thus, the film may adhere to the mucosal tissue for a longer time, such as up to several hours, which may be desirable for the delivery of certain pharmacoactive ingredients.

[0169] (film thickness and size) Desirably, the individual film doses of the pharmaceutical film can have a suitable thickness and small size, which is between about 0.0625-3 inches (1.5875 mm-76.2 mm) by about 0.0625-3 inches. The film size can also be, in at least one embodiment, greater than 0.0625 inches, greater than 0.5 inches (12.7 mm), greater than 1 inch (25.4 mm), greater than 2 inches (50.8 mm), about 3 inches (76.2 mm), and greater than 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, less than 0.0625 inches, or in another embodiment, greater than 0.0625 inches, greater than 0.5 inches, greater than 1 inch, greater than 2 inches, or greater than 3 inches, about 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, less than 0.0625 inches. The aspect ratio, including thickness, length and width, can be optimized by those skilled in the art based on the chemical and physical properties of the polymer matrix, the active pharmaceutical ingredient, dosage, enhancer and other additives involved, and the desired dimensions of the dispensing unit.The film dose must have good adhesion when placed in the buccal cavity or sublingual area of ​​the user.Furthermore, the film dose must disperse and dissolve at a moderate rate, most preferably disperse within about 1 minute and dissolve within about 3 minutes. EXAMPLES

[0170] (Example) A series of film formulations using diisobutyryl L-epinephrine (DIE) hydrochloride were produced with varying excipients and processing conditions. Formulation details are given in Table 1A. The formulations used in clinical trials are shown in Table 1B. The stability of the formulations was evaluated using a 3-day 60°C heat stress test. Each excipient change resulted in either a significant reduction in total degradants or a reduction in specific impurities. The stability data are given in Table 2. Table 1A Formulation composition of various film formulations [Table 1] Table 1B - Formulations Used in Clinical Trials [Table 2] Table 2 - Incremental stability improvement with excipients and processing solvents [Table 3] Table 3 - Effect of NaCl on film disintegration time [Table 4]

[0171] (Effect of hydrochloric acid as an acidifier on stability) Citric acid is the usual acidifier used in film formulations (Formulation 33-1-1). Inorganic acids such as hydrochloric acid were used as acidifiers (Formulation 45-1-3), and the results showed that HCl was a better acidifier since it provided better product stability. The use of HCl reduced hydrolytic degradants as well as other unknown degradants, both of which led to reduced assay loss after a 3-day heat stress test. Other acids such as phosphoric acid and hydrofluoric acid were found to be less effective than HCl.

[0172] (Effect of pH on stability) Referring to Figure 6, a series of formulations were prepared with varying pH using HCl and the stability was evaluated using a 3-day heat stress test at 60°C. Based on the data, it can be seen that a pH range of 2.5 to 3.5 is optimal for stability.

[0173] (Effect of aqueous organic solvents as process solvents for producing coating mixtures) Formulations were prepared using aqueous ethanolic solutions to produce the coating mixture. The films produced were compared for stability at T0 and after thermal stress testing. Results showed that overall unknown degradants and assay loss were further reduced in both conditions when organic solvents were used. A 50:50 mixture of ethanol and water was found to be optimal as the solvent, with reducing the amount of ethanol resulting in inhomogeneous films.

[0174] (Effect of desiccants on film stability) Ester prodrugs are generally susceptible to hydrolysis, and assay losses after storage were believed to be due to the presence of residual moisture in the films. A desiccant such as silicon dioxide was used to minimize the presence of free water. Compared to Cab-O-Sil®, Syloid 244FP used in formulation 55-1-1 was found to reduce hydrolytic degradation compared to formulation 45-1-1, which did not have a desiccant. Syloid in the formulation also resulted in a film with reduced tack.

[0175] (Effect of antioxidants on film stability) It was believed that some of the unknown degradants in the films arose from oxidative reactions of the drug. To address this, several common antioxidants such as caffeic acid, L-cysteine, and EDTA were tested, with EDTA being found to be the most effective one after heat stress testing. The use of a chelating agent such as EDTA resulted in a reduction in hydrolytic degradants as well as other unknown degradants, both of which resulted in a reduction in assay loss after a 3-day heat stress test.

[0176] (Effect of film-forming polymers on stability) To reduce stability issues typically associated with film-forming polymers such as HPMC and PEO, PVP was utilized along with pregelatinized hydroxypropyl pea starch (e.g., Lycoat® RS 780). This change in the film-forming polymer resulted in a decrease in film disintegration time and a reduction in unknown impurities leading to reduced assay loss.

[0177] (Effect of resin on stability) The use of anion exchange resins such as Amberlite® IRP64 in films (e.g., Formulation 98-1-1) resulted in either a reduction or elimination of hydrolysis and unknown degradants, which led to a reduction in assay loss after heat stress testing. The anion exchange resin may act as a scavenger of reactive species such as alkali or alkaline earth metals that react with the drug.

[0178] (Effect of salt on film disintegration) The incorporation of sodium chloride (NaCl) into the film formulation was found to increase the film disintegration time as tested by small volume disintegration. The data is summarized in Table 3. Faster disintegrating films were found to improve drug permeation as evidenced by the ex vivo buccal permeation data. The data is summarized in Figure 7. The use of NaCl resulted in faster release and permeation of the drug from the film resulting in an earlier onset. Example 1 - Dipivefrin Sublingual Film (DSF) Formulation Table 1 - DSF Formulation Examples [Table 5] Example 2 - Diisobutyryl Epinephrine Sublingual Film (DSF) Formulation Table 2 - DESF Formulation Examples [Table 6]

[0179] Example 3 - pH Adjuster Selection In this example, the DESF platform utilized a citrate buffer system to generate a target pH range of 3-4. To improve the stability profile of the formulation, the use of HCl as an acidifying agent was explored. The impact of HCl as an acidifying agent was compared between the following systems: 1.33-1-1: PVP / HMPC / PEO system, acidified with citrate buffer system, aqueous solvent 2.45-1-3: PVP / HMPC / PEO system, acidified with HCl, aqueous solvent

[0180] With HCl as the acidifying agent, the following improvements were noted compared to 33-1-1: Reduced production of hydrolysis products (e.g. epinephrine, monoisobutyryl epinephrine (MIE)) Overall reduction in unknown decomposition products Reduced assay loss

[0181] The effect of assay loss with respect to pH was investigated by evaluating a pH range of 2.5 to 6.5. It was concluded that the operational pH range of 2.5 to 3.5 utilized could be selected to minimize the impact on formulation stability.

[0182] Example 4-SVD The application of small volume collapse (SVD) to highlight solvation of a dose from a single surface and edge was examined, in this case utilizing a dose applied to the surface of a volume of aqueous medium within a Petri dish. · SVD was used for 112-1-5 dipivefrin sublingual film. -Average unit dose weight: 197mg. Main ingredients: 14.55% dipivefrin, 10.28% eugenol Film swelling was observed in approximately 2 minutes. The swelling did not significantly extend beyond the original area of ​​the unit dose. Film rupture began, on average, at 12 minutes 4 seconds (standard deviation: 48.1 seconds). -The entire film disintegrated in approximately 17 minutes.

[0183] Example 5 - Film Disintegration Profile as a Function of Formulation Referring to FIG. 1, the film disintegration profile is shown as a function of formulation. Table 3 - DSF and DESF decay profiles [Table 7]

[0184] In this system, the DSF formulation used a PVP / HMPC / PEO polymer system, 12.5% ​​dipivefrin HCl. The DESF formulation used a PVP / Lycoat® RS 780 polymer system, 12.5-30% diisobutyryl epinephrine HCl. Disintegration was measured using partial immersion disintegration (PID), USP disintegration (ARDTM-134), and small volume disintegration (SVD) methods. SVD showed significant differences in disintegration times between the DSF and DESF platforms.

[0185] Example 6 - Drug Release Test To test drug release, DSF and DESF systems were similarly designed with the following formulation: DSF: PVP / HMPC / PEO polymer system, 12.5% ​​dipivefrin HCl DESF: PVP / Lycoat® RS 780 polymer system, 12.5% ​​diisobutyryl epinephrine HCl

[0186] Utilizing the polymer / disintegrant excipient approach with a lower coating weight, the DESF platform unexpectedly demonstrated an improved and better drug release profile. Of the total dose, the following amounts of either dipivefrin or diisobutyryl epinephrine were released from the film matrix: DSF: 0.5% in 5 minutes, 21% in 2 hours DESF: 6% in 5 minutes, 42% in 2 hours

[0187] Referring to FIG. 2, both films exhibited a biphasic drug release profile, with rapid drug release from 0 to approximately 40 min, and the percent permeation continued to increase but gradually tapered off after about 40 min to 120 min.

[0188] Example 7 - Effect of disintegration time on tissue penetration Referring to Figures 5A and 5B, the effect of disintegration time on tissue permeation is shown. Figure 5A was performed using the SVD method. Figure 5B was performed using the PID method. In both methods, an increase in the percentage of API permeated correlated with films exhibiting a decrease in disintegration time.

[0189] Referring to FIG. 8, baseline corrected mean epinephrine concentrations were measured over time following administration of the prodrug (12 mg) in Formulations 1, 2, 3 and 4.

[0190] Referring to Figure 9, the median epinephrine Tmax was determined. Results are shown with bars indicating minimum and maximum. · Tmax (or time to maximum concentration) is a critical parameter for rescue medication. The highest observed Tmax values ​​observed for Formulations 1, 2, 3 and 4 at 12 mg were lower than the highest Tmax value for the autoinjector. The median Tmax values ​​for formulations 1, 2, 3 and 4 were comparable to published values ​​for autoinjectors.

[0191] Example 8 - Polymer to Drug Loading Ratio The following formulations were used to test effective polymer to drug loading ratios: Eugenol was used as a permeation enhancer and NaF was used as an esterase inhibitor. Laboratory scale results were weight normalized. Hydrolysis products and impurities were measured separately. Table 4 - Polymer and drug loading ratios [Table 8] ·Hydrolysis products (hydrolysis method) Monoisobutryryl epinephrine Epinephrine: observed under accelerated conditions (40 / 75) ·Degradation products (impurity method) · RRT 1.81: Probably eugenol related. · RRT 1.91: Probably eugenol related. Other unspecified: Remains near or below the limit of quantification after 6 months at 25°C.

[0192] Example 9 - Eight Stability Studies 3A and 3B, these studies were performed as follows to measure hydrolytic related substances of diisobutyryl epinephrine in diisobutyryl epinephrine sublingual films (DESF) by HPLC. Four formulations shown in Table 1B were used. Required Materials and Equipment 1.1 Epinephrine standard sample 1.2 Purified water or equivalent 1.3 Acetonitrile (ACN), HPLC grade or equivalent 1.4 Ammonium Formate (Am F), ACS grade or equivalent 1.5 Formic acid (FA), ACS grade or equivalent 1.6 Phosphoric acid (H3PO4), ACS grade or equivalent 1.7 Analytical balance capable of weighing to the nearest 0.01 mg 1.8 HPLC with UV / PDA detector 1.9 ACE HILIC-N 1.7μm, 3×100mm, p / n HILN-17-1003U HPLC column 1.10 Waters Empower Data Acquisition System or equivalent 1.11 List Action Shaker 1.12 Ultrasonic bath 1.13 Glass pipettes, class "A" 1.14 Volumetric flasks, class "A" 1.15 Plastic Syringe 1.16 0.45μm nylon syringe filter The wash solution was prepared as follows: 1.17 Mobile phase A - 0.1% formic acid in 200 mM ammonium formate: Accurately weigh out 12.6 g of ammonium formate and dissolve in 1 L of purified water measured in class "A" glassware. Transfer 1.0 mL of FA to the buffer solution and mix well. Degas before use. 1.18 Mobile phase B – 0.1% formic acid in acetonitrile: Transfer 1.0 mL of FA to 1 L of ACN measured in class "A" glassware and mix well. Degas before use. 1.19 Diluent A - 0.05% H3PO4 in 50 / 50 water / acetonitrile: Combine 1000 mL of purified water with 1000 mL of ACN. Transfer 1.0 mL of H3PO4 and mix well. Equilibrate the solution to room temperature before use. 1.20 Diluent B / Column Wash-2-10 / 90 Water / Acetonitrile: Combine 100 mL of purified water with 900 mL of ACN. Equilibrate the solution to room temperature prior to use. 1.21 Needle / Column Wash-1-50 / 50 Water / ACN: Combine 500 mL of purified water with 500 mL of ACN and mix well. 1.22 Seal Wash - 95 / 5 Water / ACN: Combine 950 mL of purified water with 50 mL of ACN and mix well. Standard solutions were prepared as follows: 1.23 Epinephrine stock standard solution (120 μg / mL) Accurately weigh 12 mg (± 10%) of epinephrine standard into a 100.0 mL volumetric flask. Add approximately 50 mL of Diluent A. Sonicate for 5 minutes or until completely dissolved. Dilute to volume with Diluent A and mix well. 1.24 Working standard solution 0.5% (1.2 μg / mL epinephrine) Pipette 1.0 mL of Epinephrine Stock Standard Solution into a 100 mL volumetric flask and make up to volume with Diluent B and mix well. 1.25 Epinephrine LOQ solution 0.05% (0.12 μg / mL epinephrine) Pipette 2.0 mL of Working Standard Solution into a 20 mL volumetric flask. Dilute to volume with Diluent B and mix well. Prepare fresh on the day of analysis. Sample preparation 1.26 Impurity Stock Sample Solution Weigh film sample and transfer to volumetric flask as specified in the table below. Add approximately 50% volume of Diluent A and dissolve by mechanical shaking for 30 minutes. Dilute to volume with Diluent A and mix well. Table 5 -DESF stock sample solution preparation scheme [Table 9] 1.27 Impurity working sample solution Pipette 10.0 mL of the impurity sample stock solution into a 25 mL volumetric flask, bring to volume with acetonitrile, and mix well. Filter the solution through a 0.45 μm nylon syringe filter into an HPLC vial and discard at least 1 mL of the filtrate. 1.28 Placebo Stock Solution Transfer one placebo film strip to a 20 mL volumetric flask. Add Diluent A to approximately half the volume and dissolve by mechanical shaking for 30 minutes. Dilute to volume with Diluent A and mix well. 1.29 Placebo working sample solution Pipette 5.0 mL of placebo stock solution into a 25 mL volumetric flask, bring to volume with acetonitrile, and mix well. Filter the solution through a 0.45 μm nylon syringe filter into an HPLC vial and discard at least 1 mL of the filtrate. 1.30 Diluent Blank Aliquots of Diluent B used in sample and working standard preparation are transferred to HPLC vials for analysis. 2 calculation 2.1 Standard concentration (μg / mL):

number

number

[0193] Stability was measured after 6 months, and data trends predict that ~95% assay will remain at 24 months.

[0194] After 6 months at 25° C. there is no significant change (<5%) from T=0. A distinction is observed at 40° C. Significant (>5%) changes are observed in Forms 1 and 3 at 40° C. for 6 months.

[0195] In terms of stability, formulation 4 was the most stable, formulation 2 was in second place, formulation 3 was in third place, and formulation 1 was in fourth place. Table 7: Assay Variation [Table 11]

[0196] (Clinical Trials) A Phase 1 randomized single ascending dose (SAD) study was conducted with Formulations 1, 2, 3 and 4 to evaluate the safety, tolerability, PK and PD profiles. The study was conducted in Canada pursuant to an Investigative Drug Application approved by Health Canada. Study participants received sublingually administered doses of Formulations 1, 2, 3 and 4 in an ascending fashion. The four formulation compositions were varied to evaluate the use of excipients of the invention designed to affect critical absorption coefficients, including drug loading, as well as absorption, stability and prodrug conversion. The target formulation ("Formulation #2") was designed as the lead candidate for the study. Most Important Points of the Exam Critical clinical measures of comparability with existing autoinjectors (C max , T max , and area under the curve, or AUC) were within the expected range for formulations 1, 2 (target), and 4. -Multiple formulations of T max fell into a narrower range compared to published data for autoinjectors. -The observed PD values ​​were comparable to existing autoinjector data Formulations 1, 2, 3 and 4 were generally well tolerated with no serious adverse events. Table 8: Prodrug Profile [Table 12] 1 Dworaczyk D., Hunt A., presented at the American Academy of Allergy, Asthma, Immunology (AAAAI) National Conference, March 16, 2020. brynpharma.com / media / content / docs / comparative-delivery-poster.pdf; 2 Aquestive Therapeutics, Study 160455, recorded.

[0197] This study demonstrated that formulations 1, 2, 3, and 4 were absorbed and rapidly converted to epinephrine, with the observed median T max was observed for 15 min and the geometric mean C max The study showed that the median T of 762 pg / mL was comparable to published study results for both EpiPen® and Auvi-Q®. Furthermore, the target formulation showed similar median T of 762 pg / mL at a lower dose strength. max(15 minutes and 17.5 minutes for the 6 mg and 9 mg doses, respectively). Based on the study results, Aquestive plans to continue developing the targeted formulation. For example, Dworaczyk D., Hunt A. Presented at the American Academy of Allergy, Asthma, Immunology (AAAAI) National Conference, March 16, 2020. brynpharma.com / media / content / docs / comparative-delivery-poster.pdf;Aquestive Therapeutics, Study 160455, archived;Dworaczyk D., Hunt A., J Allergy Clin Immunol Pract. 2021;147(2):(2 suppl)AB241 Presented at the American Academy of Allergy, Asthma and Immunology (AAAAI) National Conference;March 16, 2020; accessed March 2, 2021;Worm M et al., Clin Transl Allergy. 2020:10:21;Duvauchelle T et al., J Allergy Clin Immunol Pract. 2018;6(4):1257-1263; 1 See Breuer C et al., Eur J Clin Pharmacol. 2013;69:1303-1310; Edwards ES et al., Ann Allergy Asthma Immunol. 2013;111(2):132-137.

[0198] Safety data showed that Formulations 1, 2, 3, and 4 were generally well tolerated with no serious adverse events (SAEs), significant medical events, or treatment-related serious adverse events reported within the study. All treatment-emergent adverse events (TEAEs), at least of possible relevance, were mild to moderate in nature across cohorts.

[0199] PD markers measured were change from baseline in heart rate, systolic blood pressure, and diastolic blood pressure. Values ​​observed suggested comparable effects from formulations 1, 2, 3, and 4 and what would be expected for these metrics in healthy volunteers following autoinjector treatment.

[0200] Referring to Figure 10, the mean change in systolic blood pressure is shown for Formulations 1 and 2 versus Epipen®. It is generally accepted that subjects experience changes in systolic blood pressure over time following administration of epinephrine. Formulations 1 and 2 show similar changes from baseline systolic blood pressure when compared to the EpiPen® data. This pharmacodynamic "marker" secondarily informs us that Formulations 1 and 2 are working as intended following administration, respectively.

[0201] Table 9: Adverse events following 12 mg administration Adverse events (AEs) were measured following administration of the 12 mg dose of Formulations 1 to 4. Most AEs were mild in severity, and there were no serious adverse events. [Table 13]

[0202] Example 9: Effect of drug loading on hydrolysis test With reference to the formulations in Table 1B, the following tests on drug loading and sodium fluoride appear to have the strongest effect on hydrolysis. The rate of increase in hydrolysis products is greatest in formulations 3 and 1; formulation 3 omits sodium fluoride, and formulation 1 contains sodium fluoride but has a lower drug loading. These embodiments demonstrate that both the absence of sodium fluoride and the lower drug loading contribute to the increase in hydrolysis products.

[0203] (hydrolysis product) Data show that at 25°C, the trend predicts ~4% at 24 months in Formulation 1 and 2-3% in Formulation 2 / Formulation 4. Table 10: %LC / month [Table 14]

[0204] Similar results were observed on clinical films over a 3-month period.

[0205] (epinephrine) At 25°C and after 6 months, it is below the limit of quantification (0.05%).

[0206] At 40° C., at 6 months, it is 0.5% in Form 1.

[0207] Example 10 Referring to Figures 4A and 4B, the data show improved drug release of dipivefrin from both platform films.

[0208] Example 11 Dipivefrin film formulations were manufactured using the excipients and process used to manufacture DESF. The stability achieved with the DESF platform is shown in Figure 8. This shows that excellent stability is achieved even at accelerated temperatures. The data is summarized in the table below. One of the hydrolysis products is monopivaloylepinephrine (MPE). Table 11: Stability of dipivefrin in the DESF platform formulation (138-1-1) [Table 15] Example 12 Degradation can occur by several pathways, including, for example, primarily transesterification and hydrolysis. Stabilizers can protect compositions from degradation pathways or combinations of these pathways as indicated. An Arrhenius-based model was developed to predict the degradation rates of DESF impurities. The Arrhenius equation was used to study the relationship between reaction rate and temperature. The model accurately predicted monoisobutrylyl epinephrine (PD-15) degradant levels and correlated well with real-time data generated under ICH stability conditions. Predicted degradant levels were measured as %LC at the end of 6 months at 40°C, 12 months at 30°C, and 25 months at 25°C. Predicted shelf life was analyzed for 3-5 years storage at 25°C. All degradants remained within specification limits at the end of each storage period. The first degradant, PD-15, is expected to fail at 4 years (range 3.1-5.2 years) at 25°C storage. Degradation rates at 25°C are presented as %LC / day. Table 12: Impurity decomposition rate [Table 16] 11, the Arrhenius equation predicted the reaction rate as a function of temperature for the monoisobutrylyl epinephrine hydrolysis product, as reflected in Table 13 below. When the natural logarithm of the calculated reaction rate was plotted against the reciprocal of temperature, the y-intercept ln(A) and slope -E a In this equation, A and R are constants, and E a is the activation energy of the reaction. By inputting the temperature into the equation, we can calculate the reaction rate at that temperature.

number

[0209] Other aspects, embodiments, and features will be apparent from the following description, drawings, and claims.

Claims

1. Active ingredient, a film-forming polymer comprising a starch ether, and desiccant 1. A pharmaceutical composition having increased solubility comprising:

2. 10. The composition of claim 1, wherein the starch ether is a hydroxyalkyl ether of starch.

3. 3. The composition of claim 2, wherein the hydroxyalkyl ether of starch is a hydroxypropyl ether of starch.

4. 10. The composition of claim 1, wherein the film-forming polymer is pea starch.

5. 10. The composition of claim 1, wherein the desiccant comprises silica.

6. 10. The composition of claim 1, wherein the desiccant comprises fumed silica or mesoporous silica.

7. 10. The composition of claim 1, wherein the film-forming polymer and the desiccant have a weight ratio of 10:1 to 2:

1.

8. 10. The composition of claim 1, wherein the active ingredient comprises 0.1% to 80% by weight of the composition.

9. 10. The composition of claim 1, further comprising a stabilizer.

10. 10. The composition of claim 9, wherein the stabilizer comprises a chelating agent.

11. 10. The composition of claim 1, further comprising an antioxidant.

12. 10. The composition of claim 9, wherein the stabilizer comprises an ion exchange resin.

13. 13. The composition of claim 12, wherein the ion exchange resin is a cation exchange resin.

14. The composition of claim 1, further comprising a penetration enhancer.

15. 10. The composition of claim 1, further comprising a penetration enhancer comprising an adrenoceptor interactor.

16. 15. The composition of claim 14, wherein the permeation enhancer comprises eugenol.

17. 10. The composition of claim 1, further comprising a processing solvent.

18. 18. The composition of claim 17, wherein the processing solvent is an organic processing solvent.

19. 18. The composition of claim 17, wherein the processing solvent comprises one or more of ethanol, acetone, acetonitrile, t-butanol, methanol, 1-propanol, isopropanol, tetrahydrofuran, acetaldehyde, dioxane, or methyl isocyanide.

20. 18. The composition of claim 17, wherein the processing solvent comprises at least 20% ethanol, at least 30% ethanol, at least 40% ethanol, or at least 50% ethanol.

21. 10. The composition of claim 1, further comprising a plasticizer.

22. 22. The composition of claim 21, wherein the plasticizer comprises a polyol.

23. 22. The composition of claim 21, wherein the plasticizer comprises pentatol.

24. 22. The composition of claim 21, wherein the plasticizer comprises sucralose and / or a sugar alcohol (e.g., sorbitol, mannitol, or xylitol).

25. 10. The composition of claim 1, further comprising a viscosity enhancer.

26. 26. The composition of claim 25, wherein the viscosity enhancing agent comprises gelatin, xantham gum, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, microcrystalline cellulose, chitosan, natural gum, polyvinyl, cross-linked polymers, or other synthetic polymers.

27. 10. The composition of claim 1, further comprising a surfactant.

28. 28. The composition of claim 27, wherein the surfactant comprises Labrasol® or GMO.

29. 10. The composition of claim 1, further comprising an esterase inhibitor.

30. 30. The composition of claim 29, wherein the esterase inhibitor comprises NaF.

31. 10. The composition of claim 1, further comprising a sweetener.

32. 32. The composition of claim 31, wherein the sweetener comprises sucralose or Magnasweet™.

33. 10. The composition of claim 1, further comprising a flavoring or coloring agent.

34. Active ingredient, a pH adjuster comprising HCl, and Plasticizers containing non-reducing sugars 10. A pharmaceutical composition for delivering a pharmaceutical composition with increased stability, comprising:

35. 35. The composition of claim 34, wherein the non-reducing sugar is a polyol.

36. 35. The composition of claim 34, wherein the non-reducing sugar is pentatol.

37. 35. The composition of claim 34, wherein the non-reducing sugar is xylitol.

38. 10. The composition of claim 1, wherein the pH adjuster provides a formulation pH of 2.5 to 3.5 and the plasticizer has a weight ratio of 1:20 to 1:

8.

39. Active ingredient, stabilizers, plasticizer 1. A pharmaceutical film product comprising: a pharmaceutical film product having a small volume disintegration value in the range of about 1 to about 240 seconds as measured according to a small volume disintegration assay.

40. 40. The pharmaceutical film product of claim 39, having a small volume disintegration time in the range of about 2 to about 30 seconds.

41. 40. The pharmaceutical film product of claim 39, having a small volume disintegration time in the range of about 2 to about 10 seconds.

42. 1. A method for producing a pharmaceutical composition with increased stability, comprising forming a composition having a disintegration profile in the range of about 1 to about 60 seconds as measured according to a small volume disintegration assay.

43. 40. The pharmaceutical film product of claim 39, having a partial immersion disintegration value ranging from about 2 to about 30 seconds as measured according to a small volume disintegration assay.

44. 40. The pharmaceutical film product of claim 39, having a partial immersion disintegration value in the range of about 2 to about 10 seconds as measured according to a small volume disintegration assay.

45. 1. A method for producing a pharmaceutical formulation having an enhanced dissolution rate, comprising: Providing active ingredients incorporating a desiccant comprising mesoporous silica; and Applying a film-forming polymer comprising pea starch The method comprising:

46. 1. A method for producing a pharmaceutical formulation with increased stability, comprising: Providing an active ingredient, incorporating a pH adjusting agent to provide a formulation pH of 2.5 to 3.5; and Incorporating plasticizers, including xylitol The method comprising:

47. To stabilize epinephrine delivered transmucosally, Active ingredient, a pH adjuster that provides a formulation pH of 2.5 to 3.5; a desiccant comprising mesoporous silica; and Plasticizers, including xylitol wherein administration of said pharmaceutical composition achieves an effective plasma concentration of a pharmaceutically active form of epinephrine in less than one hour.

48. 47. The method of claim 46, wherein the pH adjuster is HCl.

49. 48. The pharmaceutical composition of claim 47, wherein the pH adjuster is HCl.

50. 10. The composition of claim 1, wherein the active ingredient comprises a prodrug of epinephrine.

51. 51. The composition of claim 50, further comprising a degradation product.

52. 52. The composition of claim 51, wherein the degradant is a hydrolysis product of the epinephrine prodrug or is part of the active ingredient delivered to a subject.

53. 52. The composition of claim 51, wherein the level of the degradant is present at about 3.5% or greater at the end of 6 months, about 2.3% or greater at the end of 12 months, or about 2.4% or greater at the end of 24 months.

54. The decomposition product is about 2.2 × 10 -3 53. The composition of claim 52, having a degradation rate of .

55. 53. The composition of claim 52, wherein the degradant maintains a shelf life during storage at 25°C for at least 3 years, at least 4 years, or at least 5 years.

56. 53. The composition of claim 52, wherein the rate of growth of degradants remains substantially unchanged for at least 3 months, or at least 5 months.

Images