Pharmaceutical compositions with enhanced permeation

Abstract

To provide pharmaceutical compositions having enhanced active component permeation properties.SOLUTION: A pharmaceutical composition comprises a pharmaceutically active component in a polymeric matrix and an adrenergic receptor interacter.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Claiming priority) This application is hereby granted by reference in its entirety under Section 119(e) of the United States Patent Act (35 U.S.C). The priority of U.S. Patent Application No. 62 / 331,993, filed on May 5, 2016, is incorporated within this document. It asserts a right.

[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. (Film is used.) The delivery of drugs or pharmaceuticals percutaneously or transmucosally is effective and efficient. Therefore, it may be necessary to permeate or otherwise traverse biological membranes. [Overview of the project]

[0004] (summary) Generally speaking, pharmaceutical compositions consist of a polymer matrix and pharmaceutically active compounds within this polymer matrix. It may contain a substance and an adrenergic receptor interacting substance. The pharmaceutical composition may further contain a permeation enhancer. Adrenergic receptor phase The interacting agent can be an adrenergic receptor blocker. This permeation enhancer is Furthermore, it can be a flavonoid or used in combination with a flavonoid.

[0005] In one embodiment, the adrenergic receptor interacting substance is a terpenoid, terpe This can be an alcohol or a C3-C22 alcohol or acid. This adrenergic receptor interaction The substance can be a sesquiterpene. In certain embodiments, the adrenoceptor interacting substance can include farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, or docosapentaenoic acid, or combinations thereof.

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

[0007] this polymeric matrix. In certain embodiments, the adrenoceptor interacting substance can

[0008] be a plant extract.

[0009] In certain embodiments, the permeation enhancer can be a plant extract.

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

[0011] In certain embodiments, the pharmaceutical composition can include

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

[0013] a saturated or unsaturated alcohol.

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

[0015] In another embodiment, the phenylpropanoid may be eugenol. In one embodiment, the phenylpropanoid can be eugenol acetate. In one embodiment, the phenylpropanoid can be cinnamic acid. In this embodiment, the phenylpropanoid may be a cinnamic acid ester. In this embodiment, the phenylpropanoid may be cinnamaldehyde.

[0016] In other embodiments, the phenylpropanoid may be hydrocinnamic acid. In one embodiment, the phenylpropanoid can be chavicol. In this embodiment, the phenylpropanoid may be safrole.

[0017] In one embodiment, this plant extract could be an essential oil extract of the clove plant. In another embodiment, the plant extract is an essential oil extract of the leaves of the clove plant. This can be done. This plant extract can be an essential oil extract of the flower buds of the clove plant. In this embodiment, the plant extract may be an essential oil extract from the stem of the clove plant. .

[0018] In one embodiment, the plant extract can be synthesized. Furthermore, this plant extract contains 20-95% eugenol and 40-95% eugenol. and can also contain 60-95% eugenol. In one embodiment, the plant extract The substance can 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 active pharmaceutical ingredient may be alprazolam. In one embodiment, the polymer matrix may contain polymers. In this context, the polymer may contain a water-soluble polymer.

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

[0023] In one embodiment, the polymer can be a cellulose-based polymer. In one embodiment, the cellulose polymer is hydroxypropylmethylcellulose. hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl Cellulose, methylcellulose, carboxymethylcellulose and / or carboxymethylcellulose It can be sodium cellulose.

[0024] In one embodiment, the polymer contains hydroxypropylmethylcellulose. It is possible.

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

[0026] In one embodiment, the polymer is polyethylene oxide and / or polyvinyl acetate. It can include Loridon.

[0027] In one embodiment, the polymer matrix is ​​polyethylene oxide and / or poly It can contain sugar.

[0028] In one embodiment, the polymer matrix is ​​polyethylene oxide, hydroxy It may contain propylmethylcellulose and / or polysaccharides.

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

[0030] In one embodiment, the polymer matrix is ​​selected from at least the following group It may contain one polymer: pullulan, polyvinylpyrrolidone, polyvinyl alcohol Coal, sodium alginate, polyethylene glycol, xanthan gum, tragacan Guam, guar gum, acacia gum, acacia gum, polyacrylic acid, methyl methacrylate Ethylene copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide propylene oxide, propylene oxide copolymer, collagen, albumin, poly Amino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and their derivatives.

[0031] In one embodiment, the pharmaceutical composition may further contain a stabilizer. Antioxidants can prevent the undesirable oxidation of substances by forming chelate complexes, Otherwise, metal ion saturation can deactivate trace amounts of metal ions that act as catalysts. Chaining agents, emulsifiers and surfactants that can stabilize emulsions, and substances irradiated with ultraviolet light. UV stabilizers that can protect against harmful effects, absorb UV irradiation and thus the composition UV absorbers are chemicals that prevent penetration, and instead of breaking chemical bonds... A quencher that can dissipate radiant energy as heat, or formed by ultraviolet irradiation. It may include a scavenger that can eliminate free radicals.

[0032] In yet another embodiment, the pharmaceutical composition is bound by linkage to a hydrophilic saccharide. Suitable non-toxic, non-ionic alkyl glycosides having a hydrophobic alkyl group are selected from the following: In combination with a selected mucosal delivery promoter, it may include: (a) aggregation inhibitors; (b) charge modifiers; (c) pH adjusters. (d) Degrading enzyme inhibitors; (e) Mucolytic agents or mucosal removers; (f) Ciliary quiescent agents agent); (g) membrane permeability enhancer selected from the following: (i) surfactant; (ii) bile salt; (ii) phosphorus Lipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines (v) Nitric oxide donor compounds; (vi) Long-chain amphiphilic molecules; (vii) Small hydrophobic permeation enhancers (viii) sodium or salicylic acid derivatives; (ix) glycerol ester of acetoacetic acid; (x ) Cyclodextrin or β-cyclodextrin derivative; (xi) Medium-chain fatty acid; (xii) Clean (xiii) amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (xv) (ix) enzymes that degrade selected membrane components; (x) inhibitors of fatty acid synthesis; (x) cholesterol Synthetic inhibitors; and any combination of membrane penetration enhancers listed in (xi)(i)-(x); (h) (i) Epithelial junction physiological function modifiers; (j) Vasodilators; (k) Selective transport promoters; and (k ) and the compound is effectively combined, associated, included, encapsulated or bound, and enhanced. Stabilized delivery vehicle, carrier, mucosal adhesion, resulting in compound stabilization for mucosal delivery. A substance, support, or complex-forming species of the compound, wherein the compound is accompanied by a transmucosal delivery enhancer. The formulation provides increased bioavailability of the compound in the target plasma.

[0033] Generally, the method for producing a pharmaceutical composition involves using an adrenaline receptor interacting substance as the pharmaceutically active ingredient. A pharmaceutical composition containing an adrenergic receptor interacting substance and a pharmaceutically active ingredient. It may include forming

[0034] This pharmaceutical composition is available in chewable or gelatin-based dosage forms, sprays, gums, gels, and creams. It can be a foam, tablet, liquid, or film.

[0035] Generally, pharmaceutical compositions can be dispensed from an apparatus. This apparatus can dispense chewable or gelatin tablets. As a base dosage form, spray, gum, gel, cream, tablet, liquid or film, The pharmaceutical composition can be dispensed in the determined dosage. The device uses a polymer matrix. ;Pharmacologically active ingredients in this polymer matrix;and adrenaline receptor interacting substances A housing that holds a certain amount of pharmaceutical composition, and a predetermined amount of pharmaceutical composition The apparatus may be equipped with an opening for dispensing the material. The apparatus may also contain phenylpropanoid and Alternatively, a pharmaceutical composition containing a permeation enhancer containing a plant extract can be dispensed. .

[0036] In one embodiment, the pharmaceutical composition is a polymer matrix, this polymer matrix The pharmaceutically active ingredients contained therein; and permeable enhancers containing phenylpropanoids and / or plant extracts. It can contain sensors.

[0037] Other aspects, embodiments, and features will become apparent from the following description, drawings, and claims. Ro. [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) The mucosal surface, such as the oral mucosa, is highly vascularized and permeable, allowing air to pass through the digestive system. Having nothing to do, and thus avoiding first-pass metabolism, increased biological utilization Due to the fact that it provides rapid onset of activity and action, the mucosal surface is suitable for drug delivery to the body. This is a convenient route for that purpose. In particular, oral tissues and sublingual tissues have a high degree of permeability to the oral mucosa. This is a region that allows for drug diffusion from the oral mucosa to have direct access to the systemic circulation. Because of this, these tissues provide favorable sites for drug delivery. This also means that This leads to increased convenience and therefore increased patient compliance. Certain drugs or Regarding the active pharmaceutical ingredient, the permeability enhancer overcomes the mucosal barrier and improves permeability. It can assist in this process. The permeation enhancer penetrates the barrier layer in a way that is advantageous for drug absorption. It reversibly adjusts the properties. The permeability enhancer promotes the transport of molecules through the epithelium. Absorption The rofil and their speeds are not limited to film size, drug load, enhancer Various parameters such as type / load, polymer matrix release rate, and mucosal residence time. It can be controlled and adjusted by [method].

[0040] The pharmaceutical composition is designed to deliver the pharmaceutically active ingredient in a planned and tailored manner. It is possible. However, in vivo, especially in the mouth of the target, the dissolution of the active pharmaceutical ingredient is difficult. Resolution and permeability can vary considerably. Certain classes of permeability enhancers are used to enhance the pharmaceutically active ingredients. This can improve in vivo uptake and bioavailability. In particular, When delivered to the mouth via a membrane, the permeable enhancer passes through the target mucosa and enters the bloodstream, allowing the medicinal activity to be utilized. It can improve the permeability of active ingredients. The permeability enhancer improves the absorption rate of pharmaceutical active ingredients. The degree and amount may vary depending on the other components in the composition, ranging from more than 5%, more than 10%, and more than 20%. , more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80% A lot, more than 90%, more than 100%, more than 150%, about 200% or more, or less than 200%, 15 Less than 0%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, Only percentages less than 30%, less than 20%, less than 10%, or less than 5%, or any combination of these ranges. It can be raised.

[0041] In one embodiment, the pharmaceutical composition is bound by linkage to a hydrophilic saccharide. A suitable, non-toxic, non-ionic alkyl glycoside having a hydrophobic alkyl group is selected from the following: In combination with a selected mucosal delivery promoter, it may include: (a) aggregation inhibitors; (b) charge modifiers; (c) pH adjusters. (d) Suppressants; (e) Degrading enzyme inhibitors; (f) Mucolytic agents or mucosal removers; (g) Ciliary quiescent agents; (g) From the following: Selected membrane penetration enhancers: (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed membranes Cells, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) nitric oxide donors (vi) long-chain amphiphilic molecules; (vii) small hydrophobic osmotic enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerol ester of acetoacetic acid; (x) cyclodextrin (xii) amino acids or β-cyclodextrin derivatives; (xiii) medium-chain fatty acids; (xii) chelating agents; (xiii) amino acids (xiv) Acids or salts thereof; (xv) N-acetylamino acids or salts thereof; (xv) Selected membrane components Degrading enzymes; (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) epithelial junctions (i) a regulator of physiological functions; (j) a vasodilator; (k) a selective transport promoter; and (k) the compound thereof For effective formulation, association, inclusion, encapsulation or binding, and enhanced mucosal delivery. Stabilizing delivery vehicles, carriers, mucosal adhesives, supports, or composites that stabilize the compound. A compound formulation that is a somatoform, and in this case a compound accompanied by a transmucosal delivery enhancer, is in the target plasma. This provides increased bioavailability of the compound. The permeation enhancer was developed by J. Nicolazzo et al. This is explained in the literature, J. of Controlled Disease, 105 (2005) 1-15, and this is cited by This is incorporated herein. The oral mucosa is attractive for the delivery of therapeutic agents into the systemic circulation. There are many reasons why this is the target site. For 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 is achieved when administered orally. This can be the main reason for the poor bioavailability of some compounds. In addition, oral The mucous membrane lining the area is easily accessible, which means the dosage form can be applied to the required site. And ensure that it can be easily removed in an emergency. However, like skin, The oral mucosa acts as a barrier against the absorption of foreign substances, and this means that beyond this tissue... It can prevent the permeation of compounds. As a result, a safe and effective permeation enhancer is available. Confirmation of drug delivery to the oral mucosa is a major goal to strive for in order to improve drug delivery to the oral mucosa.

[0042] A chemical permeability enhancer controls the rate at which drugs administered simultaneously pass through biological membranes. It is quality. Large-scale studies have shown how permeability enhancers alter intestinal and transdermal permeability. The focus is on gaining a better understanding of the mechanism involved in enhancing penetration in the oral cavity and sublingually. Regarding the introduction, very little is known.

[0043] The oral mucosa lines the inside of the cheek and outlines the area between the gums and the upper and lower lips, and This is based on an average surface area of ​​100 cm². 2 It has a wavy basement membrane (approximately 1- It is separated from the underlying connective tissue (lamina propria and submucosa) by a continuous layer of extracellular material that is 2 μm thick. It consists of stratified squamous epithelium. This stratified squamous epithelium is formed in the superficial region where cells shed from the basal region. As you move through the regions, the size, shape, and contents change, from the differentiated layer of cells. There are approximately 40-50 cell layers there, giving rise to the oral mucosa which is 500-600 μm thick. ru.

[0044] Structurally, the sublingual mucosa is similar to the oral mucosa, but the thickness of this epithelium is 100-200 μm. Yes, this membrane is also more permeable than the oral mucosa because it is not keratinized and is relatively thin. It has been revealed that blood flow to the sublingual mucosa is slower than to the oral mucosa, at 1.0 ml / mil. n -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. The differences are a result of structural differences between the tissues. Organized cells within the cellular spaces of the oral mucosa. The absence of lipid lamellae results in greater permeability of foreign compounds compared to keratinized epithelium of the skin. This results in; on the other hand, the increased thickness and lack of tight junctions make the oral mucosa more permeable than intestinal tissue. This results in a low rate of transient activity.

[0046] The primary barrier properties of the oral mucosa are due to the upper 1 / 3 to 1 / 4 of the oral epithelium. Researchers found that the table The permeable barrier of the non-keratinized oral mucosa, which extends beyond the surface epithelium, also allows epithelial cells to escape from membrane-coating granules. It is known that the contents are expelled into the void.

[0047] The intercellular lipids in the non-keratinized areas of the oral cavity are more abundant than the lipids in the epidermis, palate, and gums. These lipids are polar in nature, and differences in their chemical properties can be observed between these tissues. This contributes to differences in permeability. Consequently, this creates a more effective barrier through keratinization. Not only is the degree of intercellular lipids packed into the stratum corneum of the epithelium greater, but the impairment It is clear that this is also due to the chemical properties of the lipids present within the wall.

[0048] The presence of hydrophilic and lipophilic regions within the oral mucosa has led researchers to consider the paracellular cells (cells) of the oral mucosa. We hypothesized the existence of two drug transport pathways: one that passes through cells (intercellular) and another that passes through cells (transcellular).

[0049] Drug delivery through the oral mucosa is limited by the properties of the epithelium and the barriers to the areas available for absorption. Therefore, various enhancement strategies are necessary to deliver therapeutically relevant amounts of drugs into the systemic circulation. This involves various methods, including the use of chemical permeation enhancers, prodrugs, and physical methods. The law can be used to overcome the barrier properties of the oral mucosa.

[0050] Chemical permeation enhancers, or absorption promoters, can cause membrane damage and / or toxicity. Without accompanying the drug, to increase the rate of membrane permeation or absorption of the drug administered simultaneously, the drug is added to the pharmaceutical preparation. These are the substances that are added. Chemical penetration enhancers, compounds that penetrate beyond the skin, nasal mucosa, and intestines. Many studies exist to investigate the effect on delivery. In recent years, research has been conducted on the permeability of the oral mucosa. More attention is being paid to the effects of these substances. Permeability beyond the oral mucosa is Since it is considered a passive diffusion process, the steady-state flux (Jss) is Fick's According to the first law of diffusion, it should increase with the increase in donor chamber concentration (CD).

[0051] Surfactants and bile salts are used in both in vitro and in vivo studies on a variety of compounds. It has been shown that it enhances permeability beyond the oral mucosa. The enhanced permeability is due to the action of surfactants on the intercellular lipids of the mucous membrane. This strongly suggests that...

[0052] Fatty acids have been shown to enhance the skin penetration of numerous drugs, and this is Differential scanning calorimetry and Fourier transform infrared spectroscopy were used to increase the fluidity of intercellular lipids. Related findings have been shown.

[0053] In addition, pretreatment with ethanol removes tritiated water and albumin from the ventral lingual mucosa. It has been shown to enhance the permeability of caffeine and to enhance caffeine permeability beyond that of the oral mucosa of pigs. It has been found that Azone® enhances the permeability of compounds through the oral mucosa. There are also several reports on its use. Furthermore, chitosan, a biocompatible and biodegradable polymer, It has been shown to enhance drug delivery through various tissues, including the mucous membranes of the intestines and nose.

[0054] Oral transmucosal drug delivery (OTDD) is the delivery of pharmaceutically active substances through the oral mucosa to achieve systemic effects. This is administration via membrane. The permeation pathway and predictive model of OTDD are, for example, described in the literature by M. Sattar. Oral transmucosal drug delivery - Current status and future outlook "rent status and future prospects)", Int'l. Journal of Pharmaceutics, 47 (2014) This is explained in pp. 498-506, and this reference is incorporated herein by reference. OTDD It continues to attract the attention of scientists in academia and industry. Compared to the delivery routes of the skin and nose. Despite the limited characterization of the permeation pathways within the oral cavity, the oral epithelium of ionized molecules... Researchers' understanding of the degree of permeability, and the development of new analytical techniques for studying the oral cavity. Current and ongoing development of in silico models to predict intraoral and sublingual permeability; The desire has been promoted recently.

[0055] To deliver a broader class of drugs beyond the oral mucosa, the barrier function of this tissue is required. A reversible method that reduces the permeability should be used. This requirement is the control of the permeability of the oral mucosa. This is prompting research into osmotic enhancers that safely modify the oral cavity. Oral osmosis involves bile salts and ointments. Surfactants, fatty acids and their derivatives, chelating agents, cyclodextrins and chitosan, etc. Improvement can be achieved by using various classes of transmucosal and transdermal penetration enhancers. It has been shown that this is possible among the chemicals used to enhance drug permeability. Bile salts are the most common.

[0056] In vitro studies on the enhancing effect of bile salt compounds on oral permeability were conducted by Sevda Se NEL paper "Enhancement of drug permeation via oral pathways: possibilities and limitations" ent via buccal route: possibilities and limitations),” Journal of Controlled Re This is discussed in lease 72 (2001) 133-144, and this reference is cited herein. It is incorporated. The article also mentions dihydroxybile salts, glycodeoxycholate sodium Thorium (SGDC), sodium taurodeoxycholate (TDC), and trihydroxybile acid Salt, sodium glycocholate (GC), and sodium taurocholate (TC) at a concentration of 100 mM. Regarding the effects on the permeability of the oral epithelium, including changes in permeability related to histological action. The latest research on this topic is also discussed. Fluorescein isothiocyanate (FITC), sulfur Acid morphine is used as a model compound in each case.

[0057] Chitosan is also used in animal models and human subjects to develop small polar molecules and peptides / ta It has been shown to enhance the absorption of protein drugs through the nasal mucosa. Other studies have shown that it can enhance the absorption through the intestinal mucosa. It shows an enhanced effect on compound penetration beyond that of cultured Caco-2 cells.

[0058] The permeation enhancer can be a plant extract. Plant extracts are obtained by distillation of plant materials. It may be an essential oil or essential oil-containing composition extracted by a plant. The extract is a synthetic analog of a compound extracted from plant material (i.e., produced by organic synthesis). It may contain (compounds formed). Plant extracts may contain phenylpropanoids, for example, Phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, ke Ichaldehyde, hydrocinnamic acid, cavicol, or safrole, or combinations thereof. It may include the leaves, stems or of the clove plant. It can be an essential oil extract from the flower buds. The clove plant is Syzygium aromaticum (S It is *Eugenol* (Eugenol saturates). This plant extract contains 20-95% eugenol and 40-9% eugenol. Contains 5% eugenol, 60-95% eugenol, for example, 80-95% eugenol It may contain 5% to 15% eugenol acetate. This extract can also contain caryophyllene. It can also contain up to 2.1% α-humulene. It is present in clove essential oil at lower concentrations. Other volatile compounds include β-pinene, limonene, farnesol, benzaldehyde, and 2-H. It may be butanone or ethyl hexanoate. Other permeation enhancers are used to enhance the absorption of drugs. To improve yield, it may be added to the composition. Suitable permeation enhancers are natural or synthetic. Bilates such as sodium fusidate; glycocholic acid or deoxycholic acid and Salts of these; fatty acids and derivatives, such as sodium laurate, oleic acid, oleic acid, etc. Alcohols, monoolein, or palmitoylcarnitine; chelating agents, e.g., ED TA disodium, sodium citrate and sodium lauryl sulfate, azone, sodium cholate Thorium, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monophosphate Urate, octoxynonyl-9, laureth-9, polysorbate, sterol, or glycerin Lidos, such as caprylocaproyl polyoxylglyceride and labrasol, are included. The permeation enhancer may contain derivatives of plant extracts and / or monolignols. The permeation enhancer can also be a fungal extract.

[0059] Some naturally occurring plant-derived products have been shown to have vasodilatory effects. Regarding this, see the literature by McNeill JR and Jurgens, TM, Can. J. Physiol. Pharmacol. 84:803- See 821 (2006), which is incorporated herein by reference. Specifically, Oi The vasodilatory effect of genol has been reported in many animal studies. For example, Lahlou, References: S. et al., J. Cardiovasc. Pharmacol. 43:250-57 (2004), Damiani, CEN et al. Vascular Pharmacol. 40:59-66 (2003), Nishijima, H. et al., Japanese J. Pharma See col. 79:327-334 (1998), and Hume WR's literature, J. Dent Res. 62(9):1013-15 (1983). Calcium channels Blockage is the primary cause of vasodilation induced by plant essential oils, or their main component, eugenol. This has been suggested. (Interaminense LRL et al., Fundamental & Clin. Pharmaco) See l. 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 are also used in formulations due to their certain functional properties and their biocompatibility. They can also be used as components. Fatty acids, both free lipids and some complex lipids, are major It is a metabolic fuel (storage and transport energy), and an essential component of all membranes and gene regulatory factors. For the review article, see the literature by Rustan AC and Drevon, CA, Fatty Acids: Structures and Pro See perties, Encyclopedia of Life Sciences (2005), which is cited herein by reference. It is incorporated inside. There are two families of essential fatty acids that are metabolized in the human body. ω-3 and ω-6 polyunsaturated fatty acids (PUFAs). The first double bond is between the third and fourth carbon atoms from the ω-carbon. When found between carbon atoms, these are called ω-3 fatty acids. The first double bond is six When found between the 1st and 7th carbon atoms, these are called ω-6 fatty acids. PUFA Furthermore, it is metabolized in the body by the addition of carbon atoms and desaturation (removal of hydrogen). Linoleic acid, an omega-6 fatty acid, is also known as gamma-linolenic acid, dihomo-gamma-linolenic acid, and arachid dextrose acid, adrenaline acid, tetracosatetraenoic acid, tetracosapentaenoic acid and docosapenta It is metabolized into enoic acid. Alpha-linolenic acid, an omega-3 fatty acid, is metabolized into octadecatetraenoic acid, and enoic acid. Eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosape It is metabolized into tetracosahexaenoic acid, tetracosahexaenoic acid, and docosahexaenoic acid (DHA).

[0061] Fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid are Na + K + - Through a mechanism involved in the activation of the APTase pump, relaxation of porcine coronary artery smooth muscle cells and It induces hyperpolarization, and as the degree of cis-unsaturation of fatty acids increases, it becomes more potent. It has been reported that this occurs. (Reference: Pomposiello, SI et al., Hypertension 31:615-20 (199) See 8), which is incorporated herein by reference. Interestingly, Linau The pulmonary vascular response to arachidonic acid, a metabolite of uric acid, depends on the dosage, animal species, and arachidonic acid. Depending on the method of acid administration and the tone of pulmonary circulation, either vasoconstrictive or vasodilatory acid is used. It can be. For example, arachidonic acid is cyclooxygenase-dependent and cyclooxygenase-independent. It has been reported to cause residual pulmonary vasodilation. (Reference: Feddersen, CO et al., J.) See Appl. Physiol. 68(5):1799-808 (1990); also see the literature by Spannhake, E.W. et al., J.Ap. pl. Physiol. 44:397-495 (1978) and the literature by Wicks, TC et al., Circ. Res. 38:167-71 (1978) See 6), each of which is incorporated herein by reference.

[0062] Many studies have shown that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) taken orally are effective. Several studies have reported on the effects on vascular responsiveness after administration in an easily digestible form. EPA-DHA or EPA alone enhances the vasoconstrictive effect of norepinephrine in the microcirculation of the forearm. It was observed that it either inhibited or enhanced the vasodilatory response to acetylcholine. (Chin, JPF et al.) References: Hypertension 21:22-8 (1993), and the literature by Tagawa, H. et al., J Cardiovasc Pharmaco See l 33:633-40 (1999), each of which is incorporated herein by reference. The study showed that both EPA and DHA increase systemic arterial compliance and pulse pressure. We found that it tends to lower total vascular resistance. (References: Nestel, P. et al., Am J. Clin. Nu) See tr. 76:326-30 (2002), which is incorporated herein by reference. On the other hand, the study found that DHA, not EPA, was more effective in the forearm microenvironment of obese men with hyperlipidemia. We discovered that it enhanced the tubular dilation mechanism and weakened the contraction response. (References: Mori, TA et al., Ci) See rculation 102:1264-69 (2000), which is incorporated herein by reference. Another study showed that DHA has an effect on the rhythmic contraction of isolated human coronary arteries in vitro. They discovered a vasodilatory effect. (Reference: Wu, K.-T. et al., Chinese J. Physiol. 50(4):164-70 (200) See 7), which is incorporated herein by reference.

[0063] Adrenergic receptors (or adrenoleceptors) are receptors for catecholamines, particularly norepinephrine receptors. G proteins are targets of nephrine (norepinephrine) and epinephrine (adrenaline). It is a class of quality-coupled receptors. Epinephrine (adrenaline) is α- and β-adrenergic It interacts with both receptors, causing vasoconstriction and vasodilation, respectively. The α receptor is Although they have low sensitivity to epinephrine, peripheral α1 receptors are better than β-adrenoleceptors. Since there are many of them, when activated, these are mediated by β-adrenoleceptors. It neutralizes vasodilation. As a result, high levels of circulating epinephrine cause vasoconstriction. At relatively low levels of circulating epinephrine, β-adrenoleceptor stimulation is dominant. This results in vasodilation, followed by a decrease in peripheral vascular resistance. α1-adrenoleceptors are smooth Muscle contraction, pupil dilation, vasoconstriction in the skin, mucous membranes and abdominal viscera, and the gastrointestinal (GI) tract and bladder It is known in relation to sphincter contraction. The α1-adrenergic receptor is G q Protein-coupled receptors It is a member of the G superfamily. When activated, it forms a heterotrimeric G protein, G q , It activates supholipase C (PLC). Its mechanism of action involves interaction with calcium channels. It is involved in altering intracellular calcium content. For a review, see the literature by Smith RS et al., Journal See al of Neurophysiology 102(2): 1103-14 (2009), which is cited herein by reference. They are incorporated into the system. Many cells possess these receptors.

[0064] The α1-adrenergic receptor can be the primary receptor for fatty acids. For example, Saw palmetto fruit extract (SPE), widely used in the treatment of benign prostatic hyperplasia (BPH), contains α1-adrenergic compounds. Lenalinergic, muscarinergic, and 1,4-dihydropyridine (1,4-DHP) calcium compounds It has been reported to bind to channel-antagonistic receptors. (See Abe M. et al., Biol. Pharm.) Bull. 32(4) 646-650 (2009), and the literature by Suzuki M. et al., Acta Pharmacologica Sinica 3 See 0:271-81 (2009), each of which is incorporated herein by reference. PE contains lauric acid, oleic acid, myristic acid, palmitic acid and linoleic acid, It contains various fatty acids. Lauric acid and oleic acid are α1-adrenergic, muscular It non-competitively binds to carinergic and 1,4-DHP calcium channel antagonistic receptors. It is possible.

[0065] In one embodiment, the permeation enhancer is an adrenergic receptor interacting substance. Adrenergic receptor interacting substances modify the action of adrenaline receptors. This refers to a compound or substance that alters and / or otherwise modifies adrenaline. For example, adrenaline receptors Receptor-interacting substances prevent receptor stimulation by increasing or decreasing their binding ability. This is possible. Such interacting substances are provided in either a short-acting or long-acting form. It is possible. Some short-acting interacting substances can act rapidly, but The effects of these substances last only a few hours. Some long-acting interacting substances have a longer-lasting effect. It is possible, but their effects can last longer. This interacting substance is, for example If, then, one or more desired delivery and dosage, active pharmaceutical ingredient, permeation modifying factor, permeation enhancer, It can be selected and / or designed based on the matrix and the condition being treated. Adrenergic receptor interacting substances can be adrenergic receptor blockers. Drainage receptor interacting substances are terpenes (for example, derived from isoprene units, plant Volatile unsaturated hydrocarbons found in essential oils, or C3-C22 alcohols or acids, preferably Alternatively, it can be a C7-C18 alcohol or acid. In one embodiment, Narin receptor interacting substances include farnesol, linoleic acid, arachidonic acid, and docosahexaenoic acid. This acid may be anaerobic acid, eicosapentanoic acid, and / or docosapentanoic acid. This can be a carboxylic acid, phosphoric acid, sulfuric acid, hydroxamic acid, or a derivative thereof. It 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, such as optionally having at least one double bond, at least one triple bond, or at least one double bond and one triple bond, and the C 3-C22 hydrocarbon chain; the hydrocarbon chain can optionally be C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, 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 alkylo xycarbonyl, C 1-4 alkylcarbonyl, or formyl substituted; and further optionally, -O-, -N(R a )-, -N(R a )-C(O)-O-, -O-C(O)-N(R a )-, -N(R a )-C(O)-N(R b )-, or -O -C(O)-O- is sandwiched in between. Each of R a and R b is independently hydrogen, alkyl, alkeni yl, alkynyl, alkoxy, hydroxyalkyl, hydroxyl, or haloalkyl .

[0067] Fatty acids with higher degrees of unsaturation are effective candidates for enhancing drug permeation. Unsaturated fats Fatty acids show a higher enhancement than saturated fatty acids, and the enhancement increases with the number of double bonds. A. Mittal et al.'s paper, "Status of fatty acids as skin penetration enhancers - Review (Status of Fatty Acids as Skin Penetration Enhancers - A Review), Current Drug Delivery, See 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. This is due to differences in the position of the double bond. The differences in the physicochemical properties of these fatty acids affect the effectiveness of these compounds as skin penetration enhancers. This is most likely to determine the force. As the position of the double bond shifts to the hydrophilic end, Skin distribution increases. Fatty acids with double bonds at even positions have double bonds at odd positions. It acts more rapidly than fatty acids on structural perturbation in both the stratum corneum and dermis. It has also been reported that cis-unsaturation within the chain tends to increase activity.

[0068] Adrenergic receptor interacting substances can be terpenes. Terpenes in essential oils Its antihypertensive activity has been reported. Menezes IA et al., Z. Naturforsch. 65c:652- See 66 (2010), which is incorporated herein by reference. In one embodiment In this case, the permeation enhancer can be a sesquiterpene. Sesquiterpenes are, It consists of three isoprene units, and its empirical formula is C 15 H 24 It is a terpene class that possesses [a certain characteristic]. Like noterpenes, sesquiterpenes are either acyclic or have many unique combinations. It contains a ring. Biochemical modifications such as oxidation or rearrangement affect the associated sesquiterpenoid. To generate.

[0069] Adrenergic receptor interacting substances are unsaturated fatty acids such as linoleic acid. In one embodiment, the permeation enhancer can be farnesol. Farnesol is an acyclic sesquiterpene alcohol, a 15-carbon organic compound. This is the naturally occurring dephosphorylated form of farnesyl pyrophosphate. Under standard conditions, this It is a colorless liquid. It is hydrophobic and therefore insoluble in water, but oils It is miscible. Farnesol is found in citronella, neroli, cyclamen, and night-blooming celandine. It can be extracted from the oil of any plant. This is derived from mevalonic acid in vertebrates. It is an intermediate step in cholesterol biosynthesis. It has a delicate floral or faint citrus scent. It has a lime scent and is used in perfumes and fragrances. Farnesol is primary To selectively kill acute myeloid leukemia blast cells and leukocyte cell lines, prioritizing their death over hematopoietic cells. However, this has been reported. See Rioja A. et al., FEBS Lett 467 (2-3): 291-5 (2000). This is incorporated herein by reference. Vascular characteristics of farnesyl analogs Sex has been reported. (See Roullet, J.-B. et al., J. Clin. Invest., 1996, 97:2384-23) See 90, which is incorporated herein by reference. Farnesol and N-A Cetyl-S-trans,trans-farnesyl-L-cysteine ​​(AFC), farnesylated Both synthetic mimics of the carboxyl terminus of proteins cause vasoconstriction in the rat aortic circle. It inhibited it.

[0070] This pharmaceutical composition is available in chewable or gelatin-based dosage forms, sprays, gums, gels, and creams. This composition may be in the form of a foam, tablet, liquid, or film. For example, the surface may contain extremely fine particles. It may include textures such as needles or micro-protrusions. Recently, skin permeability The use of micron-scale needles in augmentation involves polymers, and in particular, transdermal needles with respect to polymers. It has been shown to significantly increase delivery. Most drug delivery studies are in vitro. It has been shown to increase skin permeability to a wide range of molecules and nanoparticles, solid (Solid) emphasizes ultra-fine needles. In vivo studies have shown oligonucleotide delivery, insulin The reduction of blood glucose levels by the vaccine, and the induction of an immune response from protein vaccines and DNA vaccines. The guide is clear. In such research, needle arrays are used for diffusion or iontophoresis. To increase transport by law, to puncture the skin, or from the surface coating of microneedles It is used as a drug carrier to release drugs into the skin. Hollow microneedles have also been developed, and The microinjection of lancelin into diabetic rats has been shown. Addressing the practical application of microneedles. In order to achieve this, the ratio of the ultra-fine needle fragmentation strength to the skin insertion strength (i.e., the safety margin) must be small. It was found to be optimal for needles with a large tip radius and wall thickness. The insertion of the microneedle was reported to be painless. In summary, these results suggest that the microneedle is widely used. This demonstrates a promising technique for delivering therapeutic compounds to the skin for a wide range of possible applications. It is inviting. Using tools from the micro-electronics industry, ultra-fine needles are available in a wide range of sizes, shapes and materials. It is processed in such a way that the microneedle can, for example, deliver encapsulated drugs in a minimally invasive manner. These can be polymeric microscopic needles, but other suitable materials can be used. ru.

[0071] The applicant claims that microneedles enhance the delivery of drugs through the oral mucosa, particularly with the claimed composition. It was acknowledged that it can be used to strengthen. The ultrafine needle is micron-sized into the oral mucosa. By creating pores, it is possible to enhance drug delivery across mucous membranes. Solid, hollow, Alternatively, soluble microneedles include, but are not limited to, metals, polymers, glass, and ceramics. It is not something that is processed, but can be processed with suitable materials. Microfabrication process is photo Lithography, silicon etching, laser cutting, metal electroplating, metal electrolytic polishing, and This may include molding. Microneedles are used to pre-treat tissue and film It may be a solid that is removed before application. Drug-loaded as described in this application Polymer films can be used as the matrix material for the microneedles themselves. These films may have microneedles or micro-protrusions processed on their surface. These formed microchannels in the mucosa through which drugs could permeate. It will dissolve later.

[0072] The term "film" refers to any shape, including rectangles, squares, or other desired shapes. It may include films and sheets. The film may be of any desired thickness and size. It is possible. In a preferred embodiment, the film is administered to the user, for example, It can have a thickness and size that allows it to be placed in the user's mouth. The film has a relatively thin thickness of approximately 0.0025 mm to approximately 0.250 mm, or the film is approximately 0.2 It can have a slightly thicker thickness of 50mm to approximately 1.0mm. For some films, the thickness These are even larger, i.e., larger than approximately 1.0 mm, or relatively thin, i.e. It may be less than approximately 0.0025 mm. The film may be single-layered or laminated. Alternatively, it can be multilayered, including multiple cast films. Transmissive enhancer and The active pharmaceutical ingredients may be combined in a single layer, each contained in a separate layer, or... Otherwise, each can be contained within separate regions of the same dosage form. In one embodiment In this process, the pharmacoactive ingredients contained in the polymer matrix are dispersed within the matrix. This is possible. In one embodiment, the permeation enhancer contained in the polymer matrix is They can be distributed within the matrix.

[0073] Oral-dissolving films can be categorized into three main classes: immediate dissolution, moderate dissolution. Dissolubility and slow dissolution. Oral dissolvable films may also be any combination of the above categories. It may include: Immediately dissolving film in the mouth for longer than 1 second, longer than 5 seconds, and 10 seconds. It can dissolve in approximately 1 to 30 seconds, including longer dissolution times, longer than 20 seconds, and less than 30 seconds. The moderately soluble film can be left in the mouth for longer than 1 minute, longer than 5 minutes, longer than 10 minutes, and 20 minutes. It can dissolve in about 1 to about 30 minutes, including longer or less than 30 minutes, and is slow to dissolve. The film can dissolve in the mouth over a period of more than 30 minutes. Generally, it dissolves immediately. The soluble film is made of a low molecular weight hydrophilic polymer (for example, with a molecular weight of approximately 1,000 to 9,000 daltons). (or contains polymers having a molecular weight of up to 200,000 daltons) (can be done). In contrast, slowly dissolving films generally use high molecular weight polymers (e.g., It contains (with a molecular weight of several million). Moderately soluble films are classified as immediately soluble films and slowly soluble films. It tends to fit between the sex films.

[0074] It is preferable to use a film that is a moderately soluble film. The substance can dissolve fairly quickly, but also maintains a good level of mucosal adhesion. Moderate Dissolvable films are also flexible, quickly wettable, and typically easy for the user to use. It is non-irritating. Such moderately soluble films are sufficiently rapid, and most preferably It can offer a dissolution rate of approximately 1 to 20 minutes, but once placed in the user's mouth... If so, an acceptable level of mucosal adhesion should be proposed so that the film cannot be easily removed. This ensures that the active pharmaceutical ingredient is delivered to the user.

[0075] A pharmaceutical composition may contain one or more pharmaceutically active ingredients. These pharmaceutically active ingredients may be single It may be a pharmaceutical ingredient or a combination of pharmaceutical ingredients. The pharmaceutically active ingredient is anti-inflammatory and analgesic. Drugs, steroid anti-inflammatory drugs, antihistamines, local anesthetics, disinfectants, antiseptics, vasoconstrictors Hemostatic agents, chemotherapy drugs, antibiotics, keratolytic agents, cauterizing agents, antiviral drugs, antirheumatic drugs, Antihypertensive drugs, bronchodilators, anticholinergics, anxiolytics, antiemetics, hormones, peph This may be a cytoplasm, protein, or vaccine. This pharmaceutically active ingredient is a compound, drug. A pharmaceutically acceptable salt, prodrug, derivative, drug conjugate, or analog of a drug. It is possible. The term "prodrug" refers to a substance that is metabolized in the body to produce a biologically active drug. This refers to biologically inert compounds that can be used for other purposes.

[0076] In some embodiments, two or more pharmaceutically active ingredients may be contained in the film. The active pharmaceutical ingredients are ACE inhibitors, angina treatments, antiarrhythmics, anti-asthma drugs, and anticholesterols. Blood pressure medications, analgesics, anesthetics, anticonvulsants, antidepressants, diabetes medications, antidiarrheal preparations, Poisons, antihistamines, antihypertensive drugs, anti-inflammatory drugs, anti-lipid drugs, anti-manic drugs, nausea treatment drugs, morbidity Anticoagulants, antithyroid preparations, amphetamines, antitumor drugs, antiviral drugs, acne treatments, Alkaloids, amino acid preparations, cough suppressants, anti-urinary tract stone agents, antiviral agents, anabolic preparations Drugs, treatments for systemic and non-systemic infections, anti-neoplastic agents, Parkinson's disease treatments, anti-liu Antipsychotics, appetite stimulants, blood modifiers, bone metabolism regulators, cardiovascular agents, central nervous system stimulants Drugs, cholinesterase inhibitors, contraceptives, decongestants, nutritional supplements, dopamine receptors Goniostomy drugs, endometriosis medications, enzymes, erectile dysfunction treatments, infertility medications, gastrointestinal drugs, homeopathy Remedies, hormones, drugs for managing hypercalcemia and hypocalcemia, immunomodulators, immunosuppressants, immunotherapy Epidemic control drugs, migraine preparations, motion sickness medications, muscle relaxants, obesity control drugs, osteoporosis preparations, children Cellulite-constricting agents, parasympathetic nerve blockers, parasympathetic nerve agonists, prostaglandins, psychotropic drugs, respiratory Inhalant drugs, sedatives, smoking cessation aids, sympathomimetic drugs, tremor treatment preparations, urethral drugs, blood vessels Dilators, laxatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants, anti-anxiety drugs, Anti-ulcer drugs, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators Psychotropic drugs, stimulants, antihypertensive drugs, vasoconstrictors, migraine medications, antibiotics , tranquilizers, antipsychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, antiemetics, Anti-cardiac drugs, anticonvulsants, neuromuscular agents, blood glucose-raising and hypoglycemic agents, thyroid and anti-thyroid drugs. Compounding drugs, diuretics, anticonvulsants, uterine relaxants, anti-obesity drugs, erythropoiesis-producing drugs, anti-asthma drugs, cough suppressants Mucolytic agents, DNA and genetic modification agents, diagnostic agents, contrast agents, dyes, or tracers, and so These can be combinations of each other.

[0077] For example, the active ingredients in this medicine are buprenorphine, naloxone, acetaminophen, and ri Luzol, clobazam, rizatriptan, propofol, methyl salicylate, salicylate Monoglycol acids, aspirin, mefenamic acid, flufenamic acid, indomethacin, dichloride Lofenac, Alclofenac, Diclofenac Sodium, Ibuprofen, Ketopro Fen, naproxen, pranoprofen, fenoprofen, sulindac, fencro Fenac, clidanac, flurbiprofen, fenthiazac, bufexamac, pyroxine Sicam, phenylbutazone, oxyfenbutazone, clofezone, pentazocine, mepi Lysol, tiaramide hydrochloride, hydrocortisone, prednisolone, dexamethasone, Liamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, phosphate Rednisolone, methylprednisolone, dexamethasone acetate, betamethasone, betamethasone valerate Metazone, flumethasone, fluorometholone, beclomethasone dipropionate, Fluocinonide, diphenhydramine hydrochloride, diphenhydramine salicylate, dife Chlorpheniramine hydrochloride, chlorpheniramine maleate, isothiocyanate Benzyl, triperenamine hydrochloride, promethazine hydrochloride, methidilazine hydrochloride, dibucaine hydrochloride Salt, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, procaine hydrochloride, tetracaine hydrochloride, tetra Lacaine, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride Salt, pipelocaine hydrochloride, diclonin, diclonin hydrochloride, thimerosal, phenol, Thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone-iodine Cetylpyridinium chloride, eugenol, trimethylammonium bromide, naphth Azoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride Salt, tramazoline hydrochloride, thrombin, phytonadione, protamine sulfate, aminocapro Tranexamic acid, carbazochrome, sodium carbazochrome sulfonate, rutin Hesperidin, sulfamine, sulfathiazole, sulfadiazine, homosulfa Min, sulfisoxazole, sulfisomidine, sulfamethizol, nitrofurazone Penicillin, methicillin, oxacillin, cephalothin, cephaloridine, erythromycin Icin, Lincomycin, Tetracycline, Chlortetracycline, Oxytetrasaturates Ikurin, metacycline, chloramphenicol, kanamycin, streptomycin , gentamicin, bacitracin, cycloserine, salicylic acid, podophyllum resin, po Drifox, cantharidin, chloroacetic acid, silver nitrate, protease inhibitor, thyme Zin kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors , adhesion and adsorption inhibitors, and nucleoside analogs, such as acyclovir, pencyclovir Viru, valacyclovir, and ganciclovir, heparin, insulin, LHRH, TRH, Interferon, oligonuclides, calcitonin, octreotide, Omeprazon, fluoxetine, ethinylestradiol, amiodipine Paroxetine, Enalapril, Lisinopril, Leuprolide, Prevastatin, Lovas Tatin, norethindrone, risperidone, olanzapine, albuterol, hydrochloride Rothiazide, pseudoephedrine, warfarin, terazosin, cisapride, iprato Lopium, busprione, methylphenidate, levothyroxine, zolpidem Mu, levonorgestrel, glybride, benazepril, medroxyprogesterone, clo Nazepam, ondansetron, losartan, quinapril, nitroglycerin, midazolam Berced, cetirizine, doxazosin, glipizide, hepatitis B vaccine, salmeterol , sumatriptan, triamcinolone acetonide, goserelin, beclomethasone, gran Steroids, desogestrel, alprazolam, estradiol, nicotine, interf Elon β1A, Cromolyn, Hosinopril, Digoxin, Fluticasone, Bisoprolol, Calcitril, Captopril, Butorphanol, Clonidine, Premarin, Testosterone Ron, sumatriptan, clotrimazole, bisacodyl, dextromethorphan, nitrite Logricerin, Nafarelin, Dinoprostone, Nicotine, Bisacodyl, Goserelin, and This can be granisetron. In one embodiment, the active pharmaceutical ingredient is epi Benzodiazepines such as nephrine, diazepam, or lorazepam, or alprazolam That is the case.

[0078] (Examples include epinephrine, diazepam, and alprazolam) In one example, a composition containing epinephrine or its salt or ester is administered by injection. Biodelivery of epinephrine, for example using an EpiPen. It can have a biodelivery profile similar to that of the file. Epinephrine is approximately 0. The dosage ranges from 0.1 mg to approximately 100 mg / dose, for example, 0.1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg It can be present in doses of 70 mg, 80 mg, 90 mg, or 100 mg, which is more than 0.1 mg and less than 5 mg. More than 20mg, more than 30mg, more than 40mg, more than 50mg, more than 60mg, 70 More than mg, more than 80 mg, more than 90 mg, or less than 100 mg, less than 90 mg, less than 80 mg, 70 mg Less than, 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 is di A biodelivery profile similar to, or better than, that of azepam tablets or gels. It may have a file. Diazepam or its salts are in amounts of approximately 0.5 mg to approximately 100 mg / dose. For example, 0.5mg, 1mg, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg It can be present in doses of g or 100 mg, which is more than 1 mg, more than 5 mg, more than 20 mg , more than 30mg, more than 40mg, more than 50mg, more than 60mg, more than 70mg, more than 80mg More than 90mg, or less than 100mg, less than 90mg, less than 80mg, less than 70mg, less than 60mg, 50mg Less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, or less than 5 mg, or any of those. Includes combinations.

[0079] In another example, a composition (for example, containing alprazolam, diazepam, or epinephrine) (m) has a hydrophobic alkyl group that is linked to a hydrophilic saccharide, A suitable non-toxic, non-ionic alkyl glycoside is combined with a mucosal delivery enhancer selected from the following: It can have: (a) aggregation inhibitor; (b) charge modifier; (c) pH adjuster; (d) enzyme inhibitor. (e) Mucolytic or mucosal decontaminating agent; (f) Ciliary stabilizing agent; (g) Membrane penetration enhancer selected from the following: Agents: (i) Surfactants; (ii) Bile salts; (ii) Phospholipid additives, mixed micelles, liposomes, etc. (iii) carriers; (iv) alcohols; (v) enamines; (v) NO donors; (vi) long-chain amphiphilic molecules (vii) Hydrophobic penetration enhancer; (viii) Sodium or salicylic acid derivative; (ix) Acetate Glycerol ester of acetate; (x) Cyclodextrin or β-cyclodextrin derivative (xi) medium-chain fatty acids; (xii) chelating agents; (xiii) amino acids or salts thereof; (xiv) N-acetyl (xv) enzymes that degrade selected membrane components; (ix) enzymes for fatty acid synthesis Inhibitors; (x) Inhibitors of cholesterol synthesis; and membrane irritants listed in (xi)(i)-(x) Any combination of pharmacokinetic agents; (h) modifiers of epithelial junction physiological function; (i) vasodilators; (j ) Selective transport-promoting agent; or (k) in which it is effectively combined, associated, and included with the compound, Stabilization of the compound for enhanced mucosal delivery by encapsulation or binding, A delivery vehicle, carrier, mucoadhesive, support or complex-forming species, wherein transmucosal Formulations of the compound with a delivery-promoting agent provide an increase in the bioavailability of the compound in the plasma of the subject. This formulation can contain approximately the same active pharmaceutical ingredient (API): enhancer ratio as in other

[0080] (Treatment or adjuvant treatment) Status epilepticus (SE) is an epileptic seizure of more than 5 minutes or two or more seizures within 5 minutes that do not return to normal between seizures. Another previous definition used a 30-minute time limit. Benzodiazepines are part of the most effective medications in the treatment of acute seizures and status epilepticus. The benzodiazepines most commonly used in the treatment of status epilepticus include diazepam (Valium), lorazepam (Ativan), or midazolam (Versed). The pharmaceutical active ingredient in a pharmaceutical composition (e.g., a pharmaceutical composition film) is Angelman syndrome (AS), childhood absence epilepsy (CAE), juvenile myoclonic absence epilepsy or Doose syndrome, Dravet syndrome, early myoclonic encephalopathy (EME), epilepsy with only generalized tonic-clonic seizures (EGTCS), epilepsy with myoclonic pre-treatment resection, glucose transporter 1 deficiency syndrome, hypothalamic hamartoma (HH), infantile spasms (also referred to as IS) or West syndrome, juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), Toad syndrome (LGS), Ohtahara syndrome (OS), Panayiotopoulos syndrome (PS), PCDH19 epilepsy, progressive Myoclonic epilepsy, Rasmussen syndrome, Circular 20 chromosome syndrome (RC20), Reflex Associated with seizures including epilepsy, TBCK-associated intellectual disability syndrome, temporal lobe epilepsy, and incontinentia pigmenti. Possible neurocutaneous syndromes, type 1 neurofibromatosis, Sturge-Weber syndrome (trigeminal nerve region of the brain) It may be a treatment or adjunct therapy for hemangiomatosis and tuberous sclerosis.

[0081] The film and / or its components may be water-soluble, water-swellable, or water-insoluble. The term "water-soluble" means that it contains water, but is not limited to water, and is found in small amounts in aqueous solvents. Both terms can refer to substances that are partially soluble. The term "water-soluble" means that a substance is not soluble in aqueous solution. It does not necessarily mean that it is 100% soluble in the medium. This refers to substances that cannot be dissolved in aqueous solvents, 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. They can be included together.

[0082] This composition may include a polymer matrix. Any desired polymer matrix If it is orally soluble or erosive, it may be used. This dosage form is easily It has sufficient bioadhesion to not be removed, and does not form a gel-like structure when administered. These must be able to dissolve moderately in the oral cavity and are particularly useful in medicine. Suitable for the delivery of active ingredients, but in combination with immediate-release, delayed-release, controlled-release, and sustained-release types. All of the finished products also exist within various intended embodiments.

[0083] (branched polymer) This pharmaceutical composition film is made of highly branched polymers with various structural architectures. It may contain dendritic polymers. Dendritic polymers are dendrimers. Dendritic polymers (dendritic grafted polymers), linear dendritic hybrids, multi It may contain an armed star-shaped polymer or a highly branched polymer.

[0084] Highly branched polymers are highly branched polymers that have imperfections in their structure. However, these can be synthesized in a single-step reaction, which offers advantages over other dendritic structures. It is a point, and therefore suitable for applications involving bulky volumes. Apart from their spherical structures, this The properties of these polymers are abundant functional groups, intramolecular cavities, low viscosity, and high solubility. Polymers are used in several drug delivery applications. For example, "as drug carriers" Dendrimers: Application via different routes of drug delivery. ions in Different Routes of Drug Administration)”, J Pharm Sci, VOL. 97, 2008, See pp. 123-143, which are incorporated herein by reference.

[0085] Dendritic polymers can have internal cavities that can encapsulate drugs. High density The steric hindrance caused by polymer chains can prevent drug crystallization. The branched polymer then formulates crystalline drugs within the polymer matrix, It can offer additional advantages.

[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(a mino acid)-based dendrons, dendrimers and highly branched polymers, poly(arylalkylene ether)-based dendrons, dendrimers and highly branched polymers, poly(alkylene im ine)-based dendrons, dendrimers and highly branched polymers, poly(amidoamine) ba ses of dendrons, dendrimers or highly branched polymers.

[0087] Other examples of highly branched polymers include poly(amine), polycarbonate, poly(ether ketone) , polyurethane, polycarbosilane, polysiloxane, poly(ester amine), poly(sul fon amine), poly(urethane urea) or polyether polyol, such as polyglycerin and the like.

[0088] The film can be made by a combination of at least one polymer and optionally other components in a solvent. The solvent may be water, a polar organic solvent including, without limitation, ethanol, isopropanol , acetone, or any combination thereof. In some embodiments , the solvent may be a nonpolar organic solvent such as methylene chloride. The film may be prepared by utilizing a selected casting or deposition method and a controlled drying process. For example, the film may include the application of heat and / or radiant energy to a wet film matrix to form a viscoelastic structure, a controlled drying process It is prepared through a process that controls the uniformity of the contents of the film. The drying process involves the top or bottom of the film, or also involves saliva or vapor deposition. Alternatively, the substrate supporting the extruded film is brought into contact with the other, or the drying process Two or more surfaces are brought into contact simultaneously or at different times in between, using air only, heat only, or heat. It can also contain air. Some of these processes are covered by U.S. Patent No. 8,765,167 and This is described in detail in U.S. Patent No. 8,652,378, which is incorporated herein by reference. It is included. Or, the film is described in U.S. Patent Publication No. 2005 / 0037055 A1. It may be extruded, and this is incorporated herein by reference.

[0089] The polymer contained in the film is either water-soluble, water-swellable, water-insoluble, or water-soluble. The polymer may be a combination of one or more of the following: water-swellable polymers and water-insoluble polymers. It may contain cellulose, cellulose derivatives, or gum. Specific examples of useful water-soluble polymers are: , polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxy Ethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, carboxy Methylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glyco Gum, xanthan gum, tragacanth gum, guar gum, acacia gum, acacia gum, Polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, den Includes, but is not limited to, pungent gelatin and combinations thereof. Useful Specific examples of water-insoluble polymers include ethylcellulose and hydroxypropyl ethylcellulose. S, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and so This includes, but is not limited to, these combinations. Regarding higher doses, lower It is desirable to incorporate a polymer that provides a high level of viscosity relative to the dose.

[0090] As used herein, the terms "water-soluble polymer" and its variations refer to at least partially water-soluble polymers. A polymer that dissolves in, and preferably completely or mainly in, water, or absorbs water. —This refers to. Polymers that absorb water are often called water-swellable polymers. Useful substances are water-soluble or water-swellable at room temperature and other temperatures, for example, at temperatures above room temperature. It is acceptable. Furthermore, these materials are water-soluble or water-swellable at pressures lower than atmospheric pressure. It may be. In some embodiments, a film formed from such a water-soluble polymer may be It may be insoluble when in contact with body fluids, yet sufficiently water-soluble.

[0091] Other polymers useful for incorporation into films include biodegradable polymers, copolymers, and blocks. Includes polymers or combinations thereof. The term "biodegradable" means that it is not physically broken down into pieces. In contrast to substances that are bio-invasive (i.e., bio-erosive substances), the intention is to include substances that are chemically decomposed. It is understood that this will be done. The polymers incorporated into the film are also biodegradable or bioinvasive. It may also include combinations of edible substances. In particular, known useful substances that meet the above criteria The polymer or polymer classes are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA) Polydioxane, polyoxalate, poly(alpha-ester), polyanhydride, Polyacetate, polycaprolactone, poly(orthoester), polyamino acid, polyami Polycarbonate, polyurethane, polycarbonate, polyamide, poly(alkylcyano) Acrylates, as well as mixtures and copolymers thereof. Additional useful polymers include L- and Stereopolymer of D-lactic acid, bis(p-carboxyphenoxy)propanoic acid and sebaciate Copolymer of, sebacate copolymer, caprolactone copolymer, poly(lactic acid) / poly( Glycolic acid / polyethylene glycol copolymer, polyurethane and (poly(lactic acid)) Polymers, alpha-amino acid and caproic acid copolymers, alpha-benzyl glutamate Copolymers of succinate esters and polyethylene glycol, succinate esters and poly(g) Recall) copolymers, polyphosphazenes, polyhydroxyalkanoates or those It contains a mixture of the following. The polymer matrix may contain 1, 2, 3, 4 or more components. It is possible.

[0092] Various different polymers may be used, but the film should have mucosal adhesion properties, and also, if desired It is desirable to select a polymer that provides a good dissolution and / or decay rate. In particular, The desired duration for maintaining contact between the mucous membrane and the active pharmaceutical ingredient contained in the composition is the duration for which the active ingredient is in contact with the mucous membrane. It depends on the type. Some active pharmaceutical ingredients require only a few minutes to be delivered through mucosal tissue. In contrast to this, other active pharmaceutical ingredients may require several hours or even longer. Yes. Therefore, in some embodiments, the aforementioned one or more water-soluble polymers make a film It may be used to form. However, in other embodiments, a water-soluble polymer and, first Use a combination of water-swellable, water-insoluble, and / or biodegradable polymers as provided. It may be desirable to have one or more water-swellable, water-insoluble and / or biodegradable materials. The inclusion of the rimer results in a slower dissolution rate than films formed solely of water-soluble polymers. This can provide a film with a decay rate. Therefore, this film can last for a maximum of several hours. It adheres to mucosal tissue for a relatively long time, and this is beneficial for the delivery of certain medicinal active ingredients. It will become desirable.

[0093] Preferably, the individual film dosage forms of the pharmaceutical film are of a suitable small thickness. It can have dimensions of approximately 0.0625-3 inches x approximately 0.0625-3 inches. The film size is also 0.0625 inches larger than 0.5 inches on at least one side. Larger than 1 inch, larger than 2 inches, or about 3 inches, or 3 inches Larger than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, less than 0.0625 inches Or, in other respects, greater than 0.0625 inches, greater than 0.5 inches, 1 inch Larger than 2 inches, or larger than 3 inches, approximately 3 inches, less than 3 inches It can also be less than 2 inches, less than 1 inch, less than 0.5 inches, or less than 0.0625 inches. The aspect ratio, including thickness, length, and width, is determined by the chemical and physical properties of the polymer matrix. The active pharmaceutical ingredients, dosage, enhancers, and other additives involved, as well as the desired distribution unit. Based on the dimensions of the product, it can be optimized by those skilled in the art. This film formulation is suitable for the user It must have good adhesion when placed in the oral cavity or sublingual region. This film formulation must disperse and dissolve at a gentle rate, most preferably. It disperses within approximately 1 minute and dissolves within approximately 3 minutes. In some embodiments, this film The lump dosage form is suitable for approximately 1 to 30 minutes, for example, approximately 1 to 20 minutes, or longer than 1 minute, longer than 5 minutes, and 7 Longer than one minute, longer than 10 minutes, longer than 12 minutes, longer than 15 minutes, longer than 20 minutes, 30 Longer than 1 minute, approximately 30 minutes, or less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, 10 minutes It is possible to disperse and dissolve at a rate of less than 1 hour, less than 7 minutes, less than 5 minutes, or less than 1 minute. Therefore, the sublingual dispersion rate can be shorter than the intraoral dispersion rate.

[0094] For example, in some embodiments, these films contain polyethylene oxide alone. It can be contained in combination with a second polymer component. The second polymer is another water-soluble polymer. Water-soluble polymers, water-swellable polymers, water-insoluble polymers, biodegradable polymers, or any of the above. This may be a combination of the above. Suitable water-soluble polymers include those previously provided, but these It is not limited to the above. In some embodiments, the water-soluble polymer is hydrophilic cellulose. hydroxypropylcellulose and / or hydroxypropylcellulose polymers, for example. Contains chill cellulose, etc. In some embodiments, one or more water-swellable, water-insoluble and The / or biodegradable polymers are also included in polyethylene oxide-based films. It is acceptable to use any of the previously provided water-swellable, water-insoluble, or biodegradable polymers. It is acceptable. The second polymer component is present in an amount of approximately 0% to approximately 80% by weight of the polymer component, and is more specific. It is used in amounts of approximately 30% to 70% by weight, and more specifically, approximately 40% to 60% by weight. Often, this is more than 5%, more than 10%, more than 15%, more than 20%, more than 30%. , more than 40%, more than 50%, more than 60%, and more than 70%, approximately 70%, less than 70%, Contains less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5% by weight. nothing.

[0095] Additives may be included in these films. Examples of additive classes include preservatives and antimicrobial agents. Biopharmaceuticals, excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, bulking agents, sweeteners Flavoring agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polio Lubricants, granulating agents, diluents, binders, buffers, absorbents, lubricants, adhesives, anti-adhesion agents, acidulants, Softeners, resins, lubricants, solvents, surfactants, emulsifiers, elastomers, anti-sticking agents, antistatic agents It contains inhibitors and mixtures thereof. These additives are added together with the pharmaceutically active ingredient(s). You may do so.

[0096] As used herein, the term “stabilizer” refers to an active pharmaceutical ingredient, another excipient, or a combination thereof. Excipients capable of preventing aggregation or other physical decomposition, as well as chemical decomposition. It means...

[0097] Stabilizers also include antioxidants and metal ions, which have been discussed previously and will be discussed in more detail below. Classified as chelating agents, pH adjusters, emulsifiers and / or surfactants, and UV stabilizers. That's good too.

[0098] Antioxidants (i.e., substances that slow down, inhibit, interrupt and / or stop oxidation processes, medical Compounds(s) or compositions(s) suitable as pharmaceuticals include, in particular, the following substances: Tocopherols and their esters, sesamol from sesame oil, and benzoic acid from benzoin resin. Coniferyl, nordihydroguaiaretic acid resin, and nordihydroguaiaretic acid (NDGA) , gallates (especially methyl gallate, ethyl gallate, propyl gallate, amyl gallate, butyl gallate, lauri gallate) (Lu), butylated hydroxyanisole (BHA / BHT, also butyl-p-cresol); ascorbyl Erythorbic acid and its salts and esters (e.g., ascorbyl palmitate), erythorbic acid (Isoascorbic acid) and its salts and esters, monothioglycerol, sodium phosphate Sodium aldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, bisulfite Sodium sulfate, potassium metabisulfite, butylated hydroxyanisole, butylated hydroxyanisole Loxytoluene (BHT), propionic acid. Typical antioxidants include tocopherol, for example, α- Tocopherol and its esters, butylated hydroxytoluene and butylated hydroxytoluene It is anisole. The term "tocopherol" also includes tocopherol esters. The known tocopherol is α-tocopherol. The term "α-tocopherol" is α - Contains esters of tocopherol (e.g., α-tocopherol acetate).

[0099] Metal ion chelating agents (i.e., another compound such as the active ingredient or another excipient, and host-gel) Any compound that can be fitted during complex formation (also known as a chelating agent) is , calcium chloride, ethylenediaminetetraacetate disodium, glucono delta- Lactone, sodium gluconate, potassium gluconate, sodium tripolyphosphate, This includes sodium xametaphosphate and combinations thereof. Metal ion chelating agents are also cyclic Oligosaccharides, such as cyclodextrin and cyclomannin (linked at the 1,4 position by α-linkage). Linked, 5 or more α-D-mannopyranose units, cyclogalactin (via β-linkage) 5 or more β-D-galactopyranoses linked at positions 1,4, cycloalthrin (α- Five or more α-D-altropyranose units linked at positions 1 and 4 by a linkage, and This also includes combinations of these.

[0100] pH adjusters include acids (e.g., tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, ascorbic acid). Acids (acetic acid, succinic acid, adipic acid and maleic acid), acidic amino acids (e.g., glutamic acid) Inorganic salts of such acidic substances (alkali metal salts, alkaline earth metal salts, etc.), such as aspartic acid. (e.g., ammonium salts), salts of such acidic substances with organic bases (e.g., basic ammonium salts) (for example, lysine, arginine and similar substances, meglumine and similar substances), and This also includes their solvates (e.g., hydrates). Other examples of pH adjusters include silica-containing microcrystals. Cellulose, magnesium aluminometasilicate, calcium salts of phosphate (e.g., phosphorus) Anhydrous or hydrated calcium oxyhydrogen, carbonate or calcium bicarbonate, and sodium. (or potassium, calcium lactate or mixtures thereof), carboxymethylcellulose Sodium and / or calcium salts of cellulose, cross-linked carboxymethylcellulose (for example) (or croscarmellose sodium and / or calcium), polaritrin potassium, Sodium ginate and / or calcium, sodium doxate, magnesium stearate Cium, calcium, aluminum, or zinc, magnesium palmitate, and This includes magnesium leate, sodium stearyl fumarate, and combinations thereof.

[0101] Examples of emulsifiers and / or surfactants include poloxamers or pluronic acid, polyethylene Recall, polyethylene glycol monostearate, polysorbate, sodium lauryl sulfate Thorium, polyethoxylated and hydrogenated castor oil, alkyl polyoside, hydrophobic main Water-soluble proteins graft-polymerized on a chain, lecithin, glyceryl monostearate, Glyceryl monostearate / polyoxyethylene stearate, ketostearyl alcohol (C) 10 -C 20 )-alkyl and alkyl Lennocarboxylates, alkyl carboxylates, aliphatic alcohol sulfates, aliphatic Alcohol ether sulfates, alkylamide sulfates and sulfonates, fatty acid alkyl Midopolyglycol ether sulfate, alkanesulfonates and hydroxyalkanesulfons Sulfonates, olefin sulfonates, acyl isethionates, α-sulfo fatty acids Esters, alkylbenzene sulfonates, alkylphenol glycol ethers Honates, sulfosuccinates, sulfosuccinates, monoesters and diesters of sulfosuccinate, aliphatic acid Sulfur ether phosphate, protein / fatty acid condensation product, alkyl monoglyceride sulfur Salts and sulfons, alkylglyceride ether sulfons, fatty acid methyl tauri D, fatty acid sarcosinates, sulfolicinolates, and acyl glutamates, quaternary ammonium compounds Chromium salt (for example, di-(C) 10 -C 24 )-alkyl-dimethylammonium chloride or bro Mido), (C 10 -C 24 )-alkyl-dimethylethylammonium chloride or bromide, (C 10 -C 24 )-Alkyl-trimethylammonium chloride or bromide (e.g., cetyltrimethyl (Ammonium chloride or bromide), (C 10 -C 24 )-alkyl-dimethylbenzylammonium Muclolide or bromide (for example, (C 12 -C 18 )-alkyl-dimethylbenzylammonium salt compound), N-(C 10 -C 18 )-alkylpyridinium chloride or bromide (for example, N-(C 12 -C 16 )-a Lukyl-pyridinium chloride or bromide), N-(C 10 -C 18 )-alkyl-isoquinolinium chloride Substances, bromides or monoalkyl sulfates, N-(C 12 -C 18 )-alkyl-polyoylaminoformyl Methylpyridinium chloride, N-(C 12 -C 18 )-alkyl-N-methylmorpholinium chloride, odor Compounds or monoalkyl sulfates, N-(C 12 -C 18 )-Alkyl-N-ethylmorpholinium chloride, Bromides or monoalkyl sulfates, (C 16 -C 18 )-alkyl-pentaoxetylammonium Loride, diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride Hydrochloric acid, acetic acid, and lactic acid of N,N-di-ethylaminoethylstearylamide and -oleylamide , citric acid, salt with phosphoric acid, N-acylaminoethyl-N,N-diethyl-N-methylammonium Chlorides, bromides or monoalkyl sulfates, and N-acylaminoethyl-N,N-dietite L-N-benzylammonium chloride, bromide, or monoalkyl sulfate (as described above, "acyl") This includes, for example, stearyl or oleyl, as well as combinations thereof.

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

[0103] In another embodiment, the stabilizer is ascorbyl palmitate, ascorbic acid, and Fatcopherol, butylated hydroxytoluene, butylated hydroxyanisole, Stain HCl, citric acid, ethylenediaminetetraacetic acid (EDTA), methionine, sodium citrate Um, sodium ascorbate, sodium thiosulfate, sodium metabisulfite, sulfur Sodium hydrogen oxyoxygen, propyl gallate, glutathione, thioglycerol, singlet oxygen Photochemical agents, hydroxyl radical scavengers, hydroperoxide removers, reducing agents, metals Includes chelating agents, cleaning agents, chaotropes, and combinations thereof. "Singlet oxygen quenching agent" Alkylimidazoles (e.g., histidine, L-camosine, histamine, imidazo) (4-acetic acid), indole (e.g., tryptophan and its derivatives, e.g., N-acetyl-5-) Methoxytryptamine, N-acetylserotonin, 6-methoxy-1,2,3,4-tetrahydrobe (T-carbolin), sulfur-containing amino acids (e.g., methionine, ethionine, diencholic acid) , lanthionine, N-formylmethionine, felinine, S-allylcysteine, S-aminoe Tyl-L-cysteine), phenolic compounds (e.g., tyrosine and its derivatives), aromatic acids (For example, ascorbates, salicylic acids, and their derivatives), azides (for example, azides) Sodium phosphate, tocopherol and related vitamin E derivatives, and carotene and related vitamin E This includes, but is not limited to, MIN A derivatives. "Benjer" contains azide, dimethyl sulfoxide, histidine, mannitol, sucrose, This includes, but is not limited to, glucose, salicylates, and L-cysteine. i. "Hydroperoxide scavengers" include catalase, pyruvate, glutathione, and Contains, but is not limited to, glutathione peroxidase. "Reducing agent" This includes, but is not limited to, cysteine ​​and mercaptoethylene. "Metal chelating agents" include EDTA, EGTA, o-phenanthroline, and citrate, but It is not limited to these. "Cleaning agent" refers to SDS and sodium lauroyl sarcosinate. This includes, but is not limited to, guanidium chloride. This includes, but is not limited to, isothiocyanates, urea, and formamide. i. As discussed herein, the stabilizer is present in an amount of 0.0001% to 50% by weight, and this , more than 0.0001%, more than 0.001%, more than 0.01%, more than 0.1%, more than 1% , more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50% Many, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1%, less than 0.1%, 0.01 Includes less than %, less than 0.001%, or less than 0.0001% by weight.

[0104] Useful additives include, for example, gelatin, vegetable proteins, such as sunflower seeds. Protein, soy protein, cottonseed protein, peanut protein, grapeseed protein Proteins such as whey protein, whey protein isolate, blood protein, egg protein Proteins, acrylic proteins, water-soluble polysaccharides, such as alginates, carrageenans, and guar gums. agar, xanthan gum, gellan gum, gum arabic and related gums (gatte Water-soluble derivatives of cellulose, such as malaya gum, tragacanth gum, and pectin: Alkylcellulose, hydroxyalkylcellulose and hydroxyalkylalkylcellulose Lurose, for example, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose Lurose, hydroxypropylcellulose, hydroxyethylmethylcellulose, Hydroxy Cellulose methylcellulose such as hydroxypropylmethylcellulose and hydroxybutylmethylcellulose Sterls and hydroxyalkylcellulose esters, for example, cellulose acetate (CAP) ), hydroxypropyl methylcellulose (HPMC); carboxyalkylcellulose, carboxymethylcellulose carboxyalkylcellulose, carboxyalkylcellulose ester, for example, Boxymethylcellulose and its alkali metal salts; water-soluble synthetic polymers, for example, polymethylcellulose. Acrylic 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 It may include; also, phthalate gelatin, succinate gelatin, cross-linked gelatin, and sheath gelatin. Lac, a water-soluble chemical derivative of starch, for example, a tertiary or quaternary amino group, is desired. If not, a cationically modified acrylate having a quaternized diethylaminoethyl group and methacrylate; or other similar polymers are also suitable.

[0105] The additional components should be in the range of up to approximately 80%, preferably about 0.005%, based on the weight of all the composition components. It can be in the range of %~50%, more preferably 1%~20%, which is more than 1%, 5 More than %, more than 10%, more than 20%, more than 30%, more than 40%, more than 50% , more than 60%, more than 70%, 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% It contains other additives such as anti-tacks, fluidizers and opacifiers, for example, magnesium, aluminum. Oxides of nium, silicon, titanium, etc., preferably based on the weight of all film components, It should be included in a concentration range of approximately 0.005% to approximately 5% by weight, and preferably approximately 0.02% to approximately 2% by weight. This is possible, and this is more than 0.02%, more than 0.2%, more than 0.5%, more than 1%, and more than 1.5%. More than 2%, more than 4%, about 5%, more than 5%, less than 4%, less than 2%, less than 1% This includes less than 0.5%, less than 0.2%, or less than 0.02%.

[0106] In one embodiment, the composition may contain a plasticizer, which is a polyalkylate. Sodium oxides, such as polyethylene glycol, polypropylene glycol, polyethylene - Low molecular weight organic plasticizers such as propylene glycol, e.g., glycerol, glycerol Lumonoacetate, diacetate, or triacetate, triacetin, polysol Bate, cetyl alcohol, propylene glycol, sugar alcohol, sorbitol, dietary Sodium sulfosuccinate, triethyl citrate, tributyl citrate, plant extracts, It may contain fatty acid esters, fatty acids, oils and similar substances, based on the weight of the composition. It is added at a concentration ranging from approximately 0.1% to approximately 40%, preferably in the range of approximately 0.5% to approximately 20%. This is more than 0.5%, more than 1%, more than 1.5%, more than 2%, more than 4%, and 5%. More than, more than 10%, more than 15%, about 20%, more than 20%, less than 20%, less than 15%, Includes less than 10%, less than 5%, less than 4%, less than 2%, less than 1%, or less than 0.5% of those hydrogens. To improve the texture properties of film materials such as animal or vegetable fats, which are preferably chemically modified. Further compounds may be added for this purpose. This composition also enhances the texture of the product. To improve performance, compounds may also be included. Other components facilitate film formation and overall It may contain binders that contribute to the general quality. Non-limiting examples of binders include starch, natural Rubber, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, carboxy Sodium methylcellulose, ethylcellulose, polyacrylamide, polyvinyl oxide Contains sazolidone or polyvinyl alcohol.

[0107] Further potential additives include substances that form encapsulation compounds with the active ingredient, and their solubility. Contains enhancers. Such substances improve the highly insoluble and / or unstable properties of the activity. These can be useful for that purpose. Generally, these materials have hydrophobic internal cavities and hydrophilic external cavities. It is a donut-shaped molecule with a part. Insoluble and / or unstable pharmaceutically active ingredients are hydrophobic. It fits into the cavity, thereby forming an inclusion complex, which is soluble in water. Therefore, the inclusion complex The formation of this compound allows highly insoluble and / or unstable pharmaceutically active ingredients to dissolve in water. A particularly desirable example of such a substance is cyclodextrin, which is derived from starch. It is a derived cyclic carbohydrate. However, other similar substances are considered to fall within the scope of this invention. It is possible.

[0108] Suitable colorants include Food, Pharmaceutical and Cosmetic Colors (FD&C), Pharmaceutical and Cosmetic Colors (D&C), or includes colors of quasi-drugs and cosmetics (Ext. D&C). These colors are pigments, their corresponding colors Lakes, as well as certain natural and derived colorants. Lakes are aluminum hydroxides. It is a pigment absorbed onto the surface. Other examples of colorants include known azo dyes, organic or inorganic. Contains pigments or colorants of natural origin. Inorganic pigments, such as oxides or iron or titanium, These oxides and the like make up about 0.001 to about 10%, and preferably about 0.5% of the total weight of the components. It is preferable to add it at a concentration in the range of approximately 3%, which is greater than 0.001%. i, more than 0.1%, more than 0.5%, more than 1%, more than 2%, more than 5%, approximately 10% , more than 10%, less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, 0.01 Includes percentages less than 0.001%.

[0109] The fragrance may be selected from natural and synthetic flavored liquids. Examples of such substances include The list includes volatile oils, synthetic flavoring oils, flavored aromatics, oils, liquids, oil-containing resins, or plants. This includes extracts derived from leaves, flowers, fruits, and stems, and combinations thereof. Examples are non-limiting. Typical examples include mint oil, cocoa oil, and citrus oils, such as lemon, orange, and lime. and grapefruit, as well as apples, pears, peaches, grapes, strawberries, raspberries, Essential oils of fruits including cherries, plums, pineapples, and apricots, or other fruit flavors. It contains. Other useful flavorings include aldehydes and esters, such as benzaldehyde (saccharin). Lamb, almond), citral, i.e., alpha citral (lemon, lime), ne Lal, that is, 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-dimethyl Octanol (vegetables (green) and fruits), or 2-dodecenal (citrus, mandarin), and those Includes combinations, etc.

[0110] The sweetener may be selected from the following non-restrictive list: glucose (corn syrup), Dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various forms. Salts, such as sodium salts; dipeptide-based sweeteners, such as aspartame, neothene Advantame; dihydrochalcone compounds; glycyrrhizin; stevia (Stevia Re baudiana) (stevioside); chlorine derivatives of sucrose, e.g., sucralose; sugar alcohols, For example, sorbitol, mannitol, xylitol, and similar substances. Also, hydrogenated... Hydrolyzed starch and synthetic sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiadi N-4-one-2,2-dioxide, especially potassium salt (acesulfame-K), and their sodium Salts and calcium salts, as well as natural, strong sweeteners, such as Lo Han Kuo. Other sweeteners may also be used.

[0111] Antifoaming and / or defoaming agents may also be used in the film. These components are in the film It helps remove air, such as trapped air, from the MU-forming composition. Air trapped inside can lead to an uneven film. Simethicone is one particularly useful... It is an antifoaming agent and / or defoaming agent. However, the present invention is not limited in this way and other preferred agents. Suitable defoaming and / or defoaming agents may be used. Simethicone and related substances are densely packed. It may be used for the purpose. More specifically, such substances include voids, air, moisture, and similar substances. This can promote the removal of similar undesirable components, thereby creating a denser film. Therefore, a more uniform film is provided. The substance or component that performs this function is a densifying agent. These are called (densification) or density-increasing substances (densifying agents). As explained above... Furthermore, trapped air or undesirable components can lead to a non-uniform film.

[0112] As mentioned earlier, U.S. Patents No. 7,425,292 and No. 8,765,167 by the same applicant Any other component listed may also be included in the film described herein.

[0113] This film composition may further contain a buffer to control the pH of the film composition. Desirable. When the pharmaceutically active ingredient is released from the composition, any desired level of the buffer is present. It is incorporated into the film composition to provide the desired pH level to be encountered. The fluid is sufficient to control the release of the pharmaceutically active ingredient from the film and / or its absorption into the body. It is preferable that it be provided in quantity. In some embodiments, the buffer is sodium citrate. It may contain citric acid, bicarbonate tartrate, and combinations thereof.

[0114] The pharmaceutical films described herein may be formed by any desired process. The process is described in U.S. Patents No. 8,652,378, No. 7,425,292 and No. 7,357,891. These are incorporated herein by reference. In one embodiment, film The dosage form composition is formed by first preparing a wet composition, which is a po This wet composition contains a rimerable carrier matrix and a therapeutically effective amount of pharmaceutically active ingredient. The saliva is poured onto the film and then thoroughly dried to form a self-supporting film composition. The wet composition is poured into individual dosage forms, or it is poured onto a sheet, and then this sheet... The product is cut into individual dosage forms.

[0115] This pharmaceutical composition can adhere to the mucous membrane surface. The present invention relates to the mouth, vagina, organs, or other Body tissues, affected areas, etc., that have a moist surface, such as the mucous membrane surface, and are susceptible to the effects of bodily fluids. , or its specific use in the local treatment of wounds is permitted. This composition is used to transport pharmaceuticals and When applied to and adhered to the mucosal surface, it provides a protective layer, and also protects the treatment site, surrounding tissue, and Delivering medicine to other bodily fluids. Controlling erosion in aqueous solutions or bodily fluids such as saliva, and related to delivery. Assuming slow and natural erosion of the accompanying or continuous film, this composition is effective in treating the area It provides a suitable residence time for effective drug delivery at the appropriate position.

[0116] The residence time of this composition depends on the erosion rate of the water-erosive polymer used in the formulation and its It is determined by the respective concentrations. The erosion rate is determined, for example, by components or chemicals with different solubility characteristics. Different polymers, for example, hydroxyethylcellulose and hydroxypropylcellulose By mixing the hydroxyethylcellulose with low and medium molecular weight hydroxyethylcellulose. By using different molecular weight grades of the same polymer, such as by mixing; various lipophilic values ​​or By using excipients or plasticizers with water solubility properties (including essentially insoluble components); water By using soluble organic and inorganic salts; for partial crosslinking, hydroxyethyl sulfate By using polymers such as lurose and crosslinking agents such as glyoxal; or Once obtained, the crystallinity or the physical state of the film, including the phase transition, can be changed. These can be adjusted by post-treatment irradiation or curing. These strategies are film It may be used alone or in combination to modify the erosion dynamics. When applied, the pharmaceutical composition The film adheres to the mucous membrane surface and is retained in place. Water absorption is performed on this composition. It makes the surface more flexible, thereby reducing the sensation of a foreign object. When this composition is placed on the mucous membrane surface, the drug Delivery is triggered. Residence time is the desired timing and duration for the delivery of the selected drug. It can be widely regulated according to the desired lifespan of the body. However, generally, the residence time is about a few seconds. The adjustment period is approximately several days. Preferably, the residence time for most pharmaceuticals is about 5 seconds to about 24 hours. The residence time is adjusted to approximately 5 seconds to approximately 30 minutes. In addition to providing protection, once the composition adheres to the mucosal surface, it also provides protection for the treatment site and prevents erosion. It acts as a bandage. Lipophilic substances slow down erosion to reduce disintegration and dissolution. It can be designed in this way.

[0117] They are sensitive to enzymes such as amylase, and unlike water-soluble organic salts and inorganic salts, they are not present in water. The erosive dynamics of this composition can also be controlled by adding easily soluble excipients. Yes, it is possible. Suitable excipients include chloride, carbonic acid, bicarbonate, citric acid, and trifluoroacetic acid. , containing benzoic acid, phosphoric acid, fluoride, sulfuric acid, or sodium and potassium salts of tartaric acid. That's fine. The amount added depends on how much the erosion dynamics are altered, as well as the other components in the composition. It can vary depending on the quantity and properties of the component.

[0118] The emulsifiers typically used in the water-based emulsions described above are preferably Linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid, cetreyl acid If selected from oleic acid or oleic acid and sodium hydroxide or potassium hydroxide, It can be obtained by, or by lauric acid esters of sorbitol and anhydrous sorbitol, palmitate tine esters, stearate esters, or oleate esters, monooleates Polyoxyethylene derivatives including monostearate, monopalmitate, and monolaurate. Body, aliphatic alcohol, alkylphenol, allyl ether, alkylaryl ether Sorbitan monostearate, sorbitan monooleate and / or sorbitan mono It is either selected from palmitate or one of the other options.

[0119] The amount of active pharmaceutical ingredient used is determined by the desired therapeutic strength and the composition of these layers. However, preferably the pharmaceutical component is about 0.001% to about 99% of the composition, more preferably about 0.003% to about It constitutes 75%, and most preferably about 0.005% to about 50% by weight, which is more than 0.005% and 0. More than 0.5%, more than 1%, more than 5%, more than 10%, more than 15% k, more than 20%, more than 30%, approximately 50%, more than 50%, less than 50%, less than 30%, less than 20% Full, 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% It contains. The amounts of other components may vary depending on the drug or other components, but typically these The components shall not exceed 50%, preferably not exceeding 30%, and most preferably exceeding 50% of the total weight of the composition. The composition should not exceed 15%.

[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 may be adjusted to vary the erosion dynamics. Preferably, the composition If it has only two layers, the thickness is 0.005 mm to 2 mm, preferably 0.01 to 1 mm, and more preferably The range is 0.1 to 0.5 mm, which means greater than 0.1 mm, greater than 0.2 mm, approximately 0.5 mm, 0 Includes thicknesses 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 is determined by the layering. The total thickness of the composition may vary by 10 to 90%, preferably by 30 to 60%, and this This includes more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, and more than 70%. More than 90%, about 90%, less than 90%, less than 70%, less than 50%, less than 40%, less than 30%, This includes less than 20% or less than 10%. Therefore, the preferred thickness of each layer is 0.01 mm to 0.9 mm, or 0 The thickness can vary between 0.03mm and 0.5mm.

[0121] As those skilled in the art will understand, when systemic delivery, for example transmucosal or transdermal delivery, is desirable, The treatment area is where the film delivers the desired level of pharmaceutical ingredients into the blood, lymph, or other bodily fluids. It may include any region that can be destroyed / or maintained. Typically, The treatment sites include the mucous membranes of the mouth, ears, eyes, anus, nose, and vagina, as well as the skin. When used as a treatment site, it is usually the upper arm or thigh, where movement can break the film's adhesion. A relatively large area of ​​skin that won't be damaged is preferable.

[0122] This pharmaceutical composition can also be used as a wound dressing. It can be washed away. By providing a physical, adaptable, oxygen and moisture permeable, and flexible barrier, the film It not only protects the wound, but also promotes healing, sterilization, and scar formation. To deliver medicine in order to relieve pain or to improve the overall condition of the affected person. It is also possible. Some of the examples provided below are well suitable for application to skin or wounds. As those skilled in the art will understand, this formulation provides good adhesion to dry skin over a long period of time. It is necessary to incorporate a specific hydrophilic / hygroscopic excipient to help maintain the properties. Another advantage of the present invention is that, when using this form, the film does not need to be noticeable on the skin. If not, the use of dyes or coloring substances is unnecessary. On the other hand, if the film is noticeable If desired, pigments or coloring substances may be used.

[0123] This pharmaceutical composition can adhere to mucosal tissue, which is originally moist tissue, while the skin It can also be used on other surfaces such as skin or wounds. This medicinal film is suitable for use on the skin. Prior to application, moisten with a water-based fluid such as water, saliva, drainage from a wound, or sweat. Even if there is a problem, it can adhere to the skin. This film can be used, for example, when washing with water or showering. - It adheres to the skin until it is eroded by contact with water, such as during bathing or washing. This film can also be peeled off easily without causing significant damage to the tissue. It can be removed.

[0124] Franz diffusion cells are used in in vitro skin penetration assays in pharmaceutical development. The Franz diffusion cell apparatus (Figure 1A) is used to separate, for example, animal or human tissue membranes. It consists of two chambers. The product under test is applied to the membrane through the upper chamber. The side chamber is used for analysis to determine the amount of activity that permeates the membrane, and then the sample is placed at regular intervals. The fluid collected is included. In relation to Figure 1A, the Franz diffusion cell 100 contains donor compound 101, Null chamber 102, membrane 103, sampling hole 104, receptor chamber 105, stirring rod 106 It is equipped with a heater / circulator 107.

[0125] Regarding Figure 1B, the pharmaceutical composition is a polymer matrix 200, and in this polymer matrix This is a film 100 containing 300 pharmaceutically active ingredients. This film is permeable enhancer. It can include 400.

[0126] Regarding Figures 2A and 2B, the graphs show the permeation of the active substance from the composition. These graphs indicate that Epinephrine base solubilized in situ, paired with essentially soluble epinephrine bitartrate. Regarding furin, no significant difference was observed. Epinephrine bitartrate is processed It was chosen for further development based on its ease of use. Flux is the amount of transmission as a function of time. It is induced as a gradient. The steady-state flux is integrated by the volume of the receiver medium. Furthermore, it is obtained from the plateau of the flux, pair, and time curve, which is normalized with respect to the transmission area.

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

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

[0129] Regarding Figure 3, this graph shows the epinephrine bitartrate as a function of concentration. Vivo permeation was observed. This test compared concentrations of 4 mg / mL, 8 mg / mL, 16 mg / mL, and 100 mg / mL. The results showed that increasing concentrations indicated increased permeability, and that higher levels of enhancement indicated higher negative permeability. It showed that the load decreased.

[0130] Regarding Figure 4, this graph shows the permeation of epinephrine bitartrate as a function of solution pH. The results show that acidic conditions were investigated to see if they promoted stability. The results showed that epinephrite bitartrate was the cause. A comparison was made between phosphorus pH3 buffer and epinephrine bitartrate pH5 buffer, and also between epinephrine bitartrate pH3 buffer and A slightly preferable phosphorus pH 5 buffer solution was observed.

[0131] Regarding Figure 5, this graph shows the amount of transmission as a function of time, and the epinephrine This shows the effect of enhancers on the permeability of [unclear]. (Labrasol, Capriol 90, Plur) Multiple ingredients including ol Oleique, labrafil, TDM, SGDC, gelcile 44 / 14 and clove oil. We screened for enhancers. Significant impact on time to start and steady-state flux. Such effects were achieved, and surprisingly, enhanced permeability was observed for clove oil and labrasol. And it was achieved.

[0132] Regarding Figures 6A and 6B, these graphs show the transmission amount (μg) versus time. Epinephrine release on the rimer platform and the effect of enhancers on its release. The use is shown. Figure 6A shows epinephrine release from different polymer platforms. 6B shows the effect of the enhancer on epinephrine release.

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

[0134] Regarding Figure 8, this graph shows the difference in concentration between 40 mg epinephrine film and 0.3 mg EpiPen. This shows the effect of no enhancer on Rophile.

[0135] Regarding Figure 9, this graph shows the difference in concentration between 40 mg epinephrine film and 0.3 mg EpiPen. This shows the effect of enhancer A (Labrasol) on rofil. Regarding Figure 10, this graph The results were obtained using two types of 40 mg epinephrine films (10-1-1) and (11-1-1), compared to the concentration of a 0.3 mg EpiPen. This shows the effect of enhancer L (clove oil) on the profile.

[0136] Regarding Figure 11, this graph shows the concentration of 40 mg epinephrine film versus 0.3 mg EpiPen. Enhancer L (clove oil) and film dimensions (10-1-1 thin and large) relative to the profile. This shows the effect of film and (11-1-1 thick, small film).

[0137] Regarding Figure 12, this graph shows the difference between Enhancer L (clove oil) and 0.3 mg EpiPen. Regarding the variation in the dose of epinephrine film in a certain matrix, concentration profile Shows a file.

[0138] Regarding Figure 13, this graph shows the difference between Enhancer L (clove oil) and 0.3 mg EpiPen. Regarding the variation in the dose of epinephrine film in a certain matrix, concentration profile Shows a file.

[0139] Regarding Figure 14, this graph shows the difference between Enhancer A (Labrazol) and 0.3 mg EpiPen. Regarding the variation in the dose of epinephrine film in a certain matrix, concentration profile Shows a file.

[0140] Regarding Figure 15, this graph shows the amount of diazepam transmitted as a function of time. This shows the effect of the enhancer on transparency.

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

[0142] Regarding Figure 17, this graph compares plasma with 40 mg epinephrine film versus 0.3 mg EpiPen. The concentration profile of farnesol and farnesol combined with linoleic acid It shows an impact.

[0143] Regarding Figure 18, this graph compares plasma with 40 mg epinephrine film versus 0.3 mg EpiPen. The concentration profile of farnesol and farnesol combined with linoleic acid It shows an impact.

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

[0145] Regarding Figure 20, this graph compares 40 mg epinephrine film versus 0.3 mg EpiPen in plasma. The concentration profile of farnesol and farnesol combined with linoleic acid It shows an impact.

[0146] The following examples describe a pharmaceutical composition, a method for producing the pharmaceutical composition and a method for using it, and the present specification. Provided to illustrate the apparatus described in this document. [Examples]

[0147] (Examples) (Example 1: Permeation enhancer - epinephrine) To enhance permeation, multiple permeation enhancers were used to increase the concentration of epinephrine bitartrate at 16.00 mg / The test was performed using mL. The results show flux enhancement as shown in the following data. 100% Regarding igenol and 100% clove oil, the results showed that the reaction was significantly faster with steady-state flux. This was achieved and demonstrated 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 were obtained from clove leaves. Obtained from clove oil derived from clove buds and / or clove stems. Based on this data, similar extracts The results of hyperpotency can be predicted from pharmaceutical compounds structurally similar to epinephrine. ru.

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

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

[0152] [Table 2]

[0153] The following excipients can also be applied for similar enhancing properties: cinnamon leaf, basil Ingredients: bay leaf, nutmeg, Kolliphor® TPGS, vitamin E PEG succinate, Kolliphor® EL, Polyoxyl 35 Castor Oil USP / NF, Menthol, N-Methyl-2-Pyroxene Lidone, SLS (SDS), SDBS, Dimethyl phthalate, Sucrose palmitate (Sisterna PS 750-C), sucrose stearate (Sisterna SP70-C), CHAPS, octyl glucoside, Triton X 100 (octoxynol-9), ethyl maltol (powdered flavoring), Brij 58 (ceteth-2) 0) Vitamin E tocopherol, tocopherol acetate or tocopherol succinate, ste Rolls, 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 transmission method is performed as follows: The bath is set to 37°C, and the receiver... Place the bar medium in a water bath to regulate the temperature and begin degassing. Obtain and prepare the donor compound. The Franz diffusion cell consists of a donor compound, a donor chamber, and a membrane. , sampling hole, receptor chamber, stirring rod, and heater / circulator Prepare. The stirring rod is inserted into the Franz diffusion cell. Place the tissue on top of the Franz diffusion cell. Place the material and ensure that the tissue completely covers the glass joint through overlapping. Place the top of the dispersed cell on top of the tissue, and secure the top of the cell to the bottom with a clamp. Approximately 5 mL of receptor medium is loaded into the receiver area, and air bubbles are trapped in the receiving portion of the cell. Ensure that it does not get lost. This means that all 5 mL fits into the receiver area. Ensure that this can be done. Start stirring and allow the temperature to equilibrium for about 20 minutes. Meanwhile, high speed Label the liquid chromatography (HPLC) vials by the number of cells and by time point. Furthermore, 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 Then, punch to match (or smaller than) the diffusion area, weigh again, and punch again. (2) Record the weight before and after; (3) Wet the donor area with approximately 100 μL of phosphate buffer. (3) Place the film on the donor surface and cover it with 400 μL of phosphate buffer, and The process of starting the timer.

[0158] Regarding solution testing, the following steps can be performed: (1) Using a micropipette (2) Distribute 500 μL of solution into each donor cell and start the timer; (3) At the following point, 200 Sampling was performed at (times = 0 min, 20 min, 40 min, 60 min, 120 min, 180 min, 240 min, 300 min, 360 min) (min) Place it in a labeled HPLC vial, and tap the sealed vial to remove air. (3) A step to ensure that it is not captured at the bottom of the vial; (4) At each sampling time, 200 μ (4) Replace with receptor medium L (maintaining 5 mL); (5) All time points are complete. Next, the process involves disassembling the cell and properly disposing of all the materials.

[0159] (Example 4: Ex vivo permeability evaluation) An example of ex vivo permeability evaluation is 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. The body is selected to ensure the sink conditions are met. 5. Tissue, donor compound, donor chamber, membrane, sampling pore, receptor channel A humb, stirring rod, and heater / circulator are arranged within a Franz diffusion cell. do. 6. Apply approximately 0.5 mL of donor solution and immerse the 8 mm circular film in 500 μL of PBS buffer. Moisten with it. 7. Take samples from the receiver chamber at predetermined intervals and place them in a fresh medium. exchange.

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

[0161] For the transmission test, the oral mucosa of a pig was cut into sheets with a thickness of 500 ± 50 μm, and this An electro-skinning knife (GA 630, Aesculap, Tuttlingen, Germany) was used to create a diffusion barrier (Sudhakar et al.). The literature, "Oral bioadhesive drug delivery - a promising option for drugs with poor oral efficacy (Buccal b ioadhesive drug delivery - A promising option for oral less efficient drugs) Journal of Controlled Release, 114 (2006) 15-40), and cut into appropriate small pieces with surgical scissors. They were aligned. Most of the lower 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 ) Specially designed with a transparent orifice It was mounted in a membrane holder. Using the membrane holder, the oral endothelium of each pig was collected in the donor compartment. It is mounted between the receptor compartment (1.5 mL) and the receptor compartment (6 mL), with a static Franz type on the epithelial side. Facing the donor chamber of the diffusion cell (Vidra Foc Barcelona, ​​Spain), and in the connective tissue area The area was positioned to face the receiver to prevent foam formation.

[0163] The infinite dosage condition is when 100 μL of saturated doxepin solution is used as the donor solution. It is applied to the scepter chamber and immediately sealed with Parafilm to prevent water evaporation. This was ensured by the following: Before conducting this experiment, the diffusion cells were checked so that the temperature inside all cells was Each cell was incubated in a water bath for 1 hour to reach equilibrium (37°C ±°C). It includes a Teflon-coated magnetic stirring rod, which during the experiment, the receptor compartment It was used to ensure that the fluid inside the container remained homogeneous.

[0164] The sink conditions are determined by first testing the doxepin saturation concentration in the receptor medium. This was confirmed in all experiments. The sample (300 μL) was subjected to a pre-selected time interval of 6 hours. Intervals (0.1, 0.2, 0.3, 0.7, 1, 2, 3, 4, 5, and 6 hours) within the receptor compartment It was extracted from the heart using a syringe. Care was taken to avoid trapping air under the membrane. However, the extracted sample volume was then converted to the same volume of fresh receptor medium (PBS; pH 7.4). It was replaced immediately. For further details, see the literature by A. Gimemo et al., "Transoral delivery of doxepin: Transbuccal delivery of doxepin: Studies on permeation and histological evaluation)”, International Journal of Pharmaceutics 477 (2014 This can be found in 650-654, which is incorporated herein by reference.

[0165] (Example 6: Oral and mucosal delivery) The histological characteristics of porcine oral mucosal tissue are similar to those of human oral mucosal tissue (Heaney TG). Jones RS's paper, "Histological study of the effects of adult porcine alveolar mucosal connective tissue on epithelial differentiation (His tological investigation of the influence of adult porcine alveolar mucosal conne Arch Oral Biol 23 (1978) 713-717 ;Squier CA and Collins P, "Between soft tissue attachment, epithelial subgrowth and surface porosity" The relationship between soft tissue attachment and epithelial downgrowth d surface porosity)”, Journal of Periodontal Research 16 (1981) 434-440). Lesch In the literature, "The Permeability of Human Oral Mucosa and Skin to Water," "Mucosa and Skin to Water" (J Dent Res 68 (9), 1345-1349, 1989) describes the oral cavity of pigs. The water permeability of the inner mucosa is not significantly different from that of human oral mucosa, but the floor of the mouth is more like human tissue. However, it was reported to be more permeable than porcine tissue. Fresh porcine tissue samples were stored at -80°C. Comparisons between the stored specimens revealed that freezing did not have a significant effect on permeability. The oral mucosal absorption of a wide range of drugs in pigs was investigated both in vitro and in vivo. The molecules were tested (for example, M. Sattar's literature, "Oral transmucosal drug delivery - latest status and Oral transmucosal drug delivery - current status and future prospects See Table 1 in International Journal of Pharmaceutics 471 (2014) 498-506, (This is incorporated herein by reference). Typically, in vitro studies are performed In a thinning chamber, Franz cell, or similar diffusion device, the oral cavity of an excised pig It is involved in the loading of tissue. The in vivo tests described in this document involve solutions, gels, or compositions. This involves the application of drugs as physical substances to the oral mucosa of pigs, and subsequent plasma sampling. ru.

[0166] The literature by Nicolazzo et al. ("Effects of various in vitro conditions on the permeability characteristics of oral mucosa") The Effect of Various in Vitro Conditions on the Permeability Characteristics of Journal of Pharmaceutical Sciences 92(12) (2002) 2399-241 0) uses caffeine and estradiol as model hydrophilic and lipophilic molecules. The study investigated the effects of various in vitro conditions on the permeability of oral tissues in pigs. Drug permeation through the mucosa was tested using a modified Ussing chamber. Comparative permeation test The experiment was conducted through full-thickness epithelial tissue, fresh tissue, and frozen tissue. Tissue integrity was full Absorption of olecein isothiocyanate (FITC)-labeled dextran 20 kDa (FD20) indicates In addition to monitoring, tissue viability was determined to be MTT(3-[4,5-dimethylthiazole-2-yl]-2,5-diphthiazole-2-yl) The phenyltetrazolium bromide was evaluated using biochemical assays and histological assessments. Permeability through the intracavitary epithelium is 1.8 times higher for caffeine compared to full-thickness oral tissue. For estradiol, the flux was greater than 16.7 times. Flux values ​​for both compounds. The results were similar for fresh and frozen oral epithelium, but histological evaluation was different for frozen tissue. The signs of cell death were identified using the MTT viability assay. It appeared to survive for two hours, 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. I looked it up. The in vitro permeation test used antipyrine and buspirone as model permeants. The test was performed using lon, bupivacaine, and caffeine. The mouths were 250, 400, 500, 600, and 700 μm thick. The permeability of model diffusers beyond the intracavitary mucosa was determined for epithelium and connective tissue. To depict the relative contribution to barrier function, a bilayer film model was developed. The relative contribution of the combined tissue area increased significantly with increasing mucosal tissue thickness. Epithelium, with its thickness Since the major permeability barriers for all diffusers have been shown, a mucosal tissue thickness of approximately 500 μm is used. The authors recommended an in vitro transoral permeability test. They also recommended a study of porcine oral mucosa. Numerous biological and experimental variables affecting the permeability of the same group of model permeators in the same context. The effects were investigated (in vitro model of pig oral mucosa: biological and experimental variables). The effect of (Kulkarni et al., J Pharm Sci. 2010 99(3):1265-77). Significantly, the permeate is more High permeability is more effective in the thinner areas of the inside of the lips (170 μm) compared to the thicker areas of the cheeks (250-280 μm). It was observed in the area of ​​~220 μm). The oral mucosa of pigs was examined in Krebs-Ringer's bicarbonate solution. At 4°C, its integrity was maintained for 24 hours. Heat was used to separate the epithelium from the underlying connective tissue. The treatment did not adversely affect the permeability and integrity characteristics compared to surgical separation.

[0168] For further details, see the literature by M. Sattar, "Oral transmucosal drug delivery - current status and future prospects (O ral transmucosal drug delivery- current status and future prospects)”, Internat This can be found in the Professional Journal of Pharmaceutics 471 (2014) 498-506, and this is cited. This is incorporated herein by means of [unspecified].

[0169] (Example 7: Cryopreservation of oral mucosa) Different regions of the oral mucosa of pigs have different patterns of permeability, particularly in the area on the inside of the lips. In this region, there is significantly higher permeability compared to the cheek area, and the reason for this is the oral mucosa of pigs. In membranes, the epithelium acts as a permeable barrier, and the thickness of the buccal epithelium is the same as the thickness of the inner lip region. This is because it is larger than (Harris and Robinson, 1992). In illustrative permeability tests, Then, fresh and frozen porcine oral mucosa from the same region is used in sheets with a thickness of 500 ± 50 μm. They are cut into pieces and used as a diffusion barrier (Sudhakar et al., 2006), and an electro-skinning knife (Model GA 6) Obtain it using 30, Aesculap, Tuttlingen (Germany), and cut it into appropriate small pieces with surgical scissors. All equipment used was sterilized beforehand. Most of the lower connective tissue was removed with a surgical scalpel. It was removed. Next, the film was removed, with a diameter of 9 mm (diffusion area 0.63 cm²). 2 ) specially designed with a transparent orifice It was mounted on a membrane holder. Using the membrane holder, the oral endothelium of each pig was collected from the donor container. It is placed between the compartment (1.5 mL) and the receptor compartment (6 mL), and the epithelial side is statically frozen. Facing the donor chamber of the Lanz-type diffusion cell (Vidra Foc Barcelona, ​​Spain), and connecting The composite tissue region was positioned to face the receiver to prevent bubble formation. The experiment was performed using PP. Furthermore, this is used as a model drug and has lipophilic characteristics (logP=1.16; n-octanol / PBS, pH7 4) It is readily ionized (ionisable) (pKa = 9.50) and has MW = 259.3 g / mol (Modamio (Et., 2000).

[0170] The infinite dosage condition is a saturated PP solution in PBS (pH 7.4) (at 37°C ± 1°C, C0 = 588005 ± 5852 μg / 300 μL of the donor solution (mL, n=6) was applied to the receptor chamber, and the water evaporated. To prevent this, it was immediately sealed with Parafilm to ensure safety.

[0171] Before conducting this experiment, the diffusion cells were set to equilibrium temperature (37°C ± 1°C) in all cells. The cells were incubated in a water bath at ℃ for 1 hour. Each cell was coated with a small Teflon film. It includes a magnetic stirring rod, which ensures that the fluid in the receptor compartment remains homogeneous during the experiment. Used to ensure that it was maintained. The sink conditions were the saturated concentration of PP in the receptor medium. After testing the degree first, we ensured it was accurate in all experiments.

[0172] The sample (300 μL) is dispensed from the center of the receptor compartment using a syringe at the following time intervals. Extracted by: 0.25, 0.5, 1, 2, 3, 4, 5 and 6 hours. Air was trapped under the skin. Carefully remove the sample volume to avoid contamination, and replace it with a fresh receptor of the same volume. The sample was immediately replaced with a medium (PBS; pH 7.4). The unit surface area (cm²) of the mucosa was measured. 2) a drug that penetrates (μ The cumulative amount of g) was corrected for the removed sample and plotted against time (h). The dispersion experiment was performed 27 times on fresh oral mucosa and 22 times on frozen oral mucosa. .

[0173] For further details, see the literature by S. Amores, "Ex vivo drug penetration using Franz diffusion cells." An improved cryopreservation method for the oral mucosa of pigs in a study. ation method for porcine buccal mucosa in ex vivo drug permeation studies using European Journal of Pharmaceutical Sciences 60 (2014) This can be recognized in sections 49-54.

[0174] (Example 8: Quinine permeation beyond the sublingual mucosal compartment) Since the oral membranes of pigs and humans are similar in composition, structure, and permeability measurements, the porcine Oral mucosa is a suitable model for human oral mucosa. Its permeability exceeds that of porcine oral mucosa. It cannot be linked to gratitude, and therefore is not important for the organization's survival.

[0175] To prepare the pig membrane, the mucous membrane of the floor of the pig's mouth and the ventral (lower) tongue is used with a surgical scalpel. It was removed by blunt excision. The removed mucosa was cut into approximately 1 cm squares and used. The sample was frozen on aluminum foil at -20°C (<2 weeks). Unfrozen ventral surface of the pig's tongue. Regarding this, the mucous membrane was used in a translucency 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 all The determination was made using a glass Franz diffusion cell. The flange of this cell is a high-performance vacuum glass. The rake smooths the membrane between the receptor compartment and the donor compartment. It was mounted between them, with the mucosal surface facing upwards. A clamp was used to hold the membrane in place, and The post-receptor compartment was filled with degassed phosphate-buffered saline (PBS) at pH 7.4. A micro-magnetic stirring bar is added to the receptor compartment, and the complete cell is placed in a 37°C water bath. This membrane was then placed in the donor compartment and allowed to equilibrate for 20 minutes with PBS. The mixture was then aspirated with a pipette. 5 μL of quinine solution or Q / 2-HP-β-CD compound in different vehicles. A 100 μL aliquot of a saturated body solution was applied to each donor compartment. Ventral side of the tongue. In a test to determine the effect of saliva on the permeation of quinine beyond the surface, sterile saliva 100 μL was added to the 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 hole and tested. Transfer a 1 mL aliquot of the sample to an HPLC automated sampler vial, and then store it at 37°C. It was replaced with PBS. Tests involving Q / 2-HP-β-CD saturated solution (unlimited dose at the start of the experiment) (Applicable to) In addition, 5 μL of each quinine solution is administered to the donor again over a maximum of 10 hours. This was applied to the phase. The purpose of this was to determine a hypothetical finite dosing regimen based on a 2-hour interval between doses. The results were presented. At least three repetitions were performed for each test.

[0178] For further details, see the literature by C. Ong, "Quinine penetration beyond the sublingual mucosa in vitro." (Permeation of quinine across sublingual mucosa, in vitro)”, International Jour This can be found in nal of Pharmaceutics 366 (2009) 58-64.

[0179] (Example 9: Ex vivo initial test - API formation) In this example, in situ, the epinephrine base, paired with, is essentially soluble. The permeability of soluble epinephrine bitartrate was tested, and no difference was observed. Pinephrine was chosen for further development based on its ease of processing. Flux was chosen over time. It is derived as a gradient of the transmission amount as a function. The steady-state flux is the receiver medium The data was extrapolated from the plateau of the flux, pair, and time curves, which were integrated by volume. (Figure 2A) F contains 8.00 mg / mL epinephrine bitartrate and 4.4 mg / mL solubilized epinephrine base. The graph in Figure 2B shows the average permeation rate versus time. The average flux, pair, and time are shown for 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 The test was conducted. 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 the concentration The increase in [value] resulted in increased transmission, 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. In this example, we investigated whether acidic conditions have the ability to promote stability. The results showed that pH 5 was slightly more preferable than pH 3. The intrinsic pH of epinephrine bitartrate is 4.5-5. pH adjustment with buffer solution is unnecessary. .

[0184] Figure 4 shows the permeation of epinephrine bitartrate as a function of solution pH. Under acidic conditions, We investigated whether it promotes stability. The results showed that it was used in combination with epinephrine hydrogen tartrate pH3 buffer and alcohol. We compared epinephrine bitartrate pH5 buffer and found that epinephrine bitartrate pH5 buffer was He quietly acknowledged that it was a good thing.

[0185] (Example 12: Effect of enhancer on epinephrine permeation) In this example, the permeation of epinephrine for transmucosal delivery is measured by the amount of permeation. The following enhancers were tested in terms of (μg), versus time (minutes). The concentration-based effects were screened in solutions containing [the substance]. The graph in Figure 5 shows the effects over time. This reveals the results of these enhancers as functions of .

[0186] [Table 6]

[0187] The enhancer is selected and designed to have functionality that affects various barriers in the mucous membrane. All tested enhancers improved permeability over time, but clove oil and ra Brazol showed a particularly significant and unexpectedly high level of permeability enhancement.

[0188] [Table 7] TIFF2023134518000008.tif223170TIFF2023134518000009.tif221170TIFF2023134518000010.tif77170

[0189] (Example 13: Effect of enhancer on epinephrine release) Determine the effect of enhancers (labrasol and clove oil) on epinephrine release. Therefore, the epinephrine release profile was tested. Figure 6A shows the results for different polymer platforms. Figure 6B shows the release of epinephrine from foam. Enhancer of epinephrine release These results show the effect. The transmission amount stabilizes between approximately 3250 and 4250 μg after about 40 minutes. It was shown that the effect was stabilized. The tested enhancer reduced the release of epinephrine from the matrix. It was indicated that there would be no restrictions on output.

[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. Figure 7 shows the graph of male Yucatan... The results of a pharmacokinetic model in miniature pigs are shown. This study compared 0.3 mg EpiPen and 0.12 mg EpiPen. Pinephrine IV and placebo will be compared.

[0193] Concentration profiles of 0.3 mg EpiPen and 40 mg Epinephrine Film without enhancer The effect of no enhancer on Ill is shown in Figure 8.

[0194] Figure 9 shows the effect of enhancer 3% labrazol, which is the same as that of a 40 mg epinephrine film. This shows the effect of enhancer A (Labrazol) on the concentration profile of 0.3 mg EpiPen. Figure 10 shows two types of 40 mg epinephrine films (10-1-1) and (11-1-1), versus a 0.3 mg EpiPen. This shows the effect of enhancer L (clove oil) on the concentration profile.

[0195] In addition, the effects of film dimensions and clove oil (3%) are shown in Figure 11. This test was , 0.30 mg EpiPen (n=4), 40 mg Epinephrine Film (10-1-1) (n=5), and 40 mg Epinephrine Film A comparison of the ointment film (11-1-1) (n=5) was performed. Sublingual or intramuscular epididymal injections were administered to male miniature pigs. This is the concentration-versus-time profile after nephrine administration.

[0196] The tests were conducted by varying the ratio of epinephrine to enhancer. These tests also The concentration, versus time-based efficacy of epinephrine administered sublingually or intramuscularly to male miniature pigs. The ratio of epinephrine to clove oil (enhancer L) was as shown in Figure 12. Results were obtained. This study involved 0.30 mg EpiPen (n=4) and 40 mg epinephrine film (12-1-1). A comparison was made between (n=5) and 20 mg epinephrine film (13-1-1) (n=5).

[0197] (Example 16) Varying dosages can be controlled with a constant dose of enhancer labrazol (3%) and clove oil (3%). The tests were performed using Trix and are shown in Figures 13 and 14, respectively. The test in Figure 13 involved 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) A comparison was made. The test in Figure 14 involved 0.30 mg EpiPen (n=4) and 40 mg Epinephrine film (1 A comparison was made between 9-1-1) (n=5) and 30 mg epinephrine film (21-1-1) (n=5). These tests The study also examined the concentration, versus time, after sublingual or intramuscular administration of epinephrine to male miniature pigs. It was a profile.

[0198] (Example 17) To determine the time-dependent effect of the enhancer (farnesol) on epinephrine concentration. Therefore, a pharmacokinetic model was tested in male miniature pigs. The graph in Figure 17 shows farnesol. Epinephrine plasma as a function of time (minutes) after sublingual or intramuscular administration of a permeable enhancer. The concentration (ng / mL) is shown. This test was conducted using 0.3 mg EpiPen (n=3) and 30 mg Epinephrine Film 31-1. -1 (n=5) and 30 mg epinephrine film 32-1-1 (n=5) were compared, and each epinephrine film was examined. It is formulated together with farnesol enhancer. As shown in this figure, 31-1 -1 film starts at approximately 30-40 minutes and continues until approximately 130 minutes, with enhanced epinephrine concentration. Stability was demonstrated.

[0199] The graph in Figure 18 was obtained from the same study as in Figure 17, but primarily compared 0.3 mg EpiPen with 30 mg Epinephrine. The data points for comparison with phosphofilm 31-1-1 (n=5) are shown.

[0200] The graph in Figure 19 was obtained from the same study as in Figure 17, but primarily compared 0.3 mg EpiPen with 30 mg Epinephrine. The data points for comparison with phosphofilm 32-1-1 (n=5) are shown.

[0201] (Example 18) Regarding Figure 20, this graph shows the time course of epinephrine concentration after sublingual or intramuscular administration. Male miniature pigs were tested to determine the effect of the enhancer (farnesol) on the following: This shows the pharmacokinetic model in [the relevant context]. Epinephrine plasma concentration (ng / mL) is given by [the relevant factor]. As a function of time (minutes) after sublingual or intramuscular administration of a farnesol permeability enhancer in a steroid. This was shown. In this study, three types of 0.3 mg epinephrine films were compared to five types of 30 mg epinephrine films (32-1-1). We compared the data from the Pipen. This data was obtained when the film started at approximately 20-30 minutes. Up to 130 minutes, the epinephrine concentration has enhanced stability. It shows the room.

[0202] (Example 19) In one embodiment, the epinephrine pharmaceutical composition film is manufactured according to the following formulation. It is possible:

[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 the time course of epinephrine plasma concentration after sublingual or intramuscular administration. To determine the effect of enhancers (6% clove oil and 6% labrasol) on the following: The pharmacokinetic model (logarithmic scale) in male miniature pigs is shown below. Epinephrine plasma concentration (ng / mL) is the sublingual or intramuscular level of farnesol permeation enhancers in epinephrine films. This is shown as a function of time (minutes) after internal administration. This data is obtained when the film is exactly 10 minutes later. From that point, starting around 30 minutes later, and continuing until approximately 100 minutes later, the elevated stability of epinephrine concentration was observed. This shows an epinephrine film having the following characteristics.

[0211] Regarding Figure 22, this graph was collected from 0.3 mg EpiPen (indicated by diamond-shaped data points). Compared to the average data, epinephrine in male miniature pigs, as mentioned in Figure 21, This shows the pharmacokinetic model of the film formulation. As this data shows, the average of 0.3 mg EpiPen Plasma concentrations peaked between 0.5 and 1 ng / mL. In contrast, epinephrine film formulations... The peak was observed between 4 and 4.5 ng / mL.

[0212] (Example 24) Regarding Figure 23, this graph shows the results after sublingual or intramuscular administration across seven animal models. The effect of enhancers (9% clove + 3% labrasol) on epinephrine concentration over time. The pharmacokinetic model tested in male miniature pigs for determination is shown. The concentration was reached between 10 and 30 minutes.

[0213] (Example 25: Alprazolam data) Regarding Figures 24A, 24B, and 24B, these graphs show oral alprazolam disintegrating tablets (OD). T) and the time course (time) of alprazolam when administered sublingually by an alprazolam pharmaceutical composition film. This shows data from a male miniature pig study comparing plasma concentrations.

[0214] Figure 24A shows the average data from alprazolam ODT (group 1). The peak dose range is between 7 and 12 ng / mL. The concentration was reached in approximately 1 to 8 hours.

[0215] Figure 24B shows the average data from the alprazolam pharmaceutical composition film (group 2). 5n More than g / mL, more than 10 ng / mL, more than 12 ng / mL, more than 15 ng / mL, more than 17 ng / mL , including less than 17 ng / mL, less than 15 ng / mL, less than 12 ng / mL, less than 10 ng / mL, less than 5 ng / mL, 5-17 ng / Peak concentrations between mL include those longer than 10 minutes, longer than 20 minutes, longer than 30 minutes, longer than 45 minutes, and 1 Longer than one hour, longer than 1.5 hours, longer than 2 hours, longer than 2.5 hours, longer than 3 hours, 3. Longer than 5 hours, or about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, 2 hours Includes periods of less than 1 hour, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes, ranging from 10 minutes to 4 We arrived in [time].

[0216] Figure 24C shows the alprazolam pharmaceutical composition film from another group of male miniature pigs (Group 3). The average data from the following ranges are shown: longer than 5 ng / mL, longer than 10 ng / mL, longer than 12 ng / mL, and 15 ng / mL. Longer than L, longer than 17 ng / mL, less than 17 ng / mL, less than 15 ng / mL, less than 12 ng / mL, less than 10 ng / mL Peak concentrations of 5-17 ng / mL, including less than 5 ng / mL, are observed for intervals longer than 10 minutes, longer than 20 minutes, and 30 minutes. Longer than 45 minutes, longer than 1 hour, longer than 1.5 hours, longer than 2 hours, longer than 2.5 hours Long, longer than 3 hours, longer than 3.5 hours, and about 4 hours, less than 4 hours, less than 3.5 hours, 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 20 The journey took between 10 minutes and 4 hours, including less than a minute.

[0217] (Example 26) Regarding Figure 25A, this graph shows oral alprazolam disintegration tablets (ODTs) (circular data points). (as shown) and two groups (square and triangular data points) using alprazolam pharmaceutical composition films This study compares the time-dependent (hourly) plasma concentrations of alprazolam after sublingual administration (as shown in the results). The data from the pig trial is used as an example.

[0218] As this graph shows, the data from alprazolam pharmaceutical composition films (both groups) Longer than 10 minutes, longer than 20 minutes, about 30 minutes, longer than 30 minutes, less than 30 minutes, less than 20 minutes, less than 15 minutes or a maximum of approximately 15-25 mg / mL in a treatment window of approximately 30 minutes or less, including less than 10 minutes. Relatively high alprazolam plasma concentrations were obtained.

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

[0220] Regarding Figure 25C, this graph shows individual data points from the 0-1 hour trial mentioned in Figure 25A. It indicates intonation.

[0221] Regarding Figure 26A, this graph shows the individual data on alprazolam ODT mentioned in Figure 25C. This indicates the data point.

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

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

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

[0225] [Table 13]

[0226] (Example 27) Regarding Figure 27A, this figure shows oral alprazolam disintegrating tablets (ODTs) (indicated by circular data points). (shown by square and triangular data points) and two groups of alprazolam pharmaceutical composition films. A study comparing the time course of alprazolam plasma concentrations after sublingual administration of (the drug) in male miniature pigs. The average data is shown as an example. As the data shows, 0.5 mg alprazolam ODT takes more than 10 minutes Long, 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 approximately 4 hours, 4 hours Less than 3 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, Between 0 and 4 hours, including periods of less than 45 minutes, less than 30 minutes, or less than 20 minutes, the peak concentration ranged from approximately 5 to 6 ng. The 0.5 mg alprazolam pharmaceutical composition film was used for longer than 10 minutes and longer than 20 minutes. i, longer than 30 minutes, longer than 45 minutes, longer than 1 hour, longer than 1.5 hours, longer than 2 hours, 2 Longer than 0.5 hours, longer than 3 hours, longer than 3.5 hours, or approximately 4 hours, less than 4 hours, 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, 30 minutes Between 0 and 4 hours, including less than 20 minutes, the peak concentrations were approximately 7-8 ng / mL and 6-7 ng / mL, respectively. It reached g / mL.

[0227] Regarding Figure 27B, this graph shows the period between 0 and 2 hours, including oral alprazolam disintegrating tablets (ODTs) (yen). (shown by shape data points) and two groups of alprazolam pharmaceutical composition films (square and triangular) The average daily data of alprazolam plasma concentration over time after sublingual administration (shown by the data points) This indicates that, unlike ODT, the therapeutic window of the alprazolam pharmaceutical composition film is 10 While the test usually starts around 15 minutes, the ODT (Optical Day Test) started at approximately 17-20 minutes.

[0228] Regarding Figure 27C, this graph shows ODT (n=4), 0.5 mg alprazolam pharmaceutical composition film 1 Figure 27 shows the results for 4-1-1 (n=5) and 0.5 mg alprazolam pharmaceutical composition film 15-1-1 (n=5). The complete data mentioned in B is illustrated.

[0229] The data from the graph mentioned earlier is also summarized in the table below.

[0230] [Table 14]

[0231] All references listed herein are incorporated herein by reference in their entirety. Other embodiments are within the scope of the following claims.

Claims

[Claim 1] Novel products, methods, and methods of manufacture substantially described in this specification.

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