Epinephrine and prodrug compositions for enhanced delivery

Abstract

To provide a pharmaceutical composition having enhanced active ingredient permeation characteristics.SOLUTION: The pharmaceutical composition comprises a polymer matrix, a pharmaceutically active ingredient comprising epinephrine or a prodrug thereof in the polymer matrix, and an adrenergic receptor interacting substance. Preferably, the pharmaceutical composition further comprises a permeation enhancer, and preferably, the pharmaceutical composition is a film further comprising a polymer matrix, and the pharmaceutically active ingredient is contained in the polymer matrix.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] (Priority Claim) This application is a continuation-in-part of U.S. patent application Ser. No. 15,791,249, filed October 23, 2017. This application is a continuation-in-part of U.S. patent application Ser. No. 15 / 717,859, filed Sep. 27, 2017. This application is a continuation-in-part of U.S. patent application Ser. No. 15 / 587,364, filed May 4, 2017. This application is a reissue of U.S. patent application Ser. No. 62 / 331,996 filed May 5, 2016. Each of these applications claims priority under 35 U.S.C. §119(e), and is incorporated by reference in its entirety. No. 60 / 699,493, filed on Oct. 1, 2003, which is incorporated herein by reference.

[0002] (Technical field) The present invention relates to pharmaceutical compositions. [Background technology]

[0003] (background) The active ingredient, such as a drug or medicine, is delivered to the patient in a planned manner. Transdermal or transmucosal drug or pharmaceutical delivery is effective and efficient. The modality may require penetrating or otherwise crossing a biological membrane. Summary of the Invention

[0004] (overview) Generally, the pharmaceutical composition comprises a polymer matrix, epinephrine in the polymer matrix, and adrenergic receptor interactors. Epinephrine is a lipophilic Prodrugs, such as dipifevrin, may be provided. In some embodiments, the pharmaceutical composition further comprises a penetration enhancer. In one embodiment, the adrenergic receptor interactor is an adrenergic receptor. In some embodiments, the adrenergic receptor antagonist may be an adrenergic receptor antagonist. The agent may also be a flavonoid or may be used in combination with a flavonoid. It is also possible.

[0005] In some embodiments, the adrenergic receptor interactor is a terpenoid, a terpenoid. The adrenergic receptor interacting agent can be a C3-C22 alcohol or acid. The active substance can be a sesquiterpene. In some embodiments, the adrenaline Receptor interactors include farnesol, linoleic acid, arachidonic acid, and docosahexaenoic acid. The compound may comprise hydroxybenzoic acid, eicosapentaenoic acid, or docosapentaenoic acid, or a combination thereof. do.

[0006] In certain embodiments, the pharmaceutical composition comprises a polymer matrix, The active pharmaceutical ingredient in the composition may include an aporphine alkaloid interacting substance.

[0007] In another embodiment, the pharmaceutical composition comprises a polymer matrix, The active pharmaceutical ingredient in the composition may include a vasodilator interacting substance.

[0008] In certain embodiments, the pharmaceutical composition comprises a film further comprising a polymer matrix. and the pharmaceutically active ingredient is contained in the polymer matrix.

[0009] In one embodiment, the adrenoceptor interactor is a plant extract. can be done.

[0010] In some embodiments, the penetration enhancer can be a plant extract.

[0011] In certain embodiments, the penetration enhancer can include a phenylpropanoid. Cut.

[0012] In certain embodiments, the pharmaceutical composition can include a fungal extract.

[0013] In certain embodiments, the pharmaceutical composition may include a saturated or unsaturated alcohol. can.

[0014] In certain embodiments, the alcohol can be benzyl alcohol.

[0015] In some cases, the flavonoids, plant extracts, phenylpropanoids, eugenol In some cases, ethanol, or a fungal extract can be used as a solubilizing agent.

[0016] In certain embodiments, the phenylpropanoid can be eugenol. In another embodiment, the phenylpropanoid is eugenol acetate. In one embodiment, the phenylpropanoid can be cinnamic acid. In another embodiment, the phenylpropanoid is a cinnamate ester. In another embodiment, the phenylpropanoid is cinnamaldehyde. can be done.

[0017] In another embodiment, the phenylpropanoid can be hydrocinnamic acid. In one embodiment, the phenylpropanoid can be chavicol. In another embodiment, the phenylpropanoid can be safrole. do.

[0018] In some embodiments, the plant extract can be an essential oil extract of a clove plant. In another example, the plant extract can be an essential oil extract of the leaves of the clove plant. do.

[0019] The plant extract can be an essential oil extract of the flower buds of the clove plant. In the present invention, the plant extract can be an essential oil extract of the stem of the clove plant.

[0020] In some embodiments, the plant extracts can be synthetic. In this manner, the plant extract contains 40-95% eugenol and 60-95% eugenol. In one embodiment, the plant extract may contain 20 to 95% eugenol. The extract may contain 80-95% eugenol.

[0021] In one embodiment, the polymer matrix can include a polymer. The polymer may include a water-soluble polymer.

[0022] In some embodiments, the polymer can be polyethylene oxide.

[0023] In some embodiments, the polymer can be a cellulosic polymer. In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose. , hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose and / or carboxymethylcellulose The cellulose acetate solution may be sodium cellulose acetate.

[0024] In some embodiments, the polymer comprises hydroxypropyl methylcellulose. This can be done.

[0025] In some embodiments, the polymer is polyethylene oxide and hydroxypropyl Methylcellulose may be included.

[0026] In some embodiments, the polymer is polyethylene oxide and / or polyvinylpyrrolidone. It may contain lolidone.

[0027] In some embodiments, the polymer matrix comprises polyethylene oxide and / or poly(ethylene oxide). It may contain sugar.

[0028] In one embodiment, the polymer matrix is ​​polyethylene oxide, hydroxy Propylmethylcellulose and / or polysaccharides may be included.

[0029] In some embodiments, the polymer matrix is ​​polyethylene oxide, cellulose The system may include a polymer, a polysaccharide, and / or polyvinylpyrrolidone.

[0030] In some embodiments, the polymer matrix is ​​made from a polymer selected from the following groups: pullulan, polyvinylpyrrolidone, and the like. Rolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, Santa gum, tragacanth gum, guar gum, acacia gum, gum arabic, polyacrylamide Acrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, Latin, ethylene oxide, propylene oxide copolymer, collagen, albumin, The polymer is selected from polyamino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof. The polymer may include at least one polymer selected from the group consisting of:

[0031] In some embodiments, the pharmaceutical composition further comprises a stabilizer. forms antioxidants, chelate complexes that can prevent unwanted oxidation of substances, Gold, which can deactivate trace amounts of metal ions that would otherwise act as catalysts Sequestering agents, emulsifiers and surfactants that can stabilize emulsions UV stabilizers, which can protect against the harmful effects of UV rays, absorb UV rays and UV absorbers are chemicals that prevent radiant energy from breaking down chemical bonds in materials. It can be formed by quenching agents or ultraviolet light, which can dissipate it as heat without Scavengers capable of scavenging free radicals may be included.

[0032] In yet another embodiment, the pharmaceutical composition comprises a saccharide linked by a bond with a hydrophilic saccharide. Suitable non-toxic, non-ionic alkyl glycosides having hydrophobic alkyl groups are selected from the group consisting of: (a) agglomerates; (b) charge modifiers; (c) pH regulators; (d) degradative enzyme inhibitors; (e) mucolytic or mucus-clearing agents; (f) a ciliostatic agent; (g) any of the following: (i) a surfactant; (ii) a bile salt; (ii) a phosphorus (iii) a lipid additive, mixed micelle, liposome, or carrier; (iv) an alcohol; (v) an enamine; ) nitric oxide donating compounds; (vi) long chain amphiphilic molecules; (vii) small molecule hydrophobic penetration enhancers; (vi (ii) sodium or salicylic acid derivatives; (ix) glycerol ester of acetoacetic acid; (x) cyclo (xi) a dextrin or β-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xi (ii) an amino acid or a salt thereof; (xiv) an N-acetylamino acid or a salt thereof; (xv) a compound that binds to a selected membrane component; (ix) inhibitors of fatty acid synthesis; (x) inhibitors of cholesterol synthesis; and (xi) a membrane permeation enhancer selected from any combination of the membrane permeation enhancers described in (i) to (x); (h) an epithelial permeation enhancer selected from any combination of the membrane permeation enhancers described in (i) to (x); (i) vasodilators; (j) selective transport enhancers; and (k) stabilized transporters. delivery vehicle, carrier, mucoadhesive, support, or complex-forming species, The compound is effectively combined, associated, contained, encapsulated, or bound to enhance The stabilizing delivery vehicle, carrier, mucous membrane, or the like provides stabilization of the compound for enhanced mucosal delivery. in combination with a mucosal delivery-enhancing agent selected from a membrane-adherent material, a support, or a complex-forming species wherein the formulation of the compound with a transmucosal delivery enhancer reduces the amount of the compound in the plasma of the subject. This provides increased bioavailability of

[0033] Generally, the method for preparing the pharmaceutical composition comprises: or a prodrug thereof, and forming a pharmaceutical composition comprising the interacting agent and the pharmaceutically active ingredient.

[0034] Generally, the pharmaceutical composition can be dispensed from a device, which comprises a polymer matrix. a pharmaceutical active ingredient comprising epinephrine in the polymer matrix; and an adrenergic receptor. A housing for holding a quantity of a pharmaceutical composition including an interacting agent, and a predetermined amount, e.g. For example, the device may include an opening for dispensing a predetermined dose of the pharmaceutical composition. The present invention provides a pharmaceutical composition containing a penetration enhancer comprising a phenylpropanoid and / or a plant extract. It can be distributed.

[0035] In some embodiments, the pharmaceutical composition comprises a polymer matrix, and causing increased blood flow or allowing tissue flushing. The composition may contain an interactive substance that alters the transmucosal uptake of the pharmaceutically active ingredient.

[0036] In certain embodiments, the pharmaceutical composition comprises a polymer matrix; and have a positive or negative heat of solution and alter (increase or decrease) transmucosal uptake. The present invention may include an interactive substance used as an adjunct to the synthesis of the compound.

[0037] In another embodiment, the pharmaceutical composition comprises a polymer matrix, and an interacting substance, the composition comprising at least one pharmaceutical active ingredient having a common border. The film is contained in a multilayer film having at least one surface.

[0038] Generally, the methods of treating a medical condition include a polymer matrix, and an adrenergic receptor interactor. The pharmaceutical composition may comprise administering an amount of epinephrine containing dipifebrine. Thus, the method of treating a medical condition can include administering a polymer matrix, a pharmaceutical active ingredient comprising dipifebrin in the polymer matrix; and administering an effective amount of a pharmaceutical composition comprising an adrenoceptor interactor. In certain embodiments, the medical condition is hypotension, cardiac arrest, heart failure, Anaphylaxis, mydriasis, asystole, pulseless electrical activity, ventricular fibrillation, pulseless ventricular tachycardia, bradycardia, These may include arrhythmia, or asthma exacerbation.

[0039] In some embodiments, the pharmaceutical film comprises a polymer matrix, A pharmaceutical active ingredient containing epinephrine or a prodrug thereof, and an adrenaline The pharmaceutical film may contain an agonist receptor interacting substance. The pharmaceutical film has a Tmax of 5 to 60 minutes and a Tmax of 0.1 In some embodiments, the Tmax is 40 minutes or less, and the Cmax is between 100 ng / ml and 2 ng / ml. wherein Cmax is 0.1 ng / ml or more. In some embodiments, Tmax is 35 minutes or less. and wherein C is 0.15 ng / ml or greater. In some embodiments, T is 30 minutes or greater. or less, and wherein Cmax is 0.2 ng / ml or more.

[0040] Cmax is 0.1ng / ml~2ng / ml, 0.15ng / ml~25ng / ml, 0.2ng / ml~1.0ng / ml, 0.2ng / ml~1. The Cmax may be greater than 0.1 ng / ml, greater than 0.15 ng / ml, or 0.2 ng / ml to 1.3 ng / ml. Cmax can be greater than 3 ng / ml, greater than 0.4 ng / ml, greater than 0.5 ng / ml, greater than 1.0 ng / ml, or greater than 1.2 ng / ml. It can be less than, less than 2 ng / ml, and less than 1.5 ng / ml.

[0041] Tmax can be 0 to 240 minutes, 10 to 60 minutes, 20 to 40 minutes, 12 to 15 minutes, and 5 to 10 minutes. , less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, and less than 10 minutes.

[0042] Other aspects, embodiments, and features are apparent from the following description, drawings, and claims. It will be. [Brief explanation of the drawings]

[0043] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] With reference to Figure 1A, the Franz diffusion cell 100 includes a donor compound 101, a donor chamber 102, a membrane 103, a sampling port 104, a receptor chamber 105, a stir bar 106, and a heater / circulator 107. With reference to Figure 1B, the pharmaceutical composition is a film 100 comprising a polymer matrix 200, in which an active pharmaceutical ingredient 300 is contained. The film can include a permeation enhancer 400. [Figure 2] With reference to Figures 2A and 2B, graphs are shown showing the permeation of an active agent from a composition. With reference to Figure 2A, the graph shows the average amount of active agent permeated versus time for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized epinephrine base. With reference to Figure 2B, the graph shows the average flux versus time for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized epinephrine base. [Figure 3] Referring to Figure 3, this graph shows the ex vivo permeation of epinephrine bitartrate as a function of concentration. [Figure 4] Referring to Figure 4, this graph shows the permeation of epinephrine bitartrate as a function of solution pH. [Figure 5] Referring to Figure 5, this graph shows the effect of enhancers on epinephrine permeation, shown as the amount permeated, as a function of time. [Figure 6] Referring to Figures 6A and 6B, these graphs show the release of epinephrine to the polymer platform (6A) and the effect of enhancers on that release (6B), plotted as permeation (µg) versus time. [Figure 7]Referring to Figure 7, this graph shows a pharmacokinetic model in male Yucatan minipigs. The study compares 0.3 mg EpiPen, 0.12 mg epinephrine IV, and a placebo film. [Figure 8] Referring to Figure 8, this graph shows the effect of the absence of an enhancer on the concentration profile of a 40 mg epinephrine film versus a 0.3 mg EpiPen. [Figure 9] Referring to Figure 9, this graph shows the effect of Enhancer A (Labrasol) on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 10] Referring to Figure 10, this graph shows the effect of Enhancer L (clove oil) on the concentration profile of two 40 mg epinephrine films (10-1-1) and (11-1-1) versus a 0.3 mg EpiPen. [Figure 11] Referring to Figure 11, this graph shows the effect of Enhancer L (clove oil) and film size (10-1-1 thin and large film and 11-1-1 thick and small film) on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 12] Referring to Figure 12, this graph shows the concentration profile for varying doses of epinephrine film in a constant matrix for Enhancer L (clove oil) for a 0.3 mg EpiPen. [Figure 13] Referring to Figure 13, this graph shows the concentration profile for varying doses of epinephrine film in a constant matrix for Enhancer L (clove oil) for a 0.3 mg EpiPen. [Figure 14] Referring to Figure 14, this graph shows the concentration profile for varying doses of epinephrine film in a constant matrix for Enhancer A (Labrasol) versus a 0.3 mg EpiPen. [Figure 15]Referring to Figure 15, this graph shows the effect of farnesol and farnesol in combination with linoleic acid on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 16] Referring to Figure 16, this graph shows the effect of farnesol on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 17] Referring to Figure 17, this graph shows the effect of farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 18] Referring to Figure 18, this graph shows the effect of farnesol and farnesol in combination with linoleic acid on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 19] Referring to Figure 19, this graph shows the effect of Enhancer A (Labrasol) in combination with Enhancer L (Clove Oil) on the concentration profile of a 40 mg epinephrine film (also shown in Figure 20) in logarithmic terms. [Figure 20] Referring to Figure 20, this graph shows the effect of Enhancer A (Labrasol) in combination with Enhancer L (Clove Oil) on the concentration profile of a 40 mg epinephrine film compared to the average data collected from a 0.3 mg EpiPen. [Figure 21] Referring to Figure 21, this graph shows the effect of Enhancer A (Labrasol) in combination with Enhancer L (Clove Oil) on the concentration profile of a 40 mg epinephrine film, shown as individual animal subjects. [Figure 22] With reference to Figures 22A and 22B, the data show the mean epinephrine plasma concentration versus time. [Figure 23] With reference to Figures 23A and 23B, the data show the mean dipifebrin plasma concentrations versus time. [Figure 24] Referring to Figure 24, the data show the mean plasma concentrations of epinephrine administered as dipivefrin. [Figure 25] Referring to Figure 25, this graph shows the conversion of dipivefrin to epinephrine. [Figure 26] With reference to Figure 26, the data shows the average mean epinephrine profile across all matrix tests. [Figure 27] With reference to Figure 27, this data presents additional data comparing the plasma concentrations of dipifebrine and epinephrine. [Figure 28] Referring to Figure 28, this graph shows the epinephrine concentration versus time profile for the phentolamine treated films. DETAILED DESCRIPTION OF THE INVENTION

[0044] (Detailed explanation) Mucosal surfaces, such as the oral mucosa, are highly vascularized and permeable, allowing fluids to pass through the digestive system. increased bioavailability because it does not undergo first-pass metabolism Mucosal surfaces are a key contributor to drug delivery to the body due to the fact that they provide potency and rapid onset of action. In particular, the buccal and sublingual tissues are convenient routes for the administration of This is the area that allows the drug to diffuse through the oral mucosa so that it has direct access to the systemic circulation. These tissues provide advantageous sites for drug delivery because they are capable of It provides increased convenience and therefore increases patient compliance. For active pharmaceutical ingredients, penetration enhancers are used to overcome mucosal barriers and improve permeability. Permeation enhancers can aid in the permeability of the barrier layer in favor of drug absorption. Permeation enhancers promote the transport of molecules across epithelia. The files and their speeds may vary depending on, but are not limited to, film size, drug loading, enhancer Various parameters such as type / loading, polymer matrix release rate and mucosal residence time can be controlled and adjusted by

[0045] Pharmaceutical compositions are designed to deliver active pharmaceutical ingredients in a planned and tailored manner. However, the in vivo dissolution of the pharmaceutically active ingredient, particularly in the mouth of a subject, The solution and permeability can vary considerably. Certain classes of permeation enhancers enhance the release of pharmaceutically active compounds. In particular, the in vivo uptake and bioavailability of the drug can be improved. When delivered to the mouth via a mucous membrane, the penetration enhancer may help to increase the rate at which the drug passes through the mucous membrane and into the bloodstream of the subject. The permeability of the active ingredient can be improved. The permeation enhancer can enhance the absorption of the pharmaceutically active ingredient. The rate and amount may vary depending on the other ingredients in the composition, such as 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 200 Less than %, 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 any combination of these ranges Only then can we improve.

[0046] In some embodiments, the pharmaceutical composition comprises a hydrophilic saccharide bond linked to a soluble saccharide. Suitable non-toxic, non-ionic alkyl glycosides having hydrophilic alkyl groups are selected from the group consisting of: (a) anti-aggregation agents; (b) charge modifiers; (c) pH adjusters; (d) degradative enzyme inhibitors; (e) mucolytic or mucus-clearing agents; (f) (g) agents that inhibit ciliary motility; (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles (iii) alcohols; (iv) enamines; (v) NO-donating compounds; (vi) long chain (vii) a small molecule hydrophobic penetration enhancer; (viii) sodium or salicylic acid (ix) Glycerol esters of acetoacetic acid; (x) Cyclodextrin or β-cyclodextrin (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) (xv) an enzyme capable of degrading a selected membrane component; (ix) a fatty acid (x) an inhibitor of cholesterol synthesis; and (xi) a membrane permeation promoter according to any one of (i) to (x). (h) a membrane permeation enhancer selected from any combination of agents; and (h) an agent for modulating epithelial junction physiology. (i) vasodilators; (j) selective transport enhancers; and (k) stabilizing delivery vehicles, carriers, mucoadhesives. a reactive material, support, or complex-forming species with which the compound is effectively formulated; and / or associated with, contained within, encapsulated within, or bound to a compound for enhanced mucosal delivery. the stabilizing delivery vehicle, carrier, mucoadhesive, support, or in combination with a mucosal delivery-enhancing agent selected from a complex-forming species, wherein the transmucosal delivery-enhancing agent Formulations of the compound that include an enhancer provide increased bioavailability of the compound in the plasma of a subject. Penetration enhancers are described in J. Nicolazzo et al., J. of Controlled Disease, 105 (200 5) 1-15, which is incorporated herein by reference.

[0047] There are many reasons why the oral mucosa is an attractive site for the delivery of therapeutic agents into the systemic circulation. Direct drainage of blood from the skin to the internal jugular vein eliminates first-pass metabolism in the liver and intestine. The first-pass effect is a biological effect of some compounds when administered orally. In addition, the mucous membranes lining the oral cavity are easily accessible. This means that the dosage form can be applied to the area where it is needed and easily removed in case of an emergency. However, like the skin, the buccal mucosa is resistant to the absorption of xenobiotics. It acts as a barrier to the permeation of compounds across this tissue. Consequently, the identification of safe and effective penetration enhancers is crucial for improving oral mucosal drug delivery. It's a major goal in the search.

[0048] Chemical permeation enhancers are substances that control the permeation rate of co-administered drugs through biological membranes. Extensive studies have investigated how permeation enhancers alter intestinal and transdermal permeability. The current focus is on gaining a better understanding of how buccal and sublingual penetration can be enhanced. Little is known about the mechanisms involved in potency.

[0049] The buccal mucosa outlines the inner lining of the cheeks and the area between the gums and the upper and lower lips. This is 100cm 2 The surface of the buccal mucosa is covered by a wavy basement membrane (approximately 1-2 cm thick). It is separated from the underlying connective tissue (lamina propria and submucosa) by a continuous layer of extracellular material (μm thick). This stratified squamous epithelium is composed of the basal region and the superficial region where cells are shed. The lamina propria consists of differentiated layers of cells that change in size, shape, and content as they move through the lining. There are approximately 40 to 50 cell layers, giving rise to a buccal mucosa 500 to 600 μm thick.

[0050] Structurally, the sublingual mucosa is similar to the buccal mucosa, but the thickness of this epithelium is 100-200 μm. This membrane is also non-keratinized and relatively thin, making it more permeable than the buccal mucosa. It has been shown that blood flow to the sublingual mucosa is slower than that to the buccal mucosa, at 1.0 ml / min. -1 / cm - 2 is in the digits.

[0051] The permeability of the buccal mucosa is greater than that of the skin but less than that of the intestine. The differences are the result of structural differences between each tissue. The absence of lamellae results in greater permeability to foreign compounds compared to the keratinized epithelium of the skin. On the other hand, the increased thickness and lack of tight junctions may make the buccal mucosa less permeable than intestinal tissue. Bring about what becomes.

[0052] The primary barrier properties of the buccal mucosa are attributed to the upper one-third to one-quarter of the buccal epithelium. reported that the permeability barrier of the non-keratinized oral mucosa beyond the surface epithelium is also due to membrane-coated granules. It is known that this is due to contents extruded from the epithelial cells into the intercellular spaces.

[0053] The intercellular lipids of the non-keratinized areas of the oral cavity are more abundant than those of the epidermis, palate, and gingiva. It is more polar in nature, and differences in the chemical properties of this lipid are observed between these tissues. This contributes to the difference in permeability that occurs between the keratinized layer and the keratinized layer, which creates a more effective barrier. Not only is there a greater degree of intercellular lipid packing in the stratum corneum of the modified epithelium, but the barrier It is clear that the chemical properties of the lipids present within the membrane are also important.

[0054] The presence of hydrophilic and lipophilic regions in the oral mucosa has allowed researchers to differentiate between two types of fluids passing through the buccal mucosa. The existence of drug transport pathways, paracellular (between cells) and transcellular (across cells), has been postulated.

[0055] Drug delivery through the buccal mucosa is limited by the barrier properties of the epithelium and the area available for absorption. Therefore, various enhancement strategies are required to deliver therapeutically relevant amounts of drugs to the systemic circulation. Various methods, including the use of chemical penetration enhancers, prodrugs, and physical methods, are available. Methods can be utilized to overcome the barrier properties of the buccal mucosa.

[0056] Chemical permeation enhancers, i.e., absorption promoters, are compounds that induce membrane damage and / or toxicity. In pharmaceutical formulations, the drug is added to increase the rate of membrane permeation or absorption of the co-administered drug without causing side effects. Chemical penetration enhancers are compounds that penetrate the skin, nasal mucosa, and intestines. There have been many studies examining the effect of steroids on the permeability of the buccal mucosa. More attention has been paid to the effects of these substances on the permeability across the buccal mucosa. Considered a passive diffusion process, the steady-state flux (Jss) is calculated by the Fickian diffusion According to the first law of diffusion, it should increase with increasing donor chamber concentration (CD).

[0057] Detergents and bile salts inhibit the activity of various compounds both in vitro and in vivo. It has been shown to enhance permeability across the buccal mucosa. The researchers found that the increased permeability was due to the action of surfactants on the intercellular lipids of the mucosa. This strongly suggests that:

[0058] Fatty acids have been shown to enhance the penetration of some drugs through the skin, and showed increased intercellular lipid fluidity by differential scanning calorimetry and Fourier transform infrared spectroscopy. It has been shown to be associated with

[0059] In addition, pretreatment with ethanol significantly reduced the amount of tritiated water and albumin across the ventral tongue mucosa. It has been shown to enhance the permeability of cephalosporins and caffeine across the buccal mucosa of pigs. In addition, the enhancing effect of Azone® on the permeability of compounds through the oral mucosa has been reported. Furthermore, chitosan, a biocompatible and biodegradable polymer, has been reported to be effective in the intestinal It has been shown to enhance drug delivery through a variety of tissues, including the nasal mucosa.

[0060] Oral transmucosal drug delivery (OTDD) is the delivery of pharmaceutical active substances to the oral mucosa to achieve systemic action. The permeation pathway and prediction model of OTDD are described in, for example, M. Sattar's paper "Oral Administration" Oral transmucosal drug delivery - Current status and future prospects nt status and future prospects)”, Int'l. Journal of Pharmaceutics, 47(2014) 49 8-506, which is incorporated herein by reference. Compared with the dermal and nasal delivery routes, Despite limited characterization of their permeation pathways within the oral cavity, recent studies have shown that ionized molecules penetrate the buccal epithelium. Researchers' growing understanding of how the body penetrates the oral cavity, as well as new assays to study the oral cavity The emergence of technologies and the ongoing development of in silico models to predict buccal and sublingual penetration; The whole is bright.

[0061] To deliver a broader class of drugs across the buccal mucosa, it is necessary to reduce the barrier capacity of this tissue. A reversible method of reducing the permeability of the buccal mucosa should be utilized. This has prompted research into penetration enhancers that safely modify the buccal permeability. anti-inflammatory agents, fatty acids and their derivatives, chelating agents, cyclodextrin and chitosan, etc. This has been improved by using various classes of transmucosal and transdermal penetration enhancers. Among these chemicals used for drug penetration enhancement, biliary The sodium chloride salt is the most common.

[0062] In vitro studies on the enhancing effect of bile salts on the buccal permeation of compounds were carried out by Sevda Sene. In the article "Drug permeation enhancement by the buccal route: possibilities and limitations" via buccal route: possibilities and limitations), Journal of Controlled Releases e 72 (2001) 133-144, which is incorporated herein by reference. The article also includes information on dihydroxy bile salts, sodium glycodeoxycholate, sodium taurodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC) and tri-hydroxy bile salts, Sodium glycocholate (GC) and sodium taurocholate (TC) at a concentration of 100 mM Recent studies on the effects of buccal epithelial permeability have also been performed to assess permeability in relation to histological effects. The changes in fluorescein isothiocyanate (FITC), morphine sulfate, and Each was used as a model compound.

[0063] Chitosan has also been shown to inhibit the activity of small polar molecules and peptides / It has been shown to enhance the absorption of protein drugs through the nasal mucosa. Other studies have shown that it enhances the absorption of protein drugs through the intestinal mucosa. and show an enhancing effect on the permeation of compounds across cultured Caco-2 cells.

[0064] The penetration enhancer can be a plant extract. The plant extract is obtained by distillation of plant material. In some circumstances, the essential oil may be an essential oil extracted by the method of the present invention or a composition containing the essential oil. In this context, plant extracts are synthetic analogs (i.e., organic compounds) of compounds extracted from plant material. The plant extract may contain phenylpropanoids (compounds produced by the synthesis of phenylpropanoids). , for example, phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester cinnamic acid, cinnamic aldehyde, hydrocinnamic acid, chavicol, or safrole, or combinations thereof The plant extract may comprise a combination of extracts from the clove plant, such as the leaves, stems, Or it can be an essential oil extract of the flower buds. The clove plant is Syzygium aromaticum The plant extract contains 20-95% eugenol and 4 Contains 0-95% eugenol, 60-95% eugenol, e.g., 80-95% eugenol The extract may also contain 5% to 15% eugenol acetate. This extract can also contain caryophyllene. This extract can also It may also contain up to 2.1% α-humulene, which is present in lower concentrations in clove essential oil. Other volatile compounds present are β-pinene, limonene, farnesol, benzaldehyde, 2 Other penetration enhancers can be ethyl hexanoate, ethyl hexanoate, and ethyl hexanoate. Suitable penetration enhancers may be added to the composition to improve absorption of substances. or synthetic bile salts, such as sodium fusidate; glycocholate or deoxycholate acids and their salts, etc.; fatty acids and derivatives, such as sodium laurate, oleic acid, chelating agents, such as oleyl alcohol, monoolein, and palmitoylcarnitine; For example, disodium EDTA, sodium citrate and sodium lauryl sulfate, Azone, Sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glycerin Cetyl monolaurate, octoxynonyl-9, laureth-9, polysorbate, sterol, or glycerides, such as caprylocaproyl polyoxylglycerides, e.g., Labrasol Penetration enhancers include derivatives of plant extracts and / or monolignols. The penetration enhancer can also be a fungal extract.

[0065] Some natural products of plant origin have been shown to have vasodilatory properties. There are several mechanisms or ways in which the products of this drug can cause vasodilation. For further details on this theory, see McNeill JR and Jurgens, T. See, e.g., .M., Can. J. Physiol. Pharmacol. 84:803-821 (2006). The vasorelaxant effects of eugenol have been reported in several animal studies. , Lahlou, S. et al., J. Cardiovasc., each of which is incorporated herein by reference. c. Pharmacol. 43:250-57 (2004), Damiani, CEN et al., Vascular Pharmacol. 40: 59-66 (2003), Nishijima, H. et al., Japanese J. Pharmacol. 79:327-334 (1998), and Hume WR, J. Dent Res. 62(9):1013-15 (1983). Calcium Channel blockade is the main mechanism behind vasorelaxation induced by plant essential oils or their main component, eugenol. It has been suggested that this is the cause. Interaminense L. See RL et al., Fundamental & Clin. Pharmacol. 21: 497-506 (2007).

[0066] Fatty acids can be used as inactive ingredients in drug preparations or drug vehicles. Fatty acids are also used in formulations due to certain of their functional effects and their biocompatible properties. Fatty acids, both free and part of complex lipids, are the main It is an essential metabolic fuel (storage and transport energy), an essential component of all membranes and gene regulators. For reviews, see Rustan AC and Drevon, CA, which are incorporated herein by reference. .'s article, "Encyclopedia of Life Sciences, Fatty Acids: Structures and Properties" See "Parties, Encyclopedia of Life Sciences" (2005). There are two families of essential fatty acids: omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). If the first double bond is found between the third and fourth carbon atoms from the ω carbon, then These are called omega-3 fatty acids. The first double bond is between the sixth and seventh carbon atoms. When used in combination with omega-6 fatty acids, they are called omega-6 fatty acids. PUFAs can also be divided into omega-6 fatty acids by adding carbon atoms and unsaturating them. Linoleic acid, an ω-6 fatty acid, is metabolized in the body by hydroxylation (removal of hydrogen). Linolenic acid, dihomo-γ-linolenic acid, arachidonic acid, adrenic acid, tetracosatetraene It is metabolized to omega-3 fatty acids, tetracosapentaenoic acid, and docosapentaenoic acid. Alpha-linolenic acid is a fatty acid that is a mixture of octadecatetraenoic acid, eicosatetraenoic acid, and eicosapentaenoic acid. EPA, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and is metabolized to docosahexaenoic acid (DHA).

[0067] Fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid Na + K + -Induces relaxation and mitochondrial function in porcine coronary artery smooth muscle cells via a mechanism involving activation of the APTase pump. and hyperpolarization, and as the degree of cis-unsaturation increased, the fatty acids showed higher potency. It has been reported that the compound has a hydroxybenzoic acid group. See SI, et al., Hypertension 31:615-20 (1998). The pulmonary vascular response to arachidonic acid, a metabolite of arachidonic acid, varies with dose, species, and arachidonic acid. Depending on the mode of administration of donic acid and the tone of the pulmonary circulation, it may be either vasoconstrictor or vasodilator. For example, arachidonic acid can be either cyclooxygenase-dependent or -independent. Each of these is incorporated herein by reference. 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, T. See .C. et al., Circ. Res. 38:167-71 (1976).

[0068] Many studies have examined the effects of EPA and DHA on vascular response after administration in oral forms. Several studies have reported effects of EPA-DHA or EPA alone on forearm microvascular function. In the circulation, it inhibits the vasoconstrictor action of norepinephrine or inhibits the vasodilator action of acetylcholine. and found that the administration of acetaminophen enhanced the tonic response. , JPF et al., Hypertension 21:22-8 (1993), and Tagawa, H. et al., J Cardiov See, e.g., J. Pharmacol 33:633-40 (1999). Another study found that both EPA and DHA contribute to the overall It tends to increase the compliance of the arterial system of the body and decrease pulse pressure and total vascular resistance. Nestel, P. et al., Am. See J. Clin. Nutr. 76:326-30 (2002). On the other hand, studies have shown that EPA, rather than DHA enhances vasodilatory mechanisms in the forearm microcirculation of overweight men with hyperlipidemia, and Mori, et al., J. Immunol. 1999, 14, 1449-1454, which is incorporated herein by reference. See TA et al., Circulation 102:1264-69 (2000). We discovered the vasodilatory effect of DHA on rhythmic contractions of isolated human coronary arteries in rats. Wu, K.-T. et al., Chinese J. Physiol. 5, incorporated herein by reference. 0(4):164-70 (2007).

[0069] Adrenergic receptors (or adrenoceptors) are receptors for catecholamines, especially norepinephrine. G protein, the target of nephrine (noradrenaline) and epinephrine (adrenaline) Epinephrine (adrenaline) is a class of receptor-coupled receptors. The α receptor interacts with both the α- and α-receptors, causing vasoconstriction and vasodilation, respectively. Although less sensitive to epinephrine, peripheral α1 receptors are more sensitive than β-adrenoreceptors. When activated, these are mediated by β-adrenoreceptors. It abolishes vasodilation. Consequently, high levels of circulating epinephrine cause vasoconstriction. At relatively low levels of circulating epinephrine, β-adrenoreceptor stimulation predominates. , causing vasodilation and a subsequent decrease in peripheral vascular resistance. Muscle contraction, mydriasis, vasoconstriction in the skin, mucous membranes, and abdominal viscera, and in the gastrointestinal (GI) tract and bladder It is known that α1-adrenergic receptors are involved in sphincter contraction. q Protein-coupled receptors Upon activation, it binds to the heterotrimeric G protein, G q Ha, Ho It activates phosphorylation of lipase C (PLC). Its mechanism of action is through interaction with calcium channels. This is accompanied by changes in intracellular calcium content. Smith RS et al., Journal of Neurophysiology 102(2): 1103-14 (2009). Many cells have these receptors.

[0070] The α1-adrenergic receptor may be the primary receptor for fatty acids. For example, Saw palmetto extract (SPE), widely used to treat benign prostatic hyperplasia (BPH), inhibits α1-adrenergic receptors. Phosphamine-, muscarinic-, and 1,4-dihydropyridine (1,4-DHP)-based calcium channel blockers Each of these is incorporated herein by reference. Abe M. et al., Biol. Pharm. Bull. 32(4) 646-650 (2009), and Suz See Uki M. et al., Acta Pharmacologica Sinica 30:271-81 (2009). Various fatty acids, including lauric acid, oleic acid, myristic acid, palmitic acid, and linoleic acid Lauric and oleic acids have alpha-1 adrenergic and muscarinic properties. Binds non-competitively to phospho- and 1,4-DHP calcium channel antagonist receptors It is possible.

[0071] In some embodiments, the penetration enhancer is an adrenergic receptor interactor. Adrenergic receptor interactors are substances that modify the action of adrenergic receptors. refers to a compound or substance that stimulates and / or otherwise alters the immune system. For example, adrenaline Receptor interactors can stimulate receptors by increasing or decreasing their binding capacity. Such interacting substances can be either short-acting or long-acting. Some short-acting interactants can be delivered in a variety of forms. However, their effects only last for a few hours. Some long-acting interactors Although they take longer to act, their effects can last longer. The interacting substances may be, for example, active pharmaceutical ingredients, permeation modifiers, permeation The selection and / or treatment is based on one or more of the enhancer, the matrix, and the condition being treated. can be designed. Adrenergic receptor interactors act as adrenergic receptor blockers. Adrenergic receptor interactors include terpenes (e.g., isobutyric acid, benzoyl peroxidase ... volatile unsaturated hydrocarbons found in plant essential oils, derived from the unit of prene, or C3-C22 alkyl It can be an alcohol or acid, preferably a C7 to C18 alcohol or acid. In some embodiments, the adrenoceptor interactor is 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 the like. The derivative may be an ester or an amide. For example, the adrenergic receptor interactor may be a fatty acid or a fatty alcohol. can be done.

[0072] The C3 to C22 alcohol or acid may be a straight chain C3 to C22 hydrocarbon, for example, optionally containing at least one divalent containing a double bond, at least one triple bond, or at least one double bond and one triple bond The hydrocarbon chain may be an alcohol or an acid having a C3 to C22 hydrocarbon chain, including to C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, hydroxyl, ha B, amino, nitro, cyano, C 3-5 Cycloalkyl, 3-5 membered heterocycloalkyl, mono Ring aryl, 5-6 membered heteroaryl, C 1-4 Alkylcarbonyloxy, C 1-4 Alkyl Oxycarbonyl, C 1-4 substituted by alkylcarbonyl, or formyl; and , and optionally, -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. R a and R b Each of is independently hydrogen, alkyl, alkyl alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or halo It's Rukiru.

[0073] Fatty acids with a higher degree of unsaturation are good candidates for enhancing drug permeation. Fatty acids showed higher enhancement than saturated fatty acids, and enhancement increased with the number of double bonds. A. Mittal et al., "Skin Penetration Enhancers," incorporated herein by reference. Status of Fatty Acids as Skin Penetration Enhancers - A Review s - A Review,” Current Drug Delivery, 2009, 6, pp. 274-279. The position of the bond also influences the enhancement of fatty acid activity. Differences in the physicochemical properties of fatty acids may affect the efficacy of these compounds as skin penetration enhancers. As the position of the double bond shifts towards the hydrophilic end, The distribution increases. Fatty acids with double bonds at even positions are more likely to be fatty acids with double bonds at odd positions. Acts more rapidly than fatty acids on perturbation of both the stratum corneum and dermis structure It has also been reported that intrachain cis-unsaturations tend to increase activity.

[0074] The adrenergic receptor interactor can be a terpene. Terpenes in essential oils The antihypertensive activity of Meneze is reported. See IA et al., Z. Naturforsch. 65c:652-66 (2010). In some embodiments, In the present invention, the penetration enhancer can be a sesquiterpene. It consists of three isoprene units and has the empirical formula C 15 H 24 It is a class of terpenes having the formula: Like monoterpenes, sesquiterpenes can be acyclic or have many unique structures. Biochemical modifications such as oxidation or rearrangement may result in the formation of related rings. Produces sesquiterpenoids.

[0075] Adrenergic receptor interactors can be unsaturated fatty acids, such as linoleic acid. In some embodiments, the penetration enhancer can be farnesol. Farnesol is a 15-carbon organic compound that is an acyclic sesquiterpene alcohol. This is the naturally occurring dephosphorylated form of farnesyl pyrophosphate. It is a colorless liquid. It is hydrophobic and therefore insoluble in water, but is soluble in oils. Farnesol is miscible with citronella, neroli, cyclamen, and gecko. It can be extracted from the oils of plants such as kelp. This is the mechanism by which mevalonate is synthesized in vertebrates. It is an intermediate step in the biosynthesis of cholesterol from the saccharin. It has a delicate floral or faint citrus scent. -has a lime scent and is used in perfumes and fragrances. Farnesol was first Selective killing of acute myeloid leukemia blasts and white blood cell lines in preference to hematopoietic cells It has been reported that Rioja A. et al., FE, incorporated herein by reference. See BS Lett 467 (2-3): 291-5 (2000). Vascular Properties of Farnesyl Analogues The activity of the hydroxybenzoates has been reported. Roullet, J.-B. et al., incorporated herein by reference. See J. Clin. Invest., 1996, 97:2384-2390. Cetyl-S-trans,trans-farnesyl-L-cysteine ​​(AFC), farnesylated Both synthetic mimetics of the carboxyl terminus of the protein induce vasoconstriction in rat aortic rings. was inhibited.

[0076] In some embodiments, the interactor can be an aporphine alkaloid. For example, the interactor can be dicentrin.

[0077] In general, the interactive agent may also be a vasodilator or a therapeutic vasodilator. A vasodilator is a drug that opens or widens blood vessels. Vasodilators are commonly used to treat conditions such as hypertension, heart failure, and angina pectoris, but is also used to treat other conditions, including glaucoma Some vasodilators (arteriodilators) that act primarily on resistance vessels can be used to Used for hypertension, heart failure, and angina; however, reflex cardiac stimulation may be present in some Arterial dilators are inappropriate for angina pectoris. Venodilators are very effective for angina pectoris and sometimes are used in heart failure but not as primary therapy for hypertension. It is a mixed (or balanced) vasodilator in that it dilates both the pulse and the veins. It can be widely used in hypertension, heart failure, and angina pectoris. Tonicity agents, due to their mechanism of action, may in some cases enhance their therapeutic utility. Another important possibility is that the For example, some calcium channel blockers not only dilate blood vessels, but also but also impair the mechanical and electrical function of the heart, thereby reducing their antihypertensive properties. It can enhance pressure action and provide additional therapeutic benefits such as blocking arrhythmias. It can be granted.

[0078] Vasodilators are classified based on their site of action (arterial vs. venous) or by mechanism of action. They can be classified as: drugs that dilate resistance vessels (arteriodilators; e.g., hydralazine) There are also drugs that primarily affect venous capacitance (venodilators; e.g., nitroglycerin). Many vasodilators, such as phentolamine, are mixed arterial and venous dilatators. (mixed dilators; e.g., α-adrenergic receptor antagonists, angiotensin receptor antagonists, (anticoagulant-converting enzyme inhibitors).

[0079] However, it is more common to classify vasodilators based on their primary mechanism of action. The diagram on the right shows the important mechanistic classes of vasodilators. Other classes that produce ductal dilation include: α-adrenergic receptor antagonists (α-blockers); Angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); β2-adrenergic receptor blockers Calcium channel blocker (CCB); centrally acting Sympatholytics; direct-acting vasodilators; endothelin receptor antagonists; ganglionic blocking agents drugs; nitrodilators; phosphodiesterase inhibitors; potassium channel openers; renin inhibitors Included.

[0080] Generally, the active or inactive ingredient or material will produce increased blood flow or tissue flushing. and substances that allow for alteration or differentiation (increase or decrease) of the transmucosal uptake of the API. or compounds, and / or compounds with positive or negative heats of solution that alter (increase or decrease) transmucosal uptake It can be a substance or compound used as an adjuvant to reduce the

[0081] (Sequence of penetration enhancer and active pharmaceutical ingredient) Arrangement of permeation enhancers and active pharmaceutical ingredients (APIs) delivered to desired mucosal surfaces ent, order, or sequence to achieve the desired pharmacokinetic profile. For example, by film, by swab, spray, gel, Apply the permeation enhancer first, either by rinsing or by applying the first layer of film. Then, either by a single film, by a swab, or by a second layer of film. PI can be applied. This arrangement can be applied, for example, by film or by swab. The API is applied first by a first layer of film, or by a film or by a swab. Penetration enhancement by a brush, spray, gel, rinse, or by a second layer of film. This can be reversed or changed by applying a filter. In this method, the permeation enhancer is applied through a film and the drug is delivered through another film. For example, depending on the desired pharmacokinetic profile, A permeation enhancer film or a film containing a permeation enhancer located under the film The film contains the API and is located underneath the capsule.

[0082] For example, a penetration enhancer may be used as a pretreatment alone or in combination with at least one API. can be used in combination to precondition the mucosa for better absorption of the API. This treatment can be followed by another treatment with neat penetration enhancer to enhance the at least one This pretreatment can be followed by application of a variety of APIs to the mucosa. , solution, swab, etc.) or as a layer within a multilayer film structure of one or more layers Similarly, the pretreatment may be a first treatment with or without a permeation enhancer or API. Another single film designed to dissolve and release into the mucosa prior to release of the second domain. The active ingredient may then be administered alone or in combination with a second treatment. It may be delivered in combination with additional penetration enhancers, in different ratios to each other, or with other treatments. Additional permeation enhancers and / or at least There may also be a third treatment or domain that delivers another API or prodrug. This allows for a tailored pharmacokinetic profile to be obtained. The product is formulated to achieve the desired absorption profile and / or pharmacodynamic effect intended. Varying the order of application, composition, concentration, or total load on the mucosa, which may lead to different amounts and / or rates of absorption The polypeptide may have a single or multiple domains containing a penetration enhancer and an API that can

[0083] This film format is designed so that there are no distinct surfaces or the film has co-terminous edges ( of a multilayer film having or meeting at a shared border or limit It can be oriented to have at least one face.

[0084] The pharmaceutical compositions may be in the form of chewable or gelatin-based dosage forms, sprays, gums, gels, creams, or other formulations. The composition may be in the form of a gel, tablet, liquid or film. For example, surface microneedles or microprojections may be included. Recently, there has been a growing interest in increasing skin permeability. The use of micron-scale needles in the transdermal delivery of drugs, including and especially with respect to macromolecules, has been shown to be beneficial. Most drug delivery studies have been performed in vitro. solid (sol) nanoparticles, which have been shown to increase skin permeability to a wide range of molecules and nanoparticles id) Microneedles are a key technology. In vivo studies have demonstrated the delivery of oligonucleotides, insulin, and Lowering blood glucose levels and inducing immune responses from protein and DNA vaccines For such studies, needle arrays have been used to puncture the skin and induce diffusion. or to enhance transport by iontophoresis or from microneedle surface coatings into the skin. Hollow microneedles have also been developed and are being used as drug carriers to release drugs. Microinjection of insulin into diabetic rats has been demonstrated. To achieve this, the ratio of microneedle crushing strength to skin insertion force (i.e., the margin of safety) must be large enough to accommodate a small tip. It was found that needles with large diameters and large wall thicknesses were optimal. The microneedle used was reported as painless. Taken together, these results suggest that microneedle is a widespread This suggests that this may be a promising technology for delivering therapeutic compounds to the skin for a variety of potential applications. Using tools from the microelectronics industry, microneedles are available in a wide range of sizes, shapes and materials. Microneedles, for example, deliver encapsulated drugs in a minimally invasive manner. , can be microscopic needles of polymer, but other suitable materials can be used. .

[0085] The applicant has demonstrated that microneedles are effective in the delivery of drugs through the oral mucosa, particularly with the claimed compositions. The researchers found that microneedles can be used to deliver microscopic particles into the oral mucosa. The solid membrane creates pores of various sizes, which can enhance the delivery of drugs across the mucosa. The present invention provides a method for manufacturing nano-needles that are flexible, hollow, or dissolvable, including metal, polymer, glass, and ceramic. The microfabrication process can be performed using any suitable material, including but not limited to: , photolithography, silicon etching, laser cutting, metal electroplating, metal electroplating The microneedles may be used to prepare tissue, and may include grinding and shaping. It can be a solid that is removed prior to application of the film. The loaded polymer film can be used as the matrix material for the microneedle itself. These films may have microneedles or microprojections fabricated on their surface. These create microchannels in the mucosa through which drugs can permeate. It will dissolve after it forms.

[0086] The term "film" refers to a film of any shape, including rectangular, square, or any other desired shape. The film may be of any desired thickness and size. In a preferred embodiment, the film can be administered to a user, e.g. The filler may have a thickness and size such that it can be placed in the oral cavity of a patient. The film has a relatively thin thickness of about 0.0025 mm to about 0.250 mm, or the film has a thickness of about 0.250 mm. For some films, the thickness may be as low as about 1.0 mm. It may also be relatively large, i.e., greater than about 1.0 mm, or relatively thin. The film may be monolayer, i.e., less than about 0.0025 mm. or the film is multi-layered, including laminated or multi-cast films. The permeation enhancer and the active pharmaceutical ingredient may be combined in a single layer or each may be in a separate layer. Each may be contained in a separate layer or may otherwise be contained in a separate region of the same dosage form. In some embodiments, the pharmaceutical active ingredient contained in the polymer matrix may be The components can be dispersed in a matrix. In some embodiments, the polymer matrix The permeation enhancer contained in the drug can be dispersed in the matrix.

[0087] Orally dissolving films are divided into three main classes: fast dissolving, moderate dissolving, and slow dissolving. Orally dissolving films can also be classified into any combination of the above categories. The fast-dissolving film can be dissolved in the mouth for more than 1 second, more than 5 seconds, more than 10 seconds, or more than 20 seconds. and can dissolve in about 1 second to about 30 seconds, including less than 30 seconds. Dissolve in the mouth for 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. The slowly dissolving film can dissolve in the mouth over a period of more than 30 minutes. Generally, fast dissolving films tend to be made with low molecular weight hydrophilic polymers (e.g., those with a molecular weight of about 1 Polymers with a molecular weight of 200,000 to 9,000 daltons or up to 200,000 daltons In contrast, slowly dissolving films generally contain highly soluble The moderately soluble film contains a polymer having a molecular weight of several million. These tend to fall somewhere between fast-dissolving and slow-dissolving films.

[0088] It may be preferable to use a film that is a moderately soluble film. The dissolvable film can dissolve fairly quickly, but also has a good level of mucoadhesion. Moderately soluble films are also flexible, rapidly wettable, and typically Such moderately soluble films are non-irritating to the user. It is desirable to provide a dissolution rate of about 1 minute to about 20 minutes, while maintaining a good oral hygiene. acceptable mucoadhesion such that the film is not easily removed once placed on the This can ensure delivery of the active pharmaceutical ingredient to the user. do.

[0089] The pharmaceutical composition may contain one or more pharmaceutically active ingredients. The active pharmaceutical ingredient may be a single pharmaceutical ingredient or a combination of pharmaceutical ingredients. Medicines, steroidal anti-inflammatory drugs, antihistamines, local anesthetics, disinfectants, antiseptics, vasoconstrictors , hemostatic agents, chemotherapy agents, antibiotics, keratolytic agents, cauterizing agents, antiviral agents, antirheumatic agents, Antihypertensives, bronchodilators, anticholinergics, antianxiety drugs, antiemetic compounds, hormones, peptidase The active pharmaceutical ingredient can be a compound, a drug, a peptide, a protein, or a vaccine. a pharmaceutically acceptable salt, prodrug, derivative, drug conjugate, or analog of the drug The term "prodrug" refers to a compound that is metabolized in the body to produce a biologically active drug. For example, the active pharmaceutical ingredient is an epidermal It can be an ester of epinephrine, for example, dipivefrin. For example, J. Anderson et al., "Intraocular hydrolysis of the prodrug dipivefrin and its and comparison of its intraocular metabolism with that of its parent compound, epinephrine (Site of ocular hydrolysis) olysis of a prodrug, dipivefrin, and a comparison of its ocular metabolism with Invest., Ophthalmol. Vis. Sci.198 Please refer to July 2010.

[0090] In some embodiments, more than one pharmaceutically active ingredient may be included in the film. The active pharmaceutical ingredients are ACE inhibitors, antianginal drugs, antiarrhythmic drugs, antiasthmatic drugs, anticholesterol drugs, Antihypertensives, analgesics, anesthetics, anticonvulsants, antidepressants, antidiabetic drugs, antidiarrheal preparations, Toxics, antihistamines, antihypertensives, anti-inflammatory drugs, antilipid drugs, antimanic drugs, antinausea drugs, Anti-inflammatory drugs, anti-thyroid preparations, amphetamines, anti-tumor drugs, antiviral drugs, acne medications, Alkaloids, amino acid preparations, antitussives, anti-urinary stone preparations, anti-viral agents, anabolic preparations Anti-inflammatory drugs, anti-neoplastic drugs, anti-Parkinson's drugs, anti-rheumatic drugs Drugs for steroids, appetite stimulants, blood modifiers, bone metabolism regulators, cardiovascular drugs, central nervous system stimulants Drugs, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor antagonists Gonists, endometriosis management drugs, enzymes, erectile dysfunction treatments, infertility medications, gastrointestinal medications, homeopathy Remedies, hormones, hypercalcemia and hypocalcemia management drugs, immunomodulators, Anti-inflammatory drugs, migraine preparations, motion sickness medicines, muscle relaxants, obesity management drugs, osteoporosis preparations, Uterine contractile agents, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic drugs, respiratory Respiratory drugs, sedatives, smoking cessation aids, sympatholytics, tremor treatment preparations, urinary drugs, vascular Dilators, laxatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants, anti-anxiety drugs, Anti-ulcer drugs, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators , psychotropic drugs, stimulants, antihypertensive drugs, vasoconstrictors, antimigraine drugs, antibiotics , tranquilizers, antipsychotics, anti-tumor drugs, anticoagulants, antithrombotic drugs, hypnotics, antiemetics, Anti-nausea, anticonvulsants, neuromuscular agents, hyperglycemic and hypoglycemic agents, thyroid and anti-thyroid Preparations, diuretics, antispasmodics, uterine relaxants, anti-obesity agents, erythropoiesis agents, anti-asthmatics, antitussives , mucolytics, DNA and gene modifying agents, diagnostic agents, contrast agents, dyes, or tracers, and It can be a combination of these.

[0091] For example, the active pharmaceutical ingredient may be buprenorphine, naloxone, acetaminophen, Luzole, clobazam, rizatriptan, propofol, methyl salicylate, salicylic acid Monoglycerin, aspirin, mefenamic acid, flufenamic acid, indomethacin, dimethicone Iclofenac, Alclofenac, Diclofenac Sodium, Ibuprofen, Ketoprofen Fen, naproxen, pranoprofen, fenoprofen, sulindac, fenclo Fenac, Clidanac, Flurbiprofen, Fentiazac, Bufexamac, Piroq Cicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepidem Lysol, tiaramide hydrochloride, hydrocortisone, prednisolone, dexamethasone, Liamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, propranolol acetate Rednisolone, methylprednisolone, dexamethasone acetate, betamethasone, betavalerate Methasone, flumethasone, fluorometholone, beclomethasone dipropionate, fluoxetine Nonide, edaravone, lurasidone, esomeprazole, lumateperone, naldemedine, Xylamine, pyridoxine, diphenhydramine hydrochloride, diphenhydramine salicylate Salt, Diphenhydramine, Chlorpheniramine Hydrochloride, Chlorpheniramine Maleate, Isothipendyl hydrochloride, Tripelennamine hydrochloride, Promethazine hydrochloride, Methdilazine hydrochloride, Dibu Caine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butyl aldehyde Aminobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, procaine hydrochloride, tetracaine , tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, Caine hydrochloride, piperocaine hydrochloride, dyclonine, dyclonine hydrochloride, thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, Povidone-iodine, cetylpyridinium chloride, eugenol, trimethylammonium bromide mido, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenyle Flin hydrochloride, tramazoline hydrochloride, thrombin, phytonadione, protamine sulfate, Minocaproic acid, tranexamic acid, carbazochrome, carbazochrome sodium sulfonate rutin, hesperidin, sulfamine, sulfathiazole, sulfadiazine, Mosulfamine, sulfisoxazole, sulfisomidine, sulfamethizole, nitrite Loflazone, penicillin, methicillin, oxacillin, cephalothin, cephaloridine (c efalordin), erythromycin, lincomycin, tetracycline, chlortetracycline Clin, oxytetracycline, methacycline, chloramphenicol, kanamycin , streptomycin, gentamicin, bacitracin, cycloserine, salicylic acid , Podophyllum resin, podolifox, cantharidin, chloroacetic acid, nitric acid Silver, protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, Protein synthesis inhibitors, adhesion and adsorption inhibitors, and nucleoside analogs, e.g., Heparin, ibuprofen, cyclovir, penciclovir, valacyclovir, and ganciclovir insulin, LHRH, TRH, interferon, oligonucleides, calcitonin octreotide, omeprazole, fluoxetine, ethinyl estradiol, amine Odipine (amiodipine), paroxetine, enalapril, lisinopril, leuprolide, Revastatin (prevastatin), lovastatin, norethindrone, risperidone, oranthraquinone Zapine, albuterol, hydrochlorothiazide, pseudoephedrine, warfarin , terazosin, cisapride, ipratropium, busprione, methylphenidate Nidate, levothyroxine, zolpidem, levonorgestrel, glyburide, benazepri medroxyprogesterone, clonazepam, ondansetron, losartan, quinap riloquinoline, nitroglycerin, midazolam, versed, cetirizine, doxazosin, glipizide , Hepatitis B vaccine, salmeterol, sumatriptan, triamcinolone acetonide, Goserelin, beclomethasone, granisteron, desogestrel, alpro Lazolam, estradiol, nicotine, interferon beta-1A, cromolyn, hoshinop fluticasone, bisoprolol, calcitril, captopril, butanol, digoxin, fluticasone Lufanol, clonidine, Premarin, testosterone, sumatriptan, clotrimazole Zolazol, bisacodyl, dextromethorphan, nitroglycerin, nafarelin, diazepam These can be prostones, nicotine, bisacodyl, goserelin, and granisetron. In some embodiments, the active pharmaceutical ingredient is epinephrine, a prodrug of epinephrine, or drugs, benzodiazepines such as diazepam or lorazepam, or alprazolam do.

[0092] (Example: epinephrine / dipifebrine) In one example, epinephrine or a salt or ester thereof (e.g., dipivefrin, etc.) The composition containing epinephrine administered by injection, for example, using an EpiPen, The biodelivery profile may be similar to that of an epidermal growth factor receptor (EGFR) receptor. Nephrin or a prodrug thereof is administered in an amount of about 0.01 mg to about 100 mg per dose, for example, 0.1 mg, 5 mg , 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg doses. These include more than 0.1 mg, more than 5 mg, more than 20 mg, more than 30 mg, more than 40 mg, more than 50 mg, more than 60 mg, more than 70 mg, More than 80 mg, more 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 In another example, the diazepam-containing composition comprises a diazepam tablet or gel. It can have a similar or better biodelivery profile. Cut.

[0093] Dipifebrin is administered 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, Can be present in 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg doses , which includes over 1mg, over 5mg, over 20mg, over 30mg, over 40mg, over 50mg, over 60mg, over 70mg, over 80mg, and over 90 More than 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.

[0094] In another example, the composition (e.g., one containing epinephrine) is a hydrophilic saccharide. Suitable non-toxic, non-ionic alkyl glycosides having hydrophobic alkyl groups linked by bonds. (a) aggregation inhibitors; (b) charge modifiers; (c) pH regulators; (d) degradative enzyme inhibitors; (e) mucus solubilizers. (f) anti-ciliary agents; (g) the following: (i) surfactants; (ii) bile salts; (ii) liposomes; (iii) an alcohol; (iv) an enamine; (v) NO-donating compounds; (vi) long-chain amphiphilic molecules; (vii) hydrophobic penetration enhancers; (viii) sodium (ix) glycerol esters of acetoacetic acid; (x) cyclodextrins (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid (xiv) an N-acetylamino acid or a salt thereof; (xv) decomposing a selected membrane component (ix) inhibitors of fatty acid synthesis; (x) inhibitors of cholesterol synthesis; and (xi) (i) to (x (h) a membrane permeation enhancer selected from any combination of the membrane permeation enhancers described in (i) a vasodilator; (j) a selective transport-enhancing agent; or (k) a stabilized delivery vehicle. a carrier, mucoadhesive, support or complex-forming species with which the compound The substance is effectively combined, associated, contained, encapsulated, or bound to the substance, resulting in enhanced viscosity. The stabilizing delivery vehicle, carrier, mucoadhesive, which results in stabilization of the compound for membrane delivery. in combination with a mucosal delivery-enhancing agent selected from a substance, support, or complex-forming species. wherein a formulation of the compound with a transmucosal delivery-enhancing agent can be used to increase the concentration of the compound in the subject's plasma. This formulation provides increased bioavailability of epinephrine, as in other examples. The composition may contain approximately the same active pharmaceutical ingredient (API):enhancer ratio as that of the composition of the present invention.

[0095] Administering epinephrine as a prodrug, such as dipifebrine, has certain advantages. For one, dipifebrin is lipophilic and therefore has a higher mucosal penetration rate. It also has a longer plasma half-life due to higher protein binding. This allows for sustained blood levels and does not interact with α-receptors. Therefore, unwanted or harmful vasoconstriction is minimized or eliminated. [ka]

[0096] Dipifeverin, like epinephrine, is available as a sublingual film. It is possible.

[0097] The film and / or its components can be water-soluble, water-swellable, or water-insoluble. The term "water soluble" refers to a compound that is at least partially dissolved in an aqueous solvent, including but not limited to water. The term "water soluble" can refer to a substance that is partially soluble in both aqueous and non-aqueous solutions. The term "water-insoluble" does not necessarily mean that the substance is 100% soluble in the solvent. refers to a substance that is insoluble in aqueous solvents, including but not limited to water. The solvent may contain water or other solvents (preferably polar solvents) either alone or in combination with water. It can include:

[0098] The composition can include a polymer matrix. Any oral dissolvable or erodible formulation may be used. It must be bioadhesive enough to resist removal and must not form a gel-like structure when administered. These should be moderately soluble in the oral cavity and have a particularly medicinal activity. Suitable for delivery of active ingredients, including immediate release, delayed release, controlled release and sustained release formulations. All of the compositions are also among the various embodiments contemplated.

[0099] (branched polymer) The pharmaceutical composition film is composed of highly branched macromolecules with various structural architectures. The dendritic polymer may include a dendritic polymer, which may include a dendritic molecule. , dendritic polymers (dendritic grafted polymers), linear-dendritic hybrids, multi It may comprise a thiamin star polymer, or a hyperbranched polymer.

[0100] Hyperbranched polymers are highly branched polymers that have imperfections in their structure. However, they can be synthesized in a single step reaction, which is similar to other dendritic structures. Apart from their spherical structure, these 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. "Dendrimers as drug carriers: different routes of drug administration" Dendrimers as Drug Carriers: Applications in Different Routes of Drug Administration inistration,” J Pharm Sci, VOL. 97, 2008, 123-143.

[0101] Dendritic polymers can have internal cavities in which drugs can be encapsulated. The steric hindrance caused by the polymer chains can prevent the drug from crystallizing. Thus, branched polymers offer the additional advantage of formulating crystalline drugs in a polymer matrix. This can provide additional benefits.

[0102] 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(a Amino acid)-based dendrons, dendrimers and hyperbranched polymers, poly(aryl alkylene Poly(alkylene ether)-based dendrons, dendrimers and hyperbranched polymers, poly ... Poly(amidoamine)-based dendrons, dendrimers and hyperbranched polymers, poly(amidoamine)-based These include dendrons, dendrimers or hyperbranched polymers.

[0103] Other examples of hyperbranched polymers are poly(amines), polycarbonates, poly(ether ketones). , polyurethane, polycarbosilane, polysiloxane, poly(esteramine), poly(s sulfonamines), poly(urethane ureas), and polyether polyols, such as polyglycerides Contains phosphorus, etc.

[0104] The film is formed by a combination of at least one polymer and a solvent, optionally containing other ingredients. The solvent can be water, but is not limited to ethanol, isopropanol, In some embodiments, the solvent may be a polar organic solvent, including acetone, or any combination thereof. In this case, the solvent may be a non-polar organic solvent, such as methylene chloride. Utilizing a controlled casting or deposition method and a controlled drying process For example, films can be prepared by adding a wet foam to form a viscoelastic structure. A controlled drying process involving the application of heat and / or radiation energy to the film matrix. The film may be prepared through a process that controls the content uniformity of the film. The drying process may be performed on the top side of the film or on the bottom side of the film, or on the casting or deposition side. contacting a substrate that supports the deposited or extruded film, or Contact with two or more surfaces at the same time or at different times during the process, including air only, heat only, Or it can involve heat and air together. Some such processes are described in U.S. Pat. No. 5,167 and U.S. Pat. No. 8,652,378, which are incorporated herein by reference. Alternatively, the film may be incorporated herein by reference. The polymer may be extruded as described in US Patent Publication No. 2005 / 0037055A1.

[0105] The polymer contained in the film may be water-soluble, water-swellable, water-insoluble, or water-soluble. The polymer may be a combination of one or more of the following: Examples of useful water-soluble polymers include cellulose, cellulose derivatives, or gums. , polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxy Ethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxy Methylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol ethanol, xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, Polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, dendrimer Examples of suitable granules include, but are not limited to, gluten, gelatin, and combinations thereof. Specific examples of suitable water-insoluble polymers include ethyl cellulose and hydroxypropyl ethyl cellulose. cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and Combinations of these include, but are not limited to, higher doses and lower doses. It may be desirable to incorporate polymers that provide a high level of viscosity relative to the dose. .

[0106] As used herein, the phrase "water soluble polymer" and variations thereof refers to a polymer that is at least partially water soluble. a polymer that is soluble in water, preferably completely or mostly soluble in water or that absorbs water; Polymers that absorb water are often called water-swellable polymers. Useful materials are water-soluble or water-swellable at room temperature and other temperatures, e.g., above room temperature. Furthermore, these materials may be water-soluble or water-swellable at subatmospheric pressures. In some embodiments, films formed from such water-soluble polymers may , may be sufficiently water soluble to be dissolved upon contact with body fluids.

[0107] Other polymers useful for incorporation into films include biodegradable polymers, copolymers, and binders. The term "biodegradable" refers to a material that can be physically broken down into small pieces, such as a polymer, a block polymer, or a combination thereof. Contains substances that chemically decompose, as opposed to substances that are destroyed (i.e., bioerodible substances) It is understood that polymers incorporated into the film may also be biodegradable or The polymer may also include a combination of bioerodible materials. Mer or polymer classes include: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxane San, polyoxalate, poly(α-ester), polyanhydride, polyacetate, polycarbonate Prolactone, poly(orthoester), polyamino acid, polyaminocarbonate, poly ethylene, polycarbonate, polyamide, poly(alkyl cyanoacrylate), and the like Mixtures and copolymers of these are included. Additional useful polymers include esters of L- and D-lactic acid. Rheopolymer, copolymer of bis(p-carboxyphenoxy)propanoic acid and sebacic acid; Sebacic acid copolymer, caprolactone copolymer, poly(lactic acid) / poly(glycolic acid) / Polyethylene glycol copolymer, copolymer of polyurethane and (poly(lactic acid)), α- Copolymers of amino acids, copolymers of α-amino acids and caproic acid, α-benzyl glutamine copolymers of phosphate esters and polyethylene glycol, succinate esters and poly(glycol) copolymers of glycerol, polyphosphazenes, polyhydroxyalkanoates or The polymer matrix may contain one, two, three, four or more components. This can be done.

[0108] A variety of different polymers may be used, but the film must have mucoadhesive properties as well as the desired It is desirable to select a polymer that provides a dissolution and / or disintegration rate. The time for which it is desirable to maintain contact of the composition with the mucosal tissue is determined by the amount of the pharmaceutically active ingredient contained in the composition. Some active pharmaceutical ingredients may take only a few minutes to be delivered through mucosal tissue. Other active pharmaceutical ingredients may require no steroid activity for up to several hours or even longer. Therefore, in some embodiments, one or more of the aforementioned aqueous solutions may be used. However, in other embodiments, a soluble polymer may be used to form the film. a water-soluble polymer and a water-swellable, water-insoluble and / or biodegradable polymer as provided above. It may be desirable to use a combination of water-swellable, water-insoluble and / or biodegradable polymers. The inclusion of one or more polymers that are degradable allows for a film formed solely of water-soluble polymers. It is possible to provide a film that has a slower dissolution or disintegration rate than a film. Therefore, the film adheres to the mucosal tissue for a relatively long time, up to several hours, and This can be desirable for the delivery of certain pharmaceutical active ingredients.

[0109] Desirably, the individual film dosages of the pharmaceutical film have a suitable thickness and small size. The size may be about 0.0625 to 3 inches (1.5875 mm x 76.2 mm) x about 0.0625 to 3 inches. The film size, in at least one embodiment, is between 0.0625 inches. More than 1 inch (25.4 mm), more than 2 inches (50.8 mm), or about 3 inches (7 6.2mm), and over 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, 0.0 or in another embodiment, greater than 0.0625 inches, greater than 0.5 inches, or 1 inch. More than 1 inch, more than 2 inches, or more than 3 inches, about 3 inches, less than 3 inches, less than 2 inches, less than 1 inch It can be less than 0.5 inches, or less than 0.0625 inches. The aspect ratio is a function of the chemical and physical properties of the polymer matrix, the active pharmaceutical ingredient, the dosage, and the enzyme. Based on the enhancer and other additives involved, and the dimensions of the desired dispensing unit, This film dosage form can be administered to the user's buccal or sublingual area. When placed in the area, the film should have good adhesion. The form should disperse and dissolve at a moderate rate, most preferably within about 1 minute. In some embodiments, the film dosage form disperses and dissolves within about 1 minute. to about 30 minutes, for example, about 1 to about 20 minutes, or more than 1 minute, more than 5 minutes, more than 7 minutes, more than 10 minutes, more than 12 minutes, more than 15 minutes, more than 20 minutes More than 30 minutes, more 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, 7 minutes The sublingual dispersion can be dispersed and dissolved at a rate of less than 1 minute, less than 5 minutes, or less than 1 minute. The velocity may be shorter than the buccal dispersion velocity.

[0110] For example, in some embodiments, these films may be made solely of polyethylene oxide. The second polymer may be contained in a water-soluble polymer component or in combination with a second polymer component. a water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer, or any of them Suitable water-soluble polymers include those provided above, but may also be a combination of these. In some embodiments, the water soluble polymer is a hydrophilic cellulose. hydroxypropyl cellulose and / or hydroxypropyl methylcellulose In some embodiments, one or more water-swellable, water-insoluble, and 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 present in an amount of about 0% to about 80% by weight of the polymer component, more specifically may be utilized in an amount of from about 30% to about 70% by weight, and even more specifically from about 40% to about 60% by weight. This means that by weight, more than 5%, more than 10%, more than 15%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, and more than 70%, approximately 70%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, Including less than 10% or less than 5%.

[0111] Additives may be included in these films. Examples of classes of additives are preservatives, antimicrobials, and the like. Biopharmaceuticals, excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, extenders, Sweeteners, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, glidants, release agents, poly All, granulating agent, diluent, binder, buffer, absorbent, lubricant, adhesive, anti-adhesion agent, acidulant , softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, anti-sticking agents, antistatic agents These additives include anti-inflammatory agents and mixtures thereof. These additives are added together with the active pharmaceutical ingredient(s). As used herein, the term "stabilizer" refers to an active pharmaceutical ingredient, another excipient, or can prevent aggregation or other physical degradation as well as chemical degradation of the combination. means an excipient in which

[0112] Stabilizers may also be antioxidants, sequestering agents, pH adjusters, emulsifiers and / or surfactants. They can be classified as anti-aging agents, anti-bacterial agents, and UV stabilizers.

[0113] Antioxidants (i.e., slowing, inhibiting, interrupting and / or stopping the oxidation process, as medicines) Compatible compound(s) or composition(s) are in particular the following substances: tocopherol and their esters, sesamol from sesame oil, coniferyl benzoate from benzoin resin, Nordihydroguaiaretic acid resin and nordihydroguaiaretic acid (NDGA), gallate ( Among others, methyl, ethyl, propyl, amyl, butyl, lauryl gallate, butylated Hydroxyanisole (also known as BHA / BHT, butyl-p-cresol); ascorbic acid and its Salts and esters (e.g., ascorbyl palmitate), erythorbic acid (isoascorbic acid), acid) and its salts and esters, monothioglycerol, sodium formaldehyde Sulfoxylates, sodium metabisulfite, sodium bisulfite, sodium sulfite , potassium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT), propionic acid. Representative antioxidants include tocopherols, e.g., α-tocopherols. ol and its esters, butylated hydroxytoluene and butylated hydroxyanisole The term "tocopherol" also includes esters of tocopherol. The term "α-tocopherol" refers to α-tocopherol. Esters of α-tocopherol (e.g., α-tocopherol acetate) are also included.

[0114] A sequestering agent (i.e., a compound, such as an active ingredient or another excipient, in combination with a host-gel Any compound capable of participating in the formation of a calcium carbonate complex (also called a sequestering agent) is suitable for calcium chloride. Calcium disodium ethylenediaminetetraacetate, Glucono delta-lactone, Sodium Gluconate, Potassium Gluconate, Sodium Tripolyphosphate, Hexamethaline Sequestering agents also include cyclic oligosaccharides, e.g., For example, cyclodextrin, cyclomannin (five or more α-linked at the 1,4 positions) α-D-mannopyranose units), cyclogalactin (linked at the 1,4 positions by β bonds, 5 or more β-D-galactopyranose units), cycloartrin (linked at the 1,4 positions by an α bond) and combinations thereof.

[0115] pH adjusters include acids (e.g., tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, ascorbic acid, acid, acetic acid, succinic acid, adipic acid, and maleic acid), acidic amino acids (e.g., glutamic acid , aspartic acid, etc.), inorganic salts of such acidic substances (alkali metal salts, alkaline earth metal salts, etc.), metal salts, ammonium salts, etc.), organic bases of such acidic substances (e.g., basic amino acids, salts with lysine, arginine, and the like, meglumine, and the like; Other examples of pH adjusters include silicified microcrystalline cellulose, silicified cellulose acetate ... Sodium, magnesium aluminometasilicate, calcium salts of phosphoric acid (e.g., hydrogen phosphate) Calcium anhydride or hydrate, calcium carbonate or hydrogen carbonate, sodium or potassium, and calcium lactate or their mixture), carboxymethylcellulose sodium and / or calcium salts, cross-linked carboxymethylcellulose (e.g., chloromethylcellulose), Scarmelose sodium and / or calcium), polacrilin potassium, sodium alginate Sodium and / or calcium docusate, magnesium stearate, calcium calcium, aluminum, or zinc, magnesium palmitate, and magnesium oleate Magnesium, sodium stearyl fumarate, and combinations thereof.

[0116] Examples of emulsifiers and / or surfactants are poloxamers or pluronics, polyethylene glycols, Recall, polyethylene glycol monostearate, polysorbate, sodium lauryl sulfate Sodium, polyethoxylated and hydrogenated castor oil, alkyl polyosides, hydrophobic base Water-soluble protein grafted onto the chain, lecithin, glyceryl monostearate, Glyceryl Monostearate / Polyoxyethylene Stearate, Ketostearyl Alcohol Sodium lauryl sulfate, carbomer, phospholipids, (C 10 ~C 20 )-Alkyl and Alkyl olefin carboxylates, carboxylic acid alkyl ethers, fatty alcohol sulfates, fatty acids Alcohol ether sulfates, alkylamide sulfates and sulfonates, fatty acid alkylamines Midopolyglycol ether sulfates, alkanesulfonates and hydroxyalkanesulfons Sulfonates, olefin sulfonates, acyl esters of isethionic acid, α-sulfo fatty acids Acid esters, alkylbenzene sulfonates, alkylphenol glycol ethers Sulfonates, sulfosuccinates, monoesters and diesters of sulfosuccinic acid, aliphatic Alcohol ether phosphate, protein / fatty acid condensation products, alkyl monoglycerides Sulfates and sulfonates, alkyl glyceride ether sulfonates, fatty acid methyl tau Lids, fatty acid sarcosinates, sulforicinolates, and acyl glutamates, quaternary Ammonium salts (e.g., di-(C 10 ~C 24)-Alkyl-dimethylammonium chloride or Romido), (C 10 ~C 24 )-Alkyl-dimethylethylammonium chloride or bromide, (C1 0~C 24 )-Alkyl-trimethylammonium chloride or bromide (e.g., cetyltrimethylammonium chloride or bromide) ammonium chloride or bromide), (C 10 ~C 24 )-Alkyl-dimethylbenzylane ammonium chloride or bromide (e.g., (C 12 ~C 18 )-Alkyl-dimethylbenzylammonium nium chloride), N-(C 10 ~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-methyl Morpholinium chloride, bromide or monoalkyl sulfate, N-(C 12 ~C 18 )-Alkyl- N-ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C 16 ~C 18 )-Al Chyl-pentaoxetyl ammonium chloride, diisobutylphenoxyethoxyethyl Dimethylbenzylammonium chloride, N,N-diethylaminoethyl stearylamide and salts of oleylamide with hydrochloric acid, acetic acid, lactic acid, citric acid, phosphoric acid, N-acylamino ethyl-N,N-diethyl-N-methylammonium chloride, bromide or monoalkyl sulfate, and N-acylaminoethyl-N,N-diethyl-N-benzylammonium chloride and bromide or monoalkyl sulfates (in the foregoing, "acyl" means, for example, stearyl or oleyl) (representing a file), as well as combinations thereof.

[0117] Examples of UV stabilizers include UV absorbers (e.g., benzophenone), UV quenchers (i.e., UV Rather than allowing the energy to decompose, it is tasked with dissipating the energy as heat. any compound), scavengers (i.e., compounds that suppress free radicals resulting from exposure to UV radiation), any compound that removes hydroxybenzoates), and combinations thereof.

[0118] In other embodiments, the stabilizer is ascorbyl palmitate, ascorbic acid, Sulfatocopherol, butylated hydroxytoluene, butylated hydroxyanisole, Cysteine ​​HCl, citric acid, ethylenediaminetetraacetic acid (EDTA), methionine, sodium citrate Sodium, Sodium Ascorbate, Sodium Thiosulfate, Sodium Metabisulfite, Sodium Nitrate Sodium hydrogen sulfate, propyl gallate, glutathione, thioglycerol, singlet oxygen Quencher, hydroxyl radical scavenger, hydroperoxide scavenger, reducing agent, gold These include chelating agents, detergents, chaotropes, and combinations thereof. The "antihistamines" include alkylimidazoles (e.g., histidine, L-camocine, histamine, imidazoline, 4-acetic acid), indole (e.g., tryptophan and its derivatives, e.g., N-acetyl -5-Methoxytryptamine, N-acetylserotonin, 6-Methoxy-1,2,3,4-tetrahydro- beta-carbolines), sulfur-containing amino acids (e.g., methionine, ethionine, dimethicone, Lanthionine, N-formylmethionine, felinine, S-allylcysteine, S-aminoethyl L-cysteine), phenolic compounds (e.g., tyrosine and its derivatives), aromatic acids ( ascorbate, salicylic acid, and their derivatives), azides (e.g., azide sodium), tocopherols and related vitamin E derivatives, and carotenes and related vitamins Hydroxyl radical scavengers include, but are not limited to, benzophenone A derivatives. "Anger" is a compound containing azide, dimethyl sulfoxide, histidine, mannitol, sucrose, including, but not limited to, glucose, salicylate, and L-cysteine "Hydroperoxide scavengers" include catalase, pyruvate, glutathione, and glutathione. "Reducing agents" include, but are not limited to, glutathione peroxidase. , cysteine, and mercaptoethylene. "Generic chelating agents" include EDTA, EGTA, o-phenanthroline, and citrate. "Detergent" includes, but is not limited to, SDS and sodium lauroyl sarcosinate. "Chaotropes" include, but are not limited to, guanidinium hydrochloride. , isothiocyanates, urea, and formamide. As discussed herein, stabilizers may be present at 0.0001% to 50% by weight. This can be greater than 0.0001%, greater than 0.001%, greater than 0.01%, greater than 0.1%, greater than 1%, greater than 5% by weight. , more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, less than 50%, less than 40%, less than 30%, less than 20% , including less than 10%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% .

[0119] Useful additives include, for example, gelatin, vegetable proteins such as sunflower oil, Protein, soy protein, cottonseed protein, peanut protein, grapeseed protein Proteins such as whey protein, whey protein isolate, blood protein, egg protein Proteins, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, and guar gum , agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, Water-soluble derivatives of cellulose, such as karaya gum, tragacanth gum, and pectin: alkyl Cellulose, hydroxyalkyl cellulose and hydroxyalkyl alkyl cellulose , such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose , hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose esters such as methyl cellulose and hydroxybutyl methyl cellulose and hydroxyalkyl cellulose esters, such as cellulose acetate phthalate (CAP), hydroxy Hydroxypropyl methylcellulose (HPMC); carboxyalkyl cellulose, carboxya alkyl alkyl cellulose, carboxy alkyl cellulose esters, e.g., carboxy Methylcellulose and their alkali metal salts; water-soluble synthetic polymers, such as polyacrylic Polyacrylic acid and polyacrylates, polymethacrylic acid and polymethacrylates, poly Polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), Contains polyvinylpyrrolidone (PVP), PVA / vinyl acetate copolymer, and polycrotonic acid. and also phthalate gelatin, succinate gelatin, cross-linked gelatin, shellac, de Water-soluble chemical derivatives of starch, such as those containing tertiary or quaternary amino groups, e.g., Cationically modified acrylates, such as those containing quaternized diethylaminoethyl groups. and methacrylates; or other similar polymers are also suitable.

[0120] The additional components may be present in an amount of up to about 80% by weight of all the composition components, preferably It can be in the range of about 0.005% to 50%, more preferably 1% to 20%, which is greater than 1%, 5% More than %, More than 10%, More than 20%, More than 30%, More than 40%, More than 50%, More than 60%, More than 70%, About 80%, More than 80%, 80 Less than %, Less than 70%, Less than 60%, Less than 50%, Less than 40%, Less than 30%, Less than 20%, Less than 10%, 5 %, about 3%, or less than 1%. Other additives include anti-blocking agents, flow agents, and opacifiers, For example, oxides of magnesium, aluminum, silicon, titanium, etc., may be used, if desired. Concentrations ranging from about 0.005% to about 5% by weight based on the weight of the film components, and if desired It can contain from about 0.02% to about 2% by weight, including greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, More than 1.5%, more than 2%, more than 4%, about 5%, more than 5%, less than 4%, less than 2%, less than 1%, less than 0.5%, 0.2% Contains less than or less than 0.02%.

[0121] In certain embodiments, the composition can include a plasticizer, which can be a polyalkylene oxides, such as polyethylene glycol, polypropylene glycol, polyethylene - Low molecular weight organic plasticizers, e.g. glycerol, glycerol, etc. Monoacetate, diacetate or triacetate, triacetin, polysol Bate, cetyl alcohol, propylene glycol, sugar alcohol sorbitol, diethyl Sodium sulfosuccinate, triethyl citrate, tributyl citrate, plant extracts, may include fatty acid esters, fatty acids, oils and the like, based on the weight of the composition and added at a concentration in the range of about 0.1% to about 40%, preferably in the range of about 0.5% to about 20%. This is more than 0.5%, more than 1%, more than 1.5%, more than 2%, more than 4%, more than 5%, more than 10%, more than 15%, and about 20%. %, over 20%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 2%, less than 1%, and Contains less than 0.5% of compounds that improve the textural properties of film materials, e.g., animal fats. Further fats such as oily or vegetable fats, preferably in their hydrogenated form, may be added. The composition may also contain compounds that improve the textural properties of the product. Included are binders that contribute to the ease of formation and overall quality of the film. Non-limiting examples include starch, natural rubber, pregelatinized starch, gelatin, and polyvinylpyrrolidone. , methylcellulose, sodium carboxymethylcellulose, ethylcellulose, poly Includes acrylamide, polyvinyloxazolidone, or polyvinyl alcohol.

[0122] Further possible additives are solubility enhancing agents, such as substances that form inclusion compounds with the active ingredient. Such substances may be used to enhance the properties of highly insoluble and / or unstable active substances. Generally, these materials have hydrophobic interior cavities and It is a doughnut-shaped molecule with a hydrophilic exterior and a hydrophilic outer layer. Insoluble and / or unstable pharmaceutical active ingredients fits into the hydrophobic cavity, resulting in an inclusion complex that is soluble in water. The formation of inclusion complexes increases the water solubility of highly insoluble and / or unstable pharmaceutical active ingredients. A particularly desirable example of such a substance is cyclodextrin, which is a cyclic carbohydrate derived from starch, but other similar substances are within the scope of this invention. It is thought to fit within.

[0123] Suitable colorants include Food, Drug, and Cosmetic Colors (FD&C), Drug and Cosmetic Colors (D&C), or topical drug and cosmetic coloring agents (Ext. D&C). These coloring agents include pigments, These are the corresponding lakes, as well as certain natural and derived colorants. Other examples of colorants include known azo dyes, organic or inorganic pigments, or colorants of natural origin. Inorganic pigments, such as oxides or iron Titanium is preferred, and these oxides are used in an amount of about 0.001 to about 10 based on the weight of all components. %, preferably from about 0.5 to about 3%, which may be greater than 0.001%, greater than 0.01%, greater than 0.1 More than %, more than 0.5%, more than 1%, more than 2%, more than 5%, about 10%, more than 10%, less than 10%, less than 5%, less than 2%, Including less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001%.

[0124] Flavoring agents may be selected from natural and synthetic flavored liquids. Exemplary of such materials are: A comprehensive list includes volatile oils, synthetic flavor oils, flavored aromatics, oils, liquids, oleoresins, or botanicals. Examples of extracts include extracts derived from the leaves, flowers, fruits, stems, and combinations thereof. A representative list includes mint oil, cocoa, and citrus oils such as lemon, orange, lime, and Grapefruit, as well as apples, pears, peaches, grapes, strawberries, raspberries, and cherry Fruit essences including rambo, plum, pineapple, apricot, or other fruit aromas Other useful flavoring agents include aldehydes and esters, such as benzaldehyde (saponins). Crumbo, almonds), 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 (cherries, almonds), 2,6-dimethyloctanol (green n) fruits), and 2-dodecenal (citrus fruits, mandarin), combinations thereof, and the like.

[0125] Sweeteners include, but are not limited to, the following list: glucose (corn syrup), dextrose, sugar, fructose, and combinations thereof; saccharin and its various salts, e.g., sodium dipeptide-based sweeteners, e.g., aspartame, neotame, advantage Dihydrochalcone compounds, glycyrrhizin; Stevia (Stevia Rebaudiana) (Steviosin) chlorine derivatives of sucrose, e.g., sucralose; sugar alcohols, e.g., sorbitol, malic acid, The sugars may be selected from ethanol, xylitol, and the like. Starch hydrolysate and synthetic sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazine-4- Acesulfame-2,2-dioxide, especially the potassium salt (acesulfame-K), as well as their sodium salts and calcium salts, as well as natural intensive sweeteners such as Lo Han Kuo. Other sweeteners may also be used.

[0126] Antifoam and / or defoamer components may also be used in the film. It aids in the removal of air, such as trapped air, from the foam-forming composition. Entrapped air can lead to an uneven film. Simethicone is one particularly useful However, the invention is not so limited and other suitable Various anti-foaming and / or de-foaming agents may be used. Simethicone and related substances are used for densification purposes. More specifically, such materials may be used to absorb voids, air, moisture, and similar substances. This can facilitate the removal of undesired components, thereby producing a denser film. This provides a more uniform film. The substance or component that performs this function is called a densifier (d These substances are called densification agents or densifying agents. Thus, trapped air or undesirable components can lead to an uneven film.

[0127] The previously mentioned U.S. Pat. Nos. 7,425,292 and 8,765,167, assigned to the assignee of the present invention, Any other optional ingredients described in may also be included in the films described herein.

[0128] The film composition may further contain a buffer to control the pH of the film composition. It is desirable that any desired level of buffering agent be present when the pharmaceutically active ingredient is released from the composition. This buffer is incorporated into the film composition to provide the desired pH level. The agent is present in an amount sufficient to control the release of the pharmaceutically active ingredient from the film and / or its absorption into the body. In some embodiments, the buffer is sodium citrate. , citric acid, bitartrate and combinations thereof.

[0129] The pharmaceutical films described herein may be formed by any desired process. The process is described in U.S. Patent Nos. 8,652,378, 7,425,292 and 7,357,891. In one embodiment, the film The dosage form composition is formed by first preparing a wetting composition, which is The wet composition comprises a polymeric carrier matrix and a therapeutically effective amount of a pharmaceutical active ingredient. The film is then dried thoroughly to form a free-standing film composition. The wet composition is cast into individual dosage forms, or it is cast into a sheet and then The sheet is cut into individual dosage forms.

[0130] The pharmaceutical composition can be attached to a mucosal surface. The present invention can be applied to the mouth, vagina, organs, or other mucosal surfaces. tissues of the body that have a moist surface and are susceptible to bodily fluids, such as various types of mucosal surfaces; The composition is particularly useful for the topical treatment of mucosal lesions, ulcers, and wounds. Upon application and attachment to the treatment area, it provides a protective layer and is resistant to the treatment area, surrounding tissue, and other bodily fluids. Control of erosion in aqueous solution or body fluids such as saliva, and simultaneous or subsequent delivery of drugs. Given the slow, natural erosion of the subsequent film, this composition provides effective drug delivery at the treatment site. Provides adequate residence time for product delivery.

[0131] The residence time of the composition depends on the erosion rate of the water-erodible polymer used in the formulation and the The erosion rate depends on the concentration of each of these components. Different polymers, such as hydroxyethyl cellulose and hydroxypropyl cellulose By mixing the low and medium molecular weight hydroxyethyl celluloses together; By using different molecular weight grades of the same polymer, such as blends; By using excipients or plasticizers with solubility properties (including essentially insoluble components); By using soluble organic and inorganic salts; for partial cross-linking, hydroxyethyl ceramide by using a polymer such as cellulose and a cross-linking agent such as glyoxal; or Once obtained, it is possible to modify the physical state of the film, including its crystallinity or phase transition. These strategies may be modulated by post-treatment irradiation or curing. These may be utilized alone or in combination to alter the erosion kinetics of the film. The drug composition film adheres to the mucosal surface and is held in place. Water absorption is While the composition is placed on the mucosal surface, The residence time depends on the desired timing of delivery of the selected drug and the carrier. This can be adjusted widely depending on the desired lifespan. However, in general, the residence time is from about a few seconds to about several Preferably, the residence time for most drugs is adjusted to between about 5 seconds and about 24 hours. More preferably, the residence time is adjusted to about 5 seconds to about 30 minutes. In addition, once the composition is attached to the mucosal surface, it also provides protection to the treatment area and is erodible. The lipophilic material acts as a slow erosion agent to reduce disintegration and dissolution. It can be designed so that

[0132] Excipients that are sensitive to enzymes such as amylase and are highly soluble in water, e.g. Adding water-soluble organic and inorganic salts, etc., to control the erosion kinetics of the composition Suitable excipients include chlorides, carbonates, bicarbonates, citrates, triphosphates, and the like. Sodium fluoroacetate, benzoate, phosphate, fluoride, sulfate, or tartrate The amount added may vary depending on the extent to which the erosion kinetics are altered. and may vary depending on the amount and nature of other ingredients in the composition.

[0133] The emulsifiers typically used in the water-based emulsions described above are preferably , linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid, cetearyl When the acid is selected from carboxylic acid or oleic acid and sodium hydroxide or potassium hydroxide, lauric acid esters of sorbitol and sorbitol anhydrides, palm oils, or other esters of lauric acid. Mitic acid ester, stearate ester, or oleic acid ester, monooleate Polyoxyethylene derivatives including monostearate, monopalmitate, and monolaurate Conductors, aliphatic alcohols, alkylphenols, allyl ethers, alkylaryl ethers sorbitan monostearate, sorbitan monooleate and / or sorbitan monostearate nopalmitate.

[0134] The amount of pharmaceutically active ingredient used will depend on the desired therapeutic strength and the composition of these layers. However, preferably the pharmaceutical ingredient comprises from about 0.001% to about 99%, more preferably from about 0.003% to about 100%, of the composition. 75%, and most preferably from about 0.005% to about 50% by weight, which is greater than 0.005%, greater than 0.05%, , more than 0.5%, more than 1%, more than 5%, more than 10%, more than 15%, more than 20%, more than 30%, about 50%, more than 50%, less than 50% Full, Less than 30%, Less than 20%, Less than 15%, Less than 10%, Less than 5%, Less than 1%, Less than 0.5%, 0.05% The amount of other ingredients may vary depending on the drug or other ingredients. However, typically these ingredients will not exceed 50%, preferably 30%, by weight of the total composition. It is preferred that the amount of HCl in the solution is not more than 15%, and most preferably not more than 15%.

[0135] The thickness of the film may vary depending on the thickness of each layer and the number of layers. Both the thickness and amount of may be adjusted to vary the erosion kinetics. If the article has only two layers, the thickness is 0.005 mm to 2 mm, preferably 0.01 to 1 mm, more preferably is in the range of 0.1 to 0.5 mm, which means more than 0.1 mm, more than 0.2 mm, about 0.5 mm, more than 0.5 mm, less than 0.5 mm The thickness of each layer is less than 10% of the total thickness of the layered composition. It may vary from 10% to 90%, preferably from 30 to 60%, which may be more than 10%, more than 20%, more than 30% , more than 40%, more than 50%, more than 70%, more 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%. Therefore, the preferred thickness of each layer is 0.01 mm to It may be 0.9 mm or may vary from 0.03 to 0.5 mm.

[0136] As will be appreciated by those skilled in the art, when systemic delivery, e.g., transmucosal or transdermal delivery, is desired, the therapeutic The site is where the film delivers and delivers the desired level of medication into the blood, lymph, or other bodily fluids. Typically, such treatment areas include any area that can be maintained. The sites include the mucosal tissues of the mouth, esophagus, ears, eyes, anus, nose, and vagina, as well as the skin. When used on a treatment site, typically the upper arm or thigh, movement can prevent the film from adhering. A relatively large area of ​​unharmed skin is preferred.

[0137] The pharmaceutical composition can also be used as a wound dressing. By providing a physical, conformable, oxygen and moisture permeable, flexible barrier that The formula not only protects the wound but also promotes healing, sterility, and scar formation. to deliver medicine to improve the overall condition of the affected person, to relieve pain, or Some of the examples provided below are well suited for application to skin or wounds. As one skilled in the art will appreciate, the formulation provides good, long-lasting relief of dry skin. Incorporating specific hydrophilic / hygroscopic excipients will help maintain proper adhesion. Another advantage of the present invention when utilized in this manner is that the film If it is not desired that the pigment or coloring material be noticeable on the skin, it is not necessary to use the pigment or coloring material. If it is desired that the film be highly visible, a dye or coloring material may be utilized.

[0138] The pharmaceutical composition is capable of adhering to mucosal tissue, which is naturally moist tissue, while It can also be used on other surfaces, such as skin or wounds. Prior to application, the device must be moistened with an aqueous-based fluid such as water, saliva, wound drainage, or perspiration. This film can be applied to the skin, for example, by washing with water, showering, It can remain on the skin until it is eroded by contact with water, such as by bathing or washing. The film is also easily peelable and removable without significant tissue damage. It can be done.

[0139] The Franz diffusion cell is an in vitro skin permeation assay used in formulation development. The Franz diffusion cell apparatus (Figure 1A) is a device for measuring the concentration of, for example, animal or human tissue, separated by a membrane. It consists of two chambers. The test product is applied to the membrane through the upper chamber. The side chamber is then filled with samples at regular intervals for analysis to determine the amount of activity that permeates the membrane. With reference to FIG. 1A, a Franz diffusion cell 100 contains a donor compound 101, a donor compound 102, a donor compound 103, a donor compound 104, a donor compound 105, a donor compound 106, a donor compound 107, a donor compound 108, a donor compound 109 ...1, Receptor chamber 102, membrane 103, sampling port 104, receptor chamber 105, stirrer 106, and a heater / circulator 107.

[0140] With reference to FIG. 1B, the pharmaceutical composition is a film 100 comprising a polymer matrix 200, The active ingredient 300 is contained within the polymer matrix. The Hanser 400 can be included.

[0141] 2A and 2B, a graph shows the permeation of the active agent from the composition. In situ solubilized epinephrine base versus inherently soluble epinephrine bitartrate This indicates that no significant difference was observed in the amount of epinephrine bitartrate in the processed food. It was selected for further development based on its ease of use. Flux is the amount of permeation as a function of time. The steady-state flux is derived as the gradient of the Obtained from the plateau of the flux versus time curve, normalized for area.

[0142] With reference to FIG. 2A, this graph shows the results for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized 1 shows the average amount of active agent permeated versus time by epinephrine base.

[0143] With reference to FIG. 2B, this graph shows the results for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized Average flux versus time with epinephrine base is shown.

[0144] Referring to Figure 3, this graph shows the excretion of epinephrine bitartrate as a function of concentration. This study compared concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL. The results showed that increasing concentrations showed increased penetration, and the higher the level of enhancement, the It was shown that the resistance decreases with load.

[0145] Referring to Figure 4, this graph shows the permeation of epinephrine bitartrate as a function of solution pH. We investigated whether acidic conditions promote stability. The results showed that epinephrine bitartrate The pH 3 buffer solution of phosphate and the pH 5 buffer solution of epinephrine bitartrate were compared, and the pH 5 buffer solution of epinephrine bitartrate was compared. Phosphorus pH 5 buffer was found to be slightly preferable.

[0146] Referring to Figure 5, this graph shows the amount of epinephrine permeation shown as a function of time. The effects of enhancers on the permeation of steroids are shown. Several ingredients, including ol Oleique, Labrafil, TDM, SGDC, Gelucire 44 / 14 and clove oil Enhancers were screened. The effects on time to onset and steady-state flux were A significant effect was achieved and surprisingly enhanced permeation was observed for clove oil and Labrasol. This was achieved.

[0147] 6A and 6B, these graphs show the amount of polymer permeated (μg) versus time. - Epinephrine release on the platform and the effect of enhancers on that release Figure 6A shows epinephrine release from different polymer platforms. Figure 6B shows , shows the effect of the enhancer on epinephrine release.

[0148] Referring to Figure 7, this graph shows the pharmacokinetic model in male Yucatan minipigs. The study compares 0.3 mg EpiPen, 0.12 mg epinephrine IV, and a placebo film.

[0149] Regarding Figure 8, this graph shows the concentration profile of 40 mg epinephrine film vs. 0.3 mg EpiPen. The effect of no enhancer on the α- and β-enhanced genomic DNA is shown.

[0150] Regarding Figure 9, this graph shows the concentration profile of 40 mg epinephrine film vs. 0.3 mg EpiPen. The effect of Enhancer A (Labrasol) on the leucine-10-one is shown.

[0151] Referring to Figure 10, this graph shows the results of two 40 mg epinephrine films (10-1-1) and (11-1-1). 1 shows the effect of Enhancer L (clove oil) on the concentration profile versus a 0.3 mg EpiPen.

[0152] Regarding Figure 11, this graph shows the concentration profile of 40mg epinephrine film vs. 0.3mg EpiPen. Enhancer L (clove oil) and film size (10-1-1 thin large film) for the file The effect of 11-1-1 on the thickness of the thin films is shown.

[0153] Regarding Figure 12, this graph shows the effect of Enhancer L (clove oil) on the 0.3 mg EpiPen. Concentration profiles for varying doses of epinephrine film in a constant matrix Indicates the file.

[0154] Regarding Figure 13, this graph shows the effect of Enhancer L (clove oil) on the 0.3 mg EpiPen. Concentration profiles for varying doses of epinephrine film in a constant matrix Indicates the file.

[0155] Regarding Figure 14, this graph shows the effect of Enhancer A (Labrasol) on the 0.3 mg EpiPen. Concentration profiles for varying doses of epinephrine film in a constant matrix Indicates the file.

[0156] Referring to Figure 15, this graph shows the plasma concentrations of 40 mg epinephrine film versus 0.3 mg EpiPen. Effect of farnesol and farnesol in combination with linoleic acid on the glycemic index profile Shows.

[0157] Referring to Figure 16, this graph shows the plasma concentrations of 40 mg epinephrine film versus 0.3 mg EpiPen. Effect of farnesol and farnesol in combination with linoleic acid on the β-amyloid profile Indicates the sound.

[0158] Referring to Figure 17, this graph shows the plasma concentrations of 40mg epinephrine film vs. 0.3mg EpiPen. 1 shows the effect of farnesol in combination with linoleic acid on the profile.

[0159] Referring to Figure 18, this graph shows the plasma concentrations of 40mg epinephrine film vs. 0.3mg EpiPen. Effect of farnesol and farnesol in combination with linoleic acid on the β-amyloid profile Indicates the sound.

[0160] The following examples illustrate the pharmaceutical compositions described herein, as well as methods of making and using the pharmaceutical compositions. The methods and apparatus are provided to illustrate the invention. [Example]

[0161] (Example) Example 1: Permeation Enhancer - Epinephrine Enhancement of permeation was achieved using several permeation enhancers, including epinephrine bitartrate at a concentration of 16.0 The results show the flux enhancement shown in the following data: For 100% eugenol and 100% clove oil, the results showed a significant difference in steady-state flux. It was shown that the temperature was reached quickly and was accompanied by an unexpectedly high flux enhancement (%). [Table 1] 1 Steady-state flux was reached fairly quickly *0.3% eugenol vs. 0.3% clove - similar flux rates

[0162] For these examples, clove oil was obtained from clove leaves. Similar results were obtained from clove buds. and / or clove oil from clove stems. To predict similar permeability-enhancing results from pharmaceutical compounds structurally similar to nephrin can be done.

[0163] Example 2 General Permeation Procedures - Ex Vivo Permeation Testing Protocol In one example, the permeabilization procedure is performed as follows: A water bath is set at 37°C, and the receiver is heated to 37°C. The bar medium is placed in a water bath to regulate the temperature and degassing is initiated. The Franz diffusion cell is obtained and prepared. , sampling port, receptor chamber, stir bar, and heater / circulator The stirring bar is inserted into the Franz diffusion cell. The tissue is placed on top of the Franz diffusion cell. and ensure that the tissue covers the entire surface with an overlap on the glass joint. Place the top of the diffusion cell on top of the tissue and clamp the top of the cell to the bottom. Approximately 5 mL of receptor medium is loaded into the receiver area, ensuring that any air bubbles are trapped in the receiving portion of the cell. This ensures that all 5 mL fits into the receiver area. Start stirring and allow the temperature to equilibrate for approximately 20 minutes. Label high performance liquid chromatography (HPLC) vials by cell number and time point Then, you should check again for bubbles as the solution degasses upon heating. .

[0164] When testing a film, the following steps are taken: (1) weigh the film and measure the thickness of the film to fit the diffusion area ( Punch the sample into a smaller size (or smaller), reweigh it, and record the weight before and after punching. (2) wetting the donor area with approximately 100 μL of phosphate buffer; (3) doping the film. The plate was placed on a surface of a container, covered with 400 μL of phosphate buffer, and a timer was started. It can be done.

[0165] For the solution test, the following steps were performed: (1) Using a micropipette, 500 μL of the solution was dispensed into each donor. (2) Dispense into cells and start timer; (3) Time points (time = 0 min, 20 min, 40 min, 60 min, 200 μL samples were taken and labeled at 120, 180, 240, 300, and 360 minutes. Place it in the HPLC vial and tap the sealed vial to ensure that air is trapped at the bottom of the vial. (3) replacing the receptor medium with 200 μL at each sampling time. (4) Once all time points are complete, disassemble the cell and discard all materials. Steps can be taken to properly dispose of the material.

[0166] Example 3: Ex vivo permeation evaluation An example of an ex vivo permeation assessment is as follows: 1. Tissue is freshly excised and stored at 4°C (e.g., overnight). 2. Tissues are processed and frozen at -20°C for up to 3 weeks before use. 3. The tissue is harvested to the correct thickness (dermatome). 4. Add approximately 5 mL of receiver medium to the receiver compartment. The body is selected to ensure sink conditions. 5. Place the tissue in the donor compound, donor chamber, membrane, sampling port, and receptor. In a Franz diffusion cell equipped with a chamber, a stir bar, and a heater / circulator Place. 6. Apply approximately 0.5 mL of donor solution and immerse the 8 mm circular film in 500 μL of PBS buffer. Moisten with. 7. Samples are taken from the receiver chamber at predetermined intervals and replaced with fresh medium. exchange.

[0167] Example 4 Buccal Delivery of Doxepin The following is an exemplary permeation study for buccal delivery of doxepin. This study was conducted at the University of Barcelona. The Animal Experiment Ethics Committee of the University of Catalonia (Spain) and the Animal Experimentation Committee of the Regional Government of Catalonia (Spain) The study was carried out under a protocol approved by the NIH Committee. Sows aged 3-4 months were used. Thiopental sodium was administered in the animal facility at the Bellvitge Campus (University of Barcelona, ​​Spain). Pigs were sacrificed using an overdose of steroid anesthesia, and the buccal mucosa from the cheek region of the pig was immediately removed. Fresh buccal tissue was placed in a container filled with Hank's solution and transported from the hospital to the laboratory. The remaining tissue samples were cryoprotected in a PBS mixture containing 4% albumin and 10% DMSO. The mixture was stored at -80°C in a container containing

[0168] For permeation studies, it contributes to a diffusion barrier (Sudhakar et al., "Buccal Bioadhesive Drug Delivery - Buccal bioadhesive drug delivery - A promising alternative for drugs with poor oral efficacy ising option for orally less efficient drugs),” Journal of Controlled Release, 114 (2006) 15-40) The buccal mucosa of pigs was harvested using an electric dermatome (GA 630, Aesculap, Tuttlingen, Germany). The sheet was cut into a thickness of 500±50 μm using a cutting tool and then cut into suitable pieces with surgical scissors. Most of the underlying connective tissue was removed with a scalpel.

[0169] The membrane was then mounted in a specially designed membrane holder with a permeate orifice diameter of 9 mm. (diffusion area 0.636 cm 2Using a membrane holder, the buccal membrane of each pig was placed in the donor compartment. The membrane was placed between the vent (1.5 mL) and the receptor compartment (6 mL), where the epithelial side was facing the donor chamber of a freestanding Franz diffusion cell (Vidra Foc Barcelona, ​​Spain). The connective tissue area was placed facing the receiver to prevent bubbles from forming.

[0170] The infinite dose condition was established by administering 100 μL of saturated doxepin solution as the donor solution. The solution was applied to the chamber and immediately sealed with parafilm to prevent water evaporation. Before carrying out this experiment, the diffusion cells were checked to ensure that the temperature in all cells was The cells were incubated in a water bath at 37°C for 1 hour. The magnetic stir bar is coated with Teflon 1, which is used to This was used to ensure that the fluid within the compartment remained homogeneous.

[0171] Sink conditions were established by first testing saturating concentrations of doxepin in the receptor medium. All experiments were performed using 300 μL samples at preselected times over a 6-hour period. In the receptor compartment at intervals (0.1, 0.2, 0.3, 0.7, 1, 2, 3, 4, 5, and 6 hours), The membrane was withdrawn from the center with a syringe, taking great care to avoid trapping air underneath. The sample volume was then immediately mixed with the same volume of fresh receptor medium (PBS; pH 7.4). It was replaced with

[0172] Additional details can be found in A. Gimemo et al., "Buccal Delivery of Doxepin: Permeation and Histological Evaluation." Transbuccal delivery of doxepin: Studies on permeation and histological "International Journal of Pharmaceutics 477 (2014), 650-654" No. 6,299,499, which is incorporated herein by reference.

[0173] Example 5 Oral Transmucosal Delivery Porcine oral mucosal tissue has histological characteristics similar to those of human oral mucosal tissue (Heaney TG, Jones RS, "Histological study of the influence of adult porcine alveolar mucosal connective tissue on epithelial differentiation (H) istological investigation of the influence of adult porcine alveolar mucosal con nective tissues on epithelial differentiation)”, Arch Oral Biol 23 (1978) 713-7 17; Squier CA, and Collins P, "Soft tissue attachment, epithelial undergrowth, and surface porosity." The relationship between soft tissue attachment and epithelial downgrowth and surface porosity)”, Journal of Periodontal Research 16 (1981) 434-440). Les In the paper by ch et al., "The Permeability of Human Oral Mucosa and Skin to Water" ral Mucosa and Skin to Water), J Dent Res 68 (9), 1345-1349, 1989) The water permeability of the oral cavity floor mucosa is not significantly different from that of the human buccal mucosa, but the water permeability of the oral cavity floor is different from that of the human tissue. reported that the permeability of porcine tissue was higher than that of fresh porcine tissue samples at -80°C. Comparison between archived specimens revealed no significant effect on permeability as a result of freezing. The buccal mucosal absorption of a wide range of drugs was demonstrated both in vitro and in vivo in pigs. The molecules have been tested (see, for example, M. Sattar's article, "Oral transmucosal drug delivery - current status and future prospects" ug delivery - current status and future prospects)”, International Journal of P (See Table 1 in Harmaceutics 471 (2014) 498-506). Typically, in vitro testing The study was carried out using isolated porcine leukocytes in an Ussing chamber, Franz cell, or similar diffusion device. The in vivo test described in this document involves attaching a solution, gel or The study involved application of the drug as a composition to the buccal mucosa of pigs, followed by plasma sampling. There are.

[0174] Nicolazzo et al. ("The Effect of Various In Vitro Conditions on the Permeability Properties of the Buccal Mucosa"). ffect of Various in Vitro Conditions on the Permeability Characteristics of the Buccal Mucosa), Journal of Pharmaceutical Sciences 92(12) (2002) 2399-2410) , using caffeine and estradiol as model hydrophilic and lipophilic molecules. The effects of various in vitro conditions on the permeability of porcine buccal tissue were investigated. The drug permeation was tested using a modified Ussing chamber. Through-thickness epithelial tissue, fresh tissue, and frozen tissue were examined. Tissue integrity was assessed using fluorescein staining. Monitored by absorption of FITC-labeled dextran 20 kDa (FD20) Tissue viability was assessed using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoli). The permeability through the buccal epithelium was assessed using a biochemical assay and histological evaluation. The transients were 1.8 times higher for caffeine and 1.8 times higher for estradiol compared with full-thickness buccal tissue. Flux values ​​for both compounds were 16.7 times greater for fresh buccal epithelium and The results were comparable for frozen buccal epithelium, but histological evaluation revealed no significant difference in cell death in frozen tissue. This tissue remained viable for up to 12 hours post-mortem using the MTT viability assay. This was confirmed by histological evaluation.

[0175] investigated the relative contribution of epithelium and connective tissue to the barrier properties of porcine buccal tissue. In vitro permeation tests were performed using antipyrine, buspirone, and methicillin as model permeants. The thicknesses were 250, 400, 500, 600, and 700 μm. The permeability of a model diffusant across the buccal mucosa of the epithelium and connective tissue was determined. A bilayer membrane model was developed to depict the relative contributions of the permeability barrier to the barrier function. The relative contribution of the connective tissue region increased significantly with increasing mucosal tissue thickness. A mucosal tissue thickness of 0.05 mm was recommended by the authors for in vitro transbuccal permeation testing. , because the epithelium represented the main permeability barrier for all diffusing substances at this thickness. also compared the permeability of the same group of model penetrants in the porcine buccal mucosa with several The effects of biological and experimental variables were investigated (porcine buccal mucosa as an in vitro model). : Effect of biological and experimental variables, Kulkarni et al., J Pharm Sci. 2010 99(3):1265-7 7) Significantly, higher permeability of the permeant was observed in the lip compared to the thicker cheek region (250-280 μm). The buccal mucosa of pigs was found to be thinner (170-220 μm) behind the The epithelium was then placed in Ringer's bicarbonate solution at 4°C for 24 hours to maintain its integrity. Heat treatment to separate from tissue is detrimental to its permeability and integrity characteristics compared to surgical separation. It had no effect on

[0176] For additional details, see M. Sattar's article, "Oral Transmucosal Drug Delivery - Current Status and Future Perspectives." (Oral transmucosal drug delivery- current status and future prospects)”, Intern National Journal of Pharmaceutics 471 (2014) 498-506, which is a citation. and is incorporated herein by reference.

[0177] Example 6: Cryopreservation of buccal mucosa Different regions of the porcine buccal mucosa have different patterns of permeability, with the most notable being the area behind the lips. There was a significantly higher permeability in the porcine buccal mucosa compared to the cheek area. In this case, the epithelium acts as a permeability barrier, and the thickness of the cheek epithelium is greater than that of the area behind the lips. (Harris and Robinson, 1992). In an exemplary permeation test and contribute to the diffusion barrier (Sudhakar et al., 2006), and fresh or frozen tissue from the same region The buccal mucosa of the porcine was cut into sheets with a thickness of 500 ± 50 μm and then cut into pieces with an electric dermatome (model GA 630). The tissue was obtained using a surgical instrument (Aesculap, Tuttlingen, Germany) and cut into suitable pieces with surgical scissors. All the equipment used was sterilized beforehand. Most of the underlying connective tissue was removed with a scalpel. The membrane was then placed in a specially designed membrane holder with a permeation orifice diameter of 9 mm. (diffusion area 0.63 cm 2 Using a membrane holder, the buccal membrane of each pig was placed on the donor compartment. The membrane was placed between the membrane (1.5 mL) and the receptor compartment (6 mL), where the epithelial side , facing the donor chamber of a static Franz-type diffusion cell (Vidra Foc Barcelona, ​​Spain). The connective tissue area was placed facing the receiver to prevent bubbles from forming. As a model drug, it has lipophilic characteristics (logP = 1.16; n-octanol / PBS, pH 7.4) and ionic This was carried out using PP, which is soluble in water (pKa = 9.50) and has a MW of 259.3 g / mol (Modamio et al. , 2000).

[0178] The infinite dose condition was determined by a saturated solution of PP in PBS (pH 7.4) at 37°C ± 1°C (C = 588005 ± 5852 μg / mL). 300 μL of the donor solution (n=6) was applied to the receptor chamber, and the water was evaporated. The container was immediately sealed with parafilm to prevent contamination.

[0179] Before performing this experiment, the diffusion cells were cooled to room temperature (37°C) to allow the temperature in all cells to equilibrate. The cells were incubated in a water bath at 25°C ± 1°C for 1 hour. The receptor compartment contains a magnetic stir bar that is attached to the reactor, which acts as a flow meter during the experiment. Sink conditions were used to ensure that the receptors remained homogeneous. The PP saturation concentration in the medium was first tested and then ensured in all experiments.

[0180] Samples (300 μL) were injected into the receptor at the following time intervals: 0.25, 0.5, 1, 2, 3, 4, 5, and 6 hours. The air was extracted from the center of the compartment with a syringe. The removed sample volume is then transferred to a fresh receptor of the same volume, taking great care to avoid contact with the sample. The mucosal surface area (cm) was measured by the vehicle (PBS; pH 7.4). 2 ) Penetrating drug (μg) The cumulative amount of β was corrected for the sample removed and plotted against time (h). Experiments were performed 27 times on fresh buccal mucosa and 22 times on frozen buccal mucosa.

[0181] Additional details can be found in S. Amores's paper, "Ex vivo drug penetration using Franz diffusion cells." An improved cryopreservation method for porcine buccal mucosa in clinical trials thod for porcine buccal mucosa in ex vivo drug permeation studies using Franz di ffusion cells)”, European Journal of Pharmaceutical Sciences 60 (2014) 49-54. It can be acknowledged.

[0182] Example 7: Quinine Permeation Across the Sublingual Mucosal Compartment Since porcine and human oral membranes are similar in composition, structure, and permeability measurements, the porcine The oral mucosa is a good model of the human oral mucosa. Permeability across the porcine oral mucosa has been shown to be comparable to that of the human oral mucosa. It is not relevant for the tissue to be viable, and therefore it is not important that the tissue be viable.

[0183] To prepare the porcine membrane, use a scalpel to remove the floor of the mouth and the ventral (lower) tongue mucosa of the pig. The mucosa was removed by blunt dissection. The removed mucosa was cut into approximately 1 cm squares and The unfrozen ventral surface of the pig tongue was frozen at -20°C on aluminum foil until frozen (<2 weeks). The mucosa was then used in the permeation study within 3 hours of removal.

[0184] The permeability of the membrane to quinine was determined using a nominal receptor volume of 3.6 mL and a diffusion area of ​​0.2 cm. 2 All of The determination was carried out using a glass Franz diffusion cell fitted with a high-performance vacuum gland. Apply a membrane between the receptor and donor compartments. The membrane was held in place using a clamp, and then the receptor The compartment was filled with degassed phosphate buffered saline (PBS) pH 7.4. A stir bar was added to the receptor compartment and the complete cell was placed in a 37°C water bath. The membrane was equilibrated for 20 min with PBS applied to the donor compartment, followed by pipetting. Five microliters of quinine solution in various vehicles or saturated fatty acids of the Q / 2-HP-β-CD complex were aspirated. A 100 μL aliquot of the neutralizing solution was applied to each donor compartment. In a test to determine the effect of saliva on the permeation of quinine beyond 100 μL of sterile saliva was added to the donor compartment, followed by 5 μL of quinine solution.

[0185] At 2, 4, 6, 8, 10 and 12 hours, the receptor phase was withdrawn from the sampling port, and A 1 mL aliquot of each sample was transferred to an HPLC autosampler vial and then stored at 37°C. The PBS was replaced with fresh PBS. In addition to the initial administration, 5 μL of each quinine solution was administered again for up to 10 hours. The purpose of this was to develop a hypothetical point-of-use finite dosing regimen based on a 2-hour interval between doses. At least three replicates were performed for each test.

[0186] Additional details can be found in C. Ong's paper, "Quinine permeation across the sublingual mucosa in vitro." (Permeation of quinine across sublingual mucosa, in vitro)”, International Jour nal of Pharmaceutics 366 (2009) 58-64.

[0187] Example 8 Ex Vivo Initial Studies - API Form In this example, in situ solubilized epinephrine base paired with inherently soluble tartaric acid The permeation of epinephrine bitartrate was tested and no differences were observed. was selected for further development based on ease of processing. The flux The steady-state flux is derived as the gradient of the permeation rate of the receiver medium multiplied by the volume of the receiver medium. The graph in Figure 2A shows the flux at 8.00 mg / mL tartaric acid. The mean permeation rate versus time for epinephrine hydrogen carbonate and 4.4 mg / mL solubilized epinephrine base is shown. The graph in Figure 2B shows the results for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized epinephrine. Figure 1 shows the average flux versus time for different bases. [Table 2]

[0188] Example 9: Concentration Dependence of Permeation / Flux In this study, the ex vivo permeation of epinephrine bitartrate as a function of concentration was measured. Figure 3 shows the ex vivo permeation of epinephrine bitartrate as a function of concentration. The study compared concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL. showed that permeation increased with increasing load, and the level of enhancement decreased at higher loads. The study compared concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL. [Table 3]

[0189] Example 10: Effect of pH In this example, the permeation of epinephrine bitartrate as a function of solution pH was examined. In this example, acidic conditions were investigated for their ability to promote stability. The results showed that pH 5 was slightly more favorable than pH 3. The inherent pH of epinephrine bitartrate in solution is 4.5-5. Adjusting the pH with a buffer is unnecessary. It was essential.

[0190] Figure 4 shows the permeation of epinephrine bitartrate as a function of solution pH. The results showed that epinephrine bitartrate pH 3 buffer and tartrate Compared with epinephrine hydrogen tartrate pH 5 buffer, epinephrine hydrogen tartrate pH 5 buffer was slightly It was found to be preferable.

[0191] Example 11: Effect of enhancers on epinephrine permeation In this example, the permeation of epinephrine to test transmucosal delivery was measured using the permeation amount The following enhancers were tested as (µg) versus time (min): The graph in Figure 5 shows the effect of concentration on the time course of the steroid hormone. The results of these enhancers as numbers are shown. [Table 4]

[0192] Enhancers are selected and designed to have functionality that affects various barriers in mucosa. All the enhancers tested improved permeation over time, but clove oil in particular and Labrasol showed significant and unexpectedly high permeation enhancement. [Table 5] TIFF2026027254000008.tif222170TIFF2026027254000009.tif222170TIFF2026027254000010.tif151170

[0193] Example 12 Effect of Enhancers on Epinephrine Release Determine the effect of enhancers (Labrasol and clove oil) on epinephrine release To investigate the release profile of epinephrine, the release profiles of different polymer platforms were examined. Figure 6B shows the release of epinephrine from the foam. These results show that the amount of permeation was between approximately 3250 and 4250 μg after about 40 minutes. The enhancers tested were those that suppressed epinephrine release from the matrix. showed that it does not limit the release of

[0194] Example 13: Accelerated Stability Different stabilizer loadings were tested. [Table 6]

[0195] Example 14: Effects of enhancers The pharmacokinetic model was tested in male Yucatan minipigs. The graph in Figure 7 shows the The results of a pharmacokinetic model in minipigs are presented. This study compared the efficacy of 0.3 mg EpiPen and 0.12 mg EpiPen. IV pinephrine and placebo will be compared.

[0196] Concentration profiles of enhancer-free 0.3 mg EpiPen and 40 mg epinephrine film The effect of no enhancer on the IL is shown in Figure 8.

[0197] The effect of the enhancer 3% Labrasol is shown in Figure 9, which shows the effect of the 40 mg epinephrine film 1 shows the effect of Enhancer A (Labrasol) on the concentration profile versus a 0.3 mg EpiPen. Figure 10 shows the concentration profiles of two 40 mg epinephrine films (10-1-1) and (11-1-1) versus a 0.3 mg EpiPen. Figure 1 shows the effect of Enhancer L (clove oil) on the profile.

[0198] Additionally, the effect of film size and the effect of clove oil (3%) are also shown in Figure 11. , 0.30 mg EpiPen (n=4), 40 mg epinephrine film (10-1-1) (n=5) and 40 mg epinephrine The concentration versus time profile was compared between the male and female mice and the male mice. after administration of epinephrine sublingually or intramuscularly to the nibuta.

[0199] Studies were performed in which the ratio of epinephrine to enhancer was varied. Concentration versus time profiles following sublingual or intramuscular epinephrine administration to male minipigs. By varying the ratio of epinephrine to clove oil (Enhancer L), The results are shown in Figure 12. This study was conducted using 0.30 mg EpiPen (n=4), 40 mg epinephrine (n=4), and 10 mg epinephrine (n=4). The study was conducted comparing the 20 mg epinephrine film (12-1-1) (n=5) and the 20 mg epinephrine film (13-1-1) (n=5). Ta.

[0200] Example 15 The variable dose was administered in a fixed matrix with enhancer Labrasol (3%) and clove oil (3%). The tests in Figure 13 were carried out using 0.30 mg EpiPen (n=4), 40 mg EpiPen (n=4), and 14 mg EpiPen (n=4). Epinephrine film (18-1-1) (n=5) and 30 mg epinephrine film (20-1-1) (n=5) were compared. The test in Figure 14 was carried out to compare the results of 0.30 mg EpiPen (n=4), 40 mg epinephrine film (19-1- 1) (n=5) and 30 mg epinephrine film (21-1-1) (n=5). also studied the concentration versus time profile following sublingual or intramuscular epinephrine administration to male minipigs. It was a file.

[0201] Example 16 To determine the time course of the enhancer (farnesol) on epinephrine levels, To investigate this, a pharmacokinetic model was tested in male minipigs. Epinephrine plasma as a function of time (min) after sublingual or intramuscular administration of penetration enhancers The concentrations (ng / mL) are shown. This study was conducted using 0.3 mg EpiPen (n=3), 30 mg epinephrine film 31-1 -1 (n=5) and 30mg epinephrine film 32-1-1 (n=5) were compared. is formulated with a farnesol enhancer. As shown in this figure, 31-1 -1 film showed enhanced epinephrine concentrations starting at approximately 30-40 minutes and continuing until approximately 130 minutes. Shows stability.

[0202] The graph in Figure 16 was taken from the same study as Figure 17, but exclusively used 0.3 mg EpiPen and 30 mg Epinephrine. Only data points compared to Rinflum 31-1-1 (n=5) are shown.

[0203] The graph in Figure 17 was taken from the same study as Figure 17, but exclusively using 0.3 mg EpiPen and 30 mg Epinephrine. Only data points comparative to Phosphorfilm 32-1-1 (n=5) are shown.

[0204] Example 17 Referring to Figure 18, this graph shows epinephrine concentrations over time after sublingual or intramuscular administration. Male minipigs tested to determine the effect of an enhancer (farnesol) on The pharmacokinetic model for epinephrine in 2000 is shown. as a function of time (min) after sublingual or intramuscular administration of the farnesol permeation enhancer in This test was conducted to compare five types of 30 mg epinephrine films (32-1-1) with three types of 0.3 mg epinephrine films. We compared data from the pens. This data started at about 20-30 minutes and continued until about 130 minutes. 1 shows an epinephrine film with enhanced stability of epinephrine concentration.

[0205] Example 18 In one embodiment, the epinephrine pharmaceutical composition film is prepared according to the following formulation: You can: [Table 7]

[0206] Example 19 An epinephrine pharmaceutical film composition was prepared with the following formulation: [Table 8]

[0207] Example 20 In another embodiment, a pharmaceutical film composition was prepared with the following formulation: [Table 9]

[0208] Example 21 In another embodiment, a pharmaceutical film composition was prepared with the following formulation: [Table 10]

[0209] Example 22 Referring to Figure 19, this graph shows epinephrine plasma concentrations over time after sublingual or intramuscular administration. To determine the effect of enhancers (6% clove oil and 6% Labrasol) on The pharmacokinetic model (logarithmic scale) in male minipigs is shown. (ng / mL) of the farnesol permeation enhancer in the epinephrine film sublingually or intramuscularly The data are presented as a function of time (minutes) after intravenous administration. The data begin just after the 10 minute time point and continue through approximately 30 minutes. Epinephrine with enhanced stability of epinephrine concentrations from 0.01 to approximately 100 minutes. Shows the film.

[0210] With reference to Figure 20, this graph shows the data collected from a 0.3 mg EpiPen (shown as diamond data points). The mean data for the epinephrine-induced thromboembolism in male minipigs as mentioned in Figure 19 were compared against the mean data. The pharmacokinetic model for the 0.3 mg EpiPen film formulation is shown in Figure 1. As shown in the data, The mean plasma concentration peaked between 0.5 and 1 ng / mL. In contrast, epinephrine film The drug peaked between 4 and 4.5 ng / mL.

[0211] Example 23 Referring to Figure 21, this graph shows the efficacy and safety of steroids after sublingual or intramuscular administration across seven animal models. The effect of enhancer (9% clove + 3% Labrasol) on epinephrine concentration over time The pharmacokinetic model in male minipigs was tested to determine the overall peak The concentration was reached between 10 and 30 minutes.

[0212] All references cited herein are incorporated by reference in their entirety. It is being done.

[0213] Example 23 In one embodiment, a dipifebrin pharmaceutical composition film is prepared according to the following formulation: You can: [Table 11]

[0214] Example 24 In another embodiment, a dipifebrin pharmaceutical composition film is prepared according to the following formulation: Can: [Table 12]

[0215] Example 25 In another embodiment, a dipifebrin pharmaceutical composition film is prepared according to the following formulation: Can: [Table 13]

[0216] Example 26 In one study, investigators evaluated the pharmacokinetics of epinephrine after administration of dipivefrin SL. Specifically, the bioavailability of epinephrine and the conversion of dipivefrin to epinephrine were investigated. The exchange rate was analyzed and compared with other routes of administration (oral, SC, and IV). [Table 14]

[0217] The study included various routes of administration: sublingual (SL), oral tablet (PO), subcutaneous (SC), and intravenous. Intravenous (IV) administration was compared. PK time points (for all groups): 0 (pre-dose), 2, 5, 10, 12, and 15 post-dose , 17, 20, 25, 30, 40, 60, 90, and 120 minutes, and 3, 4, 6, and 8 hours after administration. Oral irritation evaluation was performed by Draize scoring (SL film group): Before (0) and 24 hours after administration. Dipifebrin film (DF) is a pharmaceutical composition 1 is an exemplary embodiment of the

[0218] Referring to Figure 22A, the data shows the mean epinephrine plasma concentration versus time over a 60-minute period. Regarding 2B, the data show the mean epinephrine plasma concentration versus time over 480 minutes. Interestingly, dipifebrin film reached a target Cmax of 0.2 ng / ml to 1.5 ng / ml in less than 30 minutes. The Cmax values ​​were 0.1ng / ml to 2ng / ml, 0.15ng / ml to 1.5ng / ml, and 0.2ng / ml to 1.0ng / ml. The Cmax values ​​were greater than 0.1 ng / ml, greater than 0.15 ng / ml, greater than 0.2 ng / ml, and 0.4 ng / ml. greater than 0.5ng / ml, greater than 0.6ng / ml, greater than 0.7ng / ml, and less than 2ng / ml and less than 1.5ng / ml. It was shown that...

[0219] Tmax is given in the range of 0 to 480 minutes, including 10 to 60 minutes, 20 to 40 minutes, 12 to 15 minutes, and 5 to 10 minutes. Tmax has been shown to be less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, and less than 10 minutes. are.

[0220] Referring to Figure 23A, the data shows the mean dipifebrin plasma concentration versus time over a 60 minute period. With reference to Figure 23A, the data show the mean dipifebrin plasma concentration versus time over 480 minutes. The amount of pifebrine was shown to decrease as epinephrine was formed. The data show that the target Cmax of 0.2 ng / ml to 1.5 ng / ml and Tmax of less than 35 minutes were achieved for the subject films. Cmax values ​​range from 0.1ng / ml to 2ng / ml, 0.15ng / ml to 25ng / ml, and 0.2ng / ml to The Cmax values ​​are 1.0 ng / ml, 0.2 ng / ml to 1.2 ng / ml, and 0.2 ng / ml to 1.3 ng / ml. , more than 0.1ng / ml, more than 0.15ng / ml, more than 0.2ng / ml, more than 0.4ng / ml, more than 0.5ng / ml, more than 1.0ng / ml, 1.2ng / ml, and less than 3 ng / ml, less than 2 ng / ml, and less than 1.5 ng / ml. The max is shown in the range of 0 to 480 minutes, including 10 to 60 minutes, 20 to 40 minutes, 12 to 15 minutes, and 5 to 10 minutes. Tmax has been shown to be less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, and less than 10 minutes. .

[0221] With reference to Figure 24, this data is shown as a circular data point with epinephrine (dipivefrin SL 16-1-1 E), and dipivefrin (dipiferin SL-Dip 16-1-1 D) in square data points. This shows the mean plasma concentration of dipifebrine as epinephrine is formed. This indicates a decrease in the amount.

[0222] Referring to Figure 25, this graph shows the conversion of dipivefrin to epinephrine (SC and IV groups). The dashed line indicates dipifebrine and the solid line indicates epinephrine. [Table 15]

[0223] The results showed that there was no local irritation with the Dipivefrin SL film. Dipivefrin is rapidly converted to epinephrine; SC administration of dipivefrin provides depot action. The results showed that the IV administration of epinephrine resulted in higher and more prolonged epinephrine exposure. Results showed that IV dipivefrin administration demonstrated a faster onset of action and peak epinephrine exposure at 2 minutes. The results showed that oral administration was superior to other routes of administration in terms of the efficacy of the drug in treating rheumatoid arthritis and its subsequent elimination from the system within 2 hours. In comparison, the lowest epinephrine exposure was observed (dipivefrine concentrations were below the detection limit). In short, surprisingly, when using penetration enhancers, No difference was observed between the furin solution and the dipivefrin film solution.

[0224] Example 27 In this study, the investigators examined the conversion of dipifebrine to epinephrine. The study systematically controlled three variables: drug concentration, dose, and enhancer load. Data were analyzed to determine the rate of onset of action, Cmax, and plasma drug concentration versus time during the first 20-25 minutes. The area under the curve (AUC) was determined.

[0225] With reference to Figure 26, the data shows the average mean epinephrine concentration across all matrix tests. The average epinephrine profiles are shown. The average duration is approximately 30 minutes, 25 minutes, and 20 minutes. 10-1-1) achieved the fastest average result. [Table 16]

[0226] Referring to Figure 27, the data shows the plasma concentration (ng / ml) of dipifebrine and epinephrine versus Additional data comparing time (hours) are shown. The mean treatment window was within 20 minutes and 15 minutes. This shows that the results are achieved within 30 minutes, including each average within 30 minutes.

[0227] Example 28 Studies have shown that transmucosally administered epinephrine requires higher levels of Results confirmed the antagonistic effect of the receptor interactor. Pretreatment with phentolamine (a reversible nonselective α-adrenergic antagonist) (phen 0 Preclinical results comparing a 30 mg formulation of epinephrine sublingual film (ESF) to a 10 mg / ESF formulation This pretreatment resulted in improved plasma purification within therapeutic windows of 30 minutes, 25 minutes, and 20 minutes. Concentration levels are indicated. [Table 17]

[0228] Referring to Figure 28, this graph shows the loading of phentolamine and how it affects epinephrine. Epinephrine plasma concentration versus time profiles in a follow-up study investigating whether the effect of steroids on epinephrine absorption was significant The study used 30 mg epinephrine sublingual film (ESF). The loading was shown to be dose dependent. The results are shown graphically and summarized below: [Table 18]

[0229] As shown in the graph and the data above, the therapeutic window is 30 minutes or less, 25 minutes or less, and 20 minutes or less.

[0230] Other embodiments are within the scope of the following claims.

Claims

1. polymer matrix; a pharmaceutical active ingredient comprising epinephrine or a prodrug thereof in the polymer matrix; and Beauty Adrenergic receptor interactors A pharmaceutical composition comprising:

2. 10. The pharmaceutical composition of claim 1, further comprising a penetration enhancer.

3. The composition is a film further comprising a polymer matrix, and the pharmaceutically active ingredient is 10. The pharmaceutical composition of claim 1, wherein the polymer matrix comprises:

4. 3. The pharmaceutical composition of claim 2, wherein the penetration enhancer comprises a phenylpropanoid.

5. 3. The pharmaceutical composition of claim 2, wherein the penetration enhancer comprises farnesol or labrasol. composition.

6. 3. The pharmaceutical composition of claim 2, wherein the permeation enhancer comprises linoleic acid.

7. 10. The pharmaceutical composition of claim 1, which is a film further comprising a polymer matrix. The pharmaceutical composition, wherein the pharmaceutically active ingredient is contained in the polymer matrix.

8. Chewable or gelatin-based dosage forms, sprays, gums, gels, creams, tablets, 10. The pharmaceutical composition according to claim 1, which is a liquid or a film.

9. 5. The method of claim 4, wherein the phenylpropanoid is eugenol or eugenol acetate. The pharmaceutical composition described above.

10. The phenylpropanoid is cinnamic acid, cinnamic acid ester, cinnamic aldehyde, or hydrochloride.

5. The pharmaceutical composition of claim 4, wherein the active ingredient is cinnamic acid.

11. 5. The pharmaceutical composition of claim 4, wherein the phenylpropanoid is chavicol.

12. 5. The pharmaceutical composition of claim 4, wherein the phenylpropanoid is safrole.

13. 10. The pharmaceutical composition of claim 1, wherein the adrenergic receptor interactor is a plant extract. thing.

14. 14. The pharmaceutical composition of claim 13, wherein the plant extract further comprises an essential oil extract of a clove plant. thing.

15. 14. The medicament of claim 13, wherein the plant extract further comprises an essential oil extract of the leaves of a clove plant. composition.

16. 14. The pharmaceutical composition of claim 13, wherein the plant extract further comprises an essential oil extract of the flower buds of a clove plant. Pharmaceutical composition.

17. 14. The medicament of claim 13, wherein the plant extract further comprises an essential oil extract of the stem of a clove plant. composition.

18. 14. The pharmaceutical composition of claim 13, wherein the plant extract is synthetic or biosynthetic.

19. 14. The pharmaceutical composition of claim 13, wherein the plant extract further comprises 40 to 95% eugenol. 。

20. The adrenoceptor interacting substance is a terpenoid, a terpene, or a sesquiterpene.

2. The pharmaceutical composition of claim 1, comprising:

21. 10. The pharmaceutical composition of claim 1, wherein the polymer matrix comprises a polymer.

22. 22. The pharmaceutical composition of claim 21, wherein the polymer is a water-soluble polymer.

23. 22. The pharmaceutical composition of claim 21, wherein the polymer comprises polyethylene oxide.

24. The polymer may be selected from the group consisting of: hydroxypropyl methylcellulose, hydroxyethyl Cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, methyl a cellulose-based polymer selected from the group consisting of cellulose, cellulose, and carboxymethylcellulose; 22. The pharmaceutical composition of claim 21, comprising:

25. The polymer matrix may comprise a cellulosic polymer, polyethylene oxide, and a poly Vinylpyrrolidone, polyethylene oxide and polysaccharides, polyethylene oxide, hydroxy Propyl methylcellulose, and polysaccharides, or polyethylene oxide, hydroxypropyl 22. The pharmaceutical composition of claim 21, comprising methylcellulose, a polysaccharide, and polyvinylpyrrolidone. 。

26. The polymer matrix may be selected from the group consisting of pullulan, polyvinylpyrrolidone, polyvinyl Alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth Guar gum, acacia gum, gum arabic, polyacrylic acid, methyl methacrylate acrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide Di-propylene oxide copolymer, collagen, albumin, polyamino acids, polyphosphates At least one selected from the group consisting of phazene, polysaccharide, chitin, chitosan, and derivatives thereof 22. The pharmaceutical composition of claim 21, comprising a polymer of formula:

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

28. 10. The method of claim 1, wherein the polymer matrix comprises a dendritic polymer or a hyperbranched polymer. Pharmaceutical compositions.

29. Adrenergic receptor interactors containing epinephrine or its prodrugs Combining with ingredients; and forming a pharmaceutical composition comprising the adrenoceptor interactor and the pharmaceutically active ingredient; and 1. A method for producing a pharmaceutical composition comprising:

30. A housing holding a quantity of a pharmaceutical composition, the pharmaceutical composition comprising: polymer matrix; a pharmaceutical active ingredient comprising epinephrine or a prodrug thereof in the polymer matrix; and Phenylepropanoids and / or plant extracts the housing; and an opening for dispensing a predetermined amount of the pharmaceutical composition; An apparatus comprising:

31. polymer matrix; a pharmaceutical active ingredient comprising epinephrine or a prodrug thereof in the polymer matrix; and Beauty Aporphine alkaloid interactors A pharmaceutical composition comprising:

32. polymer matrix; a pharmaceutical active ingredient comprising epinephrine or a prodrug thereof in the polymer matrix; and Beauty Vasodilator interactors A pharmaceutical composition comprising:

33. polymer matrix; a pharmaceutical active ingredient comprising epinephrine or a prodrug thereof in the polymer matrix; and Beauty causing increased blood flow or allowing tissue flushing, thereby increasing the effectiveness of the pharmaceutical active ingredient Interacting substances that alter transmucosal uptake A pharmaceutical composition comprising:

34. polymer matrix; a pharmaceutical active ingredient comprising epinephrine or a prodrug thereof in the polymer matrix; and Beauty Phases that have positive or negative heats of solution and are used as adjuvants to modify transmucosal uptake interacting substances A pharmaceutical composition comprising:

35. polymer matrix; a pharmaceutical active ingredient comprising epinephrine or a prodrug thereof in the polymer matrix; and Beauty interacting substances A pharmaceutical composition comprising: The composition is contained in a multilayer film having at least one surface with a common border. The composition,

36. 1. A method of treating a medical condition, comprising: polymer matrix; a pharmaceutical active ingredient comprising epinephrine or a prodrug thereof in the polymer matrix; and Adrenergic receptor interactors The method comprises administering an effective amount of a pharmaceutical composition comprising:

37. 36. The method of claim 35, wherein the prodrug is dipifebrin.

38. The medical condition may be hypotension, cardiac arrest, heart failure, anaphylaxis, mydriasis, asystole, or asystole. pulsatile electrical activity, ventricular fibrillation, pulseless ventricular tachycardia, bradycardia, arrhythmia, or asthma exacerbation.

35. The method described in 35.

39. 2. The pharmaceutical composition of claim 1, wherein the prodrug is dipifebrin.

40. 30. The method of claim 29, wherein the prodrug is dipifebrin.

41. 31. The device of claim 30, wherein the prodrug is dipifebrin.

42. 32. The pharmaceutical composition of claim 31, wherein the prodrug is dipifebrin.

43. 33. The pharmaceutical composition of claim 32, wherein the prodrug is dipifebrin.

44. 34. The pharmaceutical composition of claim 33, wherein the prodrug is dipifebrin.

45. 35. The pharmaceutical composition of claim 34, wherein the prodrug is dipifebrin.

46. 36. The pharmaceutical composition of claim 35, wherein the prodrug is dipifebrin.

47. polymer matrix; A pharmaceutical active ingredient containing epinephrine or a prodrug thereof contained in the polymer matrix. Sexual components; and Adrenergic receptor interactors A pharmaceutical film comprising: The pharmaceutical film has a Tmax of 5 to 60 minutes and a Cmax of 0.1 ng / ml to 2 ng / ml.

48. 48. The method of claim 47, wherein the Tmax is 40 minutes or less and the Cmax is 0.1 ng / ml or more. Pharmaceutical film.

49. 48. The method of claim 47, wherein the Tmax is 35 minutes or less and the Cmax is 0.15 ng / ml or more. Pharmaceutical film.

50. 48. The method of claim 47, wherein the Tmax is 30 minutes or less and the Cmax is 0.2 ng / ml or more. Pharmaceutical film.

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