Pharmaceutical composition with enhanced permeability

Abstract

Pharmaceutical compositions having enhanced active ingredient permeation properties are described. [Selection diagram] None

Description

[Technical Field]

[0001] (Claiming priority) This application claims priority to U.S. Patent Application No. 62 / 331,993, filed on 5 May 2016, which is incorporated herein by reference in its entirety under Section 119(e) of the U.S. Patent Act (35 U.S.C).

[0002] (Technical field) This invention relates to a pharmaceutical composition. [Background technology]

[0003] (background) The active ingredients of drugs or pharmaceuticals are delivered to the patient in a planned manner. Transdermal or transmucosal delivery of drugs or pharmaceuticals using films may require the drug or pharmaceutical to permeate or otherwise traverse biological membranes in an effective and efficient manner. [Overview of the project]

[0004] (summary) Generally, a pharmaceutical composition may contain a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and an adrenergic receptor interacting substance. In some embodiments, the pharmaceutical composition may further contain a permeation enhancer. The adrenergic receptor interacting substance may be an adrenergic receptor blocker. The permeation enhancer may also be a flavonoid or used in combination with a flavonoid.

[0005] In some embodiments, the adrenergic receptor interacting substance may be a terpenoid, terpene, or C3-C22 alcohol or acid. The adrenergic receptor interacting substance may be a sesquiterpene. In some embodiments, the adrenergic receptor interacting substance may include farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentanoic acid, or docosapentanoic acid, or a combination thereof.

[0006] In certain embodiments, the pharmaceutical composition can be a film further containing a polymer matrix and a pharmaceutically active ingredient contained in the polymer matrix.

[0007] In certain embodiments, the adrenergic receptor interacting substance can be a plant extract.

[0008] In certain embodiments, the permeation enhancer can be a plant extract.

[0009] In certain embodiments, the permeation enhancer can contain phenylpropanoids.

[0010] In other embodiments, the phenylpropanoid can be eugenol.

[0011] In certain embodiments, the pharmaceutical composition can contain a fungal extract.

[0012] In certain embodiments, the pharmaceutical composition can contain a saturated or unsaturated alcohol.

[0013] In certain embodiments, the alcohol can be benzyl alcohol.

[0014] In some cases, flavonoids, plant extracts, phenylpropanoids, eugenol, or fungal extracts can be used as solubilizers.

[0015] In other embodiments, the phenylpropanoid may be eugenol. In some embodiments, the phenylpropanoid may be eugenol acetate. In some embodiments, the phenylpropanoid may be cinnamic acid. In other embodiments, the phenylpropanoid may be a cinnamic acid ester. In other embodiments, the phenylpropanoid may be cinnamaldehyde.

[0016] In other embodiments, the phenylpropanoid may be hydrocinnamic acid. In some embodiments, the phenylpropanoid may be chavicol. In other embodiments, the phenylpropanoid may be safrole.

[0017] In one embodiment, the plant extract may be an essential oil extract of the clove plant. In another embodiment, the plant extract may be an essential oil extract of the leaves of the clove plant. The plant extract may be an essential oil extract of the flower buds of the clove plant. In yet another embodiment, the plant extract may be an essential oil extract of the stems of the clove plant.

[0018] In one embodiment, the plant extract can be synthesized. In one embodiment, the plant extract may contain 20-95% eugenol, 40-95% eugenol, and 60-95% eugenol. In one embodiment, the plant extract may contain 80-95% eugenol.

[0019] In other embodiments, the pharmaceutically active ingredient may be epinephrine.

[0020] In one embodiment, the active pharmaceutical ingredient may be diazepam.

[0021] In one embodiment, the pharmaceutically active ingredient may be alprazolam. In one embodiment, the polymer matrix may include a polymer. In one embodiment, the polymer may include a water-soluble polymer.

[0022] In one embodiment, the polymer may be polyethylene oxide.

[0023] In one embodiment, the polymer may be a cellulosic polymer. In one embodiment, the cellulosic polymer may be hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose and / or sodium carboxymethylcellulose.

[0024] In one embodiment, the polymer may contain hydroxypropyl methylcellulose.

[0025] In one embodiment, the polymer may contain polyethylene oxide and / or hydroxypropyl methylcellulose.

[0026] In one embodiment, the polymer may contain polyethylene oxide and / or polyvinylpyrrolidone.

[0027] In one embodiment, the polymer matrix may contain polyethylene oxide and / or polysaccharides.

[0028] In one embodiment, the polymer matrix may contain polyethylene oxide, hydroxypropyl methylcellulose, and / or polysaccharides.

[0029] In one embodiment, the polymer matrix may contain polyethylene oxide, cellulosic polymers, polysaccharides, and / or polyvinylpyrrolidone.

[0030] In one embodiment, the polymer matrix may include at least one polymer selected from the following group: pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, acacia gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide, propylene oxide, propylene oxide copolymer, collagen, albumin, polyamino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof.

[0031] In one embodiment, the pharmaceutical composition may further include stabilizers. These stabilizers may include antioxidants that can prevent undesirable oxidation of a substance, metal ion chelating agents that can form chelate complexes and deactivate trace amounts of metal ions that would otherwise act as catalysts, emulsifiers and surfactants that can stabilize emulsions, UV stabilizers that can protect a substance from the harmful effects of UV irradiation, UV absorbers that are chemical substances that absorb UV irradiation and prevent it from penetrating the composition, quenchers that can dissipate radiant energy as heat instead of breaking chemical bonds, or scavengers that can eliminate free radicals formed by UV irradiation.

[0032] In yet another embodiment, the pharmaceutical composition comprises a suitable non-toxic, non-ionic alkyl glycoside having a hydrophobic alkyl group linked to a hydrophilic saccharide, in combination with a mucosal delivery promoter selected from the following: (a) agglutination inhibitor; (b) charge modifier; (c) pH adjuster; (d) degrading enzyme inhibitor; (e) mucolytic or mucosal deconjugate; (f) ciliary stabilizer. agent); (g) membrane permeability enhancers selected from the following: (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) nitric oxide donors; (vi) long-chain amphiphilic molecules; (vii) small hydrophobic permeation enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerol esters of acetoacetic acid; (x) cyclodextrin or β-cyclodextrin derivatives; (xi) medium-chain fatty acids; (xii) chelating agents; (xiii) amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (xv) selected (ix) enzymes that degrade membrane components; (x) inhibitors of fatty acid synthesis; (x) inhibitors of cholesterol synthesis; and (xi) any combination of the membrane penetration enhancers listed in (i)-(x); (h) modifiers of epithelial junction physiological function; (i) vasodilators; (j) selective transport enhancers; and (k) stabilizing delivery vehicles, carriers, mucosal adhesives, supports or complex-forming species that are effectively combined with the compound thereto, associated, contained, encapsulated or bound, resulting in enhanced stabilization of the compound for mucosal delivery, wherein formulations of the compound with transmucosal delivery enhancers provide increased bioavailability of the compound in the target plasma.

[0033] Generally, a method for producing a pharmaceutical composition may include combining an adrenaline receptor interacting substance with a pharmaceutically active ingredient, and forming a pharmaceutical composition containing both the adrenaline receptor interacting substance and the pharmaceutically active ingredient.

[0034] This pharmaceutical composition may be in the form of a chewable or gelatin-based dosage form, a spray, gum, gel, cream, tablet, liquid, or film.

[0035] Generally, pharmaceutical compositions can be dispensed from a device. This device can dispense pharmaceutical compositions in predetermined doses as chewable or gelatin-based dosage forms, sprays, gums, gels, creams, tablets, liquids, or films. The device may comprise a housing for holding a certain amount of pharmaceutical composition containing a polymer matrix; a pharmaceutically active ingredient in the polymer matrix; and an adrenergic receptor interacting substance; and an opening for dispensing the predetermined amount of pharmaceutical composition. The device can also dispense pharmaceutical compositions containing permeation enhancers, including phenylpropanoids and / or plant extracts.

[0036] In one embodiment, the pharmaceutical composition may contain a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and a permeation enhancer comprising phenylpropanoids and / or plant extracts.

[0037] Other aspects, embodiments, and features will become apparent from the following description, drawings, and claims. [Brief explanation of the drawing]

[0038] (Brief explanation of the drawing) [Figure 1] In Figure 1A, the Franz diffusion cell 100 comprises a donor compound 101, a donor chamber 102, a membrane 103, a sampling port 104, a receptor chamber 105, a stirring rod 106, and a heater / circulator 107. In Figure 1B, the pharmaceutical composition is a film 100 comprising a polymer matrix 200 and a pharmaceutically active ingredient 300 contained in the polymer matrix. This film may include a permeation enhancer 400. [Figure 2]Regarding Figures 2A and 2B, the graphs show the permeation of the active substance from the composition. Regarding Figure 2A, this graph shows the average amount versus time of permeated active substance for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized epinephrine base. Regarding Figure 2B, this graph shows the average flux versus time for 8.00 mg / mL bitartrate and 4.4 mg / mL solubilized epinephrine base. [Figure 3] Regarding Figure 3, this graph shows the ex vivo permeability of epinephrine bitartrate as a function of concentration. [Figure 4] Regarding Figure 4, this graph shows the permeation of epinephrine bitartrate as a function of the pH of the solution. [Figure 5] Regarding Figure 5, this graph shows the effect of enhancers on epinephrine permeation, expressed as the amount permeated, as a function of time. [Figure 6] Regarding Figures 6A and 6B, these graphs show the release of epinephrine onto the polymer platform (6A) and the effect of the enhancer on that release (6B), expressed as permeation amount (μg) versus time. [Figure 7] Regarding Figure 7, this graph shows the pharmacokinetic model in male Yucatan miniature pigs. This study compares 0.3 mg EpiPen, 0.12 mg epinephrine IV, and a placebo film. [Figure 8] Regarding Figure 8, this graph shows the effect of the absence of an enhancer on the concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 9] Regarding Figure 9, this graph shows the effect of enhancer A (Labrazol) on the concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 10] Regarding Figure 10, this graph shows the effect of enhancer L (clove oil) on the concentration profiles of two types of 40 mg epinephrine films (10-1-1) and (11-1-1) versus 0.3 mg EpiPen. [Figure 11] Regarding Figure 11, this graph shows the effects of enhancer L (clove oil) and film dimensions (10-1-1 thin, large film and 11-1-1 thick, small film) on the concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 12] Regarding Figure 12, this graph shows the concentration profile of the epinephrine film in a constant matrix for a 0.3 mg EpiPen with respect to varying doses. [Figure 13] Regarding Figure 13, this graph shows the concentration profile of the epinephrine film in a constant matrix for varying doses relative to 0.3 mg EpiPen with Enhancer L (clove oil). [Figure 14] Regarding Figure 14, this graph shows the concentration profile of the epinephrine film in a constant matrix for a 0.3 mg EpiPen with respect to varying doses. [Figure 15] Regarding Figure 15, this graph shows the effect of the enhancer on diazepam permeation, expressed as the amount permeated as a function of time. [Figure 16] Regarding Figure 16, this graph shows the average flux as a function of time (diazepam + enhancer). [Figure 17] Regarding Figure 17, this graph shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 18] Regarding Figure 18, this graph shows the effect of farnesol on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 19] Regarding Figure 19, this graph shows the effect of farnesol in combination with linoleic acid on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 20]Regarding Figure 20, this graph shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 21] Regarding Figure 21, this graph shows the effect of enhancer A (labrasol) combined with enhancer L (clove oil) on the concentration profile of the 40 mg epinephrine film (also shown in Figure 22), on a logarithmic scale. [Figure 22] Regarding Figure 22, this graph shows the effect of enhancer A (labrasol) in combination with enhancer L (clove oil) on the concentration profile of average data collected from 40 mg epinephrine film versus 0.3 mg EpiPen. [Figure 23] Regarding Figure 23, this graph shows the effect of enhancer A (labrasol) in combination with enhancer L (clove oil) on the concentration profile of 40 mg epinephrine film, as shown for individual animal subjects. [Figure 24] Regarding Figure 24A, this graph shows the alprazolam plasma concentration as a function of time after sublingual administration of alprazolam orally disintegrating tablets (ODTs). Regarding Figure 24B, this graph shows the alprazolam plasma concentration as a function of time after sublingual administration of an alprazolam pharmaceutical composition film. Regarding Figure 24C, this graph shows the alprazolam plasma concentration as a function of time after sublingual administration of an alprazolam pharmaceutical composition film. [Figure 25] Regarding Figure 25A, this graph shows the mean alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT and alprazolam pharmaceutical composition film. Regarding Figure 25B, this graph shows the alprazolam plasma concentration as a function of time after sublingual administration. Regarding Figure 25C, this graph shows the alprazolam plasma concentration as a function of time after sublingual administration. [Figure 26]Regarding Figure 26A, this graph shows the alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT. Regarding Figure 26B, this graph shows the alprazolam plasma concentration as a function of time after sublingual administration of the alprazolam pharmaceutical composition film. Regarding Figure 26C, this graph shows the alprazolam plasma concentration as a function of time after sublingual administration of the alprazolam pharmaceutical composition film. [Figure 27] Regarding Figure 27A, this graph shows the mean alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT and pharmaceutical composition film. Regarding Figure 27B, this graph shows the mean alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT and pharmaceutical composition film. Regarding Figure 27C, this graph shows the alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT and pharmaceutical composition film. [Modes for carrying out the invention]

[0039] (Detailed explanation) Mucosal surfaces, such as the oral mucosa, are favorable pathways for drug delivery to the body because they are highly angiogenic and permeable, do not pass through the digestive system, and thus avoid first-pass metabolism, thus providing increased bioavailability and rapid onset of action. In particular, oral and sublingual tissues are highly permeable areas of the oral mucosa, allowing for the diffusion of drugs from the oral mucosa to have direct access to the systemic circulation, thus providing favorable sites for drug delivery. This also leads to increased convenience and therefore increased patient compliance. With respect to certain drugs or pharmaceutically active ingredients, permeability enhancers can help overcome the mucosal barrier and improve permeability. Permeability enhancers reversibly adjust the permeability of the barrier layer to favor drug absorption. Permeability enhancers facilitate the transport of molecules through the epithelium. Absorption profiles and their rates can be controlled and regulated, non-limitingly, by various parameters such as film size, drug load, enhancer type / load, polymer matrix release rate, and mucosal residence time.

[0040] Pharmaceutical compositions can be designed to deliver pharmaceutically active ingredients in a planned and tailored manner. However, the solubility and permeability of pharmaceutically active ingredients in vivo, particularly in the mouth of the target, can vary considerably. Certain classes of permeability enhancers can improve the in vivo uptake and bioavailability of pharmaceutically active ingredients. In particular, when delivered to the mouth via a film, permeability enhancers can improve the permeability of pharmaceutically active ingredients through the mucous membranes of the target into the bloodstream. The permeation enhancer can improve the rate and amount of absorption of the pharmacoactive ingredient by more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 150%, about 200% or more, or less than 200%, less than 150%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or any combination of these ranges, depending on the other components in the composition.

[0041] In one embodiment, the pharmaceutical composition comprises a suitable non-toxic, nonionic alkyl glycoside having a hydrophobic alkyl group linked to a hydrophilic saccharide, in combination with a mucosal delivery enhancer selected from: (a) agglutination inhibitor; (b) charge modifier; (c) pH adjuster; (d) degrading enzyme inhibitor; (e) mucolytic or mucosal deconjugate; (f) ciliary quiescent agent; (g) membrane penetration enhancer selected from: (i) surfactant; (ii) bile salt; (ii) phospholipid additive, mixed micelle, liposome, or carrier; (iii) alcohol; (iv) enamine; (v) nitric oxide donor; (vi) long-chain amphiphilic molecule; (vii) small hydrophobic penetration enhancer; (viii) sodium or salicylic acid derivative; (ix) glycerol ester of acetoacetate; (x) cyclodextrin or β-cyclodextrin (xi) Chistrin derivatives; (xi) Medium-chain fatty acids; (xii) Chelating agents; (xiii) Amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (xv) Degrading enzymes of selected membrane components; (ix) Inhibitors of fatty acid synthesis; (x) Inhibitors of cholesterol synthesis; and any combination of the membrane penetration enhancers listed in (xi)(i)-(x); (h) Modifiers of epithelial junction physiological function; (i) Vasodilators; (j) Selective transport enhancers; and (k) Stabilizing delivery vehicles, carriers, mucosal adhesives, supports or complex-forming species, which together with the compound are effectively combined, associated, contained, encapsulated or bound, resulting in the stabilization of the compound for enhanced mucosal delivery, wherein formulations of the compound with transmucosal delivery enhancers provide increased bioavailability of the compound in the plasma of the subject. The osmotic enhancer is described in the literature by 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 the delivery of therapeutic agents into the systemic circulation. Due to the direct drainage of blood from the oral epithelium to the internal jugular vein, first-pass metabolism in the liver and intestines can be avoided. The first-pass effect can be the main reason for the poor bioavailability of some compounds when administered orally.In addition, the mucous membrane lining the oral cavity is easily accessible, ensuring that dosage forms are applied to the required site and can be easily removed in emergencies. However, like the skin, the oral mucosa acts as a barrier to the absorption of xenobiotics, which can hinder the penetration of compounds across this tissue. Consequently, identifying safe and effective penetration enhancers is a major goal for improving oral mucosal drug delivery.

[0042] Chemo-osmotic enhancers are substances that control the rate at which drugs are absorbed through biological membranes when administered simultaneously. While large-scale studies have focused on gaining a better understanding of how osmotic enhancers alter intestinal and transdermal permeability, little is known about the mechanisms involved in oral and sublingual osmotic enhancement.

[0043] The oral mucosa lining the inside of the cheeks and outlining the area between the gums and upper and lower lips, and it has an average surface area of ​​100 cm². 2 The oral mucosa has the following characteristics: The surface of the oral mucosa consists of stratified squamous epithelium, separated from the underlying connective tissue (lamina propria and submucosa) by a wavy basement membrane (a continuous layer of extracellular material approximately 1-2 μm thick). This stratified squamous epithelium consists of differentiated cell layers, whose size, shape, and contents change as they move from the basal region to the superficial region where cells are shed. There are approximately 40-50 cell layers, giving rise to the oral mucosa with a thickness of 500-600 μm.

[0044] Structurally, the sublingual mucosa is similar to the oral mucosa, but its epithelium is 100-200 μm thick. This membrane is also not keratinized and is relatively thin, making it more permeable than the oral mucosa. Blood flow to the sublingual mucosa is slower than to the oral mucosa, at 1.0 ml / min. -1 / cm -2 It is the number of digits.

[0045] The permeability of the oral mucosa is greater than that of the skin, but less than that of the intestines. This difference in permeability is a result of structural differences between the tissues. The absence of organized lipid lamellae in the cellular spaces of the oral mucosa results in greater permeability of foreign compounds compared to the keratinized epithelium of the skin; on the other hand, increased thickness and the lack of tight junctions result in the oral mucosa being less permeable than intestinal tissue.

[0046] The primary barrier properties of the oral mucosa are attributed to the upper 1 / 3 to 1 / 4 of the oral epithelium. Researchers know that the permeable barrier of the non-keratinized oral mucosa beyond the surface epithelium is also attributable to the contents pushed from membrane-coating granules into the spaces between epithelial cells.

[0047] The intercellular lipids in the non-keratinized areas of the oral cavity are more polar than those in the epidermis, palate, and gingiva, and this difference in the chemical properties of these lipids contributes to the differences in permeability observed between these tissues. Consequently, it is clear that this is not only due to the greater degree of intercellular lipids packed within the stratum corneum of keratinized epithelium, which creates a more effective barrier, but also to the chemical properties of the lipids present within that barrier.

[0048] The presence of hydrophilic and lipophilic regions within the oral mucosa led researchers to hypothesize the existence of two drug transport pathways: paracellular (intercellular) and transcellular (transcellular) transport within the oral mucosa.

[0049] Drug delivery through the oral mucosa is limited by the properties of the epithelium and the barriers in the areas available for absorption; therefore, various enhancement strategies are needed to deliver therapeutically relevant amounts of drugs into the systemic circulation. Various methods, including the use of chemiosmotic enhancers, prodrugs, and physical methods, can be utilized to overcome the barrier properties of the oral mucosa.

[0050] Chemical permeation enhancers, or absorption promoters, are substances added to pharmaceutical formulations to increase the rate of membrane permeation or absorption of co-administered drugs without causing membrane damage and / or toxicity. Numerous studies have investigated the effects of chemical permeation enhancers on the delivery of compounds beyond the skin, nasal mucosa, and intestines. In recent years, more attention has been paid to the effects of these substances on oral mucosal permeability. Since permeability beyond the oral mucosa is considered a passive diffusion process, the steady-state flux (Jss) should increase with increasing donor chamber concentration (CD), according to Fick's first law of diffusion.

[0051] Surfactants and bile salts have been shown to enhance the permeability of various compounds across the oral mucosa, both in vitro and in vivo. The data from these studies strongly suggest that this enhanced permeability is due to the surfactant's action on the intercellular lipids of the mucosa.

[0052] Fatty acids have been shown to enhance the permeability of numerous drugs through the skin, and this has been shown to be related to increased intercellular lipid fluidity by differential scanning calorimetry and Fourier transform infrared spectroscopy.

[0053] In addition, pretreatment with ethanol has been shown to enhance the permeability of tritiated water and albumin across the ventral lingual mucosa, and to enhance caffeine permeability across the oral mucosa of pigs. There are also several reports of Azone® enhancing the permeability of compounds through 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.

[0054] Oral transmucosal drug delivery (OTDD) is the administration of pharmaceutically active substances through the oral mucosa to achieve systemic effects. The OTDD pathways and predictive models are described, for example, in M. Sattar's paper, "Oral transmucosal drug delivery - Current status and future prospects," Int'l. Journal of Pharmaceutics, 47(2014) 498-506, which is incorporated herein by reference. OTDD continues to attract the attention of scientists in academia and industry. Despite the limited characterization of oral pathways compared to cutaneous and nasal delivery pathways, researchers' understanding of the extent to which ionized molecules penetrate the oral epithelium, the emergence of new analytical techniques for studying the oral cavity, and the ongoing development of in silico models to predict oral and sublingual penetration have recently accelerated the development of these prospects.

[0055] To deliver a broader class of drugs beyond the oral mucosa, reversible methods that reduce the barrier function of this tissue should be utilized. This requirement is driving research into penetration enhancers that safely alter the limitations of oral mucosal permeability. Oral penetration has been shown to be improved by using various classes of transmucosal and transdermal penetration enhancers, including bile salts, surfactants, fatty acids and their derivatives, chelators, cyclodextrins, and chitosan. Of these chemicals used to enhance drug penetration, bile salts are the most common.

[0056] In vitro studies on the enhancing effects of bile salt compounds on oral permeation are discussed in Sevda Senel's article, "Drug permeation enhancement via buccal route: possibilities and limitations," Journal of Controlled Release 72 (2001) 133-144, which is incorporated herein by reference. The article also discusses recent studies on the effects of dihydroxybile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC), and trihydroxybile salts, sodium glycocholate (GC) and sodium taurocholate (TC) on oral epithelial permeability, including histologically related changes in permeability at a concentration of 100 mM. Fluorescein isothiocyanate (FITC) and morphine sulfate are used as model compounds, respectively.

[0057] Chitosan has also been shown to enhance the absorption of small polar molecules and peptide / protein drugs through the nasal mucosa in animal models and human volunteers. Other studies have shown an enhancing effect on the penetration of compounds beyond the intestinal mucosa and cultured Caco-2 cells.

[0058] The permeation enhancer can be a plant extract. The plant extract can be an essential oil or essential oil-containing composition extracted by distillation of plant material. In some circumstances, the plant extract can include a synthetic analog of a compound extracted from plant material (i.e., a compound produced by organic synthesis). The plant extract can include phenylpropanoids, such as phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid esters, cinnamaldehyde, hydrocinnamic acid, chavicol, or safrole, or a combination thereof. The plant extract can be an essential oil extract of the clove plant, for example, the leaves, stems, or flower buds of the clove plant. The clove plant is Syzygium aromaticum. This plant extract can contain 20-95% eugenol, 40-95% eugenol, 60-95% eugenol, or, for example, 80-95% eugenol. This extract may also contain 5% to 15% eugenol acetate. This extract may also contain caryophyllene. This extract may also contain up to 2.1% α-humulene. Other volatile compounds present in lower concentrations in clove essential oil 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; glycocholic acid or deoxycholic acid and their salts; fatty acids and derivatives, such as sodium laurate, oleic acid, oleyl alcohol, monoolein, or palmitoylcarnitine; chelating agents, such as disodium EDTA, sodium citrate and sodium lauryl sulfate, azon, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth-9, polysorbate, sterols, or glycerides, such as caprylocaproyl polyoxylglyceride or labrasol. Permeation enhancers may also include derivatives of plant extracts and / or monolignols.The permeation enhancer can also be a fungal extract.

[0059] Some natural products of plant origin have been shown to have vasodilatory effects. For a review, see McNeill JR and Jurgens, TM, Can. J. Physiol. Pharmacol. 84:803-821 (2006), which is incorporated herein by reference. Specifically, the vasodilatory effect of eugenol has been reported in many animal studies. For example, see the literature by Lahlou, S. et al., J. Cardiovasc. Pharmacol. 43:250-57 (2004), the literature by Damiani, CEN et al., Vascular Pharmacol. 40:59-66 (2003), the literature by Nishijima, H. et al., Japanese J. Pharmacol. 79:327-334 (1998), and the literature by Hume WR, J. Dent Res. 62(9):1013-15 (1983), each of which is incorporated herein by reference. Calcium channel blockade has been suggested to be the primary cause of vasodilation induced by plant essential oils or their main component, eugenol. See the literature by Interaminense LRL et al., Fundamental & Clin. Pharmacol. 21: 497-506 (2007), which is incorporated herein by reference.

[0060] Fatty acids can be used as inactive components in drug preparations or drug vehicles. Fatty acids can also be used as pharmaceutical ingredients due to their certain functional properties and biocompatible nature. Both free lipids and some complex lipids contain fatty acids, which are essential components of major metabolic fuels (storage and transport energy), all membranes, and gene regulators. For a review, see Rustan AC and Drevon, CA, Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences (2005), 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). If the first double bond is located between the third and fourth carbon atoms from the ω-carbon, these are called ω-3 fatty acids. If the first double bond is located between the sixth and seventh carbon atoms, these are called ω-6 fatty acids. PUFAs are further metabolized in the body by the addition of carbon atoms and desaturation (removal of hydrogen). Linoleic acid, an omega-6 fatty acid, is metabolized into gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenaline, tetracosatetraenoic acid, tetracosapentaenoic acid, and docosapentaenoic acid. Alpha-linolenic acid, an omega-3 fatty acid, is metabolized into octadecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and docosahexaenoic acid (DHA).

[0061] Fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid are sodium + K +It has been reported that cyclooxygenase-dependent and cyclooxygenase-independent pulmonary vasodilation induces relaxation and hyperpolarization of porcine coronary artery smooth muscle cells through a mechanism involved in the activation of the APTase pump, and that the potency increases with increasing cis-unsaturation of the fatty acid. See Pomposiello, SI et al., Hypertension 31:615-20 (1998), which is incorporated herein by reference. Interestingly, the pulmonary vascular response to arachidonic acid, a metabolite of linoleic acid, can be either vasoconstrictive or vasodilatory, depending on the dose, animal species, mode of arachidonic acid administration, and tone of pulmonary circulation. For example, arachidonic acid has been reported to induce cyclooxygenase-dependent and cyclooxygenase-independent pulmonary vasodilation. See Feddersen, CO et al., J. Appl. Physiol. 68(5):1799-808 (1990); and also see Spannhake, EW et al., J. Appl. Physiol. 44:397-495 (1978) and Wicks, TC et al., Circ. Res. 38:167-71 (1976), each of which is incorporated herein by reference.

[0062] Numerous studies have reported the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on vascular responsiveness after administration in orally ingestible forms. Several studies have found that EPA-DHA or EPA alone inhibited the vasoconstrictive effect of norepinephrine or enhanced the vasodilatory response to acetylcholine in the forearm microcirculation. See Chin, JPF et al., Hypertension 21:22-8 (1993), and Tagawa, H. et al., J Cardiovasc Pharmacol 33:633-40 (1999), which are incorporated herein by reference. Another study found that both EPA and DHA tended to increase systemic arterial compliance and 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. On the other hand, a study found that DHA, not EPA, enhanced the vasodilatory mechanism and attenuated the systolic response in the forearm microenvironment of obese men with hyperlipidemia. See Mori, TA et al., Circulation 102:1264-69 (2000), which is incorporated herein by reference. Another study found the vasodilatory effect of DHA 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.

[0063] Adrenergic receptors (or adrenoleceptors) are a class of G protein-coupled receptors that are targets of catecholamines, particularly norepinephrine (noradrenaline) and epinephrine (adrenaline). Epinephrine (adrenaline) interacts with both α- and β-adrenoleceptors, causing vasoconstriction and vasodilation, respectively. α-receptors are less sensitive to epinephrine, but there are more peripheral α1 receptors than β-adrenoleceptors, so when activated, they neutralize β-adrenoleceptor-mediated vasodilation. As a result, high levels of circulating epinephrine cause vasoconstriction. At relatively low levels of circulating epinephrine, β-adrenoleceptor stimulation is dominant, resulting in vasodilation and a subsequent decrease in peripheral vascular resistance. α1-adrenergic receptors are known for their role in smooth muscle contraction, pupillary dilation, vasoconstriction in the skin, mucous membranes, and abdominal viscera, and sphincter contraction in the gastrointestinal (GI) tract and bladder. q It is a member of the protein-coupled receptor superfamily. Upon activation, it forms a heterotrimeric G protein, G q It activates phospholipase C (PLC). Its mechanism of action involves interaction with calcium channels, altering intracellular calcium content. 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.

[0064] α1-adrenergic receptors can be the primary receptors for fatty acids. For example, saw palmetto fruit extract (SPE), widely used in the treatment of benign prostatic hyperplasia (BPH), has been reported to bind to α1-adrenergic, muscarinergic, and 1,4-dihydropyridine (1,4-DHP) calcium channel antagonistic 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 contains a variety of fatty acids, including lauric acid, oleic acid, myristic acid, palmitic acid, and linoleic acid. Lauric acid and oleic acid can non-competitively bind to α1-adrenergic, muscarinergic, and 1,4-DHP calcium channel antagonistic receptors.

[0065] In certain embodiments, the permeation enhancer can be an adrenergic receptor interacting substance. An adrenergic receptor interacting substance refers to a compound or substance that modifies and / or otherwise changes the action of an adrenergic receptor. For example, an adrenergic receptor interacting substance can prevent receptor stimulation by increasing or decreasing their binding ability. Such interacting substances can be provided in either a short-acting or long-acting form. Some short-acting interacting substances can act rapidly, but their action only persists for a few hours. Some long-acting interacting substances can act longer, but their action can be longer. This interacting substance can be selected and / or designed based on, for example, one or more desired delivery and dosage, active pharmaceutical ingredient, permeation modifying factor, permeation enhancer, matrix, and the condition being treated. The adrenergic receptor interacting substance can be an adrenergic receptor blocker. The adrenergic receptor interacting substance can be a terpene (e.g., a volatile unsaturated hydrocarbon found in essential oils of plants, derived from isoprene units), or a C3-C22 alcohol or acid, preferably a C7-C18 alcohol or acid. In certain embodiments, the adrenergic receptor interacting substance can be farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, and / or docosapentaenoic acid. This acid can be a carboxylic acid, phosphoric acid, sulfuric acid, hydroxamic acid, or a derivative thereof. This derivative can be an ester or an amide. For example, the adrenergic receptor interacting substance can be a fatty acid or an aliphatic alcohol.

[0066] The C3-C22 alcohol or acid can be a straight-chain C3-C22 hydrocarbon, for example, an alcohol or acid having a C3-C22 hydrocarbon chain containing optionally at least one double bond, at least one triple bond, or at least one double bond and one triple bond; the hydrocarbon chain can optionally be C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4Alkoxy, hydroxyl, halo, amino, nitro, cyano, C 3-5 Cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4 Alkylcarbonyloxy, C 1-4 Alkyloxycarbonyl, C 1-4 Substituted with alkylcarbonyl or formyl; and further optionally, -O-, -N(R a )-,-N(R a )-C(O)-O-, -OC(O)-N(R a )-,-N(R a )-C(O)-N(R b )-, or -OC(O)-O- is inserted in between. R a and R b Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.

[0067] Fatty acids with a higher degree of unsaturation are effective candidates for enhancing drug penetration. Unsaturated fatty acids show a higher enhancement 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 enhancement of fatty acid activity. Differences in the physicochemical properties of fatty acids due to differences in the position of the double bond are most likely to determine the potency of these compounds as skin penetration enhancers. Skin distribution increases as the position of the double bond shifts to the hydrophilic end. It has also been reported that fatty acids with double bonds at even positions act more rapidly on structural perturbation in both the stratum corneum and dermis than fatty acids with double bonds at odd positions. Cis-unsaturation within the chain tends to increase activity.

[0068] Adrenergic receptor interacting substances 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 one embodiment, the permeation enhancer can be a sesquiterpene. A sesquiterpene consists of three isoprene units and has the empirical formula C 15 H 24 Sesquiterpenes are a class of terpenes that contain rings. Like monoterpenes, sesquiterpenes are acyclic or contain rings, including many unique combinations. Biochemical modifications such as oxidation or rearrangement produce the associated sesquiterpenoids.

[0069] Adrenergic receptor interacting substances can be unsaturated fatty acids, such as linoleic acid. In one embodiment, the permeation enhancer can be farnesol. Farnesol is a 15-carbon organic compound, an acyclic sesquiterpene alcohol, which is 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 citronella, neroli, cyclamen, and night-blooming celandine. It is an intermediate step in the biosynthesis of cholesterol from mevalonic acid in vertebrates. It has a delicate floral or weak citrus-lime scent and is used in perfumes and fragrances. Farnesol has been reported to selectively kill acute myeloid leukocytes and leukocyte cell lines, preferentially over primary hematopoietic cells. See Rioja A. et al., FEBS Lett 467 (2-3): 291-5 (2000), which is incorporated herein by reference. The vasoactive properties of farnesyl analogs have been reported. See Roullet, J.-B. et al., J. Clin. Invest., 1996, 97:2384-2390, which is incorporated herein by reference. Both farnesol and N-acetyl-S-trans,trans-farnesyl-L-cysteine ​​(AFC), synthetic mimics of the carboxyl terminus of farnesylated proteins, inhibited vasoconstriction in the rat aortic circle.

[0070] The pharmaceutical composition may be in the form of a chewable or gelatin-based dosage form, spray, gum, gel, cream, tablet, liquid, or film. The composition may include textures, such as microneedles or micro-protrusions, on its surface. Recently, the use of micron-scale needles in increasing skin permeability has been shown to significantly increase transdermal delivery, particularly with respect to polymers. Most drug delivery studies highlight solid microneedles, which have been shown to increase skin permeability to a wide range of molecules and nanoparticles in vitro. In vivo studies have revealed the delivery of oligonucleotides, the reduction of blood glucose levels by insulin, and the induction of immune responses from protein and DNA vaccines. In such studies, needle arrays are used to puncture the skin to increase transport by diffusion or iontophoresis, or as drug carriers to release drugs into the skin from a microneedle surface coating. Hollow microneedles have also been developed and shown to deliver insulin in micro-volumes to diabetic rats. To address the practical applications of microneedles, it was found that the ratio of microneedle fracturing strength to skin insertion strength (i.e., safety margin) is optimal for needles with small tip radii and large wall thicknesses. Microneedles inserted into the skin of human subjects were reported painless. In summary, these results suggest that microneedles represent a promising technology for delivering therapeutic compounds to the skin for a wide range of potential applications. Using tools from the microelectronics industry, microneedles are fabricated in a wide range of 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.

[0071] The applicant acknowledges that microneedles can be used to enhance the delivery of drugs through the oral mucosa, particularly with the claimed compositions. Microneedles create micron-sized pores in the oral mucosa, which can enhance the delivery of drugs beyond the mucosa. Solid, hollow, or soluble microneedles can be fabricated from suitable materials, including but not limited to metals, polymers, glass, and ceramics. Microfabrication processes can include photolithography, silicon etching, laser cutting, metal electroplating, metal electropolishing, and molding. Microneedles can be solids used to pre-treat tissue and removed before film application. Drug-loaded polymer films described in this application can be used as the matrix material for the microneedles themselves. These films may have fabricated microneedles or microprojections on their surface, which will dissolve after forming microchannels in the mucosa through which drugs can permeate.

[0072] The term “film” can include films and sheets of any shape, including rectangular, square, or other desirable shapes. Films can have any desired thickness and size. In a preferred embodiment, a film can have a thickness and size such that it can be administered to a user, for example, placed in the user’s mouth. Films 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. With respect to some films, the thickness may be even relatively larger, i.e., greater than about 1.0 mm, or relatively thin, i.e., less than about 0.0025 mm. Films can be monolayers, or films can be multilayers, including laminated or multi-layered cast films. Permeation enhancers and pharmaceutically active ingredients can be combined in a single layer, each contained in a separate layer, or otherwise each contained in separate regions of the same dosage form. In a particular embodiment, pharmaceutically active ingredients contained in a polymer matrix can be dispersed in the matrix. In one embodiment, the permeation enhancer contained in the polymer matrix can be dispersed within the matrix.

[0073] Oral-soluble films can fall into three main classes: immediate-dissolving, moderately dissolving, and slowly dissolving. Oral-soluble films may also include any combination of the above categories. Immediately dissolving films can dissolve in the mouth in about 1 second to about 30 seconds, including longer than 1 second, longer than 5 seconds, longer than 10 seconds, longer than 20 seconds, and less than 30 seconds. Moderately dissolving films can dissolve in the mouth in about 1 to about 30 minutes, including longer than 1 minute, longer than 5 minutes, longer than 10 minutes, longer than 20 minutes, or less than 30 minutes, and slowly dissolving films can dissolve in the mouth over a period of longer than 30 minutes. As a general trend, immediate-dissolving films may contain (or consist of) low molecular weight hydrophilic polymers (e.g., polymers with a molecular weight of about 1,000 to 9,000 daltons, or polymers with a molecular weight of up to 200,000 daltons). In contrast, slow-dissolving films generally contain high molecular weight polymers (e.g., those with molecular weights in the millions). Moderately dissolving films tend to fall between fast-dissolving and slow-dissolving films.

[0074] It is preferable to use a film that is moderately soluble. Moderately soluble films can dissolve fairly quickly, but also have a good level of mucosal adhesion. Moderately soluble films are also flexible, quickly wettable, and typically non-irritating to the user. Such moderately soluble films can provide a sufficiently rapid dissolution rate, most preferably about 1 minute to about 20 minutes, while providing an acceptable level of mucosal adhesion such that the film is not easily removed once placed in the user's oral cavity. This ensures that the pharmaceutically active ingredient is delivered to the user.

[0075] A pharmaceutical composition may contain one or more pharmaceutically active ingredients. These pharmaceutically active ingredients may be a single pharmaceutically active ingredient or a combination of pharmaceutically active ingredients. The pharmaceutically active ingredients may be anti-inflammatory analgesics, steroidal anti-inflammatory drugs, antihistamines, local anesthetics, bactericides, disinfectants, vasoconstrictors, hemostatic agents, chemotherapeutic agents, antibiotics, keratolytic agents, cauterizing agents, antiviral agents, antirheumatic drugs, antihypertensive agents, bronchodilators, anticholinergic agents, anxiolytic agents, antiemetic compounds, hormones, peptides, proteins, or vaccines. These pharmaceutically active ingredients may be compounds, pharmaceutically acceptable salts of drugs, prodrugs, derivatives, drug conjugates, or analogs of drugs. The term "prodrug" refers to a biologically inert compound that can be metabolized in the body to produce a biologically active drug.

[0076] In some embodiments, two or more pharmaceutically active ingredients may be included in the film. These pharmaceutically active ingredients include ACE inhibitors, anti-angina agents, antiarrhythmics, anti-asthmatics, anticholesterolemia agents, analgesics, anesthetics, anticonvulsants, antidepressants, diabetes medications, antidiarrheal preparations, detoxification agents, antihistamines, antihypertensives, anti-inflammatory drugs, anti-lipid drugs, anti-mania agents, nausea medications, stroke prevention drugs, anti-thyroid preparations, amphetamines, antitumor drugs, antiviral drugs, acne medications, alkaloids, amino acid preparations, antitussives, anti-urinary tract stone drugs, antiviral drugs, and anabolic preparations. Drugs for treating systemic and non-systemic infections, anti-neoplastic agents, Parkinson's disease drugs, anti-rheumatic drugs, appetite stimulants, blood-modifying factors, bone metabolism regulators, cardiovascular agents, central nervous system stimulants, cholinesterase inhibitors, contraceptives, decongestants, nutritional supplements, dopamine receptor agonists, endometriosis treatments, enzymes, erectile dysfunction treatments, infertility treatments, gastrointestinal drugs, homeopathic remedies, hormones, drugs for managing hypercalcemia and hypocalcemia, immunomodulators, immunosuppressants, migraine preparations Drugs, motion sickness medications, muscle relaxants, obesity control drugs, osteoporosis preparations, uterine contraction drugs, parasympathetic blockers, parasympathetic agonists, prostaglandins, psychotropic drugs, respiratory drugs, sedatives, smoking cessation aids, sympathetic blockers, tremor treatment preparations, urethral drugs, vasodilators, laxatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants, anti-anxiety drugs, anti-ulcer drugs, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, psychotropic drugs, stimulants These may include antihypertensive drugs, vasoconstrictors, migraine medications, antibiotics, tranquilizers, antipsychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, antiemetics, anti-nausea drugs, anticonvulsants, neuromuscular agents, blood glucose-raising and lowering agents, thyroid and antithyroid preparations, diuretics, anticonvulsants, uterine relaxants, anti-obesity drugs, erythropoiesis-forming agents, anti-asthmatic drugs, antitussives, mucolytics, DNA and genetic modification agents, diagnostic agents, contrast agents, dyes, or tracers, and combinations thereof.

[0077] For example, this pharmaceutical active ingredient is buprenorphine, naloxone, acetaminophen, riluzole, clobazam, rizatriptan, propofol, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac, fenclofenac, cridanac, flurbiprofen, fenthiazac, bufexamac, piroxicam, phenyl Tazone, oxyfen butazone, clofezone, pentazocine, mepirizole, tiaramide hydrochloride, hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumethasone, fluorometholone, beclomethasone dipropionate, fluocinonide, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride Salt, chlorpheniramine maleate, isotipendyl hydrochloride, triperenamine hydrochloride, promethazine hydrochloride, methidilazine hydrochloride, dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoate 2-(diethylamino)ethyl hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, pipelocaine hydrochloride, diclonin, diclonin hydrochloride, thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride Chlorhexidine, povidone-iodine, cetylpyridinium chloride, eugenol, trimethylammonium bromide, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, sodium carbazochrome sulfonate, rutin, hesperidin, sulfamine, sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole, sulfisomidine, sulfamethizolNitrofurazone, penicillin, methicillin, oxacillin, cephalothin, cephaloridine, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, salicylic acid, podophyllum resin, podolifox, cantharidin, chloroacetic acid, silver nitrate, protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural proteins Protein synthesis inhibitors, adhesion and adsorption inhibitors, and nucleoside analogs such as acyclovir, penciclovir, valacyclovir, and ganciclovir, as well as heparin, insulin, LHRH, TRH, interferon, oligonuclides, calcitonin, octreotide, omeprazone, fluoxetine, ethinylestradiol, amiodipine, paroxetine, enalapril, lisinopril, leuprolide, prevastatin, lovastatin, norethindrone, risperidone, Olanzapine, albuterol, hydrochlorothiazide, pseudoephedrine, warfarin, terazosin, cisapride, ipratropium, busprione, methylphenidate, levothyroxine, zolpidem, levonorgestrel, glybrid, benazepril, medroxyprogesterone, clonazepam, ondansetron, losartan, quinapril, nitroglycerin, midazolam, cetirizine, doxazosin, glipizide, hepatitis B vaccine, salmeterol, sumatriptan, triamcinolone The active pharmaceutical ingredient may be acetonide, goserelin, beclomethasone, granisterone, desogestrel, alprazolam, estradiol, nicotine, interferon β1A, cromolyn, hosinopril, digoxin, fluticasone, bisoprolol, calcitril, captopril, butorphanol, clonidine, premarin, testosterone, sumatriptan, clotrimazole, bisacodyl, dextromethorphan, nitroglycerin, nafarelin, dinoprostone, nicotine, bisacodyl, goserelin, or granisetron. In one embodiment, the active pharmaceutical ingredient is epinephrine,These are benzodiazepines such as diazepam or lorazepam, or alprazolam.

[0078] (Examples include epinephrine, diazepam, and alprazolam) In one example, a composition containing epinephrine or a salt or ester thereof may have a biodelivery profile similar to that of epinephrine administered by injection, for example, using an EpiPen. Epinephrine can be present in amounts ranging from approximately 0.01 mg to approximately 100 mg / dose, for example, in 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, which include amounts 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, a composition containing diazepam may have a biodelivery profile similar to, or better than, that of diazepam tablets or gels. Diazepam or its salts may be present in amounts ranging from approximately 0.5 mg to approximately 100 mg / dose, for example, in 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, which include 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.

[0079] In another example, a composition (e.g., containing alprazolam, diazepam, or epinephrine) may have a suitable non-toxic nonionic alkyl glycoside having a hydrophobic alkyl group linked to a hydrophilic saccharide, in combination with a mucosal delivery enhancer selected from: (a) agglutination inhibitors; (b) charge modifiers; (c) pH adjusters; (d) degrading enzyme inhibitors; (e) mucolytics or mucosal deconjugates; (f) ciliary quiescent agents; (g) membrane penetration enhancers selected from: (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) NO donors; (vi) long-chain amphiphilic molecules; (vii) hydrophobic penetration enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerol esters of acetoacetate; (x) cyclodex (xi) trine or β-cyclodextrin derivatives; (xi) medium-chain fatty acids; (xii) chelating agents; (xiii) amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (xv) enzymes that degrade selected membrane components; (ix) inhibitors of fatty acid synthesis; (x) inhibitors of cholesterol synthesis; and any combination of the membrane penetration enhancers listed in (xi)(i)-(x); (h) modifiers of epithelial junction physiological function; (i) vasodilators; (j) selective transport enhancers; or (k) stabilizing delivery vehicles, carriers, mucosal adhesives, supports or complex-forming species that are effectively combined with the compound thereto, associated, contained, encapsulated or bound, resulting in the stabilization of the compound for enhanced mucosal delivery, wherein formulations of the compound with transmucosal delivery enhancers provide increased bioavailability of the compound in the plasma of the subject. This formulation may contain nearly the same active ingredient (API):enhancer ratio as in other examples for diazepam and alprazolam.

[0080] (Treatment or adjunct treatment) Status epilepticus (SE) is an epileptic seizure consisting of a seizure longer than 5 minutes or two or more seizures occurring within 5 minutes of each other with no return to normal between seizures. Another earlier definition used a 30-minute time limit. Benzodiazepines are some of the most effective medications in the treatment of acute seizures and status epilepticus. The benzodiazepines most commonly used to treat status epilepticus include diazepam (Valium), lorazepam (Ativan), or midazolam (Versed). The pharmaceutically active ingredients in the pharmaceutical composition (e.g., pharmaceutical composition film) are used to treat Angelmann syndrome (AS), benign Rolandic epilepsy in children (BREC) and benign Rolandic epilepsy with central temporal spikes (BECTS), CDKL5 disorder, childhood absence epilepsy (CAE), myoclonus-astatic epilepsy or Douse syndrome, Dravet syndrome, early myoclonus encephalopathy (EME), epilepsy with generalized tonic-clonic seizures only (EGTCS), myoclonus-pre-administered resected epilepsy, glucose transporter 1 deficiency syndrome, hypothalamic hamartoma (HH), infantile spasms (also known as IS) or West syndrome, and weak-point absence epilepsy (JAE). It may be a treatment or adjunct treatment for juvenile myoclonic epilepsy (JME), Lafora disease (Lafora's 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-associated intellectual disability syndrome, neurocutaneous syndromes that may be associated with seizures, including temporal lobe epilepsy and incontinentia pigmenti, neurofibromatosis type 1, Sturge-Weber syndrome (trigeminal nerve area hemangioma), and tuberous sclerosis.

[0081] The film and / or its components may be water-soluble, water-swellable, or water-insoluble. The term "water-soluble" may refer to 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" refers to a substance that cannot be dissolved in an aqueous solvent, including but not limited to water. The solvent may contain water or other solvents (preferably polar solvents) either by themselves or in combination with water.

[0082] This composition may contain a polymer matrix. Any desired polymer matrix may be used, provided it is orally soluble or erosive. The dosage form must have sufficient bioadhesion to not be easily removed and must form a gel-like structure upon administration. These are moderately soluble in the oral cavity and particularly suitable for the delivery of pharmaceutically active ingredients, but immediate-release, delayed-release, controlled-release, and sustained-release compositions are also among the various intended embodiments.

[0083] (branched polymer) The pharmaceutical composition film may contain dendritic polymers that have various structural architectures and are highly branched polymers. The dendritic polymers may include dendrimers, dendritic polymers (dendritic grafted polymers), linear dendritic hybrids, multi-armed star polymers, or highly branched polymers.

[0084] Highly branched polymers are polymers that exhibit structural imperfections. However, they can be synthesized in a single-step reaction, which is an advantage over other dendritic structures and therefore suitable for applications requiring large volumes. Apart from their spherical structure, the properties of these polymers include abundant functional groups, intramolecular cavities, low viscosity, and high solubility. Dendritic polymers are used in several drug delivery applications. See, for example, "Dendrimers as Drug Carriers: Applications in Different Routes of Drug Administration," J Pharm Sci, VOL. 97, 2008, 123-143, which is incorporated herein by reference.

[0085] Dendritic polymers can have internal cavities that can encapsulate drugs. The steric hindrance caused by high-density polymer chains can prevent drug crystallization. Therefore, branched polymers can offer the additional advantage of formulating crystalline drugs within a polymer matrix.

[0086] Examples of suitable dendritic polymers include poly(ether)-based dendrons, dendrimers, and highly branched polymers; poly(ester)-based dendrons, dendrimers, and highly branched polymers; poly(thioether)-based dendrons, dendrimers, and highly branched polymers; poly(amino acid)-based dendrons, dendrimers, and highly branched polymers; poly(arylalkylene ether)-based dendrons, dendrimers, and highly branched polymers; poly(alkyleneimine)-based dendrons, dendrimers, and highly branched polymers; and poly(amidoamine)-based dendrons, dendrimers, or highly branched polymers.

[0087] Other examples of highly branched polymers include poly(amines), polycarbonates, poly(etherketones), polyurethanes, polycarbosilanes, polysiloxanes, poly(esteramines), poly(sulfonamines), poly(urethaneureas), or polyether polyols, such as polyglycerin.

[0088] The film can be prepared from a combination of at least one polymer and a solvent optionally containing other components. The solvent may be water, a polar organic solvent including, but not limited to, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent may be a non-polar organic solvent such as methylene chloride. The film may be prepared by utilizing a selected sloshing or deposition method and a controlled drying process. For example, the film may be prepared through a controlled drying process that includes the application of heat and / or radiation energy to a wet film matrix to form a viscoelastic structure, thereby controlling the uniformity of the film's contents. The controlled drying process may include air only, heat only, or heat and air, bringing together the top or bottom of the film, or the substrate supporting the sloshing, deposition, or extruded film, or bringing two or more surfaces into contact simultaneously or at different points in time during the drying process. Some of such processes are described in detail in U.S. Patents 8,765,167 and 8,652,378, which are incorporated herein by reference. Alternatively, the film may be extruded as described in U.S. Patent Publication No. 2005 / 0037055 A1, which is incorporated herein by reference.

[0089] The polymers contained in the film may be water-soluble, water-swellable, water-insoluble, or a combination of one or more water-soluble, water-swellable, or water-insoluble polymers. The polymers may include cellulose, cellulose derivatives, or gum. Specific examples of useful water-soluble polymers include, but are not limited to, polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, acacia gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, and combinations thereof. Specific examples of useful water-insoluble polymers include, but are not limited to, ethylcellulose, hydroxypropyl ethylcellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and combinations thereof. It is desirable to include polymers that provide a higher level of viscosity at higher doses compared to lower doses.

[0090] As used herein, the term “water-soluble polymer” and its variations refer to polymers that are at least partially soluble in water, and preferably completely or entirely soluble in water, or that absorb water. Water-absorbing polymers are often referred to as water-swellable polymers. Substances useful in the present invention may be water-soluble or water-swellable at room temperature and other temperatures, for example, above room temperature. Furthermore, these materials may be water-soluble or water-swellable at pressures lower than atmospheric pressure. In some embodiments, a film formed from such a water-soluble polymer may be sufficiently water-soluble while being insoluble when in contact with bodily fluids.

[0091] Other polymers useful for incorporation into films include biodegradable polymers, copolymers, block polymers, or combinations thereof. It is understood that the term “biodegradable” is intended to include substances that decompose chemically, as opposed to substances that are physically broken down (i.e., bio-erosive substances). Polymers incorporated into films may also include combinations of biodegradable or bio-erosive substances. Among these, known useful polymers or polymer classes that meet the above criteria are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxane, polyoxalate, poly(alpha-ester), polyanhydride, polyacetate, polycaprolactone, poly(orthoester), polyamino acid, polyaminocarbonate, polyurethane, polycarbonate, polyamide, poly(alkylcyanoacrylate), and mixtures and copolymers thereof. Additional useful polymers include stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propanoic acid and sebacic acid, sebacic acid copolymers, caprolactone copolymers, poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymers, polyurethane and (poly(lactic acid)) copolymers, alpha-amino acid and caproic acid copolymers, alpha-benzyl glutamate and polyethylene glycol copolymers, succinate and poly(glycol) copolymers, polyphosphazenes, polyhydroxyalkanoates, or mixtures thereof. The polymer matrix may contain one, two, three, four, or more components.

[0092] While various different polymers may be used, it is desirable to select polymers that provide the film with mucosal adhesion properties, as well as a desirable dissolution and / or disintegration rate. In particular, the desired duration for maintaining contact between the film and mucosal tissue depends on the type of pharmaceutically active ingredient contained in the composition. Some pharmaceutically active ingredients require only a few minutes for delivery through mucosal tissue, while others may require several hours or even longer. Therefore, in some embodiments, one or more of the aforementioned water-soluble polymers may be used to form the film. However, in other embodiments, it may be desirable to use a combination of water-soluble polymers and water-swellable, water-insoluble, and / or biodegradable polymers, as previously provided. The inclusion of one or more water-swellable, water-insoluble, and / or biodegradable polymers can provide a film with a slower dissolution or disintegration rate than a film formed solely of water-soluble polymers. Thus, this film adheres to mucosal tissue for a relatively long time, such as up to several hours, which is desirable for the delivery of certain pharmaceutically active ingredients.

[0093] Preferably, individual film dosages of the pharmaceutical film may have a small size with a suitable thickness, which is between approximately 0.0625 to 3 inches × approximately 0.0625 to 3 inches. The film size may also be greater than 0.0625 inches, greater than 0.5 inches, greater than 1 inch, greater than 2 inches, or 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, or less than 0.0625 inches on at least one side, 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 on another side. The aspect ratio, including thickness, length, and width, can be optimized by those skilled in the art based on the chemical and physical properties of the polymer matrix, the active pharmaceutical ingredient, dosage, enhancer, and other additives involved, as well as the dimensions of the desired distribution unit. This film dosage form must have good adhesion when placed in the user's oral cavity or sublingual region. Furthermore, this film dosage form must disperse and dissolve at a gentle rate, most preferably within about 1 minute and dissolve within about 3 minutes. In some embodiments, this film dosage form can disperse and dissolve at a rate of about 1 to about 30 minutes, for example, about 1 to about 20 minutes, or longer than 1 minute, longer than 5 minutes, longer than 7 minutes, longer than 10 minutes, longer than 12 minutes, longer than 15 minutes, longer than 20 minutes, longer than 30 minutes, about 30 minutes, or less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, or less than 1 minute. The sublingual dispersion rate may be shorter than the intraoral dispersion rate.

[0094] For example, in some embodiments, these films may contain polyethylene oxide alone or in combination with a second polymer component. The second polymer may be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer, or any combination thereof. Suitable water-soluble polymers include, but are not limited to, those previously provided. In some embodiments, the water-soluble polymer includes hydrophilic cellulosic polymers, such as hydroxypropylcellulose and / or hydroxypropylmethylcellulose. In some embodiments, one or more water-swellable, water-insoluble, and / or biodegradable polymers may also be included in the polyethylene oxide-based film. Any of the previously provided water-swellable, water-insoluble, or biodegradable polymers may be used. The second polymer component may be used in an amount of about 0% to about 80% by weight of the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight, which includes more than 5%, more than 10%, more than 15%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, and more than 70%, about 70%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5% by weight.

[0095] Additives may be included in these films. Examples of additive classes include preservatives, antimicrobial agents, excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, bulking agents, sweeteners, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow enhancers, release agents, polyols, granulators, diluents, binders, buffers, absorbents, lubricants, adhesives, anti-adhesion agents, acidulants, softeners, resins, viscous lubricants, solvents, surfactants, emulsifiers, elastomers, anti-tacks, antistatic agents, and mixtures thereof. These additives may be added together with the pharmaceutically active ingredient(s).

[0096] As used herein, the term “stabilizer” means an excipient capable of preventing aggregation or other physical and chemical degradation of an active pharmaceutical ingredient, another excipient, or a combination thereof.

[0097] Stabilizers may also be classified as antioxidants, metal ion chelating agents, pH adjusters, emulsifiers and / or surfactants, and ultraviolet stabilizers, as previously discussed and discussed in more detail below.

[0098] Antioxidants (i.e., pharmaceutically acceptable compounds or compositions that slow, inhibit, interrupt and / or halt oxidation processes) include, in particular, the following substances: tocopherols and their esters, sesamol from sesame oil, coniferyl benzoate from benzoin resin, nordihydroguaiaretic acid resin and nordihydroguaiaretic acid (NDGA), gallates (especially methyl, ethyl, propyl, amyl, butyl, and lauryl gallates), butylated hydroxyanisole (BHA / BHT, as well as butyl-p-cresol); ascorbic acid and its salts and esters (e.g., ascorbyl palmitate), erythorbic acid (isoascorbic acid) and its salts and esters, monothioglycerol, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT), and propionic acid. Typical antioxidants include tocopherols, such as α-tocopherol and its esters, butylated hydroxytoluene, and butylated hydroxyanisole. The term "tocopherol" also includes esters of tocopherol. A known tocopherol is α-tocopherol. The term "α-tocopherol" includes esters of α-tocopherol (e.g., α-tocopherol acetate).

[0099] Metal ion chelating agents (i.e., any compound that can interlock with another compound, such as an active ingredient or another excipient, during host-guest complex formation; also referred to as chelating agents) include calcium chloride, disodium calcium ethylenediaminetetraacetate, glucono delta-lactone, sodium gluconate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate, and combinations thereof. Metal ion chelating agents also include cyclic oligosaccharides, such as cyclodextrins, cyclomannins (5 or more α-D-mannopyranose units linked at the 1,4 positions by α-linkages), cyclogalactin (5 or more β-D-galactopyranose units linked at the 1,4 positions by β-linkages), cycloalthrins (5 or more α-D-altropyranose units linked at the 1,4 positions by α-linkages), and combinations thereof.

[0100] 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 such acidic substances (alkali metal salts, alkaline earth metal salts, ammonium salts, etc.), salts of such acidic substances with organic bases (e.g., basic amino acids, e.g., lysine, arginine, etc. and the like, meglumine, etc.), and solvates thereof (e.g., hydrates). Other examples of pH adjusters include microcrystalline cellulose containing silica, magnesium aluminometasilicate, calcium salts of phosphate (e.g., anhydrous or hydrated calcium hydrogen phosphate, calcium carbonate or bicarbonate, sodium or potassium, and calcium lactate or mixtures thereof), sodium and / or calcium salts of carboxymethylcellulose, crosslinked carboxymethylcellulose (e.g., croscarmellose sodium and / or calcium), potassium polaritrin, sodium alginate and / or calcium, sodium doxate, magnesium stearate, calcium, aluminum, or zinc, magnesium palmitate, and magnesium oleate, sodium stearyl fumarate, and combinations thereof.

[0101] Examples of emulsifiers and / or surfactants include poloxamer or pluronic acid, polyethylene glycol, polyethylene glycol monostearate, polysorbate, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil, alkyl polyosides, water-soluble proteins graft-polymerized onto hydrophobic main chains, lecithin, glyceryl monostearate, glyceryl monostearate / polyoxyethylene stearate, ketostearyl alcohol / sodium lauryl sulfate, carbomer, phospholipids, (C 10 -C 20 )-alkyl and alkylene carboxylates, alkyl carboxylates, aliphatic alcohol sulfates, aliphatic alcohol ether sulfates, alkylamide sulfates and sulfonates, fatty acid alkylamide polyglycol ether sulfates, alkanesulfonates and hydroxyalkanesulfonates, olefin sulfonates, acyl isethionates, α-sulfo fatty acid esters, alkylbenzene sulfonates, alkylphenol glycol ether sulfonates, sulfosuccinates, monoesters and diesters of sulfosuccinates, aliphatic alcohol ether phosphates, protein / fatty acid condensation products, alkyl monoglyceride sulfates and sulfonates, alkylglyceride ether sulfonates, fatty acid methyl taurids, fatty acid sarcosinates, sulfolicinolates, and acyl glutamates, quaternary ammonium salts (e.g., di-(C) 10 -C 24 (C)-alkyl-dimethylammonium chloride or bromide), (C) 10 -C 24 )-alkyl-dimethylethylammonium chloride or bromide, (C 10 -C 24 )-Alkyl-trimethylammonium chloride or bromide (e.g., cetyltrimethylammonium chloride or bromide), (C 10 -C 24 )-alkyl-dimethylbenzylammonium chloride or bromide (e.g., (C 12 -C 18 )-alkyl-dimethylbenzylammonium chloride), N-(C10 -C 18 )-alkylpyridinium chloride or bromide (for example, N-(C 12 -C 16 )-alkylpyridinium chloride or bromide), N-(C 10 -C 18 )-alkyl-isoquinolinium chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 )-Alkyl-polyoylaminoformylmethylpyridinium chloride, N-(C 12 -C 18 )-alkyl-N-methylmorpholinium chloride, bromide or monoalkyl sulfate, N-(C 12 -C 18 )-alkyl-N-ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C 16 -C 18 This includes )-alkyl-pentaoxetylammonium chloride, diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride, salts of N,N-di-ethylaminoethylstearylamide and -oleylamide with hydrochloride, acetic acid, lactic acid, citric acid, or phosphoric acid, N-acylaminoethyl-N,N-diethyl-N-methylammonium chloride, bromide, or monoalkyl sulfate, and N-acylaminoethyl-N,N-diethyl-N-benzylammonium chloride, bromide, or monoalkyl sulfate (where "acyl" above represents, for example, stearyl or oleyl), and combinations thereof.

[0102] Examples of UV stabilizers include UV absorbers (e.g., benzophenone), UV quenchers (i.e., any compound that dissipates UV energy as heat rather than causing energy decomposition), scavengers (i.e., any compound that eliminates free radicals resulting from exposure to UV radiation), and combinations thereof.

[0103] In other embodiments, the stabilizers include ascorbyl palmitate, ascorbic acid, alpha-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 quencher, hydroxyl radical scavenger, hydroperoxide remover, reducing agent, metal chelating agent, detergent, chaotrope, and combinations thereof. "Singlet oxygen quenchers" include, but are not limited to, alkylimidazoles (e.g., histidine, L-camosine, histamine, imidazole-4-acetic acid), indoles (e.g., tryptophan and its derivatives, e.g., N-acetyl-5-methoxytryptamine, N-acetylserotonin, 6-methoxy-1,2,3,4-tetrahydro-beta-carbolin), sulfur-containing amino acids (e.g., methionine, ethionine, diencholic acid, lanthionine, N-formylmethionine, felinine, S-allylcysteine, S-aminoethyl-L-cysteine), phenolic compounds (e.g., tyrosine and its derivatives), aromatic acids (e.g., ascorbates, salicylic acid, and their derivatives), azides (e.g., sodium azide), tocopherols and related vitamin E derivatives, and carotenes and related vitamin A derivatives. "Hydroxyl radical scavengers" include, but are not limited to, azides, dimethyl sulfoxides, histidine, mannitol, sucrose, glucose, salicylates, and L-cysteine. "Hydroperoxide removers" 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 citrates. "Cleaning agents" include, but are not limited to, SDS and sodium lauroyl sarcosinate."Chaotrope" includes, but is not limited to, guanidium chloride, isothiocyanates, urea, and formamide. As discussed herein, stabilizers are present in amounts from 0.0001% to 50% by weight, which includes amounts greater than 0.0001%, greater than 0.001%, greater than 0.01%, greater than 0.1%, greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001% by weight.

[0104] Useful additives include, for example, gelatin, vegetable proteins such as sunflower protein, soy protein, cottonseed protein, peanut protein, and grapeseed protein; whey protein, whey protein isolates, blood proteins, egg proteins, acrylic proteins; water-soluble polysaccharides such as alginate, carrageenan, guar gum, agar, xanthan gum, gellan gum, acacia gum and related gums (gutti gum, karaya gum, tragacanth gum); pectin; water-soluble derivatives of cellulose: alkylcellulose, hydroxyalkylcellulose, and hydroxyalkylalkylcellulose, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters, and hydroxyalkylcellulose. This may include esters, such as cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose (HPMC); carboxyalkylcellulose, carboxyalkylalkylcellulose, carboxyalkylcellulose esters, such as carboxymethylcellulose and their alkali metal salts; water-soluble synthetic polymers, such as polyacrylic acid and polyacrylic acid esters, polymethacrylic acid and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVA / vinyl acetate copolymer, or polycrotonic acid; also suitable are water-soluble chemical derivatives of phthalate gelatin, succinate gelatin, crosslinked gelatin, shellac, starch, such as cationically modified acrylates and methacrylates having tertiary or quaternary amino groups, preferably quaternized diethylaminoethyl groups; or other similar polymers.

[0105] The additional components may be in the range of up to approximately 80% of the total weight of all composition components, preferably approximately 0.005% to 50%, more preferably 1% to 20%, which includes 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%, approximately 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%, approximately 3%, or less than 1%. Other additives may include anti-tacks, fluidizers, and opacifiers, such as magnesium, aluminum, silicon, and titanium oxides, preferably in concentrations ranging from approximately 0.005% to approximately 5% by weight, and preferably from approximately 0.02% to approximately 2% by weight, based on the total weight of the film components, which may include amounts greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, greater than 1.5%, greater than 2%, greater than 4%, approximately 5%, greater than 5%, less than 4%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.02%.

[0106] In one embodiment, the composition may contain a plasticizer, which may be a low molecular weight organic plasticizer such as polyalkylene oxides, e.g., polyethylene glycol, polypropylene glycol, polyethylene-propylene glycol, etc., such as glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sugar alcohol sorbitol, sodium diethyl sulfosuccinate, triethyl citrate, citrate The composition may contain tributyl acid, plant extracts, fatty acid esters, fatty acids, oils, and similar substances, added at concentrations ranging from about 0.1% to about 40% by weight of the composition, preferably from about 0.5% to about 20%, including greater than 0.5%, greater than 1%, greater than 1.5%, greater than 2%, greater than 4%, greater than 5%, greater than 10%, greater than 15%, about 20%, greater than 20%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 2%, less than 1%, or less than 0.5%. Further compounds may be added to improve the texture properties of the film material, such as animal or vegetable fats, preferably in their hydrogenated form. The composition may also contain compounds to improve the texture properties of the product. Other components may include binders that contribute to the easy formation of the film and overall quality. Non-limiting examples of binders include starch, natural rubber, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxazolidone, or polyvinyl alcohol.

[0107] Further potential additives include solubility enhancers, such as substances that form encapsulation compounds with the active ingredient. Such substances can be useful in improving the properties of highly insoluble and / or unstable active ingredients. Generally, these substances are donut-shaped molecules with a hydrophobic internal cavity and a hydrophilic external cavity. The insoluble and / or unstable pharmaceutically active ingredient fits into the hydrophobic cavity, thereby forming an encapsulation complex that is soluble in water. Thus, the formation of the encapsulation complex allows the highly insoluble and / or unstable pharmaceutically active ingredient to become soluble in water. A particularly desirable example of such a substance is cyclodextrin, which is a cyclic carbohydrate derived from starch. However, other similar substances are considered to fall within the scope of the present invention.

[0108] Suitable colorants include food, pharmaceutical and cosmetic colors (FD&C), pharmaceutical and cosmetic colors (D&C), or quasi-drug and cosmetic colors (Ext. D&C). These colors are pigments, their corresponding lakes, and certain natural and derived colorants. Lakes are pigments 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 or iron or titanium, or oxides thereof, are preferably added in a concentration of about 0.001 to about 10%, and preferably about 0.5 to about 3%, based on the weight of the total components, which includes 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%.

[0109] The fragrances may be selected from natural and synthetic flavored liquids. An exemplary list of such substances includes volatile oils, synthetic flavored oils, flavored aromatics, oils, liquids, oleopolymers, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. A non-limiting representative list of examples includes mint oil, cocoa, and citrus oils, such as lemon, orange, lime, and grapefruit, as well as fruit essential oils or other fruit fragrances, including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, and apricot. Other useful flavorings include aldehydes and esters, such as benzaldehyde (cherry, almond), citral, i.e., alpha-citral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruit), aldehyde C-9 (citrus fruit), aldehyde C-12 (citrus fruit), toluyl aldehyde (cherry, almond), 2,6-dimethyloctanol (vegetable (green) fruit), or 2-dodecenal (citrus, mandarin), and combinations thereof.

[0110] Sweeteners may be selected from the following non-restrictive list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts, e.g., sodium salt; dipeptide-based sweeteners, e.g., aspartame, neotame, advantame; dihydrochalcone compounds, glycyrrhizin; stevia (Stevia Rebaudiana) (stevioside); chlorine derivatives of sucrose, e.g., sucralose; sugar alcohols, e.g., sorbitol, mannitol, xylitol, and the like. Also included are hydrogenated starch hydrolysates and synthetic sweeteners such as 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiadin-4-one-2,2-dioxide, especially potassium salt (acesulfame-K), and their sodium and calcium salts, as well as natural intensive sweeteners, e.g., Lo Han Kuo. Other sweeteners may also be used.

[0111] Defoaming and / or defoaming agents may also be used in the film. These agents help remove air, such as trapped air, from the film-forming composition. Such trapped air can lead to a non-uniform film. Simethicone is one particularly useful defoaming and / or defoaming agent. However, the present invention is not limited in this respect, and other suitable defoaming and / or defoaming agents may be used. Simethicone and related substances may be used for densification purposes. More specifically, such substances can facilitate the removal of voids, air, moisture, and similar undesirable components, thereby providing a denser film, and therefore a more uniform film. Substances or components that perform this function are referred to as densifying agents or density-increasing agents. As previously described, trapped air or undesirable components can lead to a non-uniform film.

[0112] Any other components described in U.S. Patents No. 7,425,292 and No. 8,765,167 by the same applicant, as mentioned above, may also be included in the films described herein.

[0113] The film composition may further preferably include a buffer to control the pH of the film composition. Any desired level of the buffer is incorporated into the film composition to provide a desired pH level that the pharmaceutically active ingredient will encounter when released from the composition. It is preferable that the buffer is provided in an amount sufficient to control the release of the pharmaceutically active ingredient from the film and / or its absorption into the body. In some embodiments, the buffer may include sodium citrate, citric acid, bicarbonate tartrate, and combinations thereof.

[0114] The pharmaceutical films described herein may be formed by any desired process. Preferred processes are described in U.S. Patents 8,652,378, 7,425,292 and 7,357,891, which are incorporated herein by reference. In one embodiment, a film dosage form composition is formed by first preparing a wet composition, which contains a polymeric carrier matrix and a therapeutically effective amount of a pharmaceutically active ingredient. This wet composition is poured onto a film and then thoroughly dried to form a self-standing film composition. This wet composition is either poured into individual dosage forms or poured onto a sheet, which is then cut into individual dosage forms.

[0115] This pharmaceutical composition can adhere to mucosal surfaces. The present invention permits specific use in the topical treatment of body tissues, affected areas, or wounds having moist surfaces and being susceptible to the effects of bodily fluids, such as the mouth, vagina, organs, or other types of mucosal surfaces. This composition delivers the pharmaceutical and provides a protective layer upon application and adhesion to mucosal surfaces, delivering the pharmaceutical to the treatment site, surrounding tissues, and other bodily fluids. Assuming control of erosion in bodily fluids such as aqueous solutions or saliva, and gradual, natural erosion of the film accompanying or continuous delivery, this composition provides a suitable residence time for effective drug delivery at the treatment site.

[0116] The residence time of this composition is determined by the erosion rate of the water-erosive polymers used in the formulation and their respective concentrations. The erosion rate may be adjusted, for example, by mixing components with different solubility characteristics or chemically different polymers, such as hydroxyethylcellulose and hydroxypropylcellulose; by using different molecular weight grades of the same polymer, such as a mixture of low and medium molecular weight hydroxyethylcellulose; by using excipients or plasticizers (including essentially insoluble components) with various lipophilic values ​​or water solubility characteristics; by using water-soluble organic and inorganic salts; by using polymers such as hydroxyethylcellulose and crosslinking agents such as glyoxal for partial crosslinking; or by post-treatment irradiation or curing, which, once obtained, can alter the physical state of the film, including its crystallinity or phase transition. These strategies may be used alone or in combination to modify the erosion dynamics of the film. Upon application, the pharmaceutical composition film adheres to and is retained in place on the mucosal surface. Water absorption makes the composition flexible, thereby reducing the sensation of a foreign body. When this composition is placed on a mucosal surface, drug delivery is triggered. The residence time can be adjusted over a wide range depending on the desired timing of drug delivery and the desired lifespan of the carrier. However, generally, the residence time is adjusted between about a few seconds and about a few days. Preferably, the residence time for most drugs is adjusted between about 5 seconds and about 24 hours. More preferably, the residence time is adjusted between about 5 seconds and about 30 minutes. In addition to providing drug delivery, once the composition adheres to the mucosal surface, it also provides protection of the treatment site and acts as an erosive bandage. Lipophilic substances can be designed to delay erosion in order to reduce disintegration and dissolution.

[0117] The erosive dynamics of this composition can also be modified by adding excipients that are sensitive to enzymes such as amylase and are highly soluble in water, such as water-soluble organic and inorganic salts. Suitable excipients may include sodium and potassium salts of chloride, carbonic acid, bicarbonate, citric acid, trifluoroacetic acid, benzoic acid, phosphoric acid, fluoride, sulfuric acid, or tartaric acid. The amount added can vary depending on the extent to which the erosive dynamics are altered, as well as the amounts and properties of other components in the composition.

[0118] The emulsifiers typically used in the water-based emulsions described above are preferably selected from linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid, cetoleic acid or oleic acid and sodium hydroxide or potassium hydroxide, which are obtained in situ, or selected from sorbitol and polyoxyethylene derivatives including lauric acid esters, palmitic acid esters, stearic acid esters or oleic acid esters of anhydrous sorbitol, monooleate, monostearate, monopalmitate, monolaurate, aliphatic alcohols, alkylphenols, allyl ethers, alkylaryl ethers, sorbitan monostearate, sorbitan monooleate and / or sorbitan monopalmitate.

[0119] The amount of pharmaceutically active ingredients used depends on the desired therapeutic strength and the composition of these layers, but preferably the pharmaceutically active ingredients constitute about 0.001% to about 99%, more preferably about 0.003% to about 75%, and most preferably about 0.005% to about 50% by weight of the composition, which includes 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 drug or other components, but typically these components constitute no more than 50%, preferably no more than 30%, and most preferably no more than 15% of the total weight of the composition.

[0120] The thickness of the film may vary depending on the thickness of each layer and the number of layers. As mentioned above, both the thickness and quantity of the layers may be adjusted to vary the erosion dynamics. Preferably, if the composition has only two layers, the thickness is in the range of 0.005 mm to 2 mm, preferably 0.01 to 1 mm, and more preferably 0.1 to 0.5 mm, which includes greater than 0.1 mm, greater than 0.2 mm, about 0.5 mm, greater than 0.5 mm, less than 0.5 mm, less than 0.2 mm, or less than 0.1 mm. The thickness of each layer may vary from 10 to 90% of the total thickness of the layered composition, 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%. Accordingly, the preferred thickness of each layer may vary from 0.01 mm to 0.9 mm, or from 0.03 mm to 0.5 mm.

[0121] As those skilled in the art will understand, when systemic delivery, such as transmucosal or transdermal delivery, is desired, the treatment site may include any area on which the film can deliver and / or maintain the desired level of pharmaceuticals in the blood, lymph, or other bodily fluids. Typically, such treatment sites include the mucous membranes of the mouth, ears, eyes, anus, nose, and vagina, as well as the skin. When skin is used as the treatment site, a relatively large area of ​​skin, such as the upper arm or thigh, is usually preferred, as movement does not disrupt the adhesion of the film.

[0122] This pharmaceutical composition can also be used as a wound dressing. By providing a washable, removable, physical, adaptable, oxygen- and water-permeable, and flexible barrier, the film can not only protect wounds but also deliver pharmaceuticals to promote healing, sterilization, scar formation, pain relief, or overall improvement of the affected person's condition. Some of the examples provided below are well suited for application to skin or wounds. As those skilled in the art will understand, this formulation requires the incorporation of a specific hydrophilic / hygroscopic excipient to help maintain good adhesion to dry skin over extended periods. Another advantage of the present invention is that, when using this form, the use of dyes or colorants is unnecessary if the film is not desired to be conspicuous on the skin. On the other hand, if the film is desired to be conspicuous, dyes or colorants can be used.

[0123] This pharmaceutical composition can adhere to mucous membranes, which are naturally moist tissues, while also being usable on other surfaces such as skin or wounds. The pharmaceutical film can adhere to skin even when moistened with an aqueous-based fluid such as water, saliva, wound drainage, or sweat prior to application. The film can remain adhered to the skin until it is eroded by contact with water, such as through washing, showering, bathing, or cleansing. The film can also be easily removed by peeling without causing significant tissue damage.

[0124] The Franz diffusion cell is an in vitro skin permeation assay used in pharmaceutical development. The Franz diffusion cell apparatus (Figure 1A) consists of two chambers separated by a membrane, for example, animal or human tissue. The product of test is applied to the membrane through the upper chamber. The lower chamber contains a fluid from which a sample is taken at regular intervals for analysis to determine the amount of activity permeating the membrane. In relation to Figure 1A, the Franz diffusion cell 100 comprises a donor compound 101, a donor chamber 102, a membrane 103, a sampling hole 104, a receptor chamber 105, a stirring rod 106, and a heater / circulator 107.

[0125] With respect to Figure 1B, the pharmaceutical composition is a film 100 containing a polymer matrix 200 and a pharmaceutically active ingredient 300 contained in the polymer matrix. This film may contain a permeation enhancer 400.

[0126] Regarding Figures 2A and 2B, the graphs show the permeation of the active substance from the composition. These graphs show no significant difference between epinephrine base, which is solubilized in situ, and epinephrine bitartrate, which is essentially soluble. Epinephrine bitartrate was selected for further development based on its ease of processing. The flux is derived as a gradient of permeation rate as a function of time. The steady-state flux is obtained from the plateau of the flux-time curve, which is integrated by the volume of the receiver medium and normalized with respect to the permeation area.

[0127] Regarding Figure 2A, this graph shows the average amount of active substance permeated, versus time, for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized epinephrine base.

[0128] Regarding Figure 2B, this graph shows the average flux, pair, and time for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized epinephrine base.

[0129] Regarding Figure 3, this graph shows the ex vivo permeability of epinephrine bitartrate as a function of concentration. This study compared concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL. The results showed that increasing concentrations resulted in increased permeability, and the level of enhancement decreased with higher loadings.

[0130] Regarding Figure 4, this graph shows the permeation of epinephrine bitartrate as a function of solution pH. We investigated whether acidic conditions promote stability. The results compared epinephrine bitartrate pH3 buffer and epinephrine bitartrate pH5 buffer, and found that epinephrine bitartrate pH5 buffer was slightly preferable.

[0131] Regarding Figure 5, this graph shows the effect of enhancers on epinephrine permeation, expressed as permeation rate as a function of time. Multiple enhancers were screened, including labrazol, capriol 90, Plurol Oleique, labrafil, TDM, SGDC, gelcile 44 / 14, and clove oil. Significant effects on time to onset and steady-state flux were achieved, and surprisingly, enhanced permeation was achieved for clove oil and labrazol.

[0132] Regarding Figures 6A and 6B, these graphs show the release of epinephrine on a polymer platform and the effect of enhancers on that release, expressed as permeation (μg) versus time. Figure 6A shows epinephrine release from different polymer platforms. Figure 6B shows the effect of enhancers on epinephrine release.

[0133] Regarding Figure 7, this graph shows the pharmacokinetic model in male Yucatan miniature pigs. This study compares 0.3 mg EpiPen, 0.12 mg epinephrine IV, and a placebo film.

[0134] Regarding Figure 8, this graph shows the effect of no enhancer on the concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen.

[0135] Regarding Figure 9, this graph shows the effect of enhancer A (Labrazol) on the concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. Regarding Figure 10, this graph shows the effect of enhancer L (clove oil) on the concentration profiles of two types of 40 mg epinephrine films (10-1-1) and (11-1-1) versus 0.3 mg EpiPen.

[0136] Regarding Figure 11, this graph shows the effects of enhancer L (clove oil) and film dimensions (10-1-1 thin, large film and 11-1-1 thick, small film) on the concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen.

[0137] Regarding Figure 12, this graph shows the concentration profile of the variation in the dose of epinephrine film in a constant matrix with respect to enhancer L (clove oil) relative to 0.3 mg EpiPen.

[0138] Regarding Figure 13, this graph shows the concentration profile of the variation in the dose of epinephrine film in a constant matrix with respect to enhancer L (clove oil) relative to 0.3 mg EpiPen.

[0139] Regarding Figure 14, this graph shows the concentration profile of the variation in the dose of epinephrine film in a constant matrix for enhancer A (Labrazol) relative to 0.3 mg EpiPen.

[0140] Regarding Figure 15, this graph shows the effect of the enhancer on diazepam permeation, expressed as permeation as a function of time.

[0141] Regarding Figure 16, this graph shows the average flux as a function of time (diazepam + enhancer).

[0142] Regarding Figure 17, this graph shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen.

[0143] Regarding Figure 18, this graph shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen.

[0144] Regarding Figure 19, this graph shows the effect of farnesol in combination with linoleic acid on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen.

[0145] Regarding Figure 20, this graph shows the effect of farnesol and farnesol combined with linoleic acid on the plasma concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen.

[0146] The following examples are provided to illustrate pharmaceutical compositions, methods for producing and using pharmaceutical compositions, and apparatus described herein. [Examples]

[0147] (Examples) (Example 1: Permeation enhancer - epinephrine) The enhancement of permeation was tested using multiple permeation enhancers at an epinephrine bitartrate concentration of 16.00 mg / mL. The results show flux enhancement as represented in the data below. For 100% eugenol and 100% clove oil, the results showed that steady-state flux was reached significantly faster, accompanied by an unexpectedly high flux enhancement rate (%).

[0148] [Table 1] 1. The steady-state flux was reached at a very early stage. * 0.3% eugenol vs. 0.3% clove - similar flux rates

[0149] In these examples, clove oil was obtained from clove leaves. Similar results can be obtained from clove oil derived from clove buds and / or clove stems. Based on this data, similar permeability enhancement results can be predicted from pharmaceutical compounds structurally similar to epinephrine.

[0150] (Example 2: Diazepam solubility and permeability) Diazepam is applied to the oral cavity (cheek) and diffuses through the oral mucosa and directly enters the bloodstream. The solubility of diazepam was also tested with various excipients. Figure 15 shows the effect of enhancers on diazepam permeation, expressed as permeation rate (ug) as a function of time. Figure 16 shows the average flux in μg / cm*min as a function of time (minutes) for diazepam and certain selected enhancers in solution.

[0151] The following excipients were also tested to improve solubility.

[0152] [Table 2]

[0153] The following excipients may also be applied for similar enhancing properties: cinnamon leaf, basil, bay leaf, nutmeg, Kolliphor® TPGS, vitamin E PEG succinate, Kolliphor® EL, polyoxyl 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 (powdered flavoring), Brij 58 (ceteth-20), vitamin E tocopherol, tocopheryl acetate or tocopheryl succinate, sterols, plant extracts, essential oils or cod liver oil.

[0154] The following results were obtained using a diazepam solution with a concentration of 8.00 mg / mL.

[0155] [Table 3]

[0156] (Example 3: General Permeation Method - Exvivo Permeation Test Protocol) In one example, the permeation method is performed as follows: The bath is set to 37°C, the receiver medium is placed in the bath to adjust the temperature, and degassing is initiated. A Franz diffusion cell is obtained and prepared. The Franz diffusion cell comprises a donor compound, a donor chamber, a membrane, a sampling hole, a receptor chamber, a stirring rod, and a heater / circulator. The stirring rod is inserted into the Franz diffusion cell. The tissue is placed on top of the Franz diffusion cell, ensuring that the tissue completely covers the area due to the overlap on the glass joint. The top of the diffusion cell is placed on top of the tissue, and the top of the cell is secured to the bottom with a clamp. Approximately 5 mL of receptor medium is loaded into the receiver area, ensuring that no air bubbles are trapped in the receiving portion of the cell. This ensures that all 5 mL can fit into the receiver area. Stirring is initiated, and the temperature is allowed to equilibrium for approximately 20 minutes. Meanwhile, high-performance liquid chromatography (HPLC) vials are labeled by the number of cells and time point. Afterward, when degassing the solution during heating, you must check for air bubbles again.

[0157] When testing the film, the following steps can be performed: (1) Weigh the film, punch it to match (or smaller than) the diffusion area, weigh it again, and record the weight before and after punching; (2) Wet the donor area with approximately 100 μL of phosphate buffer; (3) Place the film on the donor surface, cover it with 400 μL of phosphate buffer, and start the timer.

[0158] Regarding the solution test, the following steps can be performed: (1) Dispense 500 μL of the solution into each donor cell using a micropipette and start the timer; (2) Sample 200 μL at the following time points (times = 0 min, 20 min, 40 min, 60 min, 120 min, 180 min, 240 min, 300 min, 360 min), place it in a labeled HPLC vial, and tap the sealed vial to ensure that no air is trapped at the bottom of the vial; (3) Replace with 200 μL of receptor medium at each sampling time (maintaining a total volume of 5 mL); (4) Once all time points are complete, disassemble the cell and properly dispose of all material.

[0159] (Example 4: Ex vivo permeability evaluation) Examples of ex vivo permeability evaluation are as follows: 1. Extract a new tissue sample and deliver it at 4°C (for example, overnight). 2. Process the tissue and freeze it at -20°C for up to 3 weeks before use. 3. Take tissue samples to the correct thickness (dermatome). 4. Add approximately 5 mL of receiver medium to the receiver compartment. This medium should be selected to ensure proper sink conditions. 5. Place the tissue in a Franz diffusion cell, which is equipped with a donor compound, a donor chamber, a membrane, a sampling pore, a receptor chamber, a stirring rod, and a heater / circulator. 6. Apply approximately 0.5 mL of donor solution and moisten the 8 mm circular film with 500 μL of PBS buffer. 7. Samples are taken from the receiver chamber at predetermined intervals and replaced with fresh medium.

[0160] (Example 5: Transoral delivery of doxepin) The following is an empirical transmission test of doxepin via oral delivery. This test was conducted under a protocol approved by the Animal Ethics Committee of the University of Barcelona (Spain) and the Animal Ethics Committee of the Autonomous Government of Catalonia (Spain). Three-to-four-month-old female pigs were used. Oral mucosa was excised from the cheek region of the pigs, and the pigs were immediately slaughtered at the Bellvitge Campus (University of Barcelona, ​​Spain) animal facility using an overdose of thiopental sodium anesthetic. Fresh oral tissue was placed in containers filled with Hanks' solution and transferred from the hospital to the laboratory. The remaining tissue samples were stored at -80°C in containers containing a PBS mixture with 4% albumin and 10% DMSO as cryoprotectants.

[0161] For the permeability test, the oral mucosa of pigs was cut into sheets 500 ± 50 μm thick, and these were subjected to a diffusion barrier using an electro-skin collector (GA 630, Aesculap, Tuttlingen, Germany) (Sudhakar et al., "Buccal bioadhesive drug delivery - A promising option for oral less efficient drugs," Journal of Controlled Release, 114 (2006) 15-40), and then trimmed into appropriate small pieces with surgical scissors. Most of the underlying connective tissue was removed with a surgical scalpel.

[0162] Next, the film was made with a diameter of 9 mm (diffusion area 0.636 cm²). 2 The samples were mounted in a specially designed membrane holder with a permeable orifice. Using the membrane holder, the oral endothelium of each pig was placed between a donor compartment (1.5 mL) and a receptor compartment (6 mL), with the epithelial side facing the donor chamber of a static Franz-type diffusion cell (Vidra Foc Barcelona, ​​Spain), and the connective tissue region facing the receiver, thereby preventing foam formation.

[0163] Infinite dosing conditions were ensured by applying 100 μL of saturated doxepin solution as the donor solution to the receptor chamber and immediately sealing it with Parafilm to prevent water evaporation. Before performing this experiment, the diffusion cells were incubated in a water bath for 1 hour to bring the temperature in all cells to equilibrium (37°C ±°C). Each cell contained a small Teflon-coated magnetic stirring rod, which was used to ensure that the fluid in the receptor compartment remained homogeneous during the experiment.

[0164] Sink conditions were ensured in all experiments by first testing the doxepin saturation concentration in the receptor medium. Samples (300 μL) were withdrawn by syringe from the center of the receptor compartment at pre-selected time intervals (0.1, 0.2, 0.3, 0.7, 1, 2, 3, 4, 5, and 6 hours) over a period of 6 hours. The withdrawn sample volume was immediately replaced with the same volume of fresh receptor medium (PBS; pH 7.4), taking care to avoid trapping air under the membrane. Further details can be found in the paper "Transbuccal delivery of doxepin: Studies on permeation and histological evaluation" by A. Gimemo et al., International Journal of Pharmaceutics 477 (2014), 650-654, which is incorporated herein by reference.

[0165] (Example 6: Oral and mucosal delivery) The histological features of porcine oral mucosal tissue are similar to those of human oral mucosal tissue (Heaney TG and Jones RS, "Histological investigation of the influence of adult porcine alveolar mucosal 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., in their paper "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 oral mucosa was not significantly different from that of human oral mucosa, although the floor of the mouth was more permeable in human tissue than in porcine tissue. A comparison between fresh porcine tissue specimens and specimens stored at -80°C revealed that freezing did not have a significant effect on permeability. Oral mucosal absorption in porcine was tested for a wide range of drug molecules both in vitro and in vivo (see, for example, Table 1 in M. Sattar's paper "Oral transmucosal 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 the loading of excised porcine oral tissue into a Ussing chamber, Franz cell, or similar diffusion device. In vivo studies described in this literature involve the application of a drug as a solution, gel, or composition to the oral mucosa of a pig, followed by plasma sampling.

[0166] 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 oral tissue, using caffeine and estradiol as model hydrophilic and lipophilic molecules. Drug permeation through the oral mucosa was tested using a modified wasching chamber. Comparative permeability tests were performed through full-thickness epithelial tissue, fresh tissue, and frozen tissue. Tissue integrity was monitored by absorption of fluorescein isothiocyanate (FITC)-labeled dextran 20 kDa (FD20), and tissue viability was assessed using the MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) biochemical assay and histological evaluation. Permeability through oral epithelium was 1.8 times greater for caffeine and 16.7 times greater for estradiol compared to full-thickness oral tissue. Flux values ​​for both compounds were similar for fresh and frozen oral epithelium, but histological evaluation revealed signs of cell death in the frozen tissue. This tissue appeared to survive up to 12 hours postmortem using the MTT viability assay, which was also confirmed by histological evaluation.

[0167] Kulkarni et al. investigated the relative contributions of epithelium and connective tissue to the barrier properties of oral tissues in pigs. In vitro permeability tests were performed using antipyrine, buspirone, bupivacaine, and caffeine as model permeants. Permeability of model diffusers beyond oral mucosa with thicknesses of 250, 400, 500, 600, and 700 μm was determined. A bilayer membrane model was developed to depict the relative contributions of epithelium and connective tissue to barrier function. The relative contribution of the connective tissue region as a permeability barrier significantly increased with increasing mucosal tissue thickness. Since epithelium represented the major permeability barrier for all diffusers at its thickness, the authors recommended a mucosal tissue thickness of approximately 500 μm for in vitro transoral permeability tests. The authors also investigated the effects of numerous biological and experimental variables on the permeability of the same group of model urinary denaturations in the oral mucosa of pigs (Intraoral mucosa of pigs as an in vitro model: Effects of biological and experimental variables, Kulkarni et al., J Pharm Sci. 2010 99(3):1265-77). Significantly higher permeability of the urinary denaturations was observed in the thinner area on the inside of the lip (170–220 μm) compared to the thicker area on the cheek (250–280 μm). The oral mucosa of pigs maintained its integrity for 24 hours at 4°C in Krebs-Ringer bicarbonate solution. Heat treatment to separate the epithelium from the underlying connective tissue did not adversely affect its permeability and integrity characteristics compared to surgical separation.

[0168] Further details can be found in the paper by 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.

[0169] (Example 7: Cryopreservation of oral mucosa) Different regions of the oral mucosa of pigs exhibit different patterns of permeability, with the lining of the lips showing significantly higher permeability than the buccal region. This is because, in the oral mucosa of pigs, the epithelium acts as a permeability barrier, and the thickness of the buccal epithelium is greater than that of the lining of the lips (Harris and Robinson, 1992). In an illustrative permeability test, fresh and frozen oral mucosa from the same region of pigs was cut into sheets 500 ± 50 μm thick and used as a diffusion barrier (Sudhakar et al., 2006). The samples were obtained using an electrocutaneous skin collector (Model GA 630, Aesculap, Tuttlingen, Germany) and trimmed into appropriate small pieces with surgical scissors. All equipment used was sterilized beforehand. Most of the underlying connective tissue was removed with a surgical scalpel. Next, the membrane was measured in a diameter of 9 mm (diffusion area 0.63 cm²). 2 The samples were mounted in a specially designed membrane holder with a permeable orifice. Using the membrane holder, the oral endothelium of each pig was mounted between a donor compartment (1.5 mL) and a receptor compartment (6 mL), with the epithelial side facing the donor chamber of a static Franz-type diffusion cell (Vidra Foc Barcelona, ​​Spain), and the connective tissue region facing the receiver to prevent foam formation. The experiment was performed using PP, which is used as a model drug and has lipophilic characteristics (logP=1.16; n-octanol / PBS, pH7.4), is easily ionized (ionisable) (pKa=9.50), and has MW=259.3 g / mol (Modamio et al., 2000).

[0170] The condition of unlimited doses was ensured by applying 300 μL of a saturated PP solution in PBS (pH 7.4) (at 37°C ± 1°C, C0 = 588005 ± 5852 μg / mL, n = 6) as the donor solution to the receptor chamber, and immediately sealing it with Parafilm to prevent water evaporation.

[0171] Before conducting this experiment, the diffusion cells were incubated in a water bath for 1 hour to ensure that the temperature inside all cells was in equilibrium (37°C ± 1°C). Each cell contained a small Teflon-coated magnetic stirring rod, which was used to ensure that the fluid in the receptor compartment remained homogeneous during the experiment. Sink conditions were ensured in all experiments after first testing the PP saturation concentration in the receptor medium.

[0172] The sample (300 μL) was withdrawn by syringe from the center of the receptor compartment at the following time intervals: 0.25, 0.5, 1, 2, 3, 4, 5, and 6 hours. Taking care to avoid trapping air under the skin, the withdrawn sample volume was immediately replaced with the same volume of fresh receptor medium (PBS; pH 7.4). Mucosa unit surface area (cm²) 2 The cumulative amount of drug (μg) penetrating the sample was corrected for the removed sample and plotted against time (h). This diffusion experiment was performed 27 times on fresh oral mucosa and 22 times on frozen oral mucosa.

[0173] Further details can be found in the paper by S. Amores, "An improved cryopreservation method for porcine buccal mucosa in ex vivo drug permeation studies using Franz diffusion cells," European Journal of Pharmaceutical Sciences 60 (2014) 49-54.

[0174] (Example 8: Quinine permeation beyond the sublingual mucosal compartment) Because the oral membranes of pigs and humans are similar in composition, structure, and permeability measurements, the porcine oral mucosa is a suitable model for the human oral mucosa. Permeability exceeding that of the porcine oral mucosa is not linked to metabolism and is therefore not important for tissue survival.

[0175] To prepare the porcine membrane, the mucous membranes of the floor of the mouth and the ventral (lower) tongue of pigs were excised by blunt resection using a surgical scalpel. The excised mucous membranes were cut into approximately 1 cm squares and frozen on aluminum foil at -20°C until use (<2 weeks). For the ventral surface of the pig's tongue that was not frozen, this mucous membrane was used in a permeability test within 3 hours of excision.

[0176] The membrane permeability to quinine was determined using a nominal receptor volume of 3.6 mL and a diffusion area of ​​0.2 cm². 2 The determination was made using an all-glass Franz diffusion cell. The flange of this cell was smoothed with high-performance vacuum grease, and the membrane was placed between the receptor compartment and the donor compartment with the mucosal surface facing upwards. A clamp was used to hold the membrane in place, and then the receptor compartment was filled with degassed phosphate-buffered saline (PBS) pH 7.4. A micromagnetic stirrer was added to the receptor compartment, and the complete cell was placed in a 37°C water bath. The membrane was equilibrated with PBS applied to the donor compartment for 20 minutes, and then aspirated with a pipette. 5 μL of quinine solution in a different vehicle or 100 μL of saturated solution of Q / 2-HP-β-CD complex aliquots were applied to each donor compartment. In a test to determine the effect of saliva on quinine permeation beyond the ventral surface of the tongue, 100 μL of sterile saliva was added to a donor compartment, followed by 5 μL of quinine solution.

[0177] At 2, 4, 6, 8, 10, and 12 hours, the receptor phase was withdrawn from the sampling well, and a 1 mL aliquot of the sample was transferred to an HPLC automated sampler vial and replaced with fresh PBS stored at 37°C. Separately from the tests involving the Q / 2-HP-β-CD saturated solution (where an unlimited dose was applied at the start of the experiment), 5 μL of each quinine solution was again applied to the donor phase over a maximum of 10 hours. The purpose of this was to represent a hypothetical finite dosing regimen based on a 2-hour interval between doses. At least three replicates were performed for each test.

[0178] Further details can be found in the article by C. Ong, "Permeation of quinine across sublingual mucosa, in vitro," International Journal of Pharmaceutics 366 (2009) 58-64.

[0179] (Example 9: Ex vivo initial test - API formation) In this example, the permeation of in situ solubilized epinephrine base versus intrinsically soluble epinephrine bitartrate was tested, and no difference was observed. Epinephrine bitartrate was selected for further development based on its ease of processing. The flux is derived as the gradient of permeation as a function of time. The steady-state flux was extrapolated from the plateau of the flux versus time curve, which was integrated by the volume of the receiver medium. The graph in Figure 2A shows the average permeation versus time for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized epinephrine base. The graph in Figure 2B shows the average flux versus time for 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized epinephrine base.

[0180] [Table 4]

[0181] (Example 10: Concentration dependence on permeation / flux) In this study, the ex vivo permeability of epinephrine bitartrate as a function of concentration was investigated. Figure 3 shows the ex vivo permeability of epinephrine bitartrate as a function of concentration. This study compared concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL. The results showed that permeability increased with increasing concentration, and the level of enhancement decreased at higher loads. This study compared concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL.

[0182] [Table 5]

[0183] (Example 11: Effect of pH) In this example, the permeability of epinephrine bitartrate as a function of solution pH was tested. This example also investigated whether acidic conditions have the ability to promote stability. The results showed that pH 5 was slightly preferable to pH 3. The intrinsic pH of epinephrine bitartrate in the concentrations tested was 4.5–5. pH adjustment with buffer was not necessary.

[0184] Figure 4 shows the permeability of epinephrine bitartrate as a function of solution pH. We investigated whether acidic conditions promote stability. The results compared epinephrine bitartrate pH3 buffer and epinephrine bitartrate pH5 buffer, and found that the epinephrine bitartrate pH5 buffer was slightly preferable.

[0185] (Example 12: Effect of enhancer on epinephrine permeation) In this example, the permeation of epinephrine for transmucosal delivery was tested as permeation amount (μg) versus time (minutes). The following enhancers were screened for their concentration-based effects in a solution containing 16.00 mg / mL of epinephrine. The graph in Figure 5 shows the results of these enhancers as a function of time.

[0186] [Table 6]

[0187] The enhancers were selected and designed to have functionalities that affect various barriers in the mucosa. All tested enhancers improved permeability over time, but clove oil and labrasol showed particularly significant and unexpectedly high permeability enhancements.

[0188] [Table 7] TIFF0007867321000008.tif223170TIFF0007867321000009.tif221170TIFF0007867321000010.tif77170

[0189] (Example 13: Effect of enhancer on epinephrine release) To determine the effect of enhancers (labrasol and clove oil) on epinephrine release, epinephrine release profiles were tested. Figure 6A shows epinephrine release from different polymer platforms. Figure 6B shows the effect of enhancers on epinephrine release. These results showed that the permeation stabilized between approximately 3250 and 4250 μg after about 40 minutes. The tested enhancers did not restrict the release of epinephrine from the matrix.

[0190] (Example 14: Enhanced Stability) Variations of stabilizer loading were tested.

[0191] [Table 8]

[0192] (Example 15: Effect of Enhancer) A pharmacokinetic model was tested in male Yucatan miniature pigs. The graph in Figure 7 shows the results of the pharmacokinetic model in male Yucatan miniature pigs. This study compares 0.3 mg EpiPen, 0.12 mg epinephrine IV, and placebo.

[0193] Figure 8 shows the effect of the absence of enhancer on the concentration profiles of 0.3 mg EpiPen and 40 mg epinephrine film without enhancer.

[0194] Figure 9 shows the effect of enhancer 3% labrazol on the concentration profiles of 40 mg epinephrine film versus 0.3 mg EpiPen. Figure 10 shows the effect of enhancer L (clove oil) on the concentration profiles of two types of 40 mg epinephrine films (10-1-1) and (11-1-1) versus 0.3 mg EpiPen.

[0195] In addition, the effects of film dimensions and clove oil (3%) are shown in Figure 11. This study compared 0.30 mg EpiPen (n=4), 40 mg epinephrine film (10-1-1) (n=5), and 40 mg epinephrine film (11-1-1) (n=5). The figures show the concentration, vs. time profiles after sublingual or intramuscular administration of epinephrine to male miniature pigs.

[0196] The studies were conducted by varying the ratio of epinephrine to enhancer. These studies also measured the concentration, versus time profile after sublingual or intramuscular administration of epinephrine to male miniature pigs. Variations in the ratio of epinephrine to clove oil (enhancer L) resulted in the outcomes shown in Figure 12. This study performed a comparison of 0.30 mg EpiPen (n=4), 40 mg epinephrine film (12-1-1) (n=5), and 20 mg epinephrine film (13-1-1) (n=5).

[0197] (Example 16) Varying doses were performed in a constant matrix using enhancer labrazol (3%) and clove oil (3%), as shown in Figures 13 and 14, respectively. The tests in Figure 13 compared 0.30 mg EpiPen (n=4), 40 mg epinephrine film (18-1-1) (n=5), and 30 mg epinephrine film (20-1-1) (n=5). The tests in Figure 14 compared 0.30 mg EpiPen (n=4), 40 mg epinephrine film (19-1-1) (n=5), and 30 mg epinephrine film (21-1-1) (n=5). These tests also showed concentration, versus time profiles after sublingual or intramuscular epinephrine administration to male miniature pigs.

[0198] (Example 17) To determine the time-dependent effect of the enhancer (farnesol) on epinephrine concentration, a pharmacokinetic model was tested in male miniature pigs. The graph in Figure 17 shows the plasma epinephrine concentration (ng / mL) as a function of time (minutes) after sublingual or intramuscular administration of the farnesol permeable enhancer. This study compared 0.3 mg EpiPen (n=3), 30 mg epinephrine film 31-1-1 (n=5), and 30 mg epinephrine film 32-1-1 (n=5), each epinephrine film formulated with the farnesol enhancer. As shown in this figure, the 31-1-1 film demonstrated enhanced stability of epinephrine concentration, starting from approximately 30-40 minutes and continuing up to approximately 130 minutes.

[0199] The graph in Figure 18 is obtained from the same study as in Figure 17, but it primarily shows data points comparing 0.3 mg EpiPen with 30 mg epinephrine film 31-1-1 (n=5).

[0200] The graph in Figure 19 is obtained from the same study as in Figure 17, but it primarily shows data points comparing 0.3 mg EpiPen with 30 mg epinephrine film 32-1-1 (n=5).

[0201] (Example 18) Regarding Figure 20, this graph shows a pharmacokinetic model in male miniature pigs tested to determine the effect of the enhancer (farnesol) on epinephrine concentration over time after sublingual or intramuscular administration. Epinephrine plasma concentration (ng / mL) is shown as a function of time (minutes) after sublingual or intramuscular administration of the farnesol permeation enhancer in the epinephrine film. This study compared data from three 0.3 mg EpiPens with five 30 mg epinephrine films (32-1-1). This data shows epinephrine films that exhibit enhanced stability of epinephrine concentration from approximately 20-30 minutes to approximately 130 minutes.

[0202] (Example 19) In one embodiment, the epinephrine pharmaceutical composition film can be manufactured by the following formulation:

[0203] [Table 9]

[0204] (Example 20) The epinephrine pharmaceutical composition film was manufactured using the following formulation:

[0205] [Table 10]

[0206] (Example 21) In another embodiment, the pharmaceutical film composition was manufactured according to the following formulation:

[0207] [Table 11]

[0208] (Example 22) In another embodiment, the pharmaceutical film composition was manufactured according to the following formulation:

[0209] [Table 12]

[0210] (Example 23) Regarding Figure 21, this graph shows a pharmacokinetic model (logarithmic scale) in male miniature pigs tested to determine the effect of enhancers (6% clove oil and 6% labrasol) on the time course of epinephrine plasma concentration after sublingual or intramuscular administration. Epinephrine plasma concentration (ng / mL) is shown as a function of time (minutes) after sublingual or intramuscular administration of the farnesol permeable enhancer in the epinephrine film. This data shows an epinephrine film in which the film exhibits enhanced stability of epinephrine concentration, starting from approximately 10 minutes to about 30 minutes and continuing until approximately 100 minutes.

[0211] Regarding Figure 22, this graph shows the pharmacokinetic model of the epinephrine film formulation in male miniature pigs, as mentioned in Figure 21, compared to the mean data collected from 0.3 mg EpiPen (indicated by diamond-shaped data points). As this data shows, the mean plasma concentration of 0.3 mg EpiPen peaked between 0.5 and 1 ng / mL. In contrast, the epinephrine film formulation peaked between 4 and 4.5 ng / mL.

[0212] (Example 24) Regarding Figure 23, this graph shows a pharmacokinetic model in male miniature pigs tested to determine the effect of the enhancer (9% clove + 3% labrazol) on the time course of epinephrine concentration after sublingual or intramuscular administration across seven animal models. The overall peak concentration was reached between 10 and 30 minutes.

[0213] (Example 25: Alprazolam data) Figures 24A, 24B, and 24B show data from a male miniature pig study comparing the time-dependent (hourly) alprazolam plasma concentrations after sublingual administration of oral alprazolam disintegrating tablets (ODTs) and alprazolam pharmaceutical composition films.

[0214] Figure 24A shows the average data from alprazolam ODT (Group 1). Peak concentrations between 7 and 12 ng / mL were reached in approximately 1 to 8 hours.

[0215] Figure 24B shows the average data from the alprazolam pharmaceutical composition film (group 2). Peak concentrations between 5 and 17 ng / mL, including those greater than 5 ng / mL, greater than 10 ng / mL, greater than 12 ng / mL, greater than 15 ng / mL, greater 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, were reached in 10 to 4 hours, including those longer than 10 minutes, longer than 20 minutes, longer than 30 minutes, longer than 45 minutes, longer than 1 hour, longer than 1.5 hours, longer than 2 hours, longer than 2.5 hours, longer than 3 hours, longer 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.

[0216] Figure 24C shows the mean data from alprazolam pharmaceutical composition films from another group of male miniature pigs (Group 3). Peak concentrations of 5–17 ng / mL were reached in 10 minutes to 4 hours, including longer than 10 minutes, longer than 20 minutes, longer than 30 minutes, longer than 45 minutes, longer than 1 hour, longer than 1.5 hours, longer than 2 hours, longer than 2.5 hours, longer than 3 hours, longer than 3.5 hours, and 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.

[0217] (Example 26) Regarding Figure 25A, this graph illustrates data from a male miniature pig study comparing the time-course (hourly) alprazolam plasma concentrations after sublingual administration of two groups: oral alprazolam disintegrating tablets (ODTs) (shown as circular data points) and alprazolam pharmaceutical composition films (shown as square and triangular data points).

[0218] As this graph shows, data from the alprazolam pharmaceutical composition films (both groups) yielded relatively high alprazolam plasma concentrations of approximately 15-25 mg / mL in treatment windows of approximately 30 minutes or less, including longer than 10 minutes, longer than 20 minutes, approximately 30 minutes, longer than 30 minutes, less than 30 minutes, less than 20 minutes, less than 15 minutes, or less than 10 minutes.

[0219] Regarding Figure 25B, this graph shows individual data points from the tests mentioned in Figure 25A.

[0220] Regarding Figure 25C, this graph shows individual data points from the experiment mentioned in Figure 25A for the 0-1 hour period.

[0221] Regarding Figure 26A, this graph shows the individual data points for alprazolam ODT mentioned in Figure 25C.

[0222] Regarding Figure 26B, this graph shows the individual data points for the alprazolam drug film mentioned in Figure 25C.

[0223] Regarding Figure 26C, this graph shows the individual data points for the alprazolam drug film (second group) mentioned in Figure 25C.

[0224] The data from the graph mentioned earlier is also summarized in the table below.

[0225] [Table 13]

[0226] (Example 27) With respect to FIG. 27A, this figure illustrates mean data from a male minipig study comparing alprazolam plasma concentration over time after sublingual administration of oral alprazolam disintegrating tablets (ODT) (shown as circular data points) and two groups of alprazolam pharmaceutical composition films (shown as square and triangular data points). As the data show, 0.5 mg alprazolam ODT reached peak concentrations in the range of about 5 - 6 ng / mL between 0 and 4 hours, including longer than 10 minutes, longer than 20 minutes, longer than 30 minutes, longer than 45 minutes, longer than 1 hour, longer than 1.5 hours, longer than 2 hours, longer than 2.5 hours, longer than 3 hours, longer 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 0.5 mg alprazolam pharmaceutical composition film reached peak concentrations of about 7 - 8 ng / mL and 6 - 7 ng / mL, respectively, between 0 and 4 hours, including longer than 10 minutes, longer than 20 minutes, longer than 30 minutes, longer than 45 minutes, longer than 1 hour, longer than 1.5 hours, longer than 2 hours, longer than 2.5 hours, longer than 3 hours, longer 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.

[0227] With respect to FIG. 27B, this graph shows mean data of alprazolam plasma concentration over time after sublingual administration of oral alprazolam disintegrating tablets (ODT) (shown as circular data points) and two groups of alprazolam pharmaceutical composition films (shown as square and triangular data points) between 0 and 2 hours. Different from the ODT, the therapeutic window of the alprazolam pharmaceutical composition film started at 10 - 15 minutes, whereas the ODT started at approximately 17 - 20 minutes.

[0228] With respect to FIG. 27C, this graph illustrates the complete data mentioned in FIG. 27B for ODT (n = 4), 0.5 mg alprazolam pharmaceutical composition film 14 - 1 - 1 (n = 5), and 0.5 mg alprazolam pharmaceutical composition film 15 - 1 - 1 (n = 5).

[0229] The data from the graph mentioned above is also summarized in the following table.

[0230]

Table 14

[0231] All references listed in this specification are hereby incorporated by reference in their entirety. Other embodiments are within the scope of the following claims. This application provides the invention in the following embodiments. (Aspect 1) A pharmaceutical composition: Polymer matrix; The pharmaceutically active ingredients in this polymer matrix; and Adrenaline receptor interacting substances: The pharmaceutical composition containing the above. (Aspect 2) The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition further comprises a permeation enhancer. (Aspect 3) The pharmaceutical composition according to embodiment 1, wherein the adrenergic receptor interacting substance comprises a terpenoid, a terpene, or a sesquiterpene. (Aspect 4) The pharmaceutical composition according to embodiment 2, wherein the permeation enhancer comprises farnesol. (Aspect 5) The pharmaceutical composition according to embodiment 2, wherein the permeation enhancer comprises labrasol. (Aspect 6) The pharmaceutical composition according to embodiment 2, wherein the permeation enhancer contains linoleic acid. (Aspect 7) The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition contains a polymer matrix and a pharmaceutically active ingredient contained in the polymer matrix. (Pattern 8) The pharmaceutical composition according to any one of embodiments 1 to 7, wherein the adrenergic receptor interacting substance comprises a phenylpropanoid. (Aspect 9) The pharmaceutical composition according to embodiment 8, wherein the phenylpropanoid is eugenol. (Aspect 10) The pharmaceutical composition according to embodiment 8, wherein the phenylpropanoid is eugenol acetate. (Aspect 11) The pharmaceutical composition according to embodiment 8, wherein the phenylpropanoid is cinnamic acid. (Aspect 12) The pharmaceutical composition according to embodiment 8, wherein the phenylpropanoid is a cinnamic acid ester. (Aspect 13) The pharmaceutical composition according to embodiment 8, wherein the phenylpropanoid is cinnamaldehyde. (Aspect 14) The pharmaceutical composition according to embodiment 8, wherein the phenylpropanoid is hydrocinnamic acid. (Aspect 15) The pharmaceutical composition according to embodiment 8, wherein the phenylpropanoid is chavicol. (Aspect 16) The pharmaceutical composition according to embodiment 8, wherein the phenylpropanoid is safrole. (Aspect 17) The pharmaceutical composition according to embodiment 1, wherein the adrenergic receptor interacting substance is a plant extract. (Aspect 18) The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises an essential oil extract of the clove plant. (Aspect 19) The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises an essential oil extract of clove plant leaves. (Aspect 20) The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises an essential oil extract of the flower buds of a clove plant. (Aspect 21) The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises an essential oil extract of the stem of a clove plant. (Aspect 22) The pharmaceutical composition according to embodiment 17, wherein the plant extract is a synthetic or biosynthetic product. (Aspect 23) The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises 40-95% eugenol. (Aspect 24) The pharmaceutical composition according to embodiment 17, wherein the plant extract further comprises 80-95% eugenol. (Aspect 25) The pharmaceutical composition according to embodiment 1, wherein the pharmaceutically active ingredient is epinephrine. (Aspect 26) The pharmaceutical composition according to embodiment 1, wherein the pharmaceutically active ingredient is diazepam. (Aspect 27) The pharmaceutical composition according to embodiment 1, wherein the pharmaceutically active ingredient is alprazolam. (Aspect 28) The pharmaceutical composition according to embodiment 1, wherein the polymer matrix comprises a polymer. (Aspect 29) The pharmaceutical composition according to embodiment 28, wherein the polymer is a water-soluble polymer. (Aspect 30) The pharmaceutical composition according to embodiment 28, wherein the polymer comprises a cellulosic polymer selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, methylcellulose, and carboxymethylcellulose. (Aspect 31) The pharmaceutical composition according to embodiment 28, wherein the polymer comprises polyethylene oxide. (Aspect 32) The pharmaceutical composition according to embodiment 28, wherein the polymer matrix comprises a cellulosic polymer, polyethylene oxide and polyvinylpyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide, hydroxypropyl methylcellulose and polysaccharide, or polyethylene oxide, hydroxypropyl methylcellulose, polysaccharide and polyvinylpyrrolidone. (Aspect 33) The pharmaceutical composition according to embodiment 28, wherein the polymer matrix comprises at least one polymer selected from the group consisting of pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, acacia gum, 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. (Aspect 34) The pharmaceutical composition according to embodiment 1, further containing a stabilizer. (Aspect 35) The pharmaceutical composition according to embodiment 1, wherein the polymer matrix comprises a dendritic polymer. (Aspect 36) The pharmaceutical composition according to embodiment 1, wherein the polymer matrix comprises a highly branched polymer. (Aspect 37) A method for producing a pharmaceutical composition: A process of combining an adrenaline receptor interacting substance with a pharmaceutical active ingredient; and The method comprising the step of forming a pharmaceutical composition containing an adrenaline receptor interacting substance and a pharmaceutically active ingredient. (Aspect 38) It is a device: Polymer matrix; The pharmaceutically active ingredients in this polymer matrix; and A housing for holding a certain amount of a pharmaceutical composition containing a permeation enhancer comprising phenylpropanoids and / or plant extracts; and The apparatus comprising: an opening for dispensing a predetermined amount of pharmaceutical composition. (Aspect 39) A pharmaceutical composition: Polymer matrix; The pharmaceutically active ingredients in this polymer matrix; and The pharmaceutical composition comprising a permeation enhancer containing phenylpropanoids and / or plant extracts. (Approach 40) The pharmaceutical composition according to embodiment 39, wherein the phenylpropanoid is eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamaldehyde, hydrocinnamic acid, chavicol, or safrole. (Aspect 41) The pharmaceutical composition according to embodiment 39, wherein the plant extract comprises an essential oil extract of the clove plant. (Aspect 42) The method according to embodiment 17, wherein the plant extract further comprises an essential oil extract of clove plant leaves, an essential oil extract of clove plant flower buds, or an essential oil extract of clove plant stems. (Aspect 43) The pharmaceutical composition according to embodiment 17, wherein the plant extract is a synthetic or biosynthetic product. (Aspect 44) The pharmaceutical composition according to embodiment 39, wherein the plant extract further comprises 40-95% eugenol. (Aspect 45) The pharmaceutical composition according to embodiment 39, wherein the plant extract further comprises 80-95% eugenol. (Aspect 46) The pharmaceutical composition according to embodiment 39, wherein the pharmaceutically active ingredient is epinephrine. (Aspect 47) The pharmaceutical composition according to embodiment 39, wherein the pharmaceutically active ingredient is diazepam. (Aspect 48) The pharmaceutical composition according to embodiment 39, wherein the pharmaceutically active ingredient is alprazolam. (Aspect 49) The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a polymer. (Appearance 50) The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a water-soluble polymer. (Aspect 51) The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises polyethylene oxide. (Appearance 52) The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a cellulosic polymer selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose. (Aspect 53) The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises hydroxypropyl methylcellulose. (Aspect 54) The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a cellulosic polymer, polyethylene oxide and polyvinylpyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide, hydroxypropyl methylcellulose and polysaccharide, or polyethylene oxide, hydroxypropyl methylcellulose, polysaccharide and polyvinylpyrrolidone. (Aspect 55) The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises at least one polymer selected from the group consisting of pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, acacia gum, 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. (Aspect 56) The pharmaceutical composition according to embodiment 39, further containing a stabilizer. (Aspect 57) The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a dendritic polymer. (Pattern 58) The pharmaceutical composition according to embodiment 39, wherein the polymer matrix comprises a highly branched polymer. (Aspect 59) The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition is in the form of a chewable or gelatin-based dosage form, a spray, a gum, a gel, a cream, a tablet, a liquid, or a film.

Claims

1. An oral pharmaceutical composition for administration via the oral mucosa or sublingual mucosa, comprising: Polymer matrix comprising polyethylene oxide, cellulosic polymer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polysaccharide, polyethylene oxide and polyvinylpyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide and hydroxypropyl methylcellulose and polysaccharide, polyethylene oxide and hydroxypropyl methylcellulose and polysaccharide and polyvinylpyrrolidone, cellulosic polymer and polysaccharide, cellulosic polymer and polyvinylpyrrolidone, hydroxypropyl methylcellulose and polyvinylpyrrolidone, dendritic polymer, or highly branched polymer; A pharmaceutically active ingredient containing a benzodiazepine in the polymer matrix; and Adrenaline receptor interacting substances containing terpenoids that enhance the transmucosal penetration of benzodiazepines: The pharmaceutical composition containing the above.

2. The pharmaceutical composition according to claim 1, wherein the adrenergic receptor interacting substance is a terpenoid, terpene, or sesquiterpene.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a permeation enhancer, preferably the permeation enhancer comprises farnesol, labrasol, or linoleic acid.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains a polymer matrix and a pharmaceutically active ingredient contained in the polymer matrix.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the adrenergic receptor interacting substance comprises a phenylpropanoid, and preferably the phenylpropanoid is selected from eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamaldehyde, hydrocinnamic acid, chavicol, and safrole.

6. The pharmaceutical composition according to claim 1, wherein the adrenergic receptor interacting substance is a plant extract, and the plant extract is further an essential oil extract of clove plant, an essential oil extract of clove plant leaves, an essential oil extract of clove plant flower buds, or an essential oil extract of clove plant stems.

7. The pharmaceutical composition according to claim 1, wherein the polymer matrix comprises a water-soluble polymer, a dendritic polymer, or a highly branched polymer.

8. A method for producing a pharmaceutical composition for oral or sublingual administration: A step of combining an adrenergic receptor interacting substance containing a terpenoid that enhances the transmucosal permeability of benzodiazepines with a pharmaceutically active ingredient containing a benzodiazepine; and The method comprising the step of forming a pharmaceutical composition containing the adrenergic receptor interacting substance and the pharmaceutically active ingredient.

9. It is a device: Polymer matrix comprising polyethylene oxide, cellulosic polymer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polysaccharide, polyethylene oxide and polyvinylpyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide and hydroxypropyl methylcellulose and polysaccharide, polyethylene oxide and hydroxypropyl methylcellulose and polysaccharide and polyvinylpyrrolidone, cellulosic polymer and polysaccharide, cellulosic polymer and polyvinylpyrrolidone, hydroxypropyl methylcellulose and polyvinylpyrrolidone, dendritic polymer, or highly branched polymer; A pharmaceutically active ingredient containing a benzodiazepine in the polymer matrix; and A housing for holding a certain amount of a pharmaceutical composition for oral or sublingual administration containing a permeation enhancer comprising phenylpropanoids and / or plant extracts; and The apparatus comprising: an opening for dispensing a predetermined amount of the pharmaceutical composition.

10. A pharmaceutical composition for oral mucosal administration or sublingual mucosal administration, comprising: Polymer matrix comprising polyethylene oxide, cellulosic polymer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polysaccharide, polyethylene oxide and polyvinylpyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide and hydroxypropyl methylcellulose and polysaccharide, polyethylene oxide and hydroxypropyl methylcellulose and polysaccharide and polyvinylpyrrolidone, cellulosic polymer and polysaccharide, cellulosic polymer and polyvinylpyrrolidone, hydroxypropyl methylcellulose and polyvinylpyrrolidone, dendritic polymer, or highly branched polymer; A pharmaceutically active ingredient containing a benzodiazepine in the polymer matrix; and The pharmaceutical composition comprising: a permeation enhancer containing phenylpropanoids and / or plant extracts.

11. The pharmaceutical composition according to claim 10, wherein the phenylpropanoid is eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamaldehyde, hydrocinnamic acid, chavicol, or safrole, or the plant extract comprises an essential oil extract of the clove plant.

12. The pharmaceutical composition according to claim 6 or 10, wherein the plant extract is a synthetic or biosynthetic product, or the plant extract further comprises 40-95% eugenol, or the plant extract further comprises 80-95% eugenol.

13. The pharmaceutical composition according to claim 1 or 10, wherein the pharmaceutically active ingredient is diazepam or alprazolam.

14. The aforementioned polymer matrix comprises a polymer, where, (a) The polymer comprises a cellulosic polymer selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, methylcellulose, and carboxymethylcellulose, or (b) The polymer contains polyethylene oxide or (c) The polymer matrix comprises a cellulosic polymer, polyethylene oxide and polyvinylpyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide, hydroxypropyl methylcellulose and polysaccharide, or polyethylene oxide, hydroxypropyl methylcellulose, polysaccharide and polyvinylpyrrolidone, or (d) The polymer matrix comprises at least one polymer selected from the group consisting of pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, acacia gum, 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. The pharmaceutical composition according to claim 1 or 10.

15. The pharmaceutical composition according to claim 1 or 10, further containing a stabilizer.

Images