Pharmaceutical compositions with enhanced penetration

Abstract

This invention describes pharmaceutical compositions having enhanced permeability of the active ingredient.

Description

[0001] This application is a divisional application of Chinese invention patent application (application date: May 4, 2017; application number: 201780037588.X (international application number: PCT / US2017 / 031170); invention title: pharmaceutical composition with enhanced penetration). Priority requirements

[0002] This application claims priority to U.S. Patent Application Serial No. 62 / 331,993, filed May 5, 2016, pursuant to 35 USC §119(e), which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to pharmaceutical compositions. Background Technology

[0004] Active ingredients, such as drugs or medicines, are delivered to patients in a carefully controlled manner. The use of membranes for transdermal or transmucosal delivery of drugs or medicines may require the drugs or medicines to penetrate or otherwise cross biological membranes in an effective and efficient manner. Summary of the Invention

[0005] Typically, a pharmaceutical composition may comprise a polymer matrix, a pharmaceutically active ingredient within the polymer matrix, and an adrenergic receptor interactor. In some embodiments, the pharmaceutical composition may further comprise a penetration enhancer. The adrenergic receptor interactor may be an adrenergic receptor blocker. The penetration enhancer may also be a flavonoid, or used in combination with a flavonoid.

[0006] In some embodiments, the adrenergic receptor interactor may be a terpene, terpene, or C3-C22 alcohol or acid. The adrenergic receptor interactor may be a sesquiterpene. In some embodiments, the adrenergic receptor interactor may include farnesol, linoleic acid, arachidonic acid, docosahexanoic acid, eicosapentaenoic acid, or docosapentaenoic acid, or combinations thereof.

[0007] In some embodiments, the pharmaceutical composition may be a membrane further comprising a polymer matrix in which the active pharmaceutical ingredient is contained.

[0008] In some embodiments, the adrenergic receptor interactor may be a plant extract.

[0009] In some embodiments, the penetration enhancer may be a plant extract.

[0010] In some embodiments, the penetration enhancer may include phenylpropanoids.

[0011] In other embodiments, the phenylpropane-like substance may be eugenol.

[0012] In some embodiments, the pharmaceutical composition may comprise a fungal extract.

[0013] In some embodiments, the pharmaceutical composition may contain saturated or unsaturated alcohols.

[0014] In some embodiments, the alcohol may be benzyl alcohol.

[0015] In some cases, flavonoids, plant extracts, phenylpropanes, eugenol, or fungal extracts can be used as solubilizers.

[0016] In other embodiments, the phenylpropane may be eugenol. In some embodiments, the phenylpropane may be eugenol acetate. In some embodiments, the phenylpropane may be cinnamic acid. In other embodiments, the phenylpropane may be cinnamate. In other embodiments, the phenylpropane may be cinnamaldehyde.

[0017] In other embodiments, the phenylpropane-like substance may be hydrogenated cinnamic acid. In some embodiments, the phenylpropane-like substance may be chavicol. In other embodiments, the phenylpropane-like substance may be safrole.

[0018] In some embodiments, the plant extract may be an essential oil extract from the clove plant. In other examples, the plant extract may be an essential oil extract from the leaves of the clove plant. The plant extract may be an essential oil extract from the flower buds of the clove plant. In other embodiments, the plant extract may be an essential oil extract from the stem of the clove plant.

[0019] In some embodiments, the plant extract may be synthetic. In some embodiments, the plant extract may contain 20-95% eugenol, contain 40-95% eugenol, and contain 60-95% eugenol. In some embodiments, the plant extract may contain 80-95% eugenol.

[0020] In other embodiments, the active pharmaceutical ingredient may be adrenaline.

[0021] In some embodiments, the active pharmaceutical ingredient may be diazepam.

[0022] In some embodiments, the active pharmaceutical ingredient may be alprazolam.

[0023] In some embodiments, the polymer matrix may comprise a polymer. In some embodiments, the polymer may comprise a water-soluble polymer.

[0024] In some embodiments, the polymer may be polyethylene oxide.

[0025] In some embodiments, the polymer may be a cellulose polymer. In some embodiments, the cellulose polymer may be hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, and / or sodium carboxymethyl cellulose.

[0026] In some embodiments, the polymer may include hydroxypropyl methylcellulose.

[0027] In some embodiments, the polymer may include polyethylene oxide and / or hydroxypropyl methylcellulose.

[0028] In some embodiments, the polymer may include polyethylene oxide and / or polyvinylpyrrolidone.

[0029] In some embodiments, the polymer matrix may include polyethylene oxide and / or polysaccharides.

[0030] In some embodiments, the polymer matrix may include polyethylene oxide, hydroxypropyl methylcellulose, and / or polysaccharides.

[0031] In some embodiments, the polymer matrix may include polyethylene oxide, cellulose polymers, polysaccharides, and / or polyvinylpyrrolidone.

[0032] In some embodiments, the polymer matrix may comprise at least one polymer selected from the following: pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide, propylene oxide copolymer, collagen, albumin, polyamino acids, polyphosphazene, polysaccharides, chitin, chitosan and its derivatives.

[0033] In some embodiments, the pharmaceutical composition may further comprise a stabilizer. The stabilizer may include an antioxidant (which can prevent unwanted oxidation of the material), a chelating agent (which can form chelates and inactivate trace amounts of metal ions, which could otherwise act as catalysts), an emulsifier and surfactant (which can stabilize the emulsion), a UV stabilizer (which can protect the material from the harmful effects of UV radiation), a UV absorber, a chemical substance that absorbs UV radiation and prevents it from penetrating the composition, a quencher (which can dissipate the radiant energy as heat rather than break chemical bonds), or a scavenger (which can eliminate free radicals formed by UV radiation).

[0034] In another aspect, the pharmaceutical composition comprises a suitable combination of a non-toxic, nonionic alkyl glycoside and a mucosal delivery enhancer, the alkyl glycoside having a hydrophobic alkyl group linked to a hydrophilic sugar by a bond, the mucosal delivery enhancer being selected from: (a) aggregation inhibitors; (b) charge modifiers; (c) pH control agents; (d) degradative enzyme inhibitors; (e) mucolytic or mucoseptic agents; (f) ciliostatic agents; (g) membrane permeation enhancers selected from: (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) nitric oxide donor compounds; (vi) long-chain amphiphilic molecules; (vii) small hydrophobic permeation enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerides of acetoacetic acid; (x) cyclodextrins or β-cyclodextrin derivatives; (xi) medium-chain fatty acids; (xii) chelating agents; (xiii) an amino acid or a salt thereof; (xiv) an N-acetyl amino acid or a salt thereof; (xv) an enzyme that degrades selected membrane components; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) any combination of membrane permeability enhancers described in (i)-(x); (h) a regulator of epithelial junction physiology; (i) a vasodilator; (j) a selective transport enhancer; (k) a stable delivery vehicle, carrier, mucosal adhesive, support, or complex-forming agent, wherein the compound is effectively combined, conjugated, contained, encapsulated, or bound, resulting in the stability of the compound to enhance mucosal delivery, wherein formulation of the compound with a transmucosal delivery enhancer provides increased bioavailability of the compound in the subject's plasma.

[0035] Typically, methods for preparing a pharmaceutical composition may include combining an adrenergic receptor interactor with a pharmaceutical active ingredient, and forming a pharmaceutical composition comprising the adrenergic receptor interactor and the pharmaceutical active ingredient.

[0036] The pharmaceutical composition may be in the form of a chewable or gelatin-based dosage form, spray, gum, gel, cream, tablet, liquid, or film.

[0037] Typically, a pharmaceutical composition can be dispensed from a device. This device can dispense a predetermined dose of the pharmaceutical composition as a chewable or gelatin-based dosage form, spray, gum, gel, cream, tablet, liquid, or film. The device may include a shell containing a quantity of the pharmaceutical composition comprising a polymer matrix; a pharmaceutically active ingredient in the polymer matrix; and an adrenergic receptor interactor, and the device includes an opening for dispensing a predetermined amount of the pharmaceutical composition. The device may also dispense a pharmaceutical composition containing a penetration enhancer, including phenylpropane-like substances and / or plant extracts.

[0038] In some embodiments, the pharmaceutical composition may include a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and a penetration enhancer, which includes phenylpropane-like substances and / or plant extracts.

[0039] Other aspects, embodiments, and features will be apparent from the following description, figures, and claims. Brief description of the attached diagram

[0040] refer 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 receiving chamber 105, a stirring rod 106, and a heater / circulator 107.

[0041] refer to Figure 1B The pharmaceutical composition is a membrane 100 comprising a polymer matrix 200, wherein the active pharmaceutical ingredient 300 is contained within the polymer matrix. The membrane may include a permeation enhancer 400.

[0042] refer to Figure 2A and 2B This figure shows the permeation of the active substance from the composition. (Reference) Figure 2A The figure shows the average amount of permeated active substances relative to time, including 8.00 mg / mL adrenaline tartrate and 4.4 mg / mL dissolved adrenaline alkaloids.

[0043] refer to Figure 2B The figure shows the average flux over time, with 8.00 mg / mL of tartrate and 4.4 mg / mL of dissolved adrenaline.

[0044] refer to Figure 3 This figure shows the in vitro osmosis of adrenaline hydrogen tartrate as a function of concentration. (Reference) Figure 4 This figure shows the osmosis of adrenaline bitartrate as a function of solution pH. (Reference) Figure 5 The figure shows the effect of the enhancer on adrenaline permeation, expressed as a function of permeation over time.

[0045] refer to Figure 6A and 6B These figures show the release of adrenaline on the polymer platform (6A) and the effect of the enhancer on its release (6B), expressed as permeate volume (in μg) versus time. Reference Figure 7 The figure shows a pharmacokinetic model of male Yucatan miniature pigs. This study compared 0.3 mg Epipen, 0.12 mg epinephrine IV, and placebo membranes.

[0046] refer to Figure 8 The figure shows the effect of no enhancer on the concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen at the membrane. (Reference) Figure 9 This figure shows the effect of enhancer A (Labrasol) on the concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen in the membrane. (Reference) Figure 10 The figure shows the effect of enhancer L (clove oil) on the concentration distribution of two 40 mg adrenaline membranes (10-1-1) and (11-1-1) relative to 0.3 mg Epipen.

[0047] refer to Figure 11 The figure shows the effect of enhancer L (clove oil) and membrane size (10-1-1 thinner, larger membrane, 11-1-1 thicker, smaller membrane) on the concentration distribution of 40 mg adrenaline membrane relative to 0.3 mg Epipen.

[0048] refer to Figure 12 The figure shows the concentration distribution of adrenaline membrane relative to 0.3 mg Epipen in a constant matrix with different doses of enhancer L (clove oil). Reference Figure 13 The figure shows the concentration distribution of adrenaline membrane relative to 0.3 mg Epipen in a constant matrix of enhancer L (clove oil).

[0049] refer to Figure 14 The figure shows the concentration distribution of adrenaline membrane relative to 0.3 mg Epipen in a constant matrix of enhancer A (Labrasol).

[0050] refer to Figure 15 The figure shows the effect of the enhancer on diazepam permeability, expressed as a function of permeability over time.

[0051] refer to Figure 16 The figure shows the average flux as a function of time (diazepam + enhancer).

[0052] refer to Figure 17 The figure shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen.

[0053] refer to Figure 18 The figure shows the effect of farnesol on the plasma concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen.

[0054] refer to Figure 19 The figure shows the effect of the combination of farnesol and linoleic acid on the plasma concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen.

[0055] refer to Figure 20 The figure shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen.

[0056] refer to Figure 21 The figure shows the effect of the combination of enhancer A (Labrasol) and enhancer L (clove oil) on the concentration distribution of 40 mg adrenaline in the membrane (also shown in...). Figure 22 (), displayed logarithmically.

[0057] refer to Figure 22 The figure shows the effect of the combination of enhancer A (Labrasol) and enhancer L (clove oil) on the concentration distribution of 40 mg adrenaline membrane relative to the average data collected from 0.3 mg Epipens.

[0058] refer to Figure 23 The figure shows the effect of the combination of enhancer A (Labrasol) and enhancer L (clove oil) on the concentration distribution of 40 mg adrenaline in the membrane, shown in separate animal subjects.

[0059] refer to Figure 24A The figure shows the plasma concentration of alprazolam as a function of time after sublingual administration of alprazolam orally disintegrating tablets (ODT).

[0060] refer to Figure 24B The figure shows the plasma concentration of alprazolam as a function of time after sublingual administration of the alprazolam drug composition to the membrane.

[0061] refer to Figure 24C The figure shows the plasma concentration of alprazolam as a function of time after sublingual administration of the alprazolam drug composition to the membrane.

[0062] refer to Figure 25AThe figure shows the mean alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT and alprazolam drug combination membrane.

[0063] refer to Figure 25B The figure shows the plasma concentration of alprazolam as a function of time after sublingual administration.

[0064] refer to Figure 25C The figure shows the plasma concentration of alprazolam as a function of time after sublingual administration.

[0065] refer to Figure 26A The figure shows the plasma concentration of alprazolam as a function of time after sublingual administration of alprazolam ODT.

[0066] refer to Figure 26B The figure shows the plasma concentration of alprazolam as a function of time after sublingual administration of the alprazolam drug composition to the membrane.

[0067] refer to Figure 26C The figure shows the plasma concentration of alprazolam as a function of time after sublingual administration of the alprazolam drug composition to the membrane.

[0068] refer to Figure 27A The figure shows the alprazolam ODT and the mean alprazolam plasma concentration after membrane administration of the drug composition as a function of time.

[0069] refer to Figure 27B The figure shows the alprazolam ODT and the mean alprazolam plasma concentration after membrane administration of the drug composition as a function of time.

[0070] refer to Figure 27C The figure shows the plasma concentration of alprazolam as a function of time after sublingual administration of alprazolam ODT and the drug composition membrane. Invention Details

[0071] Mucosal surfaces, such as the oral mucosa, are convenient pathways for drug delivery into the body due to their high vascularization and permeability, providing increased bioavailability and rapid onset of action because they bypass the digestive system, thus avoiding first-pass metabolism. In particular, the oral cavity and sublingual tissues offer advantageous locations for drug delivery as they are highly permeable areas of the oral mucosa, allowing drugs to diffuse directly into systemic circulation. This also provides greater convenience, thus increasing patient compliance. For some drugs or active pharmaceutical ingredients, permeation enhancers can help overcome mucosal barriers and improve permeability. Permeation enhancers reversibly modulate the permeability of the barrier layer, facilitating drug absorption. Permeation enhancers promote molecular transport through the epithelium. Absorption profiles and their rates can be controlled and modulated using various parameters, such as, but not limited to, membrane size, drug loading, enhancer type / loading, polymer matrix release rate, and mucosal residence time.

[0072] Pharmaceutical compositions can be designed to deliver the active pharmaceutical ingredient in an intentional and customized manner. However, the solubility and permeability of the active pharmaceutical ingredient in vivo, particularly in the subject's oral cavity, can vary considerably. Certain classes of permeation enhancers can improve the uptake and bioavailability of the active pharmaceutical ingredient in vivo. In particular, when delivered to the oral cavity via membranes, permeation enhancers can improve the permeability of the active pharmaceutical ingredient across the mucosa and into the subject's bloodstream. Permeation enhancers can improve absorption rates and the amount of the active pharmaceutical ingredient up to: more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 150%, about 200% or more, or less than 200%, less than 150%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or combinations of these ranges, depending on the other components in the composition.

[0073] In some embodiments, the pharmaceutical composition comprises a suitable combination of a non-toxic, nonionic alkyl glycoside and a mucosal delivery enhancer, the alkyl glycoside having a hydrophobic alkyl group linked to a hydrophilic sugar by a bond, the mucosal delivery enhancer being selected from: (a) aggregation inhibitors; (b) charge modifiers; (c) pH controllers; (d) degradative enzyme inhibitors; (e) mucolytic or mucoseptic agents; (f) ciliary stabilizers; (g) membrane permeability enhancers selected from: (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) nitric oxide donor compounds; (vi) long-chain amphiphilic molecules; (vii) small hydrophobic permeability enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerides of acetoacetic acid; (x) cyclodextrins or β-cyclodextrin derivatives; (xi) medium-chain fatty acids; (xii) chelating agents; (xiii) amino acids or salts thereof; (xiv) N-acetyl amino acids or salts thereof; (xv) enzymes that degrade selected membrane components; (ix) fatty acid synthesis inhibitors; (x) cholesterol synthesis inhibitors; and any combination of membrane permeability enhancers described in (i)-(x); (h) regulators of epithelial junction physiology; (i) vasodilators; (j) selective transport enhancers; (k) stabilizing delivery vehicles, carriers, mucosal adhesives, supports, or complex-forming agents, wherein the compounds are effectively combined, conjugated, contained, encapsulated, or bound, resulting in the stability of the compounds to enhance mucosal delivery, wherein formulation of the compounds with transmucosal delivery enhancers provides increased bioavailability of the compounds in the plasma of the subject. Permeability enhancers have been described in J. Nicolazzo, et al., J. of Controlled Disease, 105 (2005) 1-15, which is incorporated herein by reference. There are many reasons why the oral mucosa is an attractive site for delivering therapeutic agents into the systemic circulation. First-pass metabolism in the liver and intestines can be avoided because blood drains directly from the buccal epithelium into the internal jugular vein. When administered orally, the first-pass effect can be a major cause of poor bioavailability for some compounds. Additionally, the oral mucosa is easily accessible, ensuring that dosage forms can be applied to the desired site and easily removed in emergencies. However, like the skin, the buccal mucosa acts as a barrier to the absorption of xenobiotics, which can impede the passage of compounds through this tissue. Therefore, identifying safe and effective penetration enhancers has become a primary goal in the search for improving drug delivery through the oral mucosa.

[0074] Chemical permeation enhancers are substances that control the rate at which co-administered drugs permeate through biological membranes. While extensive research has focused on better understanding how permeation enhancers alter intestinal and transdermal permeability, little is known about the mechanisms involved in oral and sublingual permeation enhancement.

[0075] The buccal mucosa forms the lining of the cheek and extends to the area between the gums, upper lip, and lower lip, with an average surface area of ​​100 cm². 2 The surface of the buccal mucosa is composed of layered squamous epithelium, separated from the underlying connective tissue (lamina propria and submucosa) by an undulating basement membrane (a continuous layer of extracellular material approximately 1-2 μm thick). This layered squamous epithelium consists of differentiated cell layers, the size, shape, and content of which change as they migrate from the basal region to the surface region where cells shed. There are approximately 40-50 cell layers, resulting in a buccal mucosa thickness of 500-600 μm.

[0076] Structurally, the sublingual mucosa is comparable to the buccal mucosa, but its epithelium is 100-200 μm thick. This membrane is also non-keratinized and relatively thin, and has been shown to be more permeable than the buccal mucosa. Blood flow to the sublingual mucosa is slower than to the buccal mucosa, at approximately 1.0 ml / min. -1 / cm -2 .

[0077] The buccal mucosa is more permeable than the skin, but less permeable than the intestinal mucosa. This difference in permeability is a result of structural differences between the tissues. Compared to keratinized skin epithelial cells, the buccal mucosa lacks an organized lipid layer in its intercellular spaces, leading to greater permeability to exogenous compounds; while its increased thickness and lack of tight junctions result in lower permeability compared to intestinal tissue.

[0078] The primary barrier properties of the buccal mucosa are attributed to the upper third to quarter of the buccal epithelium. Researchers have learned that, beyond the surface epithelium, the permeability barrier of the non-keratinized oral mucosa can also be attributed to contents extruded from membrane-coated particles into the intercellular spaces.

[0079] Intercellular lipids in the non-keratinized regions of the oral cavity exhibit more polar properties than those in the epidermis, palate, and gingiva, and this difference in lipid chemistry can lead to the observed differences in permeability between these tissues. Therefore, not only does a greater accumulation of intercellular lipids in the stratum corneum of keratinized epithelium create a more effective barrier, but the chemical properties of the lipids present within this barrier also contribute to its effectiveness.

[0080] The presence of both hydrophilic and lipophilic regions in the oral mucosa has led researchers to hypothesize that two drug transport pathways exist: pericellular (between cells) and transcellular (through cells) pathways via the buccal mucosa.

[0081] Because drug delivery through the buccal mucosa is limited by the barrier properties of the epithelium and the area available for absorption, various enhancement strategies are needed to deliver therapeutically relevant amounts of drug into systemic circulation. A number of approaches can be employed, including the use of chemical penetration enhancers, prodrugs, and physical methods to overcome the barrier properties of the buccal mucosa.

[0082] Chemical permeation enhancers, or absorption boosters, are substances added to pharmaceutical formulations to increase the membrane permeation or absorption of co-administered drugs without damaging the membrane and / or causing toxicity. Numerous studies have investigated the effects of chemical permeation enhancers on the delivery of compounds across the skin, nasal mucosa, and intestine. In recent years, the effects of these agents on buccal mucosal permeability have received increasing attention. Since buccal mucosal permeability is considered a passive diffusion process, according to Fick's first law of diffusion, the steady-state flux (Jss) should increase with increasing donor compartment concentration (CD).

[0083] Surfactants and bile salts have been shown to enhance the permeability of various compounds across the buccal mucosa, both in vitro and in vivo. Data from these studies strongly suggest that this enhanced permeability is due to the effects of surfactants on the intercellular lipids of the mucosa.

[0084] Fatty acids have been shown to enhance the penetration of many drugs through the skin, and differential scanning calorimetry and Fourier transform infrared spectroscopy have shown that this is associated with increased fluidity of intercellular lipids.

[0085] Furthermore, ethanol pretreatment has been shown to enhance the permeability of tritium-modified water and albumin across the ventral mucosa of the tongue, and to increase the permeability of caffeine across the buccal mucosa of pigs. There is also some information regarding Azone. ® Reports have been made of enhancing the permeability of compounds through the oral mucosa. Furthermore, chitosan (a biocompatible and biodegradable polymer) has been shown to enhance drug delivery through various tissues, including the intestinal and nasal mucosa.

[0086] Oral transmucosal drug delivery (OTDD) is the administration of a pharmaceutically active agent through the oral mucosa to achieve a systemic effect. The penetration pathways and predictive models of OTDD are described, for example, in M. Sattar, Oral transmucosal drug delivery – Current status and future prospects, Int'l. Journal of Pharmaceutics, 47(2014) 498-506, which is incorporated herein by reference. OTDD continues to attract the attention of academic and industrial scientists. Although the characterization of the oral cavity penetration pathway is limited compared to skin and nasal delivery routes, the prospects are encouraging due to recent advances in our understanding of the penetration of ionized molecules into the buccal epithelium, the emergence of new analytical techniques for studying the oral cavity, and advancements in computer models predicting buccal and sublingual penetration.

[0087] To deliver a wider range of drugs through the buccal mucosa, reversible methods that reduce the tissue's barrier potential are necessary. This necessity has spurred research into permeability enhancers that can safely alter the permeability limitations of the buccal mucosa. It has been shown that oral permeability can be improved through the use of various types of transmucosal and transdermal permeability enhancers, such as bile salts, surfactants, fatty acids and their derivatives, chelating agents, cyclodextrins, and chitosan. Among these chemicals used to enhance drug permeability, bile salts are the most common.

[0088] In vitro studies of the enhancing effects of bile salts on the oral permeability of compounds are discussed in Sevda Senel, Drugpermeation enhancement via buccal route: possibilities and limitations, Journal of Controlled Release 72 (2001) 133–144, which is incorporated herein by reference. This article also discusses recent studies on the effects of dihydroxy bile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC), and trihydroxy bile salts, sodium glycodeoxycholate (GC) and sodium taurocholate (TC) on buccal epithelial permeability at 100 mM concentrations, including changes in permeability related to histological effects. Fluorescein isothiocyanate (FITC) and morphine sulfate were each used as model compounds.

[0089] Chitosan has also been shown to promote the absorption of small polar molecules and peptide / protein drugs through the nasal mucosa in animal models and human volunteers. Other studies have demonstrated its ability to enhance the penetration of compounds across the intestinal mucosa and in cultured Caco-2 cells.

[0090] The penetration enhancer may be a plant extract. The plant extract may be an essential oil or a composition comprising an essential oil extracted from plant material by distillation. In some cases, the plant extract may include synthetic analogs of compounds extracted from plant material (i.e., compounds prepared by organic synthesis). The plant extract may include phenylpropane-like compounds, such as phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamate, cinnamaldehyde, hydrogenated cinnamic acid, cinnamyl alcohol, or safrole, or combinations thereof. The plant extract may be an essential oil extract of the clove plant, for example, from the leaves, stems, or flower buds of the clove plant. The clove plant may be clove (Syzygium aromaticum). The extract may contain 20-95% eugenol, 40-95% eugenol, 60-95% eugenol, and, for example, 80-95% eugenol. The extract may also contain 5% to 15% eugenol acetate. The extract may also include eugenolene. The extract may also contain up to 2.1% α-humulen. Other volatile compounds contained in clove essential oil at lower concentrations may be β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone, or ethyl hexanoate. Other permeation enhancers may be added to the composition to improve drug absorption. Suitable permeation enhancers include natural or synthetic bile salts, such as sodium fusidate; glycocholates or deoxycholates and their salts; fatty acids and derivatives, such as sodium laurate, oleic acid, oleyl alcohol, glyceryl monooleate, or palmitoylcarnitine; chelating agents such as disodium EDTA, sodium citrate and sodium dodecyl sulfate, azone, sodium cholate, sodium 5-methoxysalicylate, sorbitol laurate, glyceryl monolaurate, octoxynonyl-9, lauryl ether-9, polysorbate, sterols, or glycerides, such as octanoyl hexanoyl polyethylene glycol glyceride, for example, Labrasol. Penetration enhancers may include plant extract derivatives and / or monoolignol. Penetration enhancers may also be fungal extracts.

[0091] Several plant-derived natural products are known to have vasodilatory effects. For a review, see McNeill J.R. and Jurgens, TM, Can. J. Physiol. Pharmacol. 84:803-821 (2006), which is incorporated herein by reference. Specifically, the vasodilatory effects of eugenol have been reported in numerous animal studies. See, for example, Lahlou, S., et al., J. Cardiovasc. 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), each of which is incorporated herein by reference. Calcium channel blockade is thought to be the cause of vasodilation induced by plant essential oils or their main component eugenol. See Interaminense LRL et al., Fundamental & Clin. Pharmacol. 21: 497-506 (2007), which is incorporated herein by reference.

[0092] Fatty acids can be used as inactive ingredients in pharmaceutical preparations or drug carriers. They can also be used as formulation ingredients due to some of their functional effects and their biocompatibility. Fatty acids, whether free lipids or part of complex lipids, are major metabolic fuels (for storing and transporting energy) and are essential components of all membrane and gene regulators. For a review, see Rustan AC and Drevon, CA, Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences (2005), which is incorporated herein by reference. There are two families of essential fatty acids metabolized in the human body: ω-3 and ω-6 polyunsaturated fatty acids (PUFAs). They are called ω-3 fatty acids if the first double bond exists between the third and fourth carbon atoms from the ω carbon. They are called ω-6 fatty acids if the first double bond is between the sixth and seventh carbon atoms. PUFAs are further metabolized in the body through the addition of carbon atoms and through desaturation (hydrogen extraction). Linoleic acid is an omega-6 fatty acid that is metabolized into gamma-linolenic acid, dihomo-gamma-linolenic acid (LALA), arachidonic acid, adrenaline, docosahexaenoic acid (DHA), docosapentaenoic acid (DHA), and docosapentaenoic acid (DHA). Alpha-linolenic acid, an omega-3 fatty acid, is metabolized into octadecanoic acid (AHA), eicosahexaenoic acid (EPA), docosapentaenoic acid (DHA), docosapentaenoic acid (DHA), and docosahexaenoic acid (DHA).

[0093] It has been reported that fatty acids, such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid, activate Na+ through processes involving the activation of Na+. + K +The mechanism by which the -APT enzyme pump and fatty acids induce relaxation and hyperpolarization of porcine coronary artery smooth muscle cells, with increased cis-unsaturation yielding greater potency. See Pomposiello, SI et al., Hypertension 31:615-20 (1998), which is incorporated herein by reference. Interestingly, pulmonary vessels respond to arachidonic acid (a metabolite of linoleic acid) in either vasoconstriction or vasodilation, depending on the dose, animal species, route of administration of arachidonic acid, and the status of pulmonary circulation. For example, arachidonic acid has been reported to induce cyclooxygenase-dependent and non-cyclooxygenase-dependent pulmonary vasodilation. See Feddersen, CO et al., J. Appl. Physiol. 68(5):1799-808 (1990); and see also Spannhake, EW et al., J. Appl. Physiol. 44:397-495 (1978) and Wicks, TC et al., Circ. Res. 38:167-71 (1976), each incorporated herein by reference.

[0094] Numerous studies have reported the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on vascular responsiveness after administration in their ingestible forms. Some studies have found that EPA-DHA or EPA alone inhibits the vasoconstrictive effects of norepinephrine or increases the vasodilatory response of acetylcholine in the forearm microcirculation. See Chin, JPF, et al., Hypertension 21:22-8 (1993), and Tagawa, H. et al., J Cardiovasc Pharmacol 33:633-40 (1999), each incorporated herein by reference. Another study found that both EPA and DHA increase systemic arterial compliance and tend to decrease pulse pressure and total vascular resistance. See Nestel, P. et al., Am J. Clin. Nutr. 76:326-30 (2002), which is incorporated herein by reference. Meanwhile, one study found that DHA, but not EPA, enhances vasodilatory mechanisms and attenuates the constrictive response in the forearm microcirculation of overweight men with hyperlipidemia. See Mori, TA, et al., Circulation 102:1264-69 (2000), which is incorporated herein by reference. Another study found that DHA has a vasodilatory effect on rhythmic contraction of isolated human coronary arteries in vitro. See Wu, K.-T. et al., Chinese J. Physiol. 50(4):164-70 (2007), which is incorporated herein by reference.

[0095] Adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of catecholamines, particularly norepinephrine and epinephrine. Epinephrine interacts with α- and β-adrenergic receptors, causing vasoconstriction and vasodilation, respectively. Although α-receptors are less sensitive to adrenaline, when activated, they override β-adrenergic receptor-mediated vasodilation because there are more peripheral α1-receptors than β-adrenergic receptors. The result is that high levels of circulating adrenaline induce vasoconstriction. At lower levels of circulating adrenaline, β-adrenergic receptor stimulation predominates, producing vasodilation, which subsequently reduces peripheral vascular resistance. α1-adrenergic receptors are known for smooth muscle contraction, pupillary dilation, vasoconstriction of the skin, mucous membranes, and abdominal organs, as well as sphincter contraction of the gastrointestinal (GI) tract and bladder. α1-adrenergic receptors are G q A member of the protein-coupled receptor superfamily. Upon activation, the heterotrimeric G protein G... q Activation of phospholipase C (PLC). The mechanism of action involves interaction with calcium channels and alteration of calcium levels in the cell. For a review, see Smith RS et al., Journal of Neurophysiology 102(2):1103-14 (2009), which is incorporated herein by reference. Many cells possess these receptors.

[0096] Alpha-1-adrenergic receptors can be major receptors for fatty acids. For example, saw palmetto extract (SPE), widely used to treat benign prostatic hyperplasia (BPH), has been reported to bind to alpha-1-adrenergic, muscarinic, and 1,4-dihydropyridine (1,4-DHP) calcium channel antagonist receptors. See Abe M. et al., Biol. Pharm. Bull. 32(4) 646-650 (2009) and Suzuki M. et al., Acta Pharmacologica Sinica 30:271-81 (2009), each incorporated herein by reference. SPE comprises a variety of fatty acids, including lauric acid, oleic acid, myristic acid, palmitic acid, and linoleic acid. Lauric acid and oleic acid can bind to alpha-1-adrenergic, muscarinic, and 1,4-DHP calcium channel antagonist receptors non-competitively.

[0097] In some embodiments, the penetration enhancer may be an adrenergic receptor interactor. An adrenergic receptor interactor is a compound or substance that modifies and / or alters the action of adrenergic receptors. For example, an adrenergic receptor interactor can prevent receptor stimulation by increasing or decreasing its binding capacity. These interactors can be provided in short-acting or long-acting forms. Some short-acting interactors act rapidly, but their effects last only a few hours. Some long-acting interactors may require a longer time to act, but their effects last longer. Interactors can be selected and / or designed based on, for example, one or more of the desired delivery and dosage, the active pharmaceutical ingredient, the penetration modifier, the penetration enhancer, the matrix, and the condition being treated. Adrenergic receptor interactors may be adrenergic receptor blockers. Adrenergic receptor interactors may be terpenes (e.g., volatile unsaturated hydrocarbons derived from isoprene units in plant essential oils) or C3-C22 alcohols or acids, preferably C7-C18 alcohols or acids. In some embodiments, the adrenergic receptor interactor may include farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, and / or docosapentaenoic acid. The acid may be a carboxylic acid, phosphoric acid, sulfuric acid, isohydroxamic acid, or a derivative thereof. The derivative may be an ester or an amide. For example, the adrenergic receptor interactor may be a fatty acid or a fatty alcohol.

[0098] C3-C22 alcohols or acids may be alcohols or acids having a straight-chain C3-C22 hydrocarbon chain, for example, optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; said hydrocarbon chain optionally substituted with C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, hydroxyl, halogen, amino, nitro, cyano, C 3-5 Cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4 alkyl carbonyloxy group, C 1-4 Alkyloxycarbonyl, C 1-4 alkyl carbonyl or formyl group; and optionally further inserted with -O-, -N(R) a )-、-N(R a -C(O)-O-、-OC(O)-N(R) a )-、-N(R a )-C(O)-N(R b )-, or -OC(O)-O-. R a and R b Each can be independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, hydroxy, or haloalkyl.

[0099] Fatty acids with higher degrees of unsaturation are effective candidates for enhancing drug penetration. Unsaturated fatty acids exhibit a higher enhancing effect than saturated fatty acids, and this enhancement increases with the number of double bonds. See A. Mittal et al., Status of Fatty Acids as Skin Penetration Enhancers – A Review, Current Drug Delivery, 2009, 6, pp. 274-279, which is incorporated herein by reference. The position of the double bond also affects the enhancing activity of fatty acids. Differences in the physicochemical properties of fatty acids derived from differences in double bond position are most likely to determine the efficacy of these compounds as skin penetration enhancers. Skin distribution increases as the position of the double bond shifts towards the hydrophilic end. Fatty acids with double bonds at even positions have also been reported to affect the perturbation of the stratum corneum and dermis structure more rapidly than those with double bonds at odd positions. The degree of cis-unsaturation in the chain may tend to increase activity.

[0100] Adrenergic receptor interactors can be terpenes. The hypotensive activity of terpenes in essential oils has been reported. See Menezes IA et al., Z. Naturforsch. 65c:652-66 (2010), which is incorporated herein by reference. In some embodiments, the penetration enhancer can be a sesquiterpene. Sesquiterpenes are a class of terpenes composed of three isoprene units and having the empirical formula C0. 15 H 24 Like monoterpenes, sesquiterpenes can be acyclic or contain rings, encompassing many unique combinations. Biochemical modifications such as oxidation or rearrangement produce related sesquiterpene-like compounds.

[0101] Adrenergic receptor interactors may be unsaturated fatty acids such as linoleic acid. In some embodiments, the permeation enhancer may be farnesol. Farnesol is a 15-carbon organic compound, an acyclic sesquiterpene alcohol, and the naturally occurring dephosphorylated form of farnesyl pyrophosphate. Under standard conditions, it is a colorless liquid. It is hydrophobic and therefore insoluble in water, but miscible with oils. Farnesol can be extracted from plant oils such as lemongrass, orange blossom, cyclamen, and tuberose. It is an intermediate step in the biosynthesis of cholesterol from mevalonic acid in vertebrates. It has a soft floral or faint citrus-lime odor and is used in perfumes and fragrances. Farnesol has been reported to selectively kill acute myeloid leukemia blasts and leukemia cell lines, rather than primary hematopoietic cells. See Rioja A. et al., FEBS Lett 467(2-3):291-5 (2000), which is incorporated herein by reference. Vascular activity properties of farnesyl analogues have been reported. See Roullet, J.-B., et al., J. Clin. Invest., 1996, 97:2384-2390, which is incorporated herein by reference. Farnesol and N-acetyl-S-trans, trans-farnesyl-L-cysteine ​​(AFC), synthetic mimics of the carboxyl terminus of farnesylated proteins, both inhibit vasoconstriction in the rat aortic ring.

[0102] The pharmaceutical composition may be in the form of a chewable or gelatin-based dosage form, spray, chewing gum, gel, cream, tablet, liquid, or film. The composition may include, for example, textures on the surface, such as microneedles or microprotrusions. Recently, the use of micron-sized needles has been shown to increase skin permeability, thereby significantly increasing transdermal delivery, including, and especially for, macromolecules. Most drug delivery studies have highlighted solid microneedles, which have been shown to increase skin permeability to a wide range of molecules and nanoparticles in vitro. In vivo studies have demonstrated the delivery of oligonucleotides, the reduction of blood glucose levels with insulin, and the induction of immune responses to protein and DNA vaccines. For such studies, needle arrays have been used to insert pores into the skin to increase transport via diffusion or iontophoresis, or as drug carriers to release drugs from a coating on the microneedle surface into the skin. Hollow microneedles have also been developed and shown to microinject insulin into diabetic rats. To address the practical application of microneedles, the ratio of microneedle breaking force to skin insertion force (i.e., the safety margin) has been found to be optimal for needles with small tip radii and large wall thicknesses. Microneedles inserted into the skin of human subjects have been reported to be painless. In summary, these results demonstrate that microneedles represent a promising technology for delivering therapeutic compounds into the skin for a range of potential applications. Using tools from the microelectronics industry, microneedles have been fabricated in various sizes, shapes, and materials. Microneedles can be, for example, polymeric microneedles that deliver encapsulated drugs in a minimally invasive manner, but other suitable materials can be used.

[0103] The applicant has discovered that microneedles can be used to enhance drug delivery across the oral mucosa, particularly for claimed compositions. Microneedles create micron-sized pores in the oral mucosa, which can enhance drug delivery across the mucosa. Solid, hollow, or dissolved microneedles can be made from suitable materials, including but not limited to metals, polymers, glass, and ceramics. Microfabrication processes can include photolithography, silicon etching, laser cutting, metal plating, metal electropolishing, and molding. Microneedles can be solid, used for tissue pretreatment, and removed before membrane application. Drug-loaded polymer membranes described in this application can be used as matrix materials for the microneedles themselves. These membranes can have microneedles or microprotrusions fabricated on their surfaces, which dissolve after forming microchannels in the mucosa through which drugs can permeate.

[0104] The term "membrane" can include membranes and sheets of any shape, including rectangular, square, or other desired shapes. Membranes can be of any desired thickness and size. In a preferred embodiment, the membrane can have a thickness and size such that it can be applied to a user, for example, placed in the user's mouth. The membrane can have a relatively thin thickness of about 0.0025 mm to about 0.250 mm, or a slightly thicker thickness of about 0.250 mm to about 1.0 mm. For some membranes, the thickness can be greater, i.e., greater than about 1.0 mm, or thinner, i.e., less than about 0.0025 mm. The membrane can be a single layer or can be multilayered, including laminated or multilayer cast films. Permeation enhancers and pharmaceutical active ingredients can be combined into a single layer, each contained in a separate layer, or each contained in a discontinuous region of the same dosage form. In some embodiments, the pharmaceutical active ingredient contained in the polymer matrix can be dispersed in the matrix. In some embodiments, the permeation enhancer contained in the polymer matrix can be dispersed in the matrix.

[0105] Oral dissolving films can be categorized into three main types: rapidly dissolving, moderately dissolving, and slowly dissolving. Oral dissolving films may also include any combination of these categories. Rapidly dissolving films dissolve in the mouth in approximately 1 to approximately 30 seconds, including longer than 1 second, longer than 5 seconds, longer than 10 seconds, longer than 20 seconds, and less than 30 seconds. Moderately dissolving films dissolve in the mouth in approximately 1 to approximately 30 minutes, including longer than 1 minute, longer than 5 minutes, longer than 10 minutes, longer than 20 minutes, or less than 30 minutes, while slowly dissolving films dissolve in the mouth in more than 30 minutes. As a general trend, rapidly dissolving films may contain (or consist of) low molecular weight hydrophilic polymers (e.g., polymers with a molecular weight of approximately 1,000 to 9,000 Daltons, or polymers with a molecular weight up to 200,000 Daltons). Conversely, slowly dissolving films typically contain high molecular weight polymers (e.g., those with a molecular weight in the millions). Moderately dissolving films may fall somewhere between rapidly and slowly dissolving films.

[0106] A moderately dissolving membrane is preferred. A moderately dissolving membrane dissolves fairly quickly while maintaining a good level of mucosal adhesion. It can also be flexible, rapidly wettable, and generally non-irritating to the user. This moderately dissolving membrane provides a sufficiently fast dissolution rate, ideally between about 1 minute and about 20 minutes, while offering an acceptable level of mucosal adhesion so that it is not easily removed once placed in the user's mouth. This ensures the delivery of the pharmaceutically active ingredient to the user.

[0107] Pharmaceutical compositions may include one or more active pharmaceutical ingredients. The active pharmaceutical ingredient may be a single pharmaceutical component or a combination of pharmaceutical components. The active pharmaceutical ingredient may be an anti-inflammatory analgesic, a steroidal anti-inflammatory agent, an antihistamine, a local anesthetic, a bactericide, a disinfectant, a vasoconstrictor, a hemostatic agent, a chemotherapeutic agent, an antibiotic, a keratolytic agent, a causative agent, an antiviral agent, an antirheumatic agent, a bronchodilator, an anticholinergic agent, an anxiolytic, an antiemetic compound, a hormone, a peptide, a protein, or a vaccine. The active pharmaceutical ingredient may be a compound, a pharmaceutically acceptable salt of a drug, a prodrug, a derivative, a drug complex, or a drug analogue. The term "prodrug" refers to a biologically inactive compound that can be metabolized in the body to produce a biologically active drug.

[0108] In some implementations, more than one pharmaceutically active ingredient may be contained in the membrane. The pharmaceutically active ingredient may be an ACE inhibitor, antianginal drug, antiarrhythmic drug, anti-asthmatic drug, anticholinergic drug, analgesic, anesthetic, anticonvulsant, antidepressant, antidiabetic drug, antidiabetic product, antidiabetic agent, antidiabetic agent, antihistamine, antihypertensive drug, anti-inflammatory drug, antilipidemia drug, antimanic drug, antinausea drug, anti-stroke drug, antithyroid product, amphetamine, antitumor drug, antiviral agent, acne drug, alkaloid, amino acid product, antitussive, or anti-gout drug. Drugs, antiviral drugs, anabolic catabolites, systemic and nonsystemic anti-infectives, anti-tumor drugs, anti-Parkinson's drugs, antirheumatic drugs, appetite stimulants, blood regulators, bone metabolism regulators, cardiovascular drugs, central nervous system stimulants, cholinesterase inhibitors, contraceptives, decongestants, food additives, dopamine receptor agonists, endometriosis control agents, enzymes, erectile dysfunction treatment agents, fertility factors, gastrointestinal drugs, homeopathic drugs, hormones, hypercalcemia and hypocalcemia control agents, immunomodulators, immunosuppressants, migraine medications, motion sickness treatment agents, muscle relaxants, obesity control agents, osteoporosis agents, oxytocin, parasympathetic nerve blockers, parasympathomimetic drugs, prostaglandins, psychotherapeutic agents, respiratory agents, analgesics, smoking cessation drugs, sympathetic drugs. Nerve blocking agents, tremor agents, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants, anxiolytics, antiulcer agents, anti-inflammatory agents, coronary artery vasodilators, cerebral vasodilators, peripheral vasodilators, neuromyopathic drugs, stimulants, antihypertensive drugs, vasoconstrictors, migraine treatment agents, antibiotics, sedatives, antipsychotics, antitumor drugs, anticoagulants, antithrombotics, hypnotics, antiemetics, antinausea drugs, anticonvulsants, neuromuscular drugs, blood glucose-raising and blood glucose-lowering drugs, thyroid and antithyroid drugs, diuretics, antispasmodics, uterine attenuators, antiobesity drugs, erythropoiesis-stimulating agents, antiasthmatics, antitussives, mucolytics, DNA and gene-modifying drugs, diagnostic agents, imaging agents, dyes or tracers, and combinations thereof.

[0109] For example, the active pharmaceutical ingredient may be buprenorphine, naloxone, acetaminophen, riluzole, clobazine, rizatriptan, propofol, methyl salicylate, monoethylene salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenprofen, sulindac, fenclofen, cyclochloroindica, flurbiprofen, fentiac, buprofen, piroxicam, phenylbutazone, hydroxyphenylbutazone, chlorpheniramine, pentazocine, methylphenidate. Mepirizole, thiamide hydrochloride, hydrocortisone, predonisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumethasone, flumethonone, beclomethasone dipropionate, fluocinolone acetonide acetate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride (hydrochloride), chlorpheniramine maleate, isoxafenide hydrochloride, tripyramine hydrochloride, promethazine hydrochloride, methaqualone hydrochloride, dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, 2-(diethylamino)ethyl p-butylbenzoic acid hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine Cocaine hydrochloride, pipelocaine hydrochloride, dacronin, dacronin hydrochloride, thimerosal, phenol, thymol, benzalkonium chloride, benzyl chloride, chlorhexidine, povidone-iodine, cetylpyridinium chloride, eugenol, trimethylammonium bromide, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, thrombin, phytonabinone, protamine sulfate, aminocaproic acid, tranexamic acid, carbazoline, carbazoline sodium sulfonate. Sodium sulfanate), rutin, hesperidin, sulfonamide, sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole, sulfadiazine, sulfamethoxazole, sulfamethoxazole, furacilin, penicillin, methicillin, oxacillin, cefalordin, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, methacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, salicylic acid, podophyllotoxin, podolifox, cantharidin, chloroacetic acid, silver nitrate, protease inhibitors, thymadine kinase inhibitors.Inhibitors, including glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, adhesion and adsorption inhibitors, and nucleoside analogs (such as acyclovir, penciclovir, valacyclovir, and ganciclovir), heparin, insulin, LHRH, TRH, interferon, oligonucleotides, calcitonin, octreotide, omeprazole, fluoxetine, ethinylestradiol, amlodipine, paroxetine, enalapril, lisinopril, leuprorelin, prevastatin, lovastatin, norethindrone, risperidone, olanzapine, salbutamol, and hydrochloride. Thiazide, pseudoephridrine, warfarin, terazosin, cisapride, ipratropium, busprione, methylphenidate, levothyroxine, zolpidem, levonorgestrel, glibenclamide, benazepril, medroxyprogesterone acetate, clonazepam, ondansetron, losartan, quinapril, nitroglycerin, midazolam injection, cetirizine, doxazosin, glipizide, hepatitis B vaccine, salmeterol, sumatriptan, triamcinolone, goserelin, beclomethasone, granisteron, desogestrel, alprazolam, estradiol, nicotine, interferon beta 1A. Sodium cromoglycate, fosinopril, digoxin, fluticasone, bisoprolol, calcitril, captorpril, butorphanol, clonidine, premarin, testosterone, sumatriptan, clotrimazole, bisacodyl, dextromethorphan, nitroglycerin, nafarelin, dinoprostone, nicotine, bisacodyl, goserelin, or granisetron. In some embodiments, the active pharmaceutical ingredient may be adrenaline, benzodiazepine heptatriene such as diazepam or lorazepam or alprazolam.

[0110] Examples of adrenaline, diazepam, and alprazolam

[0111] In one example, a composition containing epinephrine or its salts or esters may have biodelivery characteristics similar to those of epinephrine administered by injection, for example, using an EpiPen. Epinephrine may be present in amounts from about 0.01 mg to about 100 mg per dose, for example, doses of 0.1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg, including doses greater than 0.1 mg, greater than 5 mg, greater than 20 mg, greater than 30 mg, greater than 40 mg, greater than 50 mg, greater than 60 mg, greater than 70 mg, greater than 80 mg, greater than 90 mg, 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, compositions containing diazepam may have biological delivery characteristics similar to or superior to diazepam tablets or gels. The amount of diazepam or a salt thereof may be present from about 0.5 mg to about 100 mg per dose, for example, doses of 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg, including doses of more than 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.

[0112] In another example, the composition (e.g., including alprazolam, diazepam, or epinephrine) may have a suitable combination of a non-toxic, nonionic alkyl glycoside and a mucosal delivery enhancer having a hydrophobic alkyl group linked to a hydrophilic sugar by a bond, wherein the mucosal delivery enhancer is selected from: (a) aggregation inhibitors; (b) charge modifiers; (c) pH controllers; (d) degradative enzyme inhibitors; (e) mucolytic or mucoseptic agents; (f) ciliary stabilizers; (g) membrane permeability enhancers selected from: (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) NO donor compounds; (vi) long-chain amphiphilic molecules; (vii) hydrophobic permeability enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerides of acetoacetic acid; (x) cyclodextrin or β-cyclodextrin derivatives; (xi) medium-chain fatty acids; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) an N-acetyl amino acid or a salt thereof; (xv) an enzyme that degrades selected membrane components; (ix) a fatty acid synthesis inhibitor; (x) a cholesterol synthesis inhibitor; and any combination of the membrane permeability enhancers described in (xi)(i)-(x); (h) a regulator of epithelial junction physiology; (i) a vasodilator; (j) a selective transport enhancer; or (k) a stable delivery vehicle, carrier, mucosal adhesive, support, or complex-forming agent, wherein the compound is effectively combined, conjugated, contained, encapsulated, or bound, resulting in the stability of the compound to enhance mucosal delivery, wherein formulation of the compound with a transmucosal delivery enhancer provides increased bioavailability of the compound in the subject's plasma. The formulation may contain approximately the same active pharmaceutical ingredient (API) as another example of diazepam and alprazolam: the ratio of the enhancer.

[0113] Treatment or adjuvant therapy

[0114] Status epilepticus (SE) is a seizure lasting longer than five minutes, or more than one seizure within five minutes, with no recovery between these seizures. Previous definitions used a 30-minute time limit. Benzodiazepines are among the most effective drugs for treating acute seizures and status epilepticus. The most commonly used benzodiazepines for status epilepticus include diazepam (Valium), lorazepam (Ativan), or midazolam (Versed). The active pharmaceutical ingredient in a pharmaceutical composition (e.g., a pharmaceutical composition membrane) may be for the treatment or adjunctive therapy of Angelman syndrome (AS), benign motor epilepsy of childhood (BREC) and benign motor epilepsy of childhood with centrotemporal spikes (BECTS), CDKL5 disorder, childhood absence epilepsy (CAE), myoclonic unstable epilepsy or Doose syndrome, Dravet syndrome, early myoclonic encephalopathy (EME), epilepsy alone with generalized tonic-clonic seizures (EGTCS) or epilepsy during wakefulness with tonic-clonic seizures, epilepsy with myoclonic-absence frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma (HH), infantile spasms (also known as IS), or W. St. Est syndrome, juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), Lafora progressive myoclonic epilepsy (Lafora disease), Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), Ohtahara syndrome (OS), Panayiotopoulos syndrome (PS), PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome (RC20), reflex epilepsy, TBCK-related intellectual disability syndrome, temporal lobe epilepsy, and neurocutaneous syndromes that may be associated with seizures, including pigmentary disorders, neurofibromatosis type 1, Sturge Weber syndrome (brain trigeminal angiomatosis), and tuberous sclerosis complex.

[0115] The membrane and / or its components may be water-soluble, water-swellable, or water-insoluble. The term "water-soluble" may mean a substance that is at least partially soluble in an aqueous solvent, including but not limited to water. The term "water-soluble" does not necessarily mean that the substance is 100% soluble in an aqueous solvent. The term "water-insoluble" means a substance that is insoluble in an aqueous solvent, including but not limited to water. The solvent may include water, or may include other solvents (preferably polar solvents) on their own or in combination with water.

[0116] The composition may include a polymer matrix. Any desired polymer matrix may be used, provided it is orally soluble or erodible. The dosage form should have sufficient bioadhesion to prevent removability and should form a gel-like structure upon administration. They are moderately soluble in the oral cavity and are particularly suitable for delivering the active pharmaceutical ingredient, but rapid-release, delayed-release, controlled-release, and sustained-release compositions are also considered in various embodiments.

[0117] Branched polymers

[0118] The pharmaceutical composition membrane may comprise a dendritic polymer, which may include highly branched macromolecules having various structures. Dendritic polymers may include dendritic polymers, dendritic polymers (dendrigrafted polymers), linear dendritic hybrids, multi-arm star polymers, or hyperbranched polymers.

[0119] Hyperbranched polymers are highly branched polymers with defective structures. However, they can be synthesized in a single-step reaction, which can be superior to other dendritic structures, making them suitable for batch applications. In addition to their spherical structure, these polymers possess abundant functional groups, intramolecular cavities, low viscosity, and high solubility. Dendritic polymers have been used in several drug delivery applications. See, for example, Dendrimers as Drug Carriers: Applications in Different Routes of Drug Administration. J Pharm Sci, VOL. 97, 2008, 123-143, which is incorporated herein by reference.

[0120] Dendritic polymers can have internal cavities that can encapsulate drugs. The steric hindrance caused by the high-density polymer chains can prevent drug crystallization. Therefore, branched polymers can offer additional advantages in formulating crystallizable drugs in polymer matrices.

[0121] Examples of suitable dendritic polymers include dendrons, dendritic molecules, and hyperbranched polymers based on poly(ether), dendritic molecules, dendritic molecules, and hyperbranched polymers based on poly(ester), dendritic molecules, dendritic molecules, and hyperbranched polymers based on poly(sulfide), dendritic molecules, dendritic molecules, and hyperbranched polymers based on poly(amino acid), dendritic molecules, dendritic molecules, and hyperbranched polymers based on poly(arylalkylene ether), dendritic molecules, dendritic molecules, and hyperbranched polymers based on poly(alkylimide), and dendritic molecules, dendritic molecules, or hyperbranched polymers based on poly(amide).

[0122] Other examples of hyperbranched polymers include poly(amine), polycarbonate, poly(ether ketone), polyurethane, polycarbosilane, polysiloxane, poly(ester amine), poly(sulfone amine), poly(urea carbamate), or polyether polyols such as polyglycerol.

[0123] The membrane can be prepared by a combination of at least one polymer and a solvent, optionally including other components. The solvent can be water, a polar organic solvent, including but not limited to ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent can be a nonpolar organic solvent, such as dichloromethane. The membrane can be prepared by using a selected casting or deposition method and a controlled drying method. For example, the membrane can be prepared by a controlled drying method which includes applying heat and / or radiant energy to a wet membrane substrate to form a viscoelastic structure, thereby controlling the homogeneity of the membrane contents. The controlled drying method can include contacting the top or bottom of the membrane or the substrate supporting the cast, deposited, or extruded membrane, or more than one surface, with separate air, separate heat, or heat and air together, at the same or different times during the drying process. Some such methods are described in more detail in U.S. Patent Nos. 8,765,167 and 8,652,378, which are incorporated herein by reference. Alternatively, the film can be extruded as described in U.S. Patent Publication No. 2005 / 0037055A1, which is incorporated herein by reference.

[0124] The polymer contained in the membrane may be water-soluble, water-swellable, water-insoluble, or a combination of one or more water-soluble, water-swellable, or water-insoluble polymers. The polymer may include cellulose, cellulose derivatives, or gums. Specific examples of usable water-soluble polymers include, but are not limited to, polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, gum arabic, gum arabic, polyacrylic acid, methyl methacrylate copolymers, carboxyvinyl copolymers, starch, gelatin, and combinations thereof. Specific examples of usable water-insoluble polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and combinations thereof. For higher dosages, it is necessary to incorporate polymers that provide a higher level of viscosity compared to lower dosages.

[0125] As used in this invention, the phrase "water-soluble polymer" and its variations refer to polymers that are at least partially soluble in water, and advantageously wholly or substantially soluble in water, or that absorb water. Water-absorbing polymers are generally referred to as water-swellable polymers. Materials that can be used with this invention may be water-soluble or water-swellable at room temperature and other temperatures (such as temperatures above room temperature). Furthermore, said materials may be water-soluble or water-swellable at pressures below atmospheric pressure. In some embodiments, films formed from such water-soluble polymers may have sufficient water solubility to dissolve upon contact with bodily fluids.

[0126] Other polymers that can be incorporated into membranes include: biodegradable polymers, copolymers, block polymers, or combinations thereof. It should be understood that the term "biodegradable" is intended to include chemically degradable materials, as opposed to physically degradable materials (i.e., biodegradable materials). Polymers incorporated into membranes may also include combinations of biodegradable or biodegradable materials. Known usable polymers or polymer classes that meet the above criteria are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxane, polyoxalate, poly(α-ester), polyanhydride, polyacetate, polycaprolactone, poly(orthoester), polyamino acid, polyamino carbonate, polyurethane, polycarbonate, polyamide, poly(alkyl cyanoacrylate), and mixtures and copolymers thereof. Other available polymers include stereopolymers of L-lactic acid and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propane and sebacic acid, sebacic acid copolymers, caprolactone copolymers, poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymers, polyurethane and poly(lactic acid) copolymers, copolymers of α-amino acids and hexanoic acid, copolymers of α-glutamic acid benzyl ester and polyethylene glycol, copolymers of succinate and poly(ethylene glycol), polyphosphazenes, polyhydroxyalkanoates, or mixtures thereof. The polymer matrix may contain one, two, three, four, or more components.

[0127] While a variety of different polymers can be used, it is desirable to select polymers that provide the membrane with mucosal adhesion properties and the desired dissolution and / or disintegration rate. Specifically, the desired duration of membrane contact with mucosal tissue depends on the type of pharmaceutically active ingredient contained in the composition. Some pharmaceutically active ingredients can be delivered through mucosal tissue in just a few minutes, while others may require up to several hours or even longer. Thus, in some embodiments, one or more water-soluble polymers as described above can be used to form the membrane. However, in other embodiments, it is desirable to use a combination of water-soluble polymers with water-swellable, water-insoluble, and / or biodegradable polymers, as provided above. Containing one or more water-swellable, water-insoluble, and / or biodegradable polymers provides a membrane with a lower dissolution or disintegration rate than a membrane formed solely by a water-soluble polymer. Therefore, the membrane can adhere to mucosal tissue and remain for a longer period, such as up to several hours, which is advantageous for delivering some pharmaceutically active components.

[0128] Ideally, individual drug film dosage forms can have suitable thickness and small size, ranging from about 0.0625 to 3 inches × about 0.0625 to 3 inches. Film dimensions can also be greater than 0.0625 inches, greater than 0.5 inches, greater than 1 inch, greater than 2 inches, about 3 inches, or greater than 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, less than 0.0625 inches in at least one aspect, or greater than 0.0625 inches, greater than 0.5 inches, greater than 1 inch, greater than 2 inches, or greater than 3 inches, about 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, or less than 0.0625 inches in another aspect. Those skilled in the art can optimize the aspect ratio, including thickness, length, and width, based on the chemical and physical properties of the polymer matrix, the active pharmaceutical ingredient, dosage, enhancers and other additives involved, and the dimensions of the desired dispensing unit. The film dosage form should exhibit good adhesion when placed in the user's mouth or sublingual region. Furthermore, film formulations should disperse and dissolve at a moderate rate, ideally dispersing within about 1 minute and dissolving within about 3 minutes. In some embodiments, film formulations can disperse and dissolve at a rate of about 1 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, about 30 minutes, or less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, or less than 1 minute. Sublingual dispersion rates may be lower than oral dispersion rates.

[0129] For example, in some embodiments, the membrane may comprise polyethylene oxide alone or a combination thereof with a second polymer component. The second polymer may be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer, or any combination thereof. Suitable water-soluble polymers include, but are not limited to, any of the above-provided types. In some embodiments, the water-soluble polymer may comprise a hydrophilic cellulose polymer, such as hydroxypropyl cellulose and / or hydroxypropyl methylcellulose. In some embodiments, one or more water-swellable, water-insoluble, and / or biodegradable polymers may also be included in the polyethylene oxide-based membrane. Any of the water-swellable, water-insoluble, or biodegradable polymers provided above may be used. The second polymer component may be used in the polymer component in an amount of about 0% to about 80% by weight, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight, including more than 5% by weight, more than 10% by weight, more than 15% by weight, more than 20% by weight, more than 30% by weight, more than 40% by weight, more than 50% by weight, more than 60% by weight, and more than 70% by weight, about 70% by weight, less than 70% by weight, less than 60% by weight, less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 20% by weight, less than 10% by weight, or less than 5% by weight.

[0130] Additives can be incorporated into the membrane. Examples of various additives include preservatives, antimicrobial agents, excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, extenders, sweeteners, flavorings, aromas, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, flow aids, adhesives, anti-adherents, acidifiers, softeners, resins, modifiers, solvents, surfactants, emulsifiers, elastomers, anti-adhesives, antistatic agents, and mixtures thereof. These additives can be added together with one or more pharmaceutically active ingredients.

[0131] As described in this invention, the term "stabilizer" refers to an excipient that prevents the aggregation or other physical and chemical degradation of the active pharmaceutical ingredient, other excipients, or combinations thereof.

[0132] Stabilizers can also be classified as antioxidants, chelating agents, pH modifiers, emulsifiers and / or surfactants and UV stabilizers, as discussed above and in more detail below.

[0133] Antioxidants (i.e., pharmaceutically compatible compounds or compositions that slow down, inhibit, interrupt, or stop oxidation processes) particularly include the following substances: tocopherol and its esters, sesamol of sesame oil, coniferyl benzoate of benzoin, nordihydroguaietic resin and nordihydroguaietic acid (NDGA), gallic esters (gallic esters of methyl-, ethyl-, propyl-, pentyl-, butyl-, lauryl-, etc.), butylated hydroxyanisole (BHA / BHT, also known as butyl-p-cresol); ascorbic acid and its salts and esters (e.g., ascorbate palmitate), isoascorbic acid (erythritol) and its salts and esters, thioglycerol, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT), and propionic acid. Typical antioxidants include tocopherol and its esters, such as α-tocopherol, butylated hydroxytoluene, and butylated hydroxyanisole. The term "tocopherol" also includes tocopherol esters. The known tocopherol is α-tocopherol. The term "α-tocopherol" includes esters of α-tocopherol (e.g., α-tocopherol acetate).

[0134] Chelating agents (i.e., any compound that can form a host-guest complex with other compounds, such as the active ingredient or another excipient; also called chelating agents) include calcium chloride, calcium disodium EDTA, gluconolactone, sodium gluconate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate, and combinations thereof. Chelating agents also include cyclic oligosaccharides, such as cyclodextrins, cyclomannins (five or more α-D-mannopyranose units linked at positions 1 and 4 via α bonds), cyclogalactins (five or more β-D-galactopyranose units linked at positions 1 and 4 via β bonds), cycloaltrins (five or more α-D-azolapyranose units linked at positions 1 and 4 via α bonds), and combinations thereof.

[0135] pH adjusters include acids (e.g., tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, ascorbic acid, acetic acid, succinic acid, adipic acid, and maleic acid), acidic amino acids (e.g., glutamic acid, aspartic acid, etc.), inorganic salts of the acidic substance (alkali metal salts, alkaline earth metal salts, ammonium salts, etc.), salts of the acidic substance with organic bases (e.g., basic amino acids such as lysine, arginine, meglumine, etc.), and their solvates (e.g., hydrates). Examples of other pH adjusters include silicified microcrystalline cellulose, magnesium aluminum metasilicate, calcium salts of phosphate (e.g., anhydrous or hydrated dicalcium phosphate, carbonates or bicarbonates of calcium, sodium or potassium and calcium lactate or mixtures thereof), sodium and / or calcium salts of carboxymethyl cellulose, cross-linked carboxymethyl cellulose (e.g., sodium and / or calcium cross-linked carboxymethyl cellulose), potassium polycrylamide, sodium alginate and / or calcium alginate, sodium docusate, stearates of magnesium, calcium, aluminum or zinc, magnesium palmitate and magnesium oleate, sodium stearyl fumarate, and combinations thereof.

[0136] Examples of emulsifiers and / or surfactants include poloxamer or pranic acid, polyethylene glycol, polyethylene glycol monostearate, polysorbate, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil, alkyl polyoside, water-soluble proteins grafted onto a hydrophobic backbone, lecithin, glyceryl monostearate, glyceryl monostearate / polyoxyethylene stearate, ketostearyl / sodium lauryl sulfate, carbomer, phospholipids, (C 10 -C 20 Alkyl and alkylene carboxylates, alkyl ether carboxylates, fatty alcohol sulfates, fatty alcohol ether sulfates, alkylamide sulfates and sulfonates, fatty acid alkylamide polyethylene glycol ether sulfates, alkane sulfonates and hydroxyalkane sulfonates, olefin sulfonates, acyl esters of hydroxyethyl sulfonic acid, α-sulfonyl fatty acid esters, alkylbenzene sulfonates, alkylphenol glycol ether sulfonates, sulfosuccinates, sulfosuccinate monoesters and diesters, fatty alcohol ether phosphates, protein / fatty acid condensates, alkyl monoglycerides and sulfonates, alkyl glyceride ether sulfonates, fatty acid aminoethanesulfonate methyl (methyltauride), fatty acid sarcosine esters, sulfonated castor oil, and acylglutamate esters, quaternary ammonium salts (e.g., di-(C 10 -C 24 )-alkyl-dimethylammonium chloride or ammonium bromide), (C 10 -C 24 )-alkyl-dimethylethyl ammonium chloride or bromide, (C 10 -C 24 )-alkyl-trimethylammonium chloride or bromide (e.g., cetyltrimethylammonium chloride or bromide), (C 10 -C 24 )-alkyl-dimethylbenzyl chloride or ammonium bromide (e.g., (C 12 —C 18)-alkyl-dimethylbenzylammonium chloride), N-(C 10 -C 18 )-alkyl-pyridinium chlorides or bromides (e.g., N-(C 12 -C 16 )-alkyl-pyridinium chloride or bromide), N-(C 10 -C 18 )-alkyl-isoquinoline onyx chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 )-alkyl-polyhydroxycarbamoylmethylpyridinium chloride, N-(C 12 -C 18 )-alkyl-N-methylmorpholinium chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 )-alkyl-N-ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C 16 -C 18 )-alkyl-pentoxyethylammonium chloride, diisobutylphenoxyethoxyethyl dimethylbenzylammonium chloride, N,N-diethylaminoethyl stearylamide and oleamide salts with hydrochloric acid, acetic acid, lactic acid, citric acid, phosphoric acid, chlorides, bromides or monoalkyl sulfates of N-acylaminoethyl-N,N-diethyl-N-methylammonium, and chlorides, bromides or monoalkyl sulfates of N-acylaminoethyl-N,N-diethyl-N-benzylammonium (wherein the above, "acyl" means, for example, stearyl or oleyl), and combinations thereof.

[0137] Examples of UV stabilizers include UV absorbers (such as benzophenone), UV quenchers (i.e., any compound that dissipates UV energy as heat rather than having a degrading effect on the energy), scavengers (i.e., any compound that eliminates free radicals caused by exposure to UV radiation), and combinations thereof.

[0138] In other embodiments, stabilizers include ascorbyl palmitate, ascorbic acid, α-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, cysteine ​​HCl, citric acid, ethylenediaminetetraacetic acid (EDTA), methionine, sodium citrate, sodium ascorbate, sodium thiosulfate, sodium metabisulfite, sodium bisulfite, propyl gallate, glutathione, thioglycerol, singlet oxygen quenchers, hydroxyl radical scavengers, hydrogen peroxide scavengers, reducing agents, metal chelating agents, detergents, liquid release agents, and combinations thereof. Singlet oxygen quenchers include, but are not limited to, alkyl imidazoles (e.g., histidine, L-carnosine, histamine, imidazole 4-acetic acid), indoles (e.g., tryptophan and its derivatives, such as N-acetyl-5-methoxytryptamine, N-acetylserotonin, 6-methoxy-1,2,3,4-tetrahydro-β-carboline), sulfur-containing amino acids (e.g., methionine, ethionine, linaloacetylmethionine, N-formylmethionine, fenugreekine, S-allylcysteine, S-aminoethyl-L-cysteine), phenolic compounds (e.g., tyrosine and its derivatives), aromatic acids (e.g., ascorbic acid, salicylic acid and its derivatives), azides (e.g., sodium azide), tocopherols and related vitamin E derivatives and carotene and related vitamin A derivatives. "Hydroxy radical scavengers" include, but are not limited to, azides, dimethyl sulfoxide, histidine, mannitol, sucrose, glucose, salicylates, and L-cysteine. "Hydrogen peroxide scavengers" include, but are not limited to, catalase, pyruvate, glutathione, and glutathione peroxidase. "Reducing agents" include, but are not limited to, cysteine ​​and mercaptoethylene. "Metal chelating agents" include, but are not limited to, EDTA, EGTA, o-phenanthroline, and citrate. "Detergents" include, but are not limited to, SDS and sodium lauryl sarcosinate. "Liquid release agents" include, but are not limited to, guanidine hydrochloride, isothiocyanate, urea, and formamide. As discussed in this invention, the stabilizer may be present in amounts ranging from 0.0001% to 50% by weight, including more than 0.0001% by weight, more than 0.001% by weight, more than 0.01% by weight, more than 0.1% by weight, more than 1% by weight, more than 5% by weight, more than 10% by weight, more than 20% by weight, more than 30% by weight, more than 40% by weight, more than 50% by weight, less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 20% by weight, less than 10% by weight, less than 1% by weight, less than 0.1% by weight, less than 0.01% by weight, less than 0.001% by weight, or less than 0.0001% by weight.

[0139] Available additives may include, for example: gelatin; plant proteins, such as sunflower protein, soy protein, cottonseed protein, peanut protein, grape seed protein, whey protein, whey protein isolate, hemoglobin, ovalbumin, and acrylated protein; water-soluble polysaccharides, such as alginate, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic and related gums (Indian gum, black privet gum, astragalus gum), pectin; water-soluble derivatives of cellulose: alkyl cellulose, hydroxyalkyl cellulose and hydroxyalkylalkyl cellulose, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and hydroxybutylmethylcellulose; cellulose esters and hydroxyalkyl cellulose esters, such as cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose (HPMC); Carboxyalkyl cellulose, carboxyalkyl cellulose, carboxyalkyl cellulose esters such as carboxymethyl cellulose and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acid and polyacrylate, polymethacrylic acid and polymethacrylate, polyvinyl acetate, polyvinyl alcohol, polyvinyl phthalate (PVAP), polyvinylpyrrolidone (PVP), PVA / vinyl acetate copolymer, or polycrotonic acid; suitable also include phthalated gelatin, gelatin succinate, cross-linked gelatin, shellac, water-soluble chemical derivatives of starch, cationic modified acrylates and methacrylates (which have, for example, tertiary or quaternary amino groups, such as diethylaminoethyl, which may be quaternized if desired); or other similar polymers.

[0140] Other components may range up to about 80%, ideally from about 0.005% to 50%, and more preferably from 1% to 20%, based on the weight of all composition components, including more than 1%, more than 5%, 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%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, about 3%, or less than 1%. Other additives may include anti-adhesion agents, flow agents, and opacifiers, such as oxides of magnesium, aluminum, silicon, and titanium, with an ideal concentration range of about 0.005% to about 5% by weight, and ideally about 0.02% to about 2%, based on the weight of all membrane components, including more than 0.02%, more than 0.2%, more than 0.5%, more 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%, less than 0.2%, or less than 0.02%.

[0141] In some embodiments, the composition may include a plasticizer, which may include polyepoxides such as polyethylene glycol, polypropylene glycol, polyethylene glycol-propylene glycol, organic plasticizers with low molecular weight such as glycerol, monoacetates, diacetates or triacetates of glycerol, triacetic acid glycerides, polysorbates, cetyl alcohol, propylene glycol, sugar alcohols, sorbitol, sodium diethyl sulfosuccinate, triethyl citrate, tributyl citrate, plant extracts, fatty acid esters, fatty acids, oils, etc., and the added concentration ranges from about 0.1% to about 40% based on the weight of the composition, and ideally from about 0.5% to about 20%, including 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%, about 20%, more than 20%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 2%, less than 1%, or less than 0.5%. Compounds may also be added to improve the texture properties of membrane materials such as animal or vegetable fats, ideally in their hydrogenated form. The composition may also contain compounds that improve the texture properties of the product. Other components may include binders, which contribute to ease of formation and the general quality of the membrane. Non-limiting examples of binders include starch, natural gums, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethyl cellulose, ethylcellulose, polyacrylamide, polyvinyloxazolidinone, or polyvinyl alcohol.

[0142] Other potential additives include solubility enhancers, such as substances that form inclusion compounds containing the active ingredient. Such agents can be used to improve the properties of poorly soluble and / or unstable active substances. Typically, these substances are cyclic molecules with a hydrophobic cavity and a hydrophilic exterior. Insoluble and / or unstable pharmaceutical active ingredients can be configured within this hydrophobic cavity, thereby forming water-soluble inclusion complexes. Thus, the formation of inclusion complexes makes poorly soluble and / or unstable pharmaceutical active ingredients soluble in water. A particularly advantageous example of such agents is cyclodextrin, a cyclic carbohydrate derived from starch. However, other similar substances are also considered to be entirely within the scope of this invention.

[0143] Suitable colorants include food, pharmaceutical, and cosmetic pigments (FD&C), pharmaceutical and cosmetic pigments (D&C), or topical pharmaceutical and cosmetic pigments (Ext.D&C). These pigments are dyes, their corresponding lakes, and some natural and derived colorants. A lake is a dye absorbed onto aluminum hydroxide. Other examples of colorants include known azo dyes, organic or inorganic pigments, or colorants of natural origin. Inorganic pigments, such as oxides of iron or titanium, are preferred, and the concentration of these oxides added ranges from about 0.001% to about 10% by weight of all components, and is preferably from about 0.5% to about 3%, including more than 0.001%, more than 0.01%, more than 0.1%, 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%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001%.

[0144] Flavoring agents can be selected from natural and synthetic flavoring liquids. Exemplary lists of such agents include volatile oils, synthetic flavoring oils, flavoring agents, oils, liquids, oleoresins, or extracts of plants, leaves, flowers, fruits, stems, and combinations thereof. A non-limiting list of representative examples includes peppermint oil, cocoa butter, and citrus (such as lemon, mandarin orange, lime, and grapefruit) oils, as well as fruit flavorings, including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or other fruit flavorings. Other available flavorings include aldehydes and esters, such as benzaldehyde (cherries, almonds), citral (α-citral, lemons, limes), neraldehyde (β-citral, lemons, limes), decanal (oranges, lemons), C-8 aldehydes (citrus fruits), C-9 aldehydes (citrus fruits), C-12 aldehydes (citrus fruits), toluene aldehydes (cherries, almonds), 2,6-dimethyloctanol (green fruits), or 2-dodecanoic acid (citrus fruits, mandarin), and combinations thereof.

[0145] Sweeteners may be selected from the following non-restricted list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts, such as sodium salt; dipeptide sweeteners, such as aspartame, neotame, and advanceame; dihydrochalcone compounds, glycyrrhizin; stevia (stevia glycoside); chlorinated derivatives of sucrose, such as sucralose; sugar alcohols, such as sorbitol, mannitol, and xylitol. Also included are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide, particularly its potassium (acetylsupan potassium), sodium, and calcium salts, as well as natural strong sweeteners, such as monk fruit. Other sweeteners may also be used.

[0146] Defoaming and / or defoaming components may also be used with the membrane. These components help remove air, such as entrained air, from the film-forming composition. Such entrained air can produce an uneven film. Dimethyl silicone oil is a particularly useful defoamer and / or defoamer. However, the invention is not limited thereto, and other suitable defoamers and / or defoamers may be used. Dimethyl silicone oil and related reagents can be used for densification purposes. More specifically, such reagents help remove voids, air, moisture, and similar undesirable components, thereby providing a denser and therefore more uniform film. The reagent or component that performs this function may be called a densification agent or densifying agent. As mentioned above, entrained air or undesirable components can produce an uneven film.

[0147] Any other optional components described in the commonly specified U.S. Patent Nos. 7,425,292 and 8,765,167 mentioned above may also be included in the membranes described in this invention.

[0148] The membrane composition also preferably contains a buffer to control the pH of the membrane composition. Any desired level of buffer can be incorporated into the membrane composition to provide the required pH level when the active pharmaceutical ingredient is released from the composition. The buffer is preferably provided in an amount sufficient to control the release and / or absorption of the active pharmaceutical ingredient from the membrane into the body. In some embodiments, the buffer may include sodium citrate, citric acid, hydrogen tartrate, and combinations thereof.

[0149] The pharmaceutical film of this invention can be formed by any desired method. Suitable methods are set forth in U.S. Patent Nos. 8,652,378, 7,425,292, and 7,357,891, which are incorporated herein by reference. In one embodiment, a film-forming dosage form composition is formed by first preparing a wet composition comprising a polymer carrier matrix and a therapeutically effective amount of the pharmaceutically active ingredient. The wet composition is cast into a film and then thoroughly dried to form a self-supporting film composition. The wet composition can be cast into a single dosage form or can be cast into a sheet and then slit into individual dosage forms.

[0150] The pharmaceutical composition can adhere to mucosal surfaces. This invention is particularly useful for the local treatment of body tissues, diseases, or wounds that may have a moist surface and are susceptible to the influence of bodily fluids, such as the mouth, vagina, organs, or other types of mucosal surfaces. The composition carries the drug and, upon application and adhesion to the mucosal surface, provides a protective layer and delivers the drug to the treatment site, surrounding tissues, and other bodily fluids. Taking into account the control of erosion in aqueous solutions or bodily fluids such as saliva, and the slow, natural erosion of the membrane accompanying or following delivery, the composition provides an appropriate residence time for effective drug delivery at the treatment site.

[0151] The residence time of the composition depends on the erosion rate of the water-erosible polymer used in the formulation and its respective concentration. The erosion rate can be adjusted by, for example, by mixing polymers with different solubility properties or chemically different components (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose); by using the same polymer at different molecular weight levels (e.g., mixing low and medium molecular weight hydroxyethyl cellulose); by using excipients or plasticizers with various lipophilic values ​​or water-soluble properties (including substantially insoluble components); by using water-soluble organic and inorganic salts; by using crosslinking agents for local crosslinking (e.g., glyoxal) with the polymer (e.g., hydroxyethyl cellulose); or by post-treatment irradiation or curing, which alters the physical state of the resulting film (including its crystallization or phase transition). These strategies can be used alone or in combination to modify the film's erosion kinetics. Upon application, the pharmaceutical composition film adheres to the mucosal surface and remains in place. Water absorption softens the composition, thereby reducing the foreign body sensation. Drug delivery occurs when the composition remains stationary on the mucosal surface. The residence time can be adjusted over a wide range, depending on the desired delivery time of the selected drug and the desired lifetime of the carrier. However, the residence time is typically adjusted from about a few seconds to about a few days. Preferably, the residence time for most drugs is adjusted from about 5 seconds to about 24 hours. More preferably, the residence time is adjusted from about 5 seconds to about 30 minutes. In addition to providing drug delivery, once the composition adheres to the mucosal surface, it also provides protection for the treatment site, acting as an erosive bandage. Lipophilic agents can be designed to mitigate erosivity to reduce disintegration and dissolution.

[0152] The kinetics of the erosibility of the composition can also be modulated by adding excipients sensitive to enzymes (e.g., amylases), such as water-soluble organic and inorganic salts. Suitable excipients may include sodium and potassium hydrochlorides, carbonates, bicarbonates, citrates, trifluoroacetates, benzoates, phosphates, fluorides, sulfates, or tartrates. The amount added can vary depending on the degree of alteration in erosion kinetics and the amount and properties of other components in the composition.

[0153] Emulsifiers typically used in the above-mentioned water-based emulsions are preferably obtained in situ if they are selected from the following: linoleic acid, palmitic acid, myristone acid, lauric acid, stearic acid, cetearyl acid or oleic acid and sodium hydroxide or potassium hydroxide, or laurate, palmitate, stearate or oleate, polyoxyethylene derivatives selected from sorbitol and sorbitan anhydride, including monooleate, monostearate, monopalmitate, monolaurate, fatty alcohol, alkylphenol, allyl ether, alkyl aryl ether, sorbitol monostearate, sorbitol monooleate and / or sorbitol monopalmitate.

[0154] The amount of the active pharmaceutical ingredient to be used depends on the desired therapeutic intensity and the composition of the layer, but preferably, the pharmaceutical ingredient accounts for about 0.001% to about 99% of the weight of the composition, more preferably about 0.003% to about 75%, and most preferably about 0.005% to about 50%, including more than 0.005%, more 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%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.05%, or less than 0.005%. The amounts of other components may vary depending on the pharmaceutical ingredient or other components, but generally these components account for no more than 50% of the total weight of the composition, preferably no more than 30%, and most preferably no more than 15%.

[0155] The thickness of the film can vary depending on the thickness of each layer and the number of layers. As described above, the thickness and number of layers can be adjusted to alter the erosion kinetics. Preferably, if the composition has only two layers, the thickness ranges from 0.005 mm to 2 mm, more preferably from 0.01 mm to 1 mm, and more preferably from 0.1 mm to 0.5 mm, including more than 0.1 mm, more than 0.2 mm, about 0.5 mm, more than 0.5 mm, less than 0.5 mm, less than 0.2 mm, or less than 0.1 mm. The thickness of each layer can be from 10% to 90% of the total thickness of the layered composition, and preferably from 30% to 60%, including 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 can vary between 0.01 mm and 0.9 mm, or between 0.03 mm and 0.5 mm.

[0156] As those skilled in the art will understand, when systemic delivery (e.g., transmucosal or transdermal delivery) is required, the treatment site may include any area where the membrane can deliver and / or maintain the desired drug level in the blood, lymph, or other bodily fluids. Typically, such treatment sites include the mucous membranes of the mouth, ears, eyes, anus, nasal cavity, and vagina, as well as the skin. If the skin is to be used as a treatment site, a larger area of ​​skin where movement will not disrupt the adhesion of the membrane is generally preferred, such as the upper arm or thigh.

[0157] Pharmaceutical compositions can also be used as wound dressings. By providing a physical, compatible, oxygen- and moisture-permeable, washable, flexible barrier, the membrane not only protects the wound but also delivers medication to promote healing, sterility, abrasion relief, pain relief, or improve the patient's overall condition. Some examples given below are well-suited for application to the skin or wounds. As those skilled in the art will understand, the formulation may require the incorporation of specific hydrophilic / hygroscopic excipients, which help maintain good adhesion to dry skin over an extended period. Another advantage of the invention when used in this manner is that dyes or colored substances are not required if the membrane is not desired to be visible on the skin. On the other hand, dyes or colored substances can be used if the membrane is desired to be visible.

[0158] While the pharmaceutical composition adheres to mucous membranes (which are inherently moist tissues), it can also be applied to other surfaces, such as skin or wounds. If the skin is moistened with water-based fluids such as water, saliva, wound drainage, or sweat before application, the pharmaceutical film can adhere to the skin. The film can remain on the skin until it is eroded by contact with water, such as rinsing, showering, bathing, or washing. The film can also be easily removed by peeling without causing significant damage to the tissue.

[0159] The Franz diffusion cell is an in vitro skin penetration assay used in formulation development. The Franz diffusion cell apparatus ( Figure 1A It consists of two chambers separated by a membrane, such as that of animal or human tissue. The test product is applied to the membrane through the top chamber. The bottom chamber contains a fluid from which samples are periodically taken for analysis to determine the amount of active material permeating the membrane. (See reference...) Figure 1A The Franz diffusion cell 100 includes a donor compound 101, a donor chamber 102, a membrane 103, a sampling port 104, a receiving chamber 105, a stirring rod 106, and a heater / circulator 107.

[0160] refer to Figure 1B The pharmaceutical composition is a membrane 100 comprising a polymer matrix 200, wherein the active pharmaceutical ingredient 300 is contained within the polymer matrix. The membrane may include a permeation enhancer 400.

[0161] refer to Figure 2A and 2B The figure shows the permeation of the active material from the composition. It also shows no significant difference observed between in-situ dissolved epinephrine base and the intrinsically soluble epinephrine tartrate. Epinephrine tartrate was chosen for further development based on its processability. The flux was derived from the slope of the permeation as a function of time. The steady-state flux was obtained by multiplying the plateau of the flux versus time curve by the volume of the receiving medium and normalizing it to the permeation area.

[0162] refer to Figure 2A The figure shows the average amount of active substances permeated over time, including 8.00 mg / mL of adrenaline tartrate and 4.4 mg / mL of dissolved adrenaline alkaloids.

[0163] refer to Figure 2B The figure shows the average flux over time, with 8.00 mg / mL of tartrate and 4.4 mg / mL of dissolved adrenaline.

[0164] refer to Figure 3 This figure shows the in vitro osmosis of adrenaline tartrate as a function of concentration. The study compared concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL. The results showed that increasing concentration led to increased osmosis, and the level of enhancement decreased at higher loads.

[0165] refer to Figure 4 The figure shows the osmosis of adrenaline tartrate as a function of solution pH. Acidic conditions were explored to promote stability. Results compared adrenaline tartrate pH3 and pH5 buffers, with pH5 buffer showing a slightly favorable effect.

[0166] refer to Figure 5 This figure shows the effect of enhancers on adrenaline permeation, expressed as a function of permeation amount over time. A variety of enhancers were screened, including Labrasol, capryol 90, Plurol Oleique, Labrafil, TDM, SGDC, Gelucire 44 / 14, and clove oil. Significant effects on onset time and steady-state flux were achieved, and surprisingly enhanced permeation was observed with clove oil and Labrasol.

[0167] refer to Figure 6A and 6B These figures show the release of adrenaline on the polymer platform and the effect of the enhancer on its release, expressed as permeate volume (in μg) versus time. Figure 6A The release of adrenaline from different polymer platforms is shown. Figure 6B The effect of the enhancement agent on adrenaline release was shown.

[0168] refer to Figure 7 The figure shows a pharmacokinetic model of male Yucatan miniature pigs. This study compared 0.3 mg Epipen, 0.12 mg epinephrine IV, and placebo membranes.

[0169] refer to Figure 8The figure shows the effect of no enhancer on the concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen in the membrane.

[0170] refer to Figure 9 This figure shows the effect of enhancer A (Labrasol) on the concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen in the membrane. (Reference) Figure 10 The figure shows the effect of enhancer L (clove oil) on the concentration distribution of two 40 mg adrenaline membranes (10-1-1) and (11-1-1) relative to 0.3 mg Epipen.

[0171] refer to Figure 11 The figure shows the effect of enhancer L (clove oil) and membrane size (10-1-1 thinner, larger membrane, 11-1-1 thicker, smaller membrane) on the concentration distribution of 40 mg adrenaline membrane relative to 0.3 mg Epipen.

[0172] refer to Figure 12 The figure shows the concentration distribution of enhancer L (clove oil) relative to 0.3 mg Epipen in the adrenaline membrane at different doses in a constant matrix.

[0173] refer to Figure 13 The figure shows the concentration distribution of enhancer L (clove oil) relative to 0.3 mg Epipen in the adrenaline membrane at different doses in a constant matrix.

[0174] refer to Figure 14 The figure shows the concentration distribution of enhancer A (Labrasol) relative to 0.3 mg Epipen in the adrenaline membrane at different doses in a constant matrix.

[0175] refer to Figure 15 The figure shows the effect of the enhancer on diazepam permeability, expressed as a function of permeability over time.

[0176] refer to Figure 16 The figure shows the average flux as a function of time (diazepam + enhancer).

[0177] refer to Figure 17 The figure shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen.

[0178] refer to Figure 18 The figure shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen.

[0179] refer to Figure 19The figure shows the effect of the combination of farnesol and linoleic acid on the plasma concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen.

[0180] refer to Figure 20 The figure shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen.

[0181] The following examples are provided to illustrate the pharmaceutical compositions described in this invention, as well as the methods and apparatus for preparing and using the pharmaceutical compositions. Example

[0182] Example 1

[0183] Penetration enhancer - adrenaline

[0184] Osmotic enhancement was studied using adrenaline tartrate at a concentration of 16.00 mg / mL and various osmotic enhancers. The flux enhancement results are shown in the data below. For 100% eugenol and 100% clove oil, the results showed a significant advance in steady-state flux, while unexpectedly increasing the flux enhancement.

[0185]

[0186] In these embodiments, clove oil was obtained from clove leaves. Similar results can be obtained from clove oil from clove buds and / or clove stems. Based on this data, similar enhanced permeability results can be expected from pharmaceutical compounds that are structurally similar to adrenaline.

[0187] Example 2

[0188] Diazepam solubility and permeability

[0189] Diazepam was applied to the oral region (buccal) to diffuse through the oral mucosa and directly into the bloodstream. The solubility of diazepam was also investigated using various excipients. Figure 15 The effect of the enhancer on diazepam permeation is shown, expressed as permeation amount (in μg) as a function of time. Figure 16 The average flux (in μg / cm³) in solutions of diazepam and some selected enhancers is shown. (Minute meter) is used as a function of time (minutes).

[0190] The following excipients were also investigated to improve solubility.

[0191]

[0192] Due to similar enhancing properties, the following excipients may also be used: cinnamon leaf, basil, bay leaf, nutmeg, Kolliphor® TPGS, Vitamin E PEG succinate, Kolliphor® EL, polyethylene glycol 35 castor oil USP / NF, menthol, N-methyl-2-pyrrolidone, SLS (SDS), SDBS, dimethyl phthalate, sucrose palmitate (Sisterna PS750-C), sucrose stearate (Sisterna SP70-C), CHAPS, octyl glucoside, Triton X 100 (Octoxynol-9), ethyl maltol (food flavoring powder), Brij 58 (cetyl ether-20), vitamin E tocopherol, tocopheryl acetate or tocopheryl succinate, sterols, plant extracts, essential oils or cod liver oil.

[0193] The following results were obtained in a diazepam solution with a concentration of 8.00 mg / mL.

[0194]

[0195] Example 3

[0196] General permeation procedures – Ex vivo permeation research protocols

[0197] In one example, the permeation procedure is as follows: The temperature bath is set to 37°C, and the receiving medium is placed in the water bath to regulate the temperature and begin degassing. A Franz diffusion cell is obtained and prepared. A Franz diffusion cell includes a donor compound, a donor chamber, a membrane, a sampling port, a receiving chamber, a stir bar, and a heater / circulator. The stir bar is inserted into the Franz diffusion cell. Tissue is placed on the Franz diffusion cell, ensuring the tissue covers the entire area and overlaps the glass connector. The top of the diffusion cell is placed on the tissue, and the top and bottom of the cell are clamped together. Approximately 5 mL of acceptor medium is loaded into the receiver area to ensure no air bubbles are trapped in the receiving portion of the cell. This ensures that all 5 mL can be filled into the receiver area. Stirring is started, and the temperature is equilibrated for approximately 20 minutes. Simultaneously, the high-performance liquid chromatography (HPLC) vials are labeled with the cell number and time point. Air bubbles must then be checked again, as the solution degasses during heating.

[0198] If testing the membrane, the following steps can be performed: (1) Weigh the membrane, punch it to match the diffusion area (or smaller), weigh it again, and record the weight before and after punching; (2) Wet the donor area with about 100 μL of phosphate buffer; (3) Place the membrane on the donor surface, add 400 μL of phosphate buffer on top, and start the timer.

[0199] For solution studies, the following steps can be performed: (1) Using a micropipette, dispense 500 μL of solution into each donor cell and start the timer; (2) Take 200 μL of sample at the following time points (time = 0 min, 20 min, 40 min, 60 min, 120 min, 180 min, 240 min, 300 min, 360 min) and place it in a labeled HPLC vial, ensuring that no air is trapped at the bottom of the vial by tapping the sealed vial; (3) Replace each sample time with 200 μL of acceptor medium (keep 5 mL); (4) After completing all time points, disassemble the cells and properly dispose of all materials.

[0200] Example 4

[0201] In vitro permeability evaluation

[0202] An exemplary in vitro permeability evaluation is as follows.

[0203] 1. Freshly excised tissue is transported at 4°C (e.g., overnight).

[0204] 2. Process the tissue and freeze it at -20°C for up to three weeks before use.

[0205] 3. Dermatomed the tissue to the precise thickness.

[0206] 4. Add approximately 5 mL of receiving medium to the receiving compartment. Select the appropriate medium to ensure proper settling conditions.

[0207] 5. Place the tissue in a Franz diffusion cell, which includes a donor compound, a donor chamber, a membrane, a sampling port, a receiving chamber, a stir bar, and a heater / circulator.

[0208] 6. Apply approximately 0.5 mL of donor solution or an 8 mm circular membrane and wet it with 500 μL of PBS buffer.

[0209] 7. Take samples from the receiving chamber at given intervals and replace them with fresh media.

[0210] Example 5

[0211] Doxepin via buccal delivery

[0212] The following are exemplary permeation studies of doxepin delivered via the buccal route. These studies were conducted under protocols approved by the Animal Experimentation Ethics Committee of the University of Barcelona (Spain) and the Animal Experimentation Committee of the Regional Government of Catalonia (Spain). Female pigs aged 3–4 months were used. The buccal mucosa from the cheek region was immediately excised after the pigs were euthanized in the animal facility at the Bellvitge Campus (University of Barcelona, ​​Spain) using an overdose of sodium thiopental anesthetic. Fresh buccal tissue was transferred from the hospital to the laboratory in containers containing Hank's solution. Remaining tissue samples were stored at -80°C in containers containing a mixture of PBS containing 4% albumin and 10% DMSO as cryoprotectants.

[0213] For the penetration study, porcine buccal mucosa was cut into slices 500 ± 50 μm thick, which helps the diffusion barrier (Buccalbioadhesive drug delivery — A promising option for orally less efficient drugs, Sudhakar et al., Journal of Controlled Release 114 (2006) 15–40). This was done using an electric dermabrasion knife (GA 630, Aesculap, Tuttlingen, Germany) and trimmed into appropriate pieces with surgical scissors. Most of the underlying connective tissue was removed with a scalpel.

[0214] The membrane was then installed in a specially designed membrane support with a permeate pore diameter of 9 mm (diffusion area of ​​0.636 cm²). 2 Using a membrane scaffold, each porcine buccal membrane was placed between the donor (1.5 mL) and recipient (6 mL) compartments, with its epithelial side facing the donor compartment and its connective tissue area facing the receiver (Vidra Foc Barcelona, ​​Spain) of the static Franz-type diffusion cell to avoid foam formation.

[0215] Unlimited dose conditions were ensured by applying 100 μL of a saturated doxepin solution as the donor solution to the receiver chamber and immediately sealing it with a paraffin membrane to prevent water evaporation. Before the experiment, the diffusion cells were incubated in a water bath for 1 hour to equilibrate the temperature in all cells (37°+ / - °C). Each cell contained a small Teflon1-coated magnetic stir bar to ensure that the fluid in the receiver compartment remained homogeneous during the experiment.

[0216] Sedimentation conditions were ensured in all experiments by initially testing the saturation concentration of doxepin in the receptor medium. Samples (300 μL) were aspirated from the center of the receptor compartment using a syringe at pre-selected time intervals (0.1, 0.2, 0.3, 0.7, 1, 2, 3, 4, 5, and 6 h) for up to 6 hours. The aspirated sample volume was immediately replaced with the same volume of fresh receptor medium (PBS; pH 7.4), with great care to avoid trapping air below the membrane. Further details can be found in the article A. Gimemo et al., *Transbuccal delivery of doxepin: Studies on permeation and histological evaluation*, *International Journal of Pharmaceutics* 477 (2014), 650-654, which is incorporated herein by reference.

[0217] Example 6

[0218] Oral transmucosal delivery

[0219] Porcine oral mucosa tissue exhibits histological characteristics similar to human oral mucosa tissue (Heaney TG, Jones RS, Histological investigation of the influence of adult porcine alveolarmucosal connective tissues on epithelial differentiation. Arch Oral Biol 23 (1978) 713–717; Squier CA and Collins P, The relationship between soft tissue attachment, epithelial downgrowth and surface porosity. Journal of Periodontal Research 16 (1981) 434–440). Lesch et al. (The Permeability of Human Oral Mucosa and Skin to Water, J Dent Res 68 (9), 1345–1349, 1989) reported that the water permeability of porcine buccal mucosa was not significantly different from that of human buccal mucosa, but for the floor of the oral cavity, human tissue was more permeable than porcine tissue. A comparison between fresh porcine tissue samples and samples stored at -80°C showed that freezing did not significantly affect permeability. Absorption of various drug molecules in the porcine buccal mucosa has been studied in vitro and in vivo (see, for example, Table 1, M. Sattar, Oraltransmucosal drug delivery – current status and future prospects, International Journal of Pharmaceutics 471 (2014) 498-506), which is incorporated herein by reference. Typically, in vitro studies involve placing excised porcine buccal tissue into a using chamber, Franz pool, or similar diffusion device. In vivo studies described in the literature involve applying the drug as a solution, gel, or composition to the porcine buccal mucosa, followed by plasma sampling.

[0220] Nicolazzo et al. (The Effect of Various in Vitro Conditions on the Permeability Characteristics of the Buccal Mucosa, Journal of Pharmaceutical Sciences 92(12) (2002) 2399-2410) investigated the effects of various in vitro conditions on the permeability of porcine buccal tissue, using caffeine and estradiol as model hydrophilic and lipophilic molecules, respectively. Drug penetration into the buccal mucosa was studied using a modified using chamber. Permeability studies were compared between full-thickness and epithelial tissues, and between fresh and frozen tissues. Tissue integrity was monitored by absorption of FITC-labeled dextran 20 kDa (FD20), and tissue viability was assessed using MTT (3-[4,5-dimethylthiazolyl-2-yl]-2,5-diphenyltetrazolium bromide) biochemical assays and histological evaluation. Permeability through the buccal epithelium was 1.8 times that of caffeine and 16.7 times that of estradiol compared to full-thickness buccal tissue. The flux values ​​of the two compounds were comparable for both fresh and frozen buccal epithelium, although histological evaluation showed signs of cell death in the frozen tissue. The tissue remained viable for up to 12 hours post-mortem using an MTT viability assay, which was also confirmed by histological evaluation.

[0221] Kulkarni et al. investigated the relative contributions of epithelium and connective tissue to the barrier properties of porcine buccal mucosa. In vitro permeation studies were conducted using antipyrine, buspirone, bupivacaine, and caffeine as model permeants. The permeability of these model diffusing agents across buccal mucosa thicknesses of 250, 400, 500, 600, and 700 μm was determined. A bilayer membrane model was developed to characterize the relative contributions of epithelium and connective tissue to barrier function. The relative contribution of the connective tissue region as a permeation barrier increased significantly with increasing mucosal thickness. The authors recommended a mucosal thickness of approximately 500 μm for in vitro buccal permeation studies, as the epithelium represents the primary permeation barrier for all diffusing agents at this thickness. The authors also investigated the effects of multiple biological and experimental variables on the permeability of the same set of model permeants in porcine buccal mucosa (Porcine buccal mucosa as in vitro model: effect of biological and experimental variables, Kulkarni et al., J Pharm Sci. 2010 99(3):1265-77). Notably, higher permeability of the exudate was observed in the thinner region (170-220 μm) behind the lips compared to the thicker cheek region (250-280 μm). Porcine buccal mucosa maintained its integrity for 24 hours at 4°C in Kreb bicarbonate Ringer's solution. Heat treatment that separated the epithelium from the underlying connective tissue did not adversely affect its permeability and integrity characteristics compared to surgical dissection.

[0222] Further details can be found in M. Sattar, Oral transmucosal drug delivery – current status and future prospects, International Journal of Pharmaceutics 471(2014) 498-506, which is incorporated herein by reference.

[0223] Example 7

[0224] Ultra-low temperature preservation of buccal mucosa

[0225] Different regions of the porcine buccal mucosa exhibit different permeability patterns, with the region behind the lips showing significantly higher permeability compared to the buccal region. This is because the epithelium acts as a permeability barrier in the porcine buccal mucosa, and the buccal epithelium is thicker than in the region behind the lips (Harris and Robinson, 1992). In exemplary permeability studies, fresh or frozen porcine buccal mucosa from the same region was cut into 500 ± 50 μm thick slices, which facilitated the diffusion barrier (Sudhakar et al., 2006). These slices were obtained using an electric dermabrasion knife (model GA 630, Aesculap, Tuttlingen, Germany) and trimmed into appropriate pieces with surgical scissors. All devices used were pre-sterilized. Most of the underlying connective tissue was removed with a scalpel. The membrane was then mounted in a specially designed membrane holder with a permeation pore diameter of 9 mm (diffusion area of ​​0.63 cm²). 2 Using a membrane scaffold, each porcine buccal membrane was placed between the donor (1.5 mL) and recipient (6 mL) compartments, with the epithelium facing the donor compartment and the connective tissue region facing the receiver of the static Franz-type diffusion cell (Vidra Foc, Barcelona, ​​Spain) to avoid bubble formation. PP was used as a model drug in the experiments; it is lipophilic (logP = 1.16; n-octanol / PBS, pH 7.4), ionizable (pKa = 9.50), and has a molecular weight gain (MW) of 259.3 g / mol (Modamio et al., 2000).

[0226] Unlimited dose conditions were ensured by applying 300 μL of a saturated solution of PP (CO = 588005±5852 μg / mL, 37℃±1℃, n = 6) in PBS (pH 7.4) as the donor solution to the receiving chamber and immediately sealing it with a paraffin membrane to prevent moisture evaporation.

[0227] Prior to the experiments, the diffusion cells were incubated in a water bath for 1 hour to equilibrate the temperature in all cells (37℃±1℃). Each cell included a small PTFE-coated magnetic stir bar to ensure that the fluid in the acceptor compartment remained homogeneous during the experiments. Settling conditions were ensured in all experiments after initial testing of the PP saturation concentration in the acceptor medium.

[0228] Samples (300 μL) were aspirated from the center of the receptor compartment using a syringe at the following time intervals: 0.25, 0.5, 1, 2, 3, 4, 5, and 6 hours. The aspirated sample volume was immediately replaced with the same volume of fresh receptor media (PBS; pH 7.4), taking great care to avoid trapping air under the dermis. The sample was then corrected for permeation surface area (cm²) of the mucosa. 2The cumulative amount (μg) of the drug was calculated and plotted against time (h). 27 diffusion experiments were performed on fresh material and 22 on frozen buccal mucosa.

[0229] Further details can be found in S. Amores, An improved cryopreservation method for porcine buccal mucosa in ex vivo drug permeation studies using Franzdiffusion cells, European Journal of Pharmaceutical Sciences 60 (2014) 49–54.

[0230] Example 8

[0231] Quinine penetration through sublingual mucosal slices

[0232] Because porcine and human oral mucosa are similar in composition, structure, and permeability measurements, porcine oral mucosa is a suitable model for human oral mucosa. Permeability across porcine oral mucosa is not metabolically relevant and therefore not important for tissue survival.

[0233] To prepare the porcine membrane, the tongue mucosa of the floor of the mouth and ventral (lower) side of the pig was bluntly dissected using a scalpel. The excised mucosa was cut into squares of approximately 1 cm and frozen on aluminum foil at -20°C until use (<2 weeks). For the non-frozen ventral side of the pig tongue, the mucosa was used for permeability studies within 3 hours of excision.

[0234] The permeability of the membrane to quinine was determined using an all-glass Franz diffusion cell with a nominal acceptor volume of 3.6 mL and a diffusion area of ​​0.2 cm². 2 The edges of the cell were lubricated with high-performance vacuum grease, and the membrane was mounted between the recipient and donor compartments with the mucosal surface on top. The membrane was held in place using clamps before filling the recipient compartment with degassed phosphate-buffered saline (PBS) at pH 7.4. A micromagnetic stir bar was added to the recipient compartment, and intact cells were placed in a 37°C water bath. The membrane was equilibrated with PBS applied to the donor compartment for 20 minutes and then aspirated using a pipette. Aliquots of 5 μL of quinine solution or 100 μL of a saturated solution of the Q / 2-HP-β-CD complex in different carriers were applied to each donor compartment. In a study determining the effect of saliva on quinine penetration across the ventral surface of the tongue, 100 μL of sterile saliva was added to the donor compartment before adding 5 μL of quinine solution.

[0235] At 2, 4, 6, 8, 10, and 12 hours, the recipient phase was removed from the sampling port, and a 1 mL aliquot of the sample was transferred to an HPLC autosampler vial, which was then replaced with fresh PBS stored at 37°C. Except for studies involving a saturated Q / 2-HP-β-CD solution (in which an unlimited dose was applied at the start of the experiment), 5 μL of quinine solution was subsequently added to the donor phase up to 10 hours. The aim was to represent the hypothetical limited-dose dosing regimen based on a 2-hour dose interval. Each study was performed at least three times.

[0236] Further details can be found in C. Ong, Permeation of quinine across sublingualmucosa, in vitro, International Journal of Pharmaceutics 366 (2009) 58–64.

[0237] Example 9

[0238] Initial in vitro studies – in the form of API

[0239] In this embodiment, the osmotic-in-situ dissolution of adrenaline base and its intrinsically soluble form, adrenaline tartrate, were tested, and no difference was found. Adrenaline tartrate was chosen for further development based on its processability. The flux was derived from the slope of the osmotic flow over time. The steady-state flux was calculated by multiplying the plateau of the flux-time curve by the volume of the receiving medium. Figure 2A The figure in the figure shows the relationship between average osmotic volume and time, with 8.00 mg / mL adrenaline tartrate and 4.4 mg / mL dissolved adrenaline alkaloids. Figure 2B The figure shows the relationship between average flux and time, with 8.00 mg / mL epinephrine tartrate and 4.4 mg / mL dissolved epinephrine alkaloids.

[0240]

[0241] Example 10

[0242] concentration dependence of permeation / flux

[0243] In this study, the in vitro osmosis of adrenaline tartrate as a function of concentration was investigated. Figure 3This study demonstrated the in vitro osmotic pressure of adrenaline tartrate as a function of concentration. Concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL were compared. Results showed that increasing concentration led to increased osmotic pressure, with the enhancement level decreasing at higher loadings. (This study compared concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL.)

[0244]

[0245]

[0246] Example 11

[0247] The effect of pH

[0248] In this embodiment, the osmosis of adrenaline tartrate as a function of solution pH was investigated. The ability of acidic conditions to improve stability was explored. Results showed that pH 5 was slightly more favorable than pH 3. Within the investigated concentration range, the intrinsic pH of adrenaline tartrate in solution was 4.5–5. pH adjustment with a buffer solution was not required.

[0249] Figure 4 The osmotic properties of adrenaline tartrate were shown as a function of solution pH. Acidic conditions were explored to promote stability. Results compared adrenaline tartrate pH 3 buffer and adrenaline tartrate pH 5 buffer, revealing a slightly favorable pH 5 buffer.

[0250] Example 12

[0251] Effect of enhancers on adrenaline penetration

[0252] In this embodiment, the permeation of epinephrine used to test transmucosal delivery was investigated as permeation volume (μg) versus time (in minutes). The concentration effects of the following enhancers were screened in a solution containing 16.00 mg / mL epinephrine. Figure 5 The figure in the diagram shows the results of these enhancers as a function of time.

[0253]

[0254] The selection and design of enhancers, whose functions affect different barriers in the mucosa, were crucial. While all the enhancers tested did improve the amount of penetration over time, clove oil and Labrasol showed particularly significant and unexpectedly high penetration enhancements.

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] Example 13

[0266] Effects of enhancers on adrenaline release

[0267] The profile of adrenaline release was studied to determine the effect of enhancers (Labrasol and clove oil) on adrenaline release. Figure 6A The release of adrenaline from different polymer platforms is shown. Figure 6B The effect of the enhancer on adrenaline release was shown. Results showed that the amount of osmosis plateaued after approximately 40 minutes, ranging between approximately 3250 and 4250 μg. This indicates that the tested enhancer did not restrict the release of adrenaline from the matrix.

[0268] Example 14

[0269] Accelerated stability

[0270] Variations of the load stabilizer were tested.

[0271]

[0272] Example 15

[0273] Effect of reinforcing agents

[0274] A pharmacokinetic model of male Yucatan miniature pigs was studied. Figure 7 The figure in the image shows the results of a pharmacokinetic model in male Yucatan miniature pigs. This study compared 0.3 mg Epipen, 0.12 mg epinephrine IV, and placebo.

[0275] The effects of the absence of reinforcing agents, such as Figure 8The figure shows the concentration distribution of 0.3 mg Epipen and 40 mg adrenaline membranes without the enhancer.

[0276] The effect of 3% Labrasol as a reinforcing agent is shown in Figure 9 The study showed the effect of enhancer A (Labrasol) on the concentration distribution of 40 mg adrenaline relative to 0.3 mg Epipen in the membrane. Figure 10 This study shows the effect of enhancer L (clove oil) on the concentration distribution of two 40 mg adrenaline membranes (10-1-1) and (11-1-1) relative to 0.3 mg Epipen.

[0277] also, Figure 11 The effects of membrane size and clove oil (3%) were also shown. This study was conducted to compare the concentration versus time relationship of 0.30 mg EpiPen (n = 4), 40 mg epinephrine membrane (10⁻¹⁻¹) (n = 5), and 40 mg epinephrine membrane (11⁻¹⁻¹) (n = 5) following sublingual or intramuscular administration of epinephrine to male miniature pigs.

[0278] Studies were conducted to alter the ratio of adrenaline to enhancer. These studies also investigated the relationship between the concentration and time of adrenaline administration sublingually or intramuscularly to male miniature pigs. Changing the ratio of adrenaline to clove oil (enhancer L) produced results such as... Figure 12 The results are shown. This study was conducted to compare 0.30 mg EpiPen (n = 4), 40 mg epinephrine membrane (12-1-1) (n = 5), and 20 mg epinephrine membrane (13-1-1) (n = 5).

[0279] Example 16

[0280] Dosage variations were performed in a constant matrix containing the enhancers Labrasol (3%) and clove oil (3%), as shown in [the figures]. Figure 13 and 14 In progress. Figure 13 The study compared 0.30 mg EpiPen (n=4), 40 mg epinephrine membrane (18-1-1) (n=5), and 30 mg epinephrine membrane (20-1-1) (n=5). Figure 14 The studies compared the concentration-time relationship of 0.30 mg EpiPen (n = 4), 40 mg epinephrine membrane (19-1-1) (n = 5), and 30 mg epinephrine membrane (21-1-1) (n = 5). These studies also included sublingual or intramuscular administration of epinephrine to male miniature pigs.

[0281] Example 17

[0282] A pharmacokinetic model was studied in male miniature pigs to determine the effect of the enhancer (farnesol) on adrenaline concentration over time. Figure 17 The figure shows plasma epinephrine concentrations (in ng / mL) as a function of time (in minutes) after sublingual or intramuscular administration of a farnesol permeation enhancer. This study compared 0.3 mg Epipen (n = 3), 30 mg epinephrine membrane 31-1-1 (n = 5), and 30 mg epinephrine membrane 32-1-1 (n = 5), each formulated with a farnesol enhancer. As shown in the figure, the 31-1-1 membrane exhibited enhanced epinephrine concentration stability from approximately 30–40 minutes up to approximately 130 minutes.

[0283] Figure 18 The image in the middle is obtained from and Figure 17 The same study, but only showing data points comparing 0.3 mg Epipen with 30 mg epinephrine membrane 31-1-1 (n = 5).

[0284] Figure 19 The image in the middle is obtained from and Figure 17 The same study, but only showing data points comparing 0.3 mg Epipen with 30 mg epinephrine membrane 32-1-1 (n = 5).

[0285] Example 18

[0286] refer to Figure 20 This figure shows a pharmacokinetic model of male miniature pigs used to determine the effect of a post-sublingual or intramuscular administration enhancer (farnesol) on epinephrine concentrations over time. Epinephrine plasma concentrations (in ng / mL) are shown as a function of time (in minutes) following sublingual or intramuscular administration of the farnesol permeation enhancer in an epinephrine membrane. This study compared data from three 0.3 mg Epipen treatments with five 30 mg epinephrine membranes (32-1-1). The data showed that the epinephrine membrane exhibited enhanced epinephrine concentration stability from approximately 20–30 minutes up to approximately 130 minutes.

[0287] Example 19

[0288] In one embodiment, the adrenaline drug composition membrane can be prepared using the following formulation:

[0289]

[0290] Example 20

[0291] The adrenaline drug composition membrane was prepared using the following formulation:

[0292]

[0293] Example 21

[0294] In another embodiment, the pharmaceutical film composition is prepared using the following formulation:

[0295]

[0296] Example 22

[0297] In another embodiment, the pharmaceutical film composition is prepared using the following formulation:

[0298]

[0299] Example 23

[0300] refer to Figure 21 This figure shows a pharmacokinetic model (logarithmic scale) of male miniature pigs used to determine the effect of farnesol permeation enhancers (6% clove oil and 6% Labrasol) on epinephrine plasma concentrations over time after sublingual or intramuscular administration. Epinephrine plasma concentrations (in ng / mL) are shown as a function of time (in minutes) following sublingual or intramuscular administration of the farnesol permeation enhancer to the epinephrine membrane. The data show that the epinephrine membrane exhibits enhanced epinephrine concentration stability from immediately following the 10-minute time point up to approximately 30 minutes, continuing until approximately 100 minutes.

[0301] refer to Figure 22 The figure shows Figure 21 The pharmacokinetic model of the adrenaline membrane formulation in male miniature pigs mentioned above is compared with mean data collected from 0.3 mg Epipen (indicated in the diamond data points). As the data show, the mean plasma concentration of 0.3 mg Epipen peaked between 0.5 and 1 ng / mL. In contrast, the peak concentration of the adrenaline membrane formulation peaked between 4 and 4.5 ng / mL.

[0302] Example 24

[0303] refer to Figure 23 The figure shows a pharmacokinetic model of male miniature pigs, which was used to determine the effect of a booster (9% clove + 3% Labrasol) on adrenaline concentrations over time after sublingual or intramuscular administration in seven animal models. Typical peak concentrations were reached between 10 and 30 minutes.

[0304] Alprazolam data

[0305] Example 25

[0306] Reference Figure 24A , Figure 24B and Figure 24BThese figures represent data from a study of male miniature pigs that compared plasma concentrations of alprazolam after sublingual administration of orally disintegrating tablets (ODT) and alprazolam drug compositions over time (in hours).

[0307] Figure 24A The data shown are averages from alprazolam ODT (Group 1). Peak concentrations of 7-12 ng / mL were reached in approximately 1-8 hours.

[0308] Figure 24B The data shown are averages from the alprazolam pharmaceutical composition membrane (Group 2). Peak concentrations between 5 and 17 ng / mL were reached between 10 minutes and 4 hours, including more than 5 ng / mL, more than 10 ng / mL, more than 12 ng / mL, more than 15 ng / mL, more than 17 ng / mL, less than 17 ng / mL, less than 15 ng / mL, less than 12 ng / mL, less than 10 ng / mL, and less than 5 ng / mL, for times including more than 10 minutes, more than 20 minutes, more than 30 minutes, more than 45 minutes, more than 1 hour, more than 1.5 hours, more than 2 hours, more than 2.5 hours, more than 3 hours, more than 3.5 hours, or about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes.

[0309] Figure 24C The data shown are average data for alprazolam drug composition films from another group of male miniature pigs (group 3). Peak concentrations between 5 and 17 ng / mL are reached between 10 minutes and 4 hours, including more than 5 ng / mL, more than 10 ng / mL, more than 12 ng / mL, more than 15 ng / mL, more than 17 ng / mL, less than 17 ng / mL, less than 15 ng / mL, less than 12 ng / mL, less than 10 ng / mL, and less than 5 ng / mL, with the time including more than 10 minutes, more than 20 minutes, more than 30 minutes, more than 45 minutes, more than 1 hour, more than 1.5 hours, more than 2 hours, more than 2.5 hours, more than 3 hours, more than 3.5 hours, and about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes.

[0310] Example 26

[0311] refer to Figure 25AThe figure illustrates data from a study of male miniature pigs, comparing plasma concentrations of alprazolam over time (in hours) after sublingual administration of alprazolam orally disintegrating tablets (ODT) (represented by circled data points) and two groups of alprazolam drug combination films (represented by square and triangular data points).

[0312] As shown in the figure, data from the alprazolam drug composition membranes (two groups) showed higher alprazolam plasma concentrations, up to about 15-25 mg / mL, within a treatment window of about 30 minutes or less, which includes more than 10 minutes, more than 20 minutes, about 30 minutes, more than 30 minutes, less than 30 minutes, less than 20 minutes, less than 15 minutes, or less than 10 minutes.

[0313] refer to Figure 25B The figure represents from Figure 25A The various data points involved in the research.

[0314] refer to Figure 25C The figure represents from Figure 25A The data points involved in the study range from 0 to 1 hour.

[0315] refer to Figure 26A The diagram shows Figure 25C The data points involved in the alprazolam ODT.

[0316] refer to Figure 26B The diagram shows Figure 25C The data points for the alprazolam drug membrane involved.

[0317] refer to Figure 26C The diagram shows Figure 25C The data points for the alprazolam drug membrane (Group 2) involved in the study.

[0318] The data mentioned in the above graph is also summarized in the table below:

[0319]

[0320] Example 27

[0321] refer to Figure 27AThis figure illustrates data from a male miniature pig study comparing plasma alprazolam plasma concentrations over time after sublingual administration of alprazolam orally disintegrating tablets (ODT) (represented by circled data points) and two groups of alprazolam drug combination films (represented by square and triangular data points). As the data show, the peak concentrations reached by 0.5 mg alprazolam ODT ranged from approximately 5-6 ng / mL in the range of 0–4 hours, including more than 10 minutes, more than 20 minutes, more than 30 minutes, more than 45 minutes, more than 1 hour, more than 1.5 hours, more than 2 hours, more than 2.5 hours, more than 3 hours, more than 3.5 hours, or approximately 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes. Between 0 and 4 hours, including more than 10 minutes, more than 20 minutes, more than 30 minutes, more than 45 minutes, more than 1 hour, more than 1.5 hours, more than 2 hours, more than 2.5 hours, more than 3 hours, more than 3.5 hours, or about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes, the peak concentrations reached by the 0.5 mg alprazolam pharmaceutical composition membrane were about 7-8 ng / mL and 6-7 ng / mL, respectively.

[0322] refer to Figure 27B This figure illustrates the plasma concentrations of alprazolam over time after sublingual administration of alprazolam orally disintegrating tablets (ODT) (represented by circled data points) and two groups of alprazolam drug combination films (represented by square and triangular data points) between 0 and 2 hours. Unlike ODT, the therapeutic window of alprazolam drug combination films begins at 10–15 minutes, while that of ODT begins at approximately 17–20 minutes.

[0323] refer to Figure 27C The figure illustrates Figure 27B The complete data involved are for ODT (n = 4), 0.5 mg alprazolam drug composition membrane 14-1-1 (n = 5) and 0.5 mg alprazolam drug composition membrane 15-1-1 (n = 5).

[0324] The data from the above-mentioned graphs are summarized in the table below:

[0325]

[0326] This application specifically involves the following implementation plan:

[0327] 1. A pharmaceutical composition comprising:

[0328] Polymer matrix;

[0329] The active pharmaceutical ingredient in the polymer matrix; and

[0330] Adrenergic receptor interactors.

[0331] 2. The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition further comprises a penetration enhancer.

[0332] 3. The pharmaceutical composition according to embodiment 1, wherein the adrenergic receptor interactor comprises terpenoids, terpenes, or sesquiterpenes.

[0333] 4. The pharmaceutical composition according to embodiment 2, wherein the penetration enhancer comprises farnesol.

[0334] 5. The pharmaceutical composition according to embodiment 2, wherein the penetration enhancer comprises Labrasol.

[0335] 6. The pharmaceutical composition according to embodiment 2, wherein the penetration enhancer comprises linoleic acid.

[0336] 7. The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition comprises a polymer matrix and the active pharmaceutical ingredient is contained in the polymer matrix.

[0337] 8. The pharmaceutical composition according to embodiments 1-7, wherein the adrenergic receptor interactor comprises phenylpropane-like substances.

[0338] 9. The pharmaceutical composition according to embodiment 8, wherein the phenylpropane-like substance is eugenol.

[0339] 10. The pharmaceutical composition according to embodiment 8, wherein the phenylpropane-like substance is eugenol acetate.

[0340] 11. The pharmaceutical composition according to embodiment 8, wherein the phenylpropane-like substance is cinnamic acid.

[0341] 12. The pharmaceutical composition according to embodiment 8, wherein the phenylpropane-like substance is a cinnamic ester.

[0342] 13. The pharmaceutical composition according to embodiment 8, wherein the phenylpropane-like substance is cinnamaldehyde.

[0343] 14. The pharmaceutical composition according to embodiment 8, wherein the phenylpropane-like substance is hydrogenated cinnamic acid.

[0344] 15. The pharmaceutical composition according to embodiment 8, wherein the phenylpropane-like substance is guanosine.

[0345] 16. The pharmaceutical composition according to embodiment 8, wherein the phenylpropane-like substance is safrole.

[0346] 17. The pharmaceutical composition according to embodiment 1, wherein the adrenergic receptor interactor is a plant extract.

[0347] 18. The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises an essential oil extract of clove plant.

[0348] 19. The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises an essential oil extract of clove leaves.

[0349] 20. The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises an essential oil extract of clove flower buds.

[0350] 21. The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises an essential oil extract of clove plant stem.

[0351] 22. The pharmaceutical composition according to embodiment 17, wherein the plant extract is synthetic or biosynthetic.

[0352] 23. The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises 40-95% eugenol.

[0353] 24. The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises 80-95% eugenol.

[0354] 25. The pharmaceutical composition according to embodiment 1, wherein the active pharmaceutical ingredient is adrenaline.

[0355] 26. The pharmaceutical composition according to embodiment 1, wherein the active pharmaceutical ingredient is diazepam.

[0356] 27. The pharmaceutical composition according to embodiment 1, wherein the active pharmaceutical ingredient is alprazolam.

[0357] 28. The pharmaceutical composition according to embodiment 1, wherein the polymer matrix comprises a polymer.

[0358] 29. The pharmaceutical composition according to embodiment 28, wherein the polymer is a water-soluble polymer.

[0359] 30. The pharmaceutical composition according to embodiment 28, wherein the polymer comprises a cellulose polymer selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, hydroxypropylcellulose, methylcellulose, and carboxymethylcellulose.

[0360] 31. The pharmaceutical composition according to embodiment 28, wherein the polymer comprises polyethylene oxide.

[0361] 32. The pharmaceutical composition according to embodiment 28, wherein the polymer matrix comprises a cellulose polymer, polyethylene oxide and polyvinylpyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide, hydroxypropyl methylcellulose and polysaccharide, or polyethylene oxide, hydroxypropyl methylcellulose, polysaccharide and polyvinylpyrrolidone.

[0362] 33. The pharmaceutical composition according to embodiment 28, wherein the polymer matrix comprises at least one polymer selected from: pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, gum arabic, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide, propylene oxide copolymer, collagen, albumin, polyamino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof.

[0363] 34. The pharmaceutical composition according to embodiment 1 further comprises a stabilizer.

[0364] 35. The pharmaceutical composition according to embodiment 1, wherein the polymer matrix comprises a dendritic polymer.

[0365] 36. The pharmaceutical composition according to embodiment 1, wherein the polymer matrix comprises a hyperbranched polymer.

[0366] 37. A method for preparing a pharmaceutical composition, comprising:

[0367] Combining adrenergic receptor interactors with active pharmaceutical ingredients, and

[0368] A pharmaceutical composition comprising the adrenergic receptor interactor and the active pharmaceutical ingredient is formed.

[0369] 38. An apparatus comprising

[0370] A shell containing a quantity of a pharmaceutical composition comprising:

[0371] Polymer matrix;

[0372] The active pharmaceutical ingredient in the polymer matrix; and

[0373] Penetration enhancers, including phenylpropane-like substances and / or plant extracts; and

[0374] An opening for dispensing a predetermined amount of the pharmaceutical composition.

[0375] 39. A pharmaceutical composition comprising:

[0376] Polymer matrix;

[0377] The active pharmaceutical ingredient in the polymer matrix; and

[0378] Penetration enhancers, including phenylpropane-like substances and / or plant extracts.

[0379] 40. The pharmaceutical composition of embodiment 39, wherein the phenylpropane-like substance is eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamaldehyde, hydrogenated cinnamic acid, cinnamic acid, or safrole.

[0380] 41. The pharmaceutical composition according to embodiment 39, wherein the plant extract comprises an essential oil extract of the clove plant.

[0381] 42. The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises an essential oil extract of clove leaves, an essential oil extract of clove flower buds, or an essential oil extract of clove stems.

[0382] 43. The pharmaceutical composition according to embodiment 17, wherein the plant extract is synthetic or biosynthetic.

[0383] 44. The pharmaceutical composition according to embodiment 39, wherein the plant extract further comprises 40-95% eugenol.

[0384] 45. The pharmaceutical composition according to embodiment 39, wherein the plant extract further comprises 80-95% eugenol.

[0385] 46. ​​The pharmaceutical composition according to embodiment 39, wherein the active pharmaceutical ingredient is adrenaline.

[0386] 47. The pharmaceutical composition according to embodiment 39, wherein the active pharmaceutical ingredient is diazepam.

[0387] 48. The pharmaceutical composition according to embodiment 39, wherein the active pharmaceutical ingredient is alprazolam.

[0388] 49. The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a polymer.

[0389] 50. The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a water-soluble polymer.

[0390] 51. The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises polyethylene oxide.

[0391] 52. The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a cellulose polymer selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, hydroxypropylcellulose, and carboxymethylcellulose.

[0392] 53. The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises hydroxypropyl methylcellulose.

[0393] 54. The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a cellulose polymer, polyethylene oxide and polyvinylpyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide, hydroxypropyl methylcellulose and polysaccharide, or polyethylene oxide, hydroxypropyl methylcellulose, polysaccharide and polyvinylpyrrolidone.

[0394] 55. The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises at least one polymer selected from: pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, gum arabic, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide, propylene oxide copolymer, collagen, albumin, polyamino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof.

[0395] 56. The pharmaceutical composition according to embodiment 39 further comprises a stabilizer.

[0396] 57. The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a dendritic polymer.

[0397] 58. The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a hyperbranched polymer.

[0398] 59. The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition is a chewable or gelatin-based dosage form, spray, chewing gum, gel, cream, tablet, liquid or film.

[0399] All references cited in this invention are incorporated herein by reference in their entirety.

[0400] Other implementations are within the scope of the following claims.

Claims

1. A pharmaceutical composition comprising: Polymer matrix; The active pharmaceutical ingredient in the polymer matrix; and Adrenergic receptor interactors.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a penetration enhancer.

3. The pharmaceutical composition according to claim 1, wherein the adrenergic receptor interactor comprises terpenoids, terpenes, or sesquiterpenes.

4. The pharmaceutical composition of claim 2, wherein the penetration enhancer comprises farnesol.

5. The pharmaceutical composition of claim 2, wherein the penetration enhancer comprises Labrasol.

6. The pharmaceutical composition according to claim 2, wherein the penetration enhancer comprises linoleic acid.

7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a polymer matrix, and the active pharmaceutical ingredient is contained in the polymer matrix.

8. The pharmaceutical composition according to claims 1-7, wherein the adrenergic receptor interactor comprises phenylpropane-like substances.

9. The pharmaceutical composition according to claim 8, wherein the phenylpropane-like substance is eugenol.

10. The pharmaceutical composition according to claim 8, wherein the phenylpropane is eugenol acetate.

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