JP7431724B2 - Pharmaceutical compositions with enhanced penetration - Google Patents

Description

(Claim of priority)
This application is a continuation-in-part of U.S. patent application Ser. 35 U.S.C. 119(e) priority to U.S.C. 119(e) and U.S. Patent Application No. 62/735,822 filed on September 24, 2018. A portion of U.S. Patent Application No. 15/717,856, filed September 27, 2017, which is a continuation-in-part of United States Patent Application No. 15/587,376, filed May 4, 2017. Continuation Applications, each of which is incorporated herein by reference in its entirety.

(Technical field)
PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions.

(background)
Active ingredients, such as drugs or pharmaceuticals, are delivered to a patient in a scheduled manner. Transdermal or transmucosal drug or medicament delivery using films requires that the drug or medicament permeate or otherwise traverse biological membranes in an effective and efficient manner. There are things to do.

(overview)
Generally, a pharmaceutical composition can contain a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and an adrenergic receptor interacting agent. In certain embodiments, the pharmaceutical composition can further include a permeation enhancer. The adrenergic receptor interactor can be an adrenergic receptor blocker. The present permeation enhancers are also flavonoids or can be used in combination with flavonoids.

In certain embodiments, the adrenergic receptor interactor can be a terpenoid, a terpene, or a C3-C22 alcohol or acid. The adrenergic receptor interactor can be a sesquiterpene. In certain embodiments, the adrenergic receptor interactor can include farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentanoic acid, or docosapentanoic acid, or combinations thereof.

In certain embodiments, the pharmaceutical composition can include a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and an aporphine alkaloid interactor.

In another embodiment, the pharmaceutical composition can include a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and a vasodilator-interactive agent.

In certain embodiments, the pharmaceutical composition can be a film further comprising a polymer matrix, and the pharmaceutically active ingredient is contained in the polymer matrix.

In certain embodiments, the adrenergic receptor interactor can be a plant extract.

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

In certain embodiments, the permeation enhancer can include a phenylpropanoid.

In another embodiment, the phenylpropanoid can be eugenol.

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

In certain embodiments, the pharmaceutical composition can include a saturated or unsaturated alcohol.

In certain embodiments, the alcohol can be benzyl alcohol.

In some cases, the flavonoids, plant extracts, phenylpropanoids, eugenol, or fungal extracts can be used as solubilizing agents.

In other embodiments, the phenylpropanoid can be eugenol. In certain embodiments, the phenylpropanoid can be eugenol acetate. In certain embodiments, the phenylpropanoid can be cinnamic acid. In other embodiments, the phenylpropanoid can be a cinnamic acid ester. In other embodiments, the phenylpropanoid can be cinnamaldehyde.

In other embodiments, the phenylpropanoid can be hydrocinnamic acid. In certain embodiments, the phenylpropanoid can be moldicol. In other embodiments, the phenylpropanoid can be safrole.

In certain embodiments, the plant extract can be an essential oil extract of the clove plant. In another example, the plant extract can be an essential oil extract of the leaves of a clove plant. The plant extract can be an essential oil extract of the flower buds of a clove plant. In other embodiments, the plant extract can be an essential oil extract of clove plant stems.

In certain embodiments, the plant extract can be synthetic. In certain embodiments, the plant extract can contain 20-95% eugenol, including 40-95% eugenol, and 60-95% eugenol. In certain embodiments, the plant extract can contain 80-95% eugenol.

In other embodiments, the pharmaceutically active ingredient can be epinephrine.

In certain embodiments, the pharmaceutically active ingredient can be diazepam.

In certain embodiments, the pharmaceutically active ingredient can be alprazolam.

In some embodiments, the polymer matrix can include a polymer. In some embodiments, the polymer can include a water-soluble polymer.

In certain embodiments, the polymer can be polyethylene oxide.

In certain embodiments, the polymer can be a cellulosic polymer. In certain embodiments, the cellulosic polymer can be hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, and/or sodium carboxymethylcellulose.

In some embodiments, the polymer can include hydroxypropyl methylcellulose.

In some embodiments, the polymer can include polyethylene oxide and/or hydroxypropyl methylcellulose.

In certain embodiments, the polymer can include polyethylene oxide and/or polyvinylpyrrolidone.

In certain embodiments, the polymer matrix can include polyethylene oxide and/or polysaccharide.

In certain embodiments, the polymer matrix can include polyethylene oxide, hydroxypropyl methylcellulose, and/or polysaccharide.

In certain embodiments, the polymer matrix can include polyethylene oxide, cellulosic polymers, polysaccharides, and/or polyvinylpyrrolidone.

In certain embodiments, the polymer matrix comprises the following groups: pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth, guar gum, gum acacia, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl It can include at least one polymer selected from copolymers, starch, gelatin, ethylene oxide, propylene oxide copolymers, collagen, albumin, polyamino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof.

In certain embodiments, the pharmaceutical composition can further include a stabilizing agent. Stabilizers are antioxidants that can prevent unwanted oxidation of substances, sequestrants that can form chelate complexes and deactivate trace metal ions that would otherwise act as catalysts. agents, emulsifiers and surfactants that can stabilize emulsions, UV stabilizers that can protect substances from the harmful effects of UV radiation, chemicals that absorb UV radiation and prevent it from entering the composition They can include UV absorbers that are UV absorbers, quenchers that allow the radiant energy to dissipate as heat without breaking chemical bonds, or scavengers that can scavenge free radicals formed by ultraviolet radiation.

In yet another embodiment, the pharmaceutical composition comprises a suitable non-toxic non-ionic alkyl glycoside having a hydrophobic alkyl group linked by a bond to a hydrophilic saccharide as follows: (a) an aggregation inhibitor; (b) charge modifier; (c) pH regulator; (d) degrading enzyme inhibitor; (e) mucolytic or mucus-removal agent; (f) ciliostatic agent; (g) (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) nitric oxide-donating compounds. (vi) long chain amphiphilic molecules; (vii) small molecule hydrophobic penetration enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerol esters of acetoacetic acid; (x) cyclodextrins or β-cyclodextrin derivatives; (xi) medium-chain fatty acids; (xii) chelating agents; (xiii) amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (xv) enzymes degrading for selected membrane components; ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) a membrane permeation enhancer selected from any combination of membrane permeation enhancers described in (i) to (x); h) modulators of epithelial junction physiology; (i) vasodilators; (j) selective transport enhancers; and (k) stabilizing delivery vehicles, carriers, mucoadhesives, supports, or complexing species. a stabilizing delivery vehicle with which the compound is effectively formulated, associated, contained, encapsulated, or bound to provide stabilization of the compound for enhanced mucosal delivery. , a carrier, a mucoadhesive, a support, or a complex-forming species, wherein the formulation of the compound comprising a transmucosal delivery-enhancing agent comprises a transmucosal delivery-enhancing agent selected from Provides increased bioavailability of the compound in plasma.

Generally, methods of making a pharmaceutical composition include combining an adrenergic receptor interacting agent with a pharmaceutically active ingredient and forming a pharmaceutical composition comprising the adrenergic receptor interacting agent and the pharmaceutically active ingredient. Can be done.

The pharmaceutical composition can be a chewable or gelatin-based dosage form, spray, gum, gel, cream, tablet, liquid or film.

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

In certain embodiments, the pharmaceutical composition can include a polymeric matrix, a pharmaceutically active ingredient in the polymeric matrix; and a permeation enhancer comprising a phenylpropanoid and/or a botanical extract.

In certain embodiments, the pharmaceutical composition comprises a polymeric matrix; a pharmaceutically active ingredient in the polymeric matrix; and a transmucosal uptake of the pharmaceutically active ingredient that produces increased blood flow or allows tissue flushing. can contain interacting substances that change the

In certain embodiments, the pharmaceutical composition has a polymeric matrix; a pharmaceutically active ingredient in the polymeric matrix; and a positive or negative heat of solution, used as an adjuvant to alter (increase or decrease) transmucosal uptake. may contain interacting substances.

In another embodiment, a pharmaceutical composition comprises a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and an interactive agent, the composition having at least one surface bordered by edges. Contained in multilayer films.

Generally, a method of treating a medical condition can include administering an effective amount of a pharmaceutical composition comprising a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and an adrenergic receptor interactor. The pharmaceutical active ingredient may be epinephrine, diazepam, or alprazolam. Medical conditions can include symptoms of epilepsy, such as seizures. In certain embodiments, the method includes administering the pharmaceutical composition comprising diazepam during an ictal state. In certain embodiments, the method includes administering the pharmaceutical composition comprising diazepam during a periictal state. In certain embodiments, the method includes administering the pharmaceutical composition comprising diazepam during an interictal state. The medical condition can also include anxiety, drug withdrawal, parasomnias, alcohol withdrawal, muscle spasms, or seizure disorders. This medical condition may include treatment as a sedative. The medical condition can also include sedation for medical procedures.

Other aspects, implementations, and features will be apparent from the following description, drawings, and claims.

(brief description of drawing)
With respect to FIG. 1A, Franz diffusion cell 100 comprises donor compound 101, donor chamber 102, membrane 103, sampling port 104, receptor chamber 105, stirrer 106, and heater/circulator 107. With respect to FIG. 1B, the pharmaceutical composition is a film 100 that includes a polymer matrix 200, and a pharmaceutically active ingredient 300 is contained within the polymer matrix. The film can include a transmission enhancer 400. With respect to Figures 2A and 2B, the graphs show the permeation of active agent from the composition. With respect to FIG. 2A, this graph shows the average amount of active permeated versus time with 8.00 mg/mL epinephrine bitartrate and 4.4 mg/mL solubilized epinephrine base. Referring to FIG. 2B, this graph shows the average flux versus time with 8.00 mg/mL bitartrate and 4.4 mg/mL solubilized epinephrine base. Referring to Figure 3, this graph shows the ex vivo permeation of epinephrine bitartrate as a function of concentration. Referring to Figure 4, this graph shows the permeation of epinephrine bitartrate as a function of solution pH. Referring to FIG. 5, this graph shows the effect of the enhancer on the permeation of epinephrine, expressed as the amount permeated, as a function of time. Referring to Figures 6A and 6B, these graphs show the release of epinephrine (6A) and the effect of the enhancer on that release (6B) on the polymer platform, expressed as permeation (μg) versus time. Referring to Figure 7, this graph shows a pharmacokinetic model in male Yucatan minipigs. This study is comparing 0.3 mg EpiPen, 0.12 mg epinephrine IV, and Placebo Film. Referring to Figure 8, this graph shows the effect of the absence of enhancer on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. Referring to FIG. 9, this graph shows the effect of Enhancer A (Labrasol) on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. Referring to FIG. 10, this graph shows the effect of Enhancer L (clove oil) on the concentration profile of two 40 mg epinephrine films (10-1-1) and (11-1-1) versus 0.3 mg EpiPen. With respect to Figure 11, this graph shows the effect of Enhancer L (clove oil) and film size (10-1-1 thin, large film and 11-1-1 thick, small film) on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. show. Referring to FIG. 12, this graph shows the concentration profile for varying doses of epinephrine film in a constant matrix for Enhancer L (clove oil) for 0.3 mg EpiPen. Referring to FIG. 13, this graph shows the concentration profile for varying doses of epinephrine film in a constant matrix for Enhancer L (clove oil) for 0.3 mg EpiPen. Referring to FIG. 14, this graph shows the concentration profile for varying doses of epinephrine film in a constant matrix for Enhancer A (Labrasol) for 0.3 mg EpiPen. Referring to FIG. 15, this graph shows the effect of the enhancer on the permeation of diazepam, expressed as the amount permeated, as a function of time. Referring to Figure 16, this graph shows the average flux as a function of time (Diazepam + Enhancer). Referring to FIG. 17, this graph shows the effect of farnesol in combination with farnesol and linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. Referring to FIG. 18, this graph shows the effect of farnesol on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. Referring to FIG. 19, this graph shows the effect of farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. Referring to Figure 20, this graph shows the effect of farnesol in combination with farnesol and linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. Referring to Figure 21, this graph shows the effect of Enhancer A (Labrasol) in combination with Enhancer L (Clove Oil) on the concentration profile of a 40 mg epinephrine film (also shown in Figure 22) in logarithmic representation. Referring to Figure 22, this graph shows the effect of Enhancer A (Labrasol) in combination with Enhancer L (Clove Oil) on the concentration profile of a 40 mg epinephrine film compared to the average data collected from a 0.3 mg EpiPen. Referring to FIG. 23, this graph shows the effect of Enhancer A (Labrasol) in combination with Enhancer L (Clove Oil) on the concentration profile of a 40 mg epinephrine film presented as an individual animal subject. Referring to FIG. 24A, this graph shows alprazolam plasma concentrations as a function of time after sublingual administration of alprazolam orally disintegrating tablets (ODT). Referring to FIG. 24B, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of an alprazolam pharmaceutical composition film. Referring to FIG. 24C, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of an alprazolam pharmaceutical composition film. Referring to FIG. 25A, this graph shows mean alprazolam plasma concentrations as a function of time after sublingual administration of alprazolam ODT and alprazolam pharmaceutical composition film. Referring to Figure 25B, this graph shows alprazolam plasma concentrations as a function of time after sublingual administration. Referring to Figure 25C, this graph shows alprazolam plasma concentrations as a function of time after sublingual administration. Referring to FIG. 26A, this graph shows alprazolam plasma concentrations as a function of time after sublingual administration of alprazolam ODT. Referring to FIG. 26B, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of an alprazolam pharmaceutical composition film. Referring to FIG. 26C, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of an alprazolam pharmaceutical composition film. Referring to FIG. 27A, this graph shows mean alprazolam plasma concentrations as a function of time after sublingual administration of alprazolam ODT and pharmaceutical composition film. Referring to FIG. 27B, this graph shows mean alprazolam plasma concentrations as a function of time after sublingual administration of alprazolam ODT and pharmaceutical composition film. Referring to FIG. 27C, this graph shows alprazolam plasma concentrations as a function of time after sublingual administration of alprazolam ODT and pharmaceutical composition film.

(detailed explanation)
Mucosal surfaces, such as the oral mucosa, are highly vascularized and permeable, resulting in increased bioavailability and efficacy because they do not pass through the digestive system, thereby avoiding first-pass metabolism. Mucosal surfaces are a convenient route for drug delivery to the body due to the fact that they provide a rapid onset of. In particular, the buccal and sublingual tissues are highly permeable areas of the oral mucosa, allowing the diffusion of drugs from the oral mucosa to have direct access to the systemic circulation, so these tissues , providing an advantageous site for drug delivery. This also provides increased convenience and thus increases patient compliance. For certain drugs or pharmaceutical active ingredients, permeation enhancers can help overcome mucosal barriers and improve permeability. Permeation enhancers reversibly adjust the permeability of the barrier layer to favor drug absorption. Permeation enhancers facilitate the transport of molecules across the epithelium. Absorption profiles and their rates can be controlled and adjusted by various parameters, including, but not limited to, film size, drug loading, enhancer type/loading, polymer matrix release rate and mucosal residence time.

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

In certain embodiments, the pharmaceutical composition comprises a suitable non-toxic non-ionic alkyl glycoside having a hydrophobic alkyl group linked by a bond to a hydrophilic saccharide: (a) an aggregation inhibitor; b) Charge modifying agent; (c) pH adjusting agent; (d) Degrading enzyme inhibitor; (e) Mucolytic or mucosal removing agent; (f) Ciliary dyskinesia agent; (g) Below: (i) Interface (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) NO-donating compounds; (vi) long-chain amphiphiles (vii) Small molecule hydrophobic penetration enhancer; (viii) Sodium or salicylic acid derivative; (ix) Glycerol ester of acetoacetic acid; (x) Cyclodextrin or β-cyclodextrin derivative; (xi) Medium-chain fatty acid; ( xii) chelating agents; (xiii) amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (xv) enzymes degrading to selected membrane components; (ix) inhibitors of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) a membrane permeation enhancer selected from any combination of membrane permeation enhancers described in (i) to (x); (h) modulation of epithelial junction physiology. (i) a vasodilator; (j) a selective transport enhancer; and (k) a stabilizing delivery vehicle, carrier, mucoadhesive, support, or complexing species, together with Said stabilizing delivery vehicle, carrier, mucoadhesive material with which the compound is effectively formulated, associated, contained, encapsulated, or attached to provide stabilization of the compound for enhanced mucosal delivery. A formulation of the compound in combination with a mucosal delivery-enhancing agent selected from a transmucosal delivery-enhancing agent selected from a transmucosal delivery-enhancing agent, a support, or a complex-forming species, wherein the formulation of the compound includes a transmucosal delivery-enhancing agent. Provides increased scientific availability. Penetration enhancers are described in J. Nicolazzo et al., J. of Controlled Disease, 105 (2005) 1-15, which is incorporated herein by reference. There are many reasons why the oral mucosa is an attractive site for delivery of therapeutic agents to the systemic circulation. Due to the direct drainage of blood from the buccal epithelium to the internal jugular vein, first-pass metabolism in the liver and intestines can be avoided. First-pass effects can be a major reason for the poor bioavailability of some compounds when administered orally. In addition, the mucous membranes lining the oral cavity are easily accessible, which ensures that the dosage form can be applied to the required site and easily removed in case of emergency. However, like the skin, the buccal mucosa acts as a barrier to the absorption of xenobiotics, which can impede the permeation of compounds across this tissue. Consequently, the identification of safe and effective penetration enhancers has become a major goal in the quest to improve oral mucosal drug delivery.

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

The buccal mucosa lines the inside of the cheek as well as the area between the gums and the upper and lower lips, and it has an average surface area of 100 cm ² . The surface of the buccal mucosa consists of stratified squamous epithelium separated from the underlying connective tissue (lamina propria and submucosa) by an undulating basement membrane (a continuous layer of extracellular material approximately 1-2 μm thick). This stratified squamous epithelium consists of differentiated layers of cells that change in size, shape, and content as they move from the basal region to the superficial region where cells are shed. Approximately 40 to 50 cell layers are present, creating a buccal mucosa 500 to 600 μm thick.

Structurally, the sublingual mucosa is comparable to the buccal mucosa, but the thickness of this epithelium is 100-200 μm. This membrane has also been shown to be nonkeratinized and relatively thin, making it more permeable than the buccal mucosa. Blood flow to the sublingual mucosa is slower than that to the buccal mucosa, on the order of 1.0 ml/min ^-1 /cm ^-2 .

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

The primary barrier properties of the buccal mucosa are attributed to the upper 1/3 to 1/4 of the buccal epithelium. Researchers know that the permeability barrier of non-keratinized oral mucosa beyond the surface epithelium is also attributable to the contents extruded from membrane-coated granules into the epithelial cell spaces.

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

The presence of hydrophilic and lipophilic regions within the oral mucosa has led researchers to point out the existence of two types of drug transport routes across the buccal mucosa: paracellular (between cells) and transcellular (across cells). I made an assumption.

Because drug delivery across the buccal mucosa is limited by the nature of the barrier of the epithelium and the area available for absorption, various enhancement strategies are available to deliver therapeutically relevant amounts of drug into the systemic circulation. is necessary. A variety of methods can be utilized to overcome the barrier properties of the buccal mucosa, including the use of chemical penetration enhancers, prodrugs, and physical methods.

Chemical penetration enhancers, or absorption promoters, are substances added to pharmaceutical formulations to increase the rate of membrane permeation or absorption of co-administered drugs without damaging the membranes and/or causing toxicity. be. There are many studies examining the effects of chemical penetration enhancers on the delivery of compounds across the skin, nasal mucosa, and intestines. In recent years, more attention has been paid to the effect of these substances on the permeability of the buccal mucosa. Since permeability across the buccal mucosa is considered to be a passive diffusion process, the steady-state flux (Jss) should increase with increasing donor chamber concentration (CD), according to Fick's first law of diffusion.

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

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

In addition, pretreatment with ethanol has been shown to enhance permeability of tritiated water and albumin across the ventral lingual mucosa and to enhance permeability of caffeine across the buccal mucosa of pigs. There are also some reports of the enhancing effect of Azone® on the permeability of compounds across the oral mucosa. Additionally, chitosan, a biocompatible and biodegradable polymer, has been shown to enhance drug delivery through various tissues, including the intestinal and nasal mucosa.

Oral transmucosal drug delivery (OTDD) is the administration of pharmaceutically active substances through the oral mucosa to achieve systemic effects. The permeation route and predictive model for OTDD can be found, for example, in the literature by M. Sattar, "Oral transmucosal drug delivery- Current status and future prospects", Int'l. Journal of Pharmaceutics, 47(2014) 498-506, which is incorporated herein by reference. OTDD continues to attract the attention of scientists in academia and industry. Recent advances in researchers' understanding of the extent to which ionized molecules penetrate the buccal epithelium, as well as the ability to study the oral cavity, despite the limited characterization of intraoral permeation routes compared to cutaneous and nasal delivery routes. The outlook is bright with the advent of new analytical techniques for this purpose, as well as the ongoing development of in silico models to predict buccal and sublingual transmission;

To deliver a broader class of drugs beyond the buccal mucosa, reversible methods that reduce the barrier capacity of this tissue should be utilized. This requirement has prompted research into penetration enhancers that safely alter the permeability constraints of the buccal mucosa. Buccal penetration is improved by using various classes of transmucosal and transdermal penetration enhancers, such as bile salts, surfactants, fatty acids and their derivatives, chelating agents, cyclodextrins and chitosan. It has been shown that it can be obtained. Among these chemicals used for drug permeation enhancement, bile salts are the most common.

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

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

The permeation enhancer can be a plant extract. Plant extracts can be essential oils extracted by distillation of plant material or compositions containing essential oils. In certain situations, plant extracts can include synthetic analogs of compounds extracted from plant material (ie, compounds produced by organic synthesis). The plant extract can include phenylpropanoids, such as phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid esters, cinnamaldehyde, hydrocinnamic acid, moldichol, or safrole, or combinations thereof. The plant extract can be a clove plant, such as an essential oil extract of the leaves, stems, or flower buds of a clove plant. The clove plant is Syzygium aromaticum. The plant extract may contain 20-95% eugenol, 40-95% eugenol, 60-95% eugenol, such as 80-95% eugenol. The extract may also contain 5% to 15% eugenol acetate. This extract may also contain caryophyllene. This extract may also contain up to 2.1% α-humulene. Other volatile compounds contained in lower concentrations in clove essential oil may be β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone or ethyl hexanoate. Other permeation enhancers may be added to the composition to improve absorption of the drug. Suitable permeation enhancers are natural or synthetic bile salts such as sodium fusidate; such as glycocholic acid or deoxycholic acid and their salts; fatty acids and derivatives such as sodium laurate, oleic acid, oleyl alcohol, monoolein, or palmitoylcarnitine; chelating agents such as disodium EDTA, sodium citrate and sodium lauryl sulfate, azone, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth- 9, polysorbates, sterols, or glycerides, such as caprylocaproyl polyoxylglyceride, such as Labrasol. Permeation enhancers can include derivatives of plant extracts and/or monolignols. The permeation enhancer can also be a fungal extract.

Some natural products of plant origin are known to have vasodilatory effects. There are several mechanisms or ways in which plant-based products can cause vasodilation. For a review, see McNeill J.R. and Jurgens, T.M., Can. J. Physiol. Pharmacol. 84:803-821 (2006), incorporated herein by reference. Specifically, the vasorelaxant effects of eugenol have been reported in several animal studies. For example, Lahlou, S. et al., J. Cardiovasc. Pharmacol. 43:250-57 (2004), Damiani, C.E.N. et al., Vascular Pharmacol. 40, each of which is incorporated herein by reference. :59-66 (2003), Nishijima, H. et al., Japanese J. Pharmacol. 79:327-334 (1998), and Hume W.R., J. Dent Res. 62(9):1013-15 ( (1983). It has been suggested that calcium channel blockade is the main cause of vasorelaxation induced by plant essential oils, or their main component eugenol. See Interaminense L.R.L. et al., Fundamental & Clin. Pharmacol. 21: 497-506 (2007), which is incorporated herein by reference.

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

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

A number of studies have reported the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on vascular reactivity after administration as orally ingestible forms. Several studies found that EPA-DHA or EPA alone suppressed the vasoconstrictor effects of norepinephrine or enhanced the vasodilator response to acetylcholine in the forearm microcirculation. Chin, J.P.F. et al., Hypertension 21:22-8 (1993), and Tagawa, H. et al., J Cardiovasc Pharmacol 33:633-40 (1999), each of which is incorporated herein by reference. ). Another study found that both EPA and DHA tend to increase systemic arterial system compliance and lower pulse pressure and total vascular resistance. See Nestel, P. et al., Am J. Clin. Nutr. 76:326-30 (2002), incorporated herein by reference. On the other hand, studies found that DHA, but not EPA, enhanced vasodilatory mechanisms and attenuated contractile responses in the forearm microcirculation of overweight men with hyperlipidemia. See Mori, T.A. et al., Circulation 102:1264-69 (2000), incorporated herein by reference. Another study found a vasodilatory effect of DHA on rhythmic contractions of isolated human coronary arteries in vitro. See Wu, K.-T. et al., Chinese J. Physiol. 50(4):164-70 (2007), incorporated herein by reference.

Adrenergic receptors (or adrenoreceptors) are a class of G protein-coupled receptors that are targets of catecholamines, particularly norepinephrine (noradrenaline) and epinephrine (adrenaline). Epinephrine (adrenaline) interacts with both alpha- and beta-adrenoceptors, causing vasoconstriction and vasodilation, respectively. Alpha receptors are less sensitive to epinephrine, but peripheral alpha 1 receptors are more abundant than beta-adrenoceptors, so when activated these override the vasodilation mediated by beta-adrenoceptors. Make it. As a result, high levels of circulating epinephrine cause vasoconstriction. At relatively low levels of circulating epinephrine, β-adrenoceptor stimulation predominates, resulting in vasodilation and subsequent reduction in peripheral vascular resistance. α1-adrenoreceptors are known for smooth muscle contraction, mydriasis, vasoconstriction in the skin, mucous membranes and abdominal viscera, and sphincter contraction of the gastrointestinal (GI) tract and bladder. α1-adrenergic receptors are members of the G _q protein-coupled receptor superfamily. Upon activation, the heterotrimeric G protein, G _q , activates phospholipase C (PLC). Its mechanism of action involves interaction with calcium channels, altering intracellular calcium content. For a review, see Smith RS et al., Journal of Neurophysiology 102(2): 1103-14 (2009), incorporated herein by reference. Many cells have these receptors.

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

In certain embodiments, the permeation enhancer can be an adrenergic receptor interactor. Adrenergic receptor interactors refer to compounds or substances that modify and/or otherwise alter the action of adrenergic receptors. For example, adrenergic receptor interactors can prevent stimulation of receptors by increasing or decreasing their binding capacity. Such interactants can be provided in either short-acting or long-acting forms. Certain short-acting interactors can act quickly, but their action lasts only a few hours. Certain long-acting interactors take a long time to work, but their effects can last longer. The interactor can be selected and/or designed based on, for example, one or more of the desired delivery and dosage, active pharmaceutical ingredient, permeation modifier, permeation enhancer, matrix, and the condition being treated. Can be done. The adrenergic receptor interactor can be an adrenergic receptor blocker. The adrenergic receptor interacting substance is a terpene (e.g. a volatile unsaturated hydrocarbon found in plant essential oils, derived from units of isoprene), or a C3-C22 alcohol or acid, preferably a C7-C18 alcohol or acid. Something can happen. In certain embodiments, the adrenergic receptor interactor can include farnesol, linoleic acid, arachidonic acid, docosahexanoic acid, eicosapentanoic acid, and/or docosapentanoic acid. The acid can be a carboxylic acid, phosphoric acid, sulfuric acid, hydroxamic acid, or a derivative thereof. This derivative can be an ester or an amide. For example, the adrenergic receptor interactor can be a fatty acid or an aliphatic alcohol.

A C3-C22 alcohol or acid is a straight-chain C3-C22 hydrocarbon, such as a C3-C22 carbide optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond. It can be an alcohol or an acid with a hydrogen chain; the hydrocarbon chain is optionally 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 alkyloxycarbonyl, substituted with C _1-4 alkylcarbonyl or formyl; and further optionally -O-, -N(R ^a )-, -N(R ^a )-C(O)-O-, -OC (O)-N(R ^a )-, -N(R ^a )-C(O)-N(R ^b )-, or -OC(O)-O- is sandwiched between them. Each of R ^a and R ^b is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.

Fatty acids with higher degrees of unsaturation are effective candidates for enhancing drug permeation. Unsaturated fatty acids showed higher enhancement than saturated fatty acids, and enhancement increased with the number of double bonds. A. Mittal et al., “Status of Fatty Acids as Skin Penetration Enhancers - A Review,” Current Drug Delivery, 2009, incorporated herein by reference. , 6, pp. 274-279. The position of the double bond also influences the enhancement of fatty acid activity. Differences in the physicochemical properties of fatty acids due to differences in double bond position most likely determine the efficacy of these compounds as skin penetration enhancers. Skin distribution increases as the position of the double bond is shifted towards the hydrophilic end. It has also been reported that fatty acids with double bonds in even-numbered positions act more rapidly on perturbation of the structure of both the stratum corneum and the dermis than fatty acids with double bonds in odd-numbered positions. . Cis-unsaturation within the chain tends to increase activity.

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

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

In certain embodiments, the interacting agent can be an aporphine alkaloid. For example, the interacting agent can be dicentrin.

In general, the interacting agent can also be a vasodilator or therapeutic vasodilator. Vasodilators are drugs that open or widen blood vessels. Vasodilators are commonly used to treat hypertension, heart failure, and angina, but can also be used to treat other conditions, including, for example, glaucoma. Some vasodilators (arterodilators), which act primarily on resistant blood vessels, are used in hypertension, and heart failure, and angina; however, reflex cardiac stimulation Make dilators inappropriate for angina pectoris. Venodilators are very effective in angina pectoris and are sometimes used in heart failure, but are not used as primary therapy for hypertension. Vasodilators can be mixed (or balanced) vasodilators in that they dilate both arteries and veins, and therefore have wide application in hypertension, heart failure, and angina pectoris. Because of their mechanism of action, some vasodilators have different properties, which in some cases can enhance their therapeutic utility or provide some additional therapeutic benefit. It also has important effects. For example, some calcium channel blockers not only dilate blood vessels but also reduce the mechanical and electrical functions of the heart, which can enhance their antihypertensive effects and prevent arrhythmias. Additional therapeutic benefits may be conferred, such as blocking.

Vasodilators can be classified based on their site of action (arterial vs. venous) or by mechanism of action. Some drugs primarily dilate resistance vessels (arterodilators; eg, hydralazine); others primarily affect venous capacitance vessels (venodilators; eg, nitroglycerin). Many vasodilators, such as phentolamine, have mixed arterial and venous dilator properties (mixed dilators; eg, alpha-adrenoceptor antagonists, angiotensin-converting enzyme inhibitors).

However, it is more common to classify vasodilators based on their primary mechanism of action. The diagram on the right represents important mechanistic classes of vasodilators. These classes of drugs, as well as others that produce vasodilation, include: alpha-adrenergic receptor antagonists (alpha-blockers); angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); beta ₂ -adrenergic receptor agonists (β ₂ -agonists); calcium channel blockers (CCBs); centrally acting sympatholytic agents; direct-acting vasodilators; endothelin receptor antagonists; ganglionic blockers; nitrodilators; Includes phosphodiesterase inhibitors; potassium channel openers; renin inhibitors.

Generally, the active or inactive ingredient or material is a substance or compound that causes increased blood flow or tissue flushing, allowing for a change or difference (increase or decrease) in transmucosal uptake of the API, and/or Or it can be a substance or compound that has a positive or negative heat of solution and is used as an adjuvant to alter (increase or decrease) transmucosal uptake.

(Permeation enhancer and active pharmaceutical ingredient arrangement)
The arrangement, order, or sequence of the permeation enhancer and active pharmaceutical ingredient (API) delivered to the desired mucosal surface can be varied to achieve the desired pharmacokinetic profile. . For example, first apply the transmission enhancer by a film, by a swab, spray, gel, rinse, or by a first layer of film, and then apply a transmission enhancer by a single film, by a swab, or by a second layer of film. APIs can be applied by layer. The present arrangement is such that, for example, the API is first applied by a film, by a swab, or by a first layer of the film, and then by a second layer of the film, by a swab, a spray, a gel, a rinse, or by a second layer of the film. It can be reversed or modified by applying transmission enhancers by layer. In another embodiment, the permeation enhancer may be applied by a film and the drug by another film. For example, a permeation enhancer film under a film containing an API, or a film containing an API under a film containing a permeation enhancer, depending on the desired pharmacokinetic profile.

For example, a permeation enhancer can be used as a pretreatment alone or in combination with at least one API to precondition the mucosa for further absorption of the API. This treatment can be followed by another treatment with a neat permeation enhancer, followed by application of said at least one API to the mucosa. The pretreatment can be applied as a separate treatment (film, gel, solution, swab, etc.) or as a layer within a multilayer film structure of one or more layers. Similarly, the pretreatment is contained within separate domains of a single film designed to dissolve and release into the mucosa prior to release of the second domain, which may or may not contain a permeation enhancer or API. Good too. The active ingredient can then be delivered from the second treatment alone or in combination with additional permeation enhancers. Even if there is a third treatment or domain that delivers an additional permeation enhancer and/or at least one API or prodrug, either in different proportions to each other or in different proportions compared to the total loading of the other treatments. good. This makes it possible to obtain tailored pharmacokinetic profiles. As such, the product may differ in the order of application, composition, concentration, or total load to the mucosa leading to the desired amount and/or rate of absorption to achieve the intended pharmacokinetic profile and/or pharmacodynamic effect. It can have single or multiple domains containing transparency enhancers and APIs that can be configured.

The present film format comprises at least one layer of a multilayer film such that there are no distinct surfaces or where the edges co-terminate (have or touch at a shared border or limit). It can be oriented so that it has a surface.

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

Applicants have discovered that microneedles can be used to enhance the delivery of drugs across the oral mucosa, particularly by the claimed compositions. Microneedles create micron-sized pores in the oral mucosa, which can enhance delivery of drugs across the mucosa. Solid, hollow, or dissolvable microneedles can be made of any suitable material, including, but not limited to, metals, polymers, glasses, and ceramics. Microfabrication processes can include photolithography, silicon etching, laser cutting, metal electroplating, metal electropolishing, and molding. Microneedles can be solid objects used to pre-treat tissue and removed before application of the film. The drug-loaded polymer films described in this application can be used as the matrix material for the microneedles themselves. These films can have microneedles or microprotrusions created on their surface, and these will dissolve after forming microchannels in the mucosa through which drugs can permeate. .

The term "film" can include films and sheets of any shape, including rectangular, square, or other desired shapes. The film can be of any desired thickness and size. In preferred embodiments, the film can have a thickness and size such that it can be administered to a user, eg, placed into the user's oral cavity. The film can have a relatively thin thickness of about 0.0025 mm to about 0.250 mm, or the film can have a slightly thicker thickness of about 0.250 mm to about 1.0 mm. For some films, the thickness may also be relatively large, ie, greater than about 1.0 mm, or relatively thin, ie, less than about 0.0025 mm. The film can be single layer, or the film can be multilayer, including laminated or multicast films. The permeation enhancer and the pharmaceutically active ingredient may be combined in a single layer, each contained in separate layers, or each otherwise contained in separate regions of the same dosage form. can be done. In certain embodiments, the pharmaceutically active ingredient contained in the polymer matrix can be dispersed within the matrix. In certain embodiments, the permeation enhancer contained within the polymer matrix can be dispersed within the matrix.

Orally dissolving films can be classified into three major classes: immediate dissolving, moderately dissolving and slowly dissolving. Orally dissolvable films can also include combinations of any of the above categories. Instantly dissolving films can dissolve in the mouth in about 1 second to about 30 seconds, including more than 1 second, more than 5 seconds, more than 10 seconds, more than 20 seconds, and less than 30 seconds. Moderately dissolving films can dissolve in the mouth in about 1 to about 30 minutes, including more than 1 minute, more than 5 minutes, more than 10 minutes, more than 20 minutes, or less than 30 minutes, and slowly dissolving films can dissolve in the mouth over 30 minutes. As a general trend, instant-dissolve films may comprise (or consist of) low molecular weight hydrophilic polymers, such as polymers with a molecular weight of about 1,000 to 9,000 Daltons, or polymers with a molecular weight of up to 200,000 Daltons. In contrast, slowly dissolving films generally include high molecular weight polymers (eg, having molecular weights in the millions). Moderately dissolving films tend to fall between quickly dissolving and slowly dissolving films.

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

Pharmaceutical compositions can include one or more pharmaceutically active ingredients. The pharmaceutically active ingredient can be a single pharmaceutical ingredient or a combination of pharmaceutical ingredients. Pharmaceutical active ingredients include anti-inflammatory analgesics, steroidal anti-inflammatory drugs, antihistamines, local anesthetics, bactericidal agents, disinfectants, vasoconstrictors, hemostatic agents, chemotherapeutic agents, antibiotics, keratolytic agents, cautery It can be a drug, antiviral, antirheumatic, antihypertensive, bronchodilator, anticholinergic, anxiolytic, antiemetic compound, hormone, peptide, protein or vaccine. The pharmaceutically active ingredient can be a compound, a pharmaceutically acceptable salt of a drug, a prodrug, a derivative, a drug conjugate or an analog of a drug. The term "prodrug" refers to a biologically inactive compound that can be metabolized within the body to produce a biologically active drug.

In some embodiments, more than one pharmaceutically active ingredient may be included in the film. This pharmaceutical active ingredient is an ACE inhibitor, an anti-angina drug, an anti-arrhythmic drug, an anti-asthma drug, an anti-cholesterolemic drug, an analgesic, an anesthetic, an anti-convulsant, an anti-depressant, and a diabetic drug. , anti-diarrheal preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory drugs, anti-lipid drugs, anti-manic drugs, anti-nausea drugs, anti-stroke drugs, anti-thyroid preparations, amphetamines, anti-tumor drugs. Medicines, antiviral drugs, anti-acne drugs, alkaloids, amino acid preparations, antitussives, anti-urolithiasis drugs, anti-viral drugs, anabolic preparations, drugs for the treatment of systemic and non-systemic infections, anti- Neoplastic drugs, anti-Parkinson drugs, anti-rheumatic drugs, appetite stimulants, blood modifiers, bone metabolism regulators, cardiovascular agents, central nervous system stimulants, cholinesterase inhibitors, contraceptives, decongestants, nutrition Supplements, dopamine receptor agonists, endometriosis control drugs, enzymes, erectile dysfunction treatments, infertility drugs, gastrointestinal drugs, homeopathic remedies, hormones, hypercalcemia and hypocalcemia control drugs, immunomodulators, immunity Depressants, migraine preparations, motion sickness drugs, muscle relaxants, obesity management drugs, osteoporosis preparations, uterotonic drugs, parasympatholytic drugs, parasympathomimetic drugs, prostaglandins, psychotherapeutic drugs, respiratory drugs drugs, sedatives, smoking cessation aids, sympatholytic drugs, tremor treatment preparations, urethral drugs, vasodilators, laxatives, antacids, ion exchange resins, hypopyretics, appetite suppressants, expectorants medicines, anti-anxiety drugs, anti-ulcer drugs, anti-inflammatory substances, coronary vasodilators, cerebral dilators, peripheral vasodilators, psychotropic drugs, stimulants, antihypertensive drugs, Vasoconstrictors, migraine drugs, antibiotics, tranquilizers, antipsychotics, anti-tumor drugs, anticoagulants, antithrombotics, hypnotics, antiemetics, anti-nausea drugs, anticonvulsants, neuromuscular agents , hypoglycemic and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, anticonvulsants, uterine relaxants, anti-obesity agents, erythropoiesis, anti-asthmatic agents, antitussives, mucolytics, DNA and genes. It can be a modifying agent, a diagnostic agent, a contrast agent, a dye, or a tracer, and combinations thereof.

For example, the pharmaceutical active ingredients include buprenorphine, naloxone, acetaminophen, riluzole, clobazam, rizatriptan, propofol, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen. , Ketoprofen, Naproxen, Pranoprofen, Fenoprofen, Sulindac, Fenclofenac, Clidanac, Flurbiprofen, Fentiazac, Bufexamac, Piroxicam, Phenylbutazone, Oxyphenbutazone, Clofezone, Pentazocine, Mepirizole, Tiaramide Hydrochloride , hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumethasone, fluorometholone, beclomethasone dipropionate, fluocinonide, edaravone, lurasidone , esomeprazole, lumateperone, naldemedine, doxylamine, pyridoxine, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate, isothipendyl hydrochloride, tripelenamine hydrochloride, promethazine hydrochloride, methdilazine hydrochloride, dibucaine hydrochloride , dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride , piperocaine hydrochloride, dyclonine, dyclonine hydrochloride, thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone iodine, cetylpyridinium chloride, eugenol, trimethylammonium bromide, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, Phenylephrine hydrochloride, tramazoline hydrochloride, thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, sodium carbazochrome sulfonate, rutin, hesperidin, sulfamine, sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole, sulfisomidine , sulfamethizole, nitrofurazone, penicillin, methicillin, oxacillin, cephalothin, cefalordin, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, methacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin , cycloserine, salicylic acid, podophyllum resin, podolifox, cantharidin, chloroacetic acid, silver nitrate, protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, adhesion and adsorption inhibition agents, and nucleoside analogs such as acyclovir, penciclovir, valacyclovir, and ganciclovir, heparin, insulin, LHRH, TRH, interferon, oligonuclides, calcitonin, octreotide, omeprazone, fluoxetine, ethinylestradiol, amiodipine, paroxetine, Enalapril, lisinopril, leuprolide, prevastatin, lovastatin, norethindrone, risperidone, olanzapine, albuterol, hydrochlorothiazide, pseudoephedrine, warfarin, terazosin, cisapride, ipratropium, busprione, methylphenidate, levothyroxine, zolpidem, levonorgestrel , glyburide, benazepril, medroxyprogesterone, clonazepam, ondansetron, losartan, quinapril, nitroglycerin, midazolam versade, cetirizine, doxazosin, glipizide, hepatitis B vaccine, salmeterol, sumatriptan, triamcinolone acetonide, goserelin, beclomethasone, Granisteron, desogestrel, alprazolam, estradiol, nicotine, interferon beta 1A, cromolyn, fosinopril, digoxin, fluticasone, bisoprolol, calcitril, captopril, butorphanol, clonidine, Premarin, testosterone, sumatriptan, clotrimazole, bisacodyl, dextromethorphan , nitroglycerin, nafarelin, dinoprostone, nicotine, bisacodyl, goserelin, or granisetron. In certain embodiments, the pharmaceutically active ingredient is epinephrine, a benzodiazepine such as diazepam or lorazepam, or alprazolam.

(Examples of epinephrine, diazepam and alprazolam)
In one example, a composition containing epinephrine or a salt or ester thereof can have a biodelivery profile similar to that of epinephrine administered by injection, eg, using an EpiPen. Epinephrine can be present in an amount of about 0.01 mg to about 100 mg/dose, such as a 0.1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg dose; >0.1mg, >5mg, >20mg, >30mg, >40mg, >50mg, >60mg, >70mg, >80mg, >90mg, or <100mg, <90mg, <80mg, <70mg, <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 combination thereof. In another example, a composition containing diazepam can have a biodelivery profile similar to or better than that of a diazepam tablet or gel. Diazepam or a salt thereof is present in an amount of about 0.5 mg to about 100 mg/dose, such as a 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg dose. This can be more than 1 mg, more than 5 mg, more than 20 mg, more than 30 mg, more than 40 mg, more than 50 mg, more than 60 mg, more than 70 mg, more than 80 mg, more than 90 mg, or less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg. less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, or less than 5 mg, or any combination thereof.

In another example, the composition (e.g., one containing alprazolam, diazepam or epinephrine) comprises a suitable non-toxic, non-ionic alkyl glycoside having a hydrophobic alkyl group linked by a bond to a hydrophilic saccharide. (a) aggregation inhibitors; (b) charge modifiers; (c) pH regulators; (d) degradative enzyme inhibitors; (e) mucolytic or mucus-removal agents; (f) ciliary dysmotility. (g): (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) NO-donating compounds; (vi) long-chain amphiphilic molecules; (vii) hydrophobic penetration enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerol esters of acetoacetic acid; (x) cyclodextrins or β-cyclodextrin derivatives (xi) medium-chain fatty acids; (xii) chelating agents; (xiii) amino acids or salts thereof; (xiv) N-acetylamino acids or salts thereof; (xv) enzymes degrading for selected membrane components; (ix) an inhibitor of fatty acid synthesis; (x) an inhibitor of cholesterol synthesis; and (xi) a membrane permeation enhancer selected from any combination of the membrane permeation enhancers described in (i) to (x); (h) a modulator of epithelial junction physiology; (i) a vasodilator; (j) a selective transport enhancer; or (k) a stabilizing delivery vehicle, carrier, mucoadhesive, support, or conjugate. a stable species with which the compound is effectively formulated, associated, contained, encapsulated, or bound, resulting in stabilization of the compound for enhanced mucosal delivery; transmucosal delivery-enhancing agents selected from transmucosal delivery vehicles, carriers, mucoadhesives, supports or complex-forming species, wherein the transmucosal delivery-enhancing agent of the present compound The formulation provides increased bioavailability of the compound in the subject's plasma. This formulation can include approximately the same active pharmaceutical ingredient (API):enhancer ratio as in other examples for diazepam and alprazolam.

(Treatment or auxiliary treatment)
Status epilepticus (SE) is an epileptic seizure with seizures lasting longer than 5 minutes or two or more seizures within 5 minutes with no return to normality between seizures. Another previous definition used a 30 minute time limit. Benzodiazepines are some of the most effective drugs in the treatment of acute seizures and status epilepticus. The benzodiazepines most commonly used to treat status epilepticus include diazepam (Valium), lorazepam (Ativan), or midazolam (Versed). The pharmaceutical active ingredient in the pharmaceutical composition (e.g., pharmaceutical composition film) can be used to treat diseases such as Angelman syndrome (AS), benign rolandic epilepsy in children (BREC) and benign rolandic epilepsy with centrotemporal spike waves (BECTS), CDKL5 disorder, childhood absence epilepsy (CAE), myoclonic-astatic epilepsy or Douzet syndrome, Dravet syndrome, early myoclonic encephalopathy (EME), epilepsy with generalized tonic-clonic seizures only (EGTCS), waking tonic-clonic Epilepsy with seizures, myoclonic absence epilepsy, frontal lobe epilepsy, glucose transporter 1 deficiency syndrome, hypothalamic hamartoma (HH), petit seizures (also known as IS) or West syndrome, juvenile absence epilepsy (JAE) , juvenile myoclonic epilepsy (JME), Lafora progressive myoclonic epilepsy (Lafora disease), Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), Ohtawara syndrome (OS), Panayiotopoulos syndrome (PS), PCDH19 epilepsy, progressive myoclonus Epilepsy, Rasmussen syndrome ring chromosome 20 syndrome (RC20), reflex epilepsy, TBCK-related intellectual disability syndrome, neurocutaneous syndromes that can be associated with seizures, including temporal lobe epilepsy and ataxia pigmentosa, type 1 neurofibromatosis , Sturge-Weber syndrome (brain trigeminal angiomatosis), and tuberous sclerosis.

The film and/or its components can be water-soluble, water-swellable or water-insoluble. The term "water-soluble" can refer to a substance that is at least partially soluble in an aqueous solvent, including, but not limited to, water. The term "water soluble" does not necessarily mean that the substance is 100% soluble in an aqueous solvent. The term "water-insoluble" refers to a substance that does not dissolve in aqueous solvents, including, but not limited to, water. The solvents may include water or may include other solvents, preferably polar solvents, either alone or in combination with water.

The composition can include a polymer matrix. Any desired polymeric matrix may be used, provided it is orally dissolvable or erodible. The dosage form must be sufficiently bioadhesive to not be easily removed and form a gel-like structure when administered. Although they are moderately soluble in the oral cavity and are particularly suitable for the delivery of pharmaceutically active ingredients, immediate-release, delayed-release, controlled-release and sustained-release compositions all also include Among the various implementations contemplated.

(branched polymer)
The pharmaceutical composition film can include dendritic polymers, which can include highly branched macromolecules with a variety of structural architectures. Dendritic polymers can include dendrimers, dendritic polymers (dendritic grafted polymers), linear dendritic hybrids, multi-arm star polymers, or hyperbranched polymers.

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

Dendritic polymers can have internal cavities in which drugs can be encapsulated. Steric hindrance caused by dense polymer chains can prevent drug crystallization. Thus, branched polymers can provide the added advantage of formulating crystalline drugs in polymer matrices.

Examples of suitable dendritic polymers are poly(ether) based dendrons, dendrimers and hyperbranched polymers, poly(ester) based dendrons, dendrimers and hyperbranched polymers, poly(thioether) based dendrons, dendrimers and hyperbranched polymers. Polymers, poly(amino acid)-based dendrons, dendrimers and hyperbranched polymers, poly(aryl alkylene ether)-based dendrons, dendrimers and hyperbranched polymers, poly(alkylene imine)-based dendrons, dendrimers and hyperbranched polymers, poly(amidoamines) ) based dendrons, dendrimers or hyperbranched polymers.

Other examples of hyperbranched polymers are poly(amines), polycarbonates, poly(etherketones), polyurethanes, polycarbosilanes, polysiloxanes, poly(ester amines), poly(sulfonamines), poly(urethaneureas) or poly Includes ether polyols such as polyglycerin.

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

The polymer contained in the film may be water-soluble, water-swellable, water-insoluble, or a combination of one or more of water-soluble, water-swellable, and water-insoluble polymers. The polymer may include cellulose, cellulose derivatives or gums. Examples of useful water-soluble polymers include polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, gum acacia, These include, but are not limited to, gum arabic, polyacrylic acid, methyl methacrylate copolymers, carboxyvinyl copolymers, starch, gelatin, and combinations thereof. Examples of useful water-insoluble polymers include, but are not limited to, ethylcellulose, hydroxypropylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and combinations thereof. For higher doses, it may be desirable to incorporate polymers that provide higher levels of viscosity than for lower doses.

As used herein, the phrase "water-soluble polymer" and variations thereof refer to polymers that are at least partially soluble in water, desirably completely or mostly soluble in water, or that absorb water. Polymers that absorb water are often referred to as water-swellable polymers. Materials useful in the invention may be water-soluble or water-swellable at room temperature and other temperatures, such as at temperatures above room temperature. Additionally, these materials may be water-soluble or water-swellable at subatmospheric pressures. In some embodiments, films formed from such water-soluble polymers may be sufficiently water-soluble to be able to dissolve upon contact with body fluids.

Other polymers useful for incorporation into the film include biodegradable polymers, copolymers, block polymers or combinations thereof. It is understood that the term "biodegradable" is intended to include materials that degrade chemically, as opposed to materials that are physically broken apart (ie, bioerodible materials). The polymers incorporated into the film can also include a combination of biodegradable or bioerodible materials. Known useful polymers or polymer classes meeting the above criteria include: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxane, polyoxalate, poly(α-ester), polyanhydride. polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkylcyanoacrylates), and mixtures and copolymers thereof. Additional useful polymers are stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propanoic acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid)/poly(glycolic acid) / polyethylene glycol copolymer, copolymer of polyurethane and (poly(lactic acid)), copolymer of α-amino acid and caproic acid, copolymer of α-benzylglutamate and polyethylene glycol, copolymer of succinate ester and poly(glycol), polyphosphazene, Contains polyhydroxy-alkanoates or mixtures thereof. The polymer matrix can include 1, 2, 3, 4 or more components.

Although a variety of different polymers may be used, it is desirable to select a polymer that provides the film with mucoadhesive properties and desired dissolution and/or disintegration rates. In particular, the length of time it is desirable to maintain the film in contact with the mucosal tissue will depend on the type of pharmaceutically active ingredient contained in the composition. Some pharmaceutically active ingredients may require only a few minutes for delivery across mucosal tissues, whereas other pharmaceutically active ingredients may require up to several hours or even longer. Sometimes. Thus, in some embodiments, one or more of the water-soluble polymers described above may be used to form the film. However, in other embodiments, it may be desirable to use a combination of water-soluble polymers and water-swellable, water-insoluble and/or biodegradable polymers as provided above. The inclusion of one or more polymers that are water-swellable, water-insoluble, and/or biodegradable provides a film with a slower rate of dissolution or disintegration than a film formed with only water-soluble polymers. Can be done. The film thus adheres to the mucosal tissue for a relatively long period of time, such as up to several hours, which may be desirable for the delivery of certain pharmaceutically active ingredients.

Desirably, the individual film dosage of the pharmaceutical film can have a suitable thickness and small size, such as about 0.0625 to 3 inches (1.5875 mm x 76.2 mm) by about 0.0625 to 3 inches. It is between. The film size is also, in at least one embodiment, greater than 0.0625 inches, greater than 0.5 inches (12.7 mm), greater than 1 inch (25.4 mm), greater than 2 inches (50.8 mm), or about 3 inches (76.2 mm), or 3 more than 0.0625 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, less than 0.0625 inches, or in another embodiment, more than 0.0625 inches, more than 0.5 inches, more than 1 inch, more than 2 inches, or 3 It can also be more than an inch, about 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inch, or less than 0.0625 inch. Aspect ratios, including thickness, length, and width, are determined based on the chemical and physical properties of the polymer matrix, the active pharmaceutical ingredient, dosage, enhancer, and other additives involved, and the dimensions of the desired dispensing unit. Can be optimized by the vendor. The film dosage form must have good adhesion when placed in the user's buccal oral cavity or sublingual area. Additionally, the film dosage form must disperse and dissolve at a moderate rate, most desirably dispersing within about 1 minute and dissolving within about 3 minutes. In some embodiments, the film dosage form lasts for about 1 to about 30 minutes, such as about 1 to about 20 minutes, or more than 1 minute, more than 5 minutes, more than 7 minutes, more than 10 minutes, more than 12 minutes, 15 minutes More than 30 minutes, more than 20 minutes, more than 30 minutes, about 30 minutes, or less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, or less than 1 minute can be dispersed and dissolved. The sublingual dispersion rate may be shorter than the buccal dispersion rate.

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

Additives may be included in these films. Examples of additive classes are preservatives, antimicrobials, excipients, lubricants, buffers, stabilizers, blowing agents, pigments, colorants, fillers, fillers, sweeteners, flavoring agents, Fragrances, release modifiers, adjuvants, plasticizers, glidants, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, lubricants, adhesives, anti-adhesion agents, acidulants, softeners agents, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, antiblocking agents, antistatic agents and mixtures thereof. These additives may be added together with the pharmaceutically active ingredient(s).

As used herein, the term "stabilizer" is capable of preventing aggregation or other physical degradation, as well as chemical degradation, of an active pharmaceutical ingredient, another excipient, or a combination thereof. Refers to certain excipients.

Stabilizers are also classified as antioxidants, sequestrants, pH modifiers, emulsifiers and/or surfactants, and UV stabilizers, as described above and in more detail below. obtain.

Antioxidants (i.e. pharmaceutically compatible compound(s) or composition(s) that slow down, inhibit, interrupt and/or stop oxidative processes) include in particular the following substances: tocopherols and their Esters, sesamol from sesame oil, coniferyl benzoate from benzoin resin, nordihydroguaiaretic acid resin and nordihydroguaiaretic acid (NDGA), gallates (among others, methyl, ethyl, propyl, amyl, butyl, lauryl gallate) ), butylated hydroxyanisole (BHA/BHT, also butyl-p-cresol); ascorbic acid and its salts and esters (e.g. ascorbyl palmitate), erythorbic acid (isoascorbic acid) and its salts and esters, monothioglycerol , sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT), propionic acid. Typical antioxidants are tocopherols, such as alpha-tocopherol and its esters, butylated hydroxytoluene and butylated hydroxyanisole. The term "tocopherol" also includes esters of tocopherol. A known tocopherol is α-tocopherol. The term "α-tocopherol" includes esters of α-tocopherol (eg, α-tocopherol acetate).

Sequestering agents (i.e., any compound that can participate during host-guest complex formation with the active ingredient or another compound such as another excipient; also referred to as a sequestering agent) include calcium chloride, ethylenediamine, Includes calcium tetraacetate disodium, glucono delta-lactone, sodium gluconate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate, and combinations thereof. Sequestering agents also include cyclic oligosaccharides such as cyclodextrin, cyclomannin (5 or more α-D-mannopyranose units linked at the 1,4 position by α-linkages), cyclogalactin (by β-linkages), 5 or more β-D-galactopyranose units linked in the 1,4 position), cycloalthrin (5 or more α-D-altropyranose units linked in the 1,4 position by an α bond) , and combinations thereof.

pH adjusting agents include acids (e.g. tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, ascorbic acid, acetic acid, succinic acid, adipic acid and maleic acid), acidic amino acids (e.g. glutamic acid, aspartic acid, etc.), Inorganic salts of acidic substances such as alkali metal salts, alkaline earth metal salts, ammonium salts, organic bases of such acidic substances such as basic amino acids such as lysine, arginine and the like, meglumine and the like. and similar salts), as well as their solvates (e.g. hydrates). Other examples of pH regulators are silicified microcrystalline cellulose, magnesium aluminometasilicate, calcium salts of phosphoric acid (e.g. anhydrous or hydrated calcium hydrogen phosphate, calcium carbonate or hydrogen carbonate, sodium or potassium , and calcium lactate or mixtures thereof), sodium and/or calcium salts of carboxymethylcellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium and/or calcium), polacrilin potassium, sodium and/or calcium alginate, doc including sodium sate, magnesium stearate, calcium, aluminum, or zinc, magnesium palmitate, and magnesium oleate, sodium stearyl fumarate, and combinations thereof.

Examples of emulsifiers and/or surfactants are poloxamers or pluronics, polyethylene glycols, polyethylene glycol monostearates, polysorbates, sodium lauryl sulphate, polyethoxylated and hydrogenated castor oils, alkylpolyosides, on hydrophobic backbones. Water-soluble proteins grafted onto, lecithin, glyceryl monostearate, glyceryl monostearate/polyoxyethylene stearate, ketostearyl alcohol/sodium lauryl sulfate, carbomer, phospholipids, (C ₁₀ -C ₂₀ )-alkyl and Alkylene carboxylates, carboxylic acid alkyl ethers, fatty alcohol sulfates, fatty alcohol ether sulfates, alkylamides sulfates and sulfonates, fatty acid alkylamide polyglycol ether sulfates, alkanesulfonates and hydroxyalkanesulfonates , olefin sulfonates, acyl esters of isethionic acid, α-sulfo fatty acid esters, alkylbenzene sulfonates, alkylphenol glycol ether sulfonates, sulfosuccinates, monoesters and diesters of sulfosuccinic acid, fatty alcohol ether phosphates, Protein/fatty acid condensation products, alkyl monoglyceride sulfates and sulfonates, alkylglyceride ether sulfonates, fatty acid methyltaurides, fatty acid sarcosinates, sulforisinolates, and acylglutamates, quaternary ammonium salts (e.g., di-(C _{(C 10} -C ₂₄ )-alkyl-dimethylethylammonium chloride or bromide), (C ₁₀ -C ₂₄ )-alkyl-dimethylethylammonium chloride or bromide, (C ₁₀ -C ₂₄ )-alkyl-trimethylammonium chloride or bromide (e.g. cetyltrimethylammonium chloride or bromide), (C ₁₀ -C ₂₄ )-alkyl-dimethylbenzylammonium chloride or bromide (e.g. (C ₁₂ -C ₁₈ )-alkyl-dimethylbenzylammonium chloride), N-(C ₁₀ -C ₁₈ )-Alkyl-pyridinium chloride or bromide (e.g. N-(C ₁₂ -C ₁₆ )-alkyl-pyridinium chloride or bromide), N-(C ₁₀ -C ₁₈ )-alkyl-isoquinolinium chloride, bromide or Monoalkyl sulfate, N-(C ₁₂ -C ₁₈ )-alkyl-poloylaminoformylmethylpyridinium chloride, N-(C ₁₂ -C ₁₈ )-alkyl-N-methylmorpholinium chloride, bromide or monoalkyl sulfate Salt, N-(C ₁₂ -C ₁₈ )-alkyl-N-ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C ₁₆ -C ₁₈ )-alkyl-pentaoxetyl ammonium chloride, diisobutylphenoxyethoxyethyldimethyl Benzyl ammonium chloride, N,N-di-ethylaminoethyl stearylamide and -oleylamide salts with hydrochloric acid, acetic acid, lactic acid, citric acid, phosphoric acid, N-acylaminoethyl-N,N-diethyl-N-methyl ammonium chloride, bromide or monoalkyl sulfate, and N-acylaminoethyl-N,N-diethyl-N-benzylammonium chloride, bromide or monoalkyl sulfate (in the foregoing, "acyl" refers to, for example, stearyl or oleyl); ), as well as combinations thereof.

Examples of UV stabilizers are UV absorbers (e.g., benzophenone), UV quenchers (i.e., any compound that dissipates UV energy as heat rather than imparting it with a degrading effect), scavengers ( i.e., any compound that scavenges free radicals resulting from exposure to UV radiation), and combinations thereof.

In other embodiments, the stabilizing agent is ascorbyl palmitate, ascorbic acid, alpha-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, cysteine HC1, citric acid, ethylenediaminetetraacetic acid (EDTA), methionine, sodium citrate, Sodium ascorbate, sodium thiosulfate, sodium metabisulfite, sodium bisulfite, propyl gallate, glutathione, thioglycerol, singlet oxygen quencher, hydroxyl radical scavenger, hydroperoxide removal agent, reducing agent, metal chelating agent, cleaning agents, chaotropes, and combinations thereof. "Singlet oxygen quenchers" include alkylimidazoles (e.g. histidine, L-camosine, histamine, imidazole 4-acetic acid), indoles (e.g. tryptophan and its derivatives, e.g. N-acetyl-5-methoxytryptamine, N-acetyl Serotonin, 6-methoxy-1,2,3,4-tetrahydro-beta-carboline), sulfur-containing amino acids (e.g. methionine, ethionine, diencholic acid, lanthionine, N-formylmethionine, felinine, S-allylcysteine, S- aminoethyl-L-cysteine), phenolic compounds (e.g. tyrosine and its derivatives), aromatic acids (e.g. ascorbate, salicylic acid and their derivatives), azides (e.g. sodium azide), tocopherols and related Including, but not limited to, vitamin E derivatives, and carotene and related vitamin A derivatives. "Hydroxyl radical scavengers" include, but are not limited to, azide, dimethyl sulfoxide, histidine, mannitol, sucrose, glucose, salicylate, and L-cysteine. "Hydroperoxide scavengers" include, but are not limited to, catalase, pyruvate, glutathione, and glutathione peroxidase. "Reducing agents" include, but are not limited to, cysteine and mercaptoethylene. "Metal chelators" include, but are not limited to, EDTA, EGTA, o-phenanthroline, and citrate. "Cleaning agents" include, but are not limited to, SDS and sodium lauroyl sarcosinate. "Chaotropes" include, but are not limited to, guanidium hydrochloride, isothiocyanates, urea, and formamide. As discussed herein, the stabilizer can be present from 0.0001% to 50% by weight, which includes, by weight, greater than 0.0001%, greater than 0.001%, greater than 0.01%, greater than 0.1%, 1 More than %, more than 5%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1% , less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001%.

Useful additives include, for example, gelatin, vegetable proteins such as sunflower protein, soybean protein, cottonseed protein, peanut protein, grapeseed protein, whey protein, whey protein isolate, blood protein, egg protein, etc. Acrylated proteins, water-soluble polysaccharides such as alginate, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic and related gums (gutti, karaya, tragacanth), pectin, water-soluble derivatives of cellulose: alkylcellulose, hydroxyalkylcellulose and hydroxyalkylalkylcelluloses, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters, such as cellulose acetate phthalate (CAP), hydroxy Propyl methyl cellulose (HPMC); carboxyalkyl cellulose, carboxyalkyl alkyl cellulose, carboxyalkyl cellulose esters such as carboxymethyl cellulose and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acid and polyacrylic esters, polymethacrylic acid and May include methacrylate esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVA/vinyl acetate copolymers, or polycrotonic acid; also phthalate gelatin, succinate gelatin, crosslinked gelatin , shellac, water-soluble chemical derivatives of starch, such as cationically modified acrylates and methacrylates having tertiary or quaternary amino groups, such as diethylaminoethyl groups which are quaternized if desired; or other Similar polymers are also suitable.

Additional ingredients can range up to about 80%, preferably from about 0.005% to 50%, more desirably from 1% to 20%, based on the weight of all composition ingredients; >1%, >5%, >10%, >20%, >30%, >40%, >50%, >60%, >70%, approximately 80%, >80%, <80%, 70 %, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, about 3%, or less than 1%. Other additives may include anti-adhesives, flow agents and opacifiers, such as oxides of magnesium, aluminum, silicon, titanium, etc., if desired, in concentrations ranging from about 0.005% to about 0.005%, based on the weight of all film components. about 5% by weight, and if desired from about 0.02% to about 2%, including more than 0.02%, more than 0.2%, more than 0.5%, more than 1%, more than 1.5%, more than 2%, Includes more than 4%, about 5%, more than 5%, less than 4%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.02%.

In certain embodiments, the composition may include a plasticizer, such as a polyalkylene oxide, such as polyethylene glycol, polypropylene glycol, polyethylene-propylene glycol, a low molecular weight organic plasticizer, such as glycerol, glycerol mono Acetate, diacetate or triacetate, such as triacetin, polysorbate, cetyl alcohol, propylene glycol, sugar alcohol sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, plant extracts, fatty acid esters, fatty acids, oils and the like. may be added at concentrations ranging from about 0.1% to about 40%, desirably from about 0.5% to about 20%, based on the weight of the composition, which is greater than 0.5%; More than 1%, more than 1.5%, more than 2%, more than 4%, more than 5%, more than 10%, more than 15%, about 20%, more than 20%, less than 20%, less than 15%, less than 10%, 5% including less than, less than 4%, less than 2%, less than 1%, or less than 0.5%. Compounds that improve the textural properties of the film material, such as animal or vegetable fats, preferably in their hydrogenated form, may also be added. The composition can also include compounds that improve the textural properties of the product. Other ingredients include binders that contribute to the ease of formation and overall quality of the film. Non-limiting examples of binders include starch, natural gum, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxazolidone, or polyvinyl alcohol.

Further possible additives include solubility enhancers, such as substances that form encapsulating compounds with the active ingredient. Such substances can be useful for improving the properties of highly insoluble and/or unstable active substances. Generally, these materials are donut-shaped molecules with a hydrophobic interior cavity and a hydrophilic exterior. The insoluble and/or labile pharmaceutically active ingredient fits within the hydrophobic cavity, thereby creating an inclusion complex, which is soluble in water. The formation of an inclusion complex therefore allows highly insoluble and/or labile pharmaceutical active ingredients to be dissolved in water. A particularly desirable example of such a material is cyclodextrin, which is a cyclic carbohydrate derived from starch. However, other similar materials are considered to fall within the scope of this invention.

Suitable colorants include Food, Drug and Cosmetic Colors (FD&C), Drug and Cosmetic Colors (D&C), or External Drug and Cosmetic Colors (Ext. D&C). These colorants are pigments, their corresponding lakes, and certain natural and derived colorants. Lakes are dyes absorbed onto aluminum hydroxide. Other examples of colorants include known azo dyes, organic or inorganic pigments, or colorants of natural origin. Inorganic pigments, such as oxides or iron or titanium, are preferred, and these oxides are added in concentrations ranging from about 0.001 to about 10%, preferably from about 0.5 to about 3%, based on the weight of all ingredients; This is more than 0.001%, more than 0.01%, more than 0.1%, more than 0.5%, more than 1%, more than 2%, more than 5%, about 10%, more than 10%, less than 10%, less than 5%, less than 2%, Includes less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001%.

Flavoring agents may be selected from natural and synthetic flavored liquids. An exemplary list of such substances includes volatile oils, synthetic flavor oils, flavored aromatics, oils, liquids, oleoresins, or derived from plants, leaves, flowers, fruits, stems, and combinations thereof. Contains extracts. A non-limiting representative list of examples includes mint oil, cocoa, and citrus oils such as lemon, orange, lime, and grapefruit, as well as apples, pears, peaches, grapes, strawberries, raspberries, cherries, plums, pineapples, apricots. or other fruit flavorings. Other useful flavoring agents are aldehydes and esters, such as benzaldehyde (cherry, almond), citral, i.e. alpha-citral (lemon, lime), neral, i.e. beta-citral (lemon, lime), decanal (orange, lemon). , Aldehyde C-8 (citrus fruits), Aldehyde C-9 (citrus fruits), Aldehyde C-12 (citrus fruits), Tolyl aldehyde (cherries, almonds), 2,6-dimethyloctanol (green fruits), or 2-dodecenal (citrus, mandarin), combinations thereof, etc.

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

Antifoam and/or defoamer components may also be used in the film. These ingredients aid in the removal of air, such as entrapped air, from the film-forming composition. Such trapped air can lead to uneven films. Simethicone is one particularly useful antifoam and/or defoamer. However, the invention is not so limited and other suitable defoamers and/or defoamers may be used. Simethicone and related substances may be utilized for densification purposes. More specifically, such materials can facilitate the removal of voids, air, moisture, and similar undesirable components, thereby providing denser and therefore more uniform films. . Substances or components that perform this function are referred to as densification agents or densifying agents. As previously explained, trapped air or undesirable components can lead to non-uniform films.

Any other optional components described in commonly assigned US Pat. Nos. 7,425,292 and 8,765,167, mentioned above, may also be included in the films described herein.

Desirably, the film composition further contains a buffering agent to control the pH of the film composition. Any desired level of buffering agent is incorporated into the film composition to provide the desired pH level encountered when the pharmaceutically active ingredient is released from the composition. Preferably, the buffering agent is provided in an amount sufficient to control the release of the pharmaceutically active ingredient from the film and/or absorption into the body. In some embodiments, the buffer may include sodium citrate, citric acid, bitartrate, and combinations thereof.

The pharmaceutical films described herein may be formed by any desired process. Suitable processes are described in US Pat. Nos. 8,652,378, 7,425,292 and 7,357,891, which are incorporated herein by reference. In one embodiment, a film dosage composition is formed by first preparing a wet composition that includes a polymeric carrier matrix and a therapeutically effective amount of the pharmaceutically active ingredient. This wet composition is cast into a film and then thoroughly dried to form a free-standing film composition. The wet composition can be cast into individual dosage forms, or it can be cast into sheets, which are then cut into individual dosage forms.

The pharmaceutical composition is capable of adhering to mucosal surfaces. The present invention is particularly useful for the local treatment of body tissues, affected areas, or wounds that have moist surfaces and are susceptible to body fluids, such as the mouth, vagina, organs, or other types of mucosal surfaces. . The composition carries the medicament and, upon application and attachment to mucosal surfaces, provides a protective layer and delivers the medicament to the treatment site, surrounding tissues, and other body fluids. Given control of erosion in body fluids such as aqueous solutions or saliva, and slow, natural erosion of the film simultaneously with or subsequent to delivery, the composition has a residence time suitable for effective drug delivery at the treatment site. provide.

The residence time of the composition depends on the erosion rate of the water-erodible polymers used in the formulation and their respective concentrations. The erosion rate can be increased, for example, by mixing together components with different solubility properties or chemically different polymers, e.g. hydroxyethyl cellulose and hydroxypropyl cellulose; by using molecular weight grades; by using excipients or plasticizers (including essentially insoluble components) of varying lipophilicity or water solubility properties; by using water-soluble organic and inorganic salts; by using polymers such as hydroxyethylcellulose and crosslinking agents such as glyoxal for partial crosslinking; or by changing the physical state of the film, including its crystallinity or phase transitions, once obtained; may be regulated by post-treatment irradiation or curing, which can change the These strategies may be utilized alone or in combination to alter the erosion kinetics of the film. Upon application, the pharmaceutical composition film adheres to the mucosal surface and is held in place. Absorption of water softens the composition, thereby reducing the foreign body feel. Delivery of the drug occurs while the composition is placed on the mucosal surface. Residence time can be adjusted widely depending on the desired timing of delivery of the selected drug and the desired lifetime of the carrier. Generally, however, the residence time will be adjusted to between about a few seconds and about a few days. Preferably, the residence time for most medicaments is adjusted from about 5 seconds to about 24 hours. More preferably, the residence time is adjusted from about 5 seconds to about 30 minutes. In addition to providing drug delivery, once the composition is attached to the mucosal surface, it also provides protection for the treatment site, acting as an erodible bandage. Lipophilic materials can be designed to retard erodibility to reduce disintegration and dissolution.

The erosive behavior of the composition can also be adjusted by adding excipients that are sensitive to enzymes such as amylase and are highly soluble in water, such as water-soluble organic and inorganic salts. It is possible. Suitable excipients include sodium and potassium salts of chloride, carbonate, bicarbonate, citrate, trifluoroacetate, benzoate, phosphate, fluoride, sulfate, or tartrate. may be included. The amount added may vary depending on how much the erosion kinetics are to be altered and the amounts and nature of other ingredients in the composition.

Emulsifiers typically used in the water-based emulsions described above are preferably linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid, cetoleic acid or oleic acid and sodium hydroxide or water. Potassium oxide, obtained in situ or lauric, palmitic, stearic, or oleic esters of sorbitol and sorbitol anhydride, monooleate, monostearate, monopalmitate, monolaurate; sorbitan monostearate, sorbitan monooleate and/or sorbitan monopalmitate.

The amount of pharmaceutically active ingredient used will depend on the desired therapeutic strength and the composition of these layers, but preferably the pharmaceutical ingredient will be from about 0.001% to about 99% of the composition, more preferably from about 0.003% to about 75% of the composition. %, and most preferably from about 0.005% to about 50% by weight, including greater than 0.005%, greater than 0.05%, greater than 0.5%, greater than 1%, greater than 5%, greater than 10%, greater than 15%, and 20%. super, more than 30%, about 50%, more than 50%, less than 50%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.05%, Or contains less than 0.005%. The amounts of other ingredients may vary depending on the drug or other ingredients, but typically these ingredients will not exceed 50%, and preferably will not exceed 30%, by total weight of the composition. , and most preferably not more than 15%.

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

As will be understood by those skilled in the art, if systemic delivery, e.g. transmucosal or transdermal delivery, is desired, the treatment site will be such that the film delivers and/or maintains the desired level of the drug in the blood, lymph, or other body fluid. may include any area in which it is possible to Typically, such treatment sites include the mucosal tissues of the mouth, esophagus, ears, eyes, anus, nose, and vagina, as well as the skin. When skin is utilized as a treatment site, a relatively large area of skin where movement does not interfere with film deposition is usually preferred, such as the upper arm or thigh.

The pharmaceutical composition can also be used as a wound dressing. By providing a physical, compatible, oxygen and moisture permeable, flexible barrier that can be washed and removed, the film not only protects the wound, but also prevents healing, sterility, and scarring ( Medications can also be delivered to promote scarification, relieve pain, or generally improve the condition of the patient. Some of the examples provided below are well suited for skin or wound applications. As those skilled in the art will appreciate, the formulation requires the incorporation of specific hydrophilic/hygroscopic excipients, which will help maintain good adhesion on dry skin over long periods of time. will be. Another advantage of the invention when utilized in this manner is that the use of pigments or coloring substances is not necessary if the film is not desired to stand out on the skin. On the other hand, if it is desired that the film stand out, dyes or colored substances may be utilized.

While the pharmaceutical composition can adhere to mucosal tissue, which is naturally a moist tissue, it can also be used on other surfaces, such as the skin or wounds. The pharmaceutical film can also adhere to the skin if it is moistened by an aqueous-based fluid such as water, saliva, wound drainage or perspiration prior to application to the skin. This film can adhere to the skin until it is eroded due to contact with water, for example by washing, showering, bathing or washing. The film can also be easily peeled and removed without significant tissue damage.

The Franz diffusion cell is an in vitro skin permeation assay used in formulation development. The Franz diffusion cell device (FIG. 1A) consists of two chambers separated by a membrane of, for example, animal or human tissue. The test product is applied to the membrane via the upper chamber. The lower chamber contains a fluid from which samples are taken at regular intervals for analysis to determine the amount of activity that permeates the membrane. With respect to FIG. 1A, Franz diffusion cell 100 comprises donor compound 101, donor chamber 102, membrane 103, sampling port 104, receptor chamber 105, stirrer 106, and heater/circulator 107.

With respect to FIG. 1B, the pharmaceutical composition is a film 100 that includes a polymer matrix 200, and a pharmaceutically active ingredient 300 is contained within the polymer matrix. The film can include a transmission enhancer 400.

With respect to Figures 2A and 2B, the graphs show the permeation of active agent from the composition. This graph shows that no significant difference was observed for epinephrine bases solubilized in situ versus essentially soluble epinephrine bitartrate. Epinephrine bitartrate was selected for further development based on ease of processing. Flux is induced as a gradient in permeation as a function of time. Steady state flux is obtained from the plateau of the flux versus time curve multiplied by the volume of the receiver medium and normalized to the permeation area.

Referring to FIG. 2A, this graph shows the average amount of active permeated versus time with 8.00 mg/mL epinephrine bitartrate and 4.4 mg/mL solubilized epinephrine base.

Referring to FIG. 2B, this graph shows the average flux versus time with 8.00 mg/mL epinephrine bitartrate and 4.4 mg/mL solubilized epinephrine base.

Referring to Figure 3, this graph shows the ex vivo permeation of epinephrine bitartrate as a function of concentration. This study compared concentrations of 4 mg/mL, 8 mg/mL, 16 mg/mL and 100 mg/mL. The results showed that increasing concentration showed increased permeation and that the level of enhancement decreased at higher loads.

Referring to Figure 4, this graph shows the permeation of epinephrine bitartrate as a function of solution pH. We investigated whether acidic conditions promote stability. The results compared epinephrine bitartrate pH 3 buffer and epinephrine bitartrate pH 5 buffer and found that the epinephrine bitartrate pH 5 buffer was slightly preferred.

Referring to FIG. 5, this graph shows the effect of the enhancer on the permeation of epinephrine, expressed as the amount of permeation as a function of time. Multiple enhancers were screened including Labrasol, Capriol 90, Plurol Oleique, Labrafil, TDM, SGDC, Gelucire 44/14 and Clove Oil. Significant effects on time to onset and steady state flux were achieved and surprisingly enhanced permeation was achieved for clove oil and labrasol.

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

Referring to Figure 7, this graph shows a pharmacokinetic model in male Yucatan minipigs. This study compares 0.3 mg EpiPen, 0.12 mg epinephrine IV, and Placebo Film.

Referring to Figure 8, this graph shows the effect of no enhancer on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.

Referring to FIG. 9, this graph shows the effect of Enhancer A (Labrasol) on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.

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

With respect to Figure 11, this graph shows the effect of Enhancer L (clove oil) and film size (10-1-1 thin and large film and 11-1-1 thick and small film) on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen. shows.

Referring to FIG. 12, this graph shows the concentration profile for varying doses of epinephrine film in a constant matrix for Enhancer L (clove oil) for 0.3 mg EpiPen.

Referring to FIG. 13, this graph shows the concentration profile for varying doses of epinephrine film in a constant matrix for Enhancer L (clove oil) for 0.3 mg EpiPen.

Referring to FIG. 14, this graph shows the concentration profile for varying doses of epinephrine film in a fixed matrix for Enhancer A (Labrasol) for 0.3 mg EpiPen.

Referring to FIG. 15, this graph shows the effect of the enhancer on the permeation of diazepam, shown as the amount of permeation as a function of time.

Referring to Figure 16, this graph shows the average flux (Diazepam + Enhancer) as a function of time.

Referring to FIG. 17, this graph shows the effect of farnesol in combination with farnesol and linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.

Referring to FIG. 18, this graph shows the effect of farnesol in combination with farnesol and linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.

Referring to FIG. 19, this graph shows the effect of farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.

Referring to Figure 20, this graph shows the effect of farnesol in combination with farnesol and linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.

The following examples are provided to illustrate the pharmaceutical compositions, as well as methods of making and using the pharmaceutical compositions, and devices described herein.

¹定常状態フラックスにかなり早い時点で到達した
*0.3％オイゲノール対0.3％クローブ-互いに類似したフラックス速度 (Example)
(Example 1 Transmission enhancer-epinephrine)
Enhancement of permeation was tested using several permeation enhancers and with an epinephrine bitartrate concentration of 16.00 mg/mL. The results show flux enhancement expressed in the data below. For 100% eugenol and 100% clove oil, the results showed that steady state flux was reached significantly faster, with an unexpectedly elevated % flux enhancement.

¹ Steady-state flux was reached fairly early.
*0.3% eugenol vs. 0.3% clove - similar flux rates to each other

For these examples, clove oil was obtained from clove leaves. Similar results would be obtained with clove oil derived from clove buds and/or clove stems. Based on this data, similar permeability enhancement results can be expected from pharmaceutical compounds that are structurally similar to epinephrine.

(Example 2 Diazepam solubility and permeability)
Diazepam was applied to the buccal area (cheeks) and diffused through the oral mucosa and directly into the bloodstream. The solubility of diazepam was also tested using various excipients. Figure 15 shows the effect of enhancers on the permeation of diazepam, expressed as permeation (ug) as a function of time. Figure 16 shows the average flux, expressed as μg/cm*min, of diazepam and certain selected enhancers in solution as a function of time (min).

The following excipients have also been tested to improve solubility.

Excipients: Cinnamon Leaf, Basil, Bay Leaf, Nutmeg, Kolliphor® TPGS, Vitamin E PEG Succinate, Kolliphor® EL, Polyoxyl 35 Castor Oil USP/NF, Menthol, N-Methyl-2 -Pyrrolidone, SLS (SDS), SDBS, dimethyl phthalate, sucrose palmitate (Sisterna PS750-C), sucrose stearate (Sisterna SP70-C), CHAPS, octyl glucoside, Triton X 100 (octoxynol) -9), ethyl maltol (powdered flavor), Brij 58 (cetheth-20), vitamin E tocopherol, tocopherol acetate or tocopherol succinate, sterols, plant extracts, essential oils or cod liver oil for similar enhancing properties. It can be applied to

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

(Example 3 General Permeation Method - Ex Vivo Permeation Testing Protocol)
In one example, the transparent technique is performed as follows. Set the hot bath to 37 °C and place the receiver medium in the water bath to adjust the temperature and begin degassing. Obtain and prepare a Franz diffusion cell. A Franz diffusion cell includes a donor compound, a donor chamber, a membrane, a sampling port, a receptor chamber, a stir bar, and a heater/circulator. A stirrer is inserted into the Franz diffusion cell. Place the tissue over the Franz diffusion cell and ensure that the tissue covers the entire surface with overlap over the glass joint. The top of the diffusion cell is placed on top of the tissue and the top of the cell is clamped to the bottom. Load approximately 5 mL of receptor medium into the receiver area, ensuring that no air bubbles are trapped in the receiving portion of the cell. This ensures that all 5 mL can fit into the receiver area. Start stirring and allow temperature to equilibrate for approximately 20 minutes. Meanwhile, label high performance liquid chromatography (HPLC) vials by cell number and time point. Then, as gas escapes from the solution during heating, bubbles must be checked again.

When testing a film, the following steps are followed: (1) Weigh the film, punch it to match (or be smaller than) the diffusion area, weigh it again, and record the weight before and after punching; 2) wetting the donor area with approximately 100 μL of phosphate buffer; (3) placing the film on the donor surface, covering with 400 μL of phosphate buffer, and starting a timer. Can be done.

For solution testing, the following steps: (1) Dispense 500 μL of solution into each donor cell using a micropipette and start a timer; (2) Dispense at the following time points (time = 0 min, 20 min, 40 min, 60 min) minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, 360 minutes), sample and place 200 μL into a labeled HPLC vial and tap the sealed vial to ensure that air is at the bottom of the vial. (3) At each sampling time, replace with 200 μL of receptor medium (to maintain 5 mL); (4) Once all time points are complete, disassemble the cell and remove all Steps can be taken to properly dispose of the material.

(Example 4 Ex vivo permeation evaluation)
Examples of ex vivo permeation evaluations are as follows:
1. Tissue is freshly excised and shipped at 4°C (eg, overnight).
2. Process and freeze tissue at -20°C for up to 3 weeks before use.
3. Dermatome the tissue to the correct thickness.
4. Add approximately 5 mL of receiver medium to the receiver compartment. This medium is selected to ensure sink conditions.
5. Place the tissue in a Franz diffusion cell containing donor compound, donor chamber, membrane, sampling port, receptor chamber, stir bar, and heater/circulator.
6. Apply approximately 0.5 mL of donor solution and wet the 8 mm circular film with 500 μL of PBS buffer.
7. At predetermined intervals, samples are taken from the receiver chamber and replaced with fresh media.

(Example 5 Transbuccal delivery of doxepin)
Below is an exemplary permeation study of transbuccal delivery of doxepin. This study was carried out under a protocol approved by the Ethics Committee for Animal Experiments of the University of Barcelona (Spain) and the Animal Experiment Committee of the Regional Autonomous Government of Catalonia (Spain). Three to four month old sows were used. Buccal mucosa from the buccal region of the pigs was immediately excised after the pigs were sacrificed using an overdose of sodium thiopental anesthesia in the animal facility of the Bellvitge Campus (University of Barcelona, Spain). Fresh buccal tissue was placed in a container filled with Hank's solution and transferred from the hospital to the laboratory. The remaining tissue specimens were stored at -80°C in a container containing a PBS mixture containing 4% albumin and 10% DMSO as a cryoprotectant.

For permeation studies, it contributes to the diffusion barrier (see Sudhakar et al., "Buccal bioadhesive drug delivery - A promising option for orally less efficient drugs"). ), Journal of Controlled Release, 114 (2006) 15-40) Porcine buccal mucosa was cut into sheets with a thickness of 500 ± 50 μm using an electrodermatome (GA 630, Aesculap, Tuttlingen, Germany). and trimmed into appropriate pieces with surgical scissors. Most of the lower connective tissue was removed with a scalpel.

The membrane was then mounted in a specially designed membrane holder with a transmission orifice diameter of 9 mm (diffusion area 0.636 cm ² ). Using a membrane holder, the buccal membrane of each pig was attached between the donor compartment (1.5 mL) and the receptor compartment (6 mL), where the epithelial side was placed in a static Franz-type diffusion cell (Vidra Foc Barcelona, Spain). facing the donor chamber and the connective tissue area facing the receiver to prevent bubble formation.

Infinite dose conditions were ensured by applying 100 μL of saturated doxepin solution as donor solution into the receptor chamber and immediately sealing with parafilm to prevent water evaporation. Before carrying out this experiment, the diffusion cells were incubated for 1 hour in a water bath to ensure that the temperature within all cells was equal (37°C±°C). Each cell contained a small Teflon-1 coated magnetic stir bar, which was used to ensure that the fluid within the receptor compartment remained homogeneous during the experiment.

Sink conditions were ensured in all experiments by first testing the saturating concentration of doxepin in the receptor medium. Samples (300 μL) were withdrawn via syringe from the center of the receptor compartment at preselected time intervals (0.1, 0.2, 0.3, 0.7, 1, 2, 3, 4, 5, and 6 hours) over 6 hours. The removed sample volume was immediately replaced with an equal volume of fresh receptor medium (PBS; pH 7.4), taking great care to avoid trapping air on the underside of the membrane.

Additional details can be found in A. Gimemo et al., “Transbuccal delivery of doxepin: Studies on permeation and histological evaluation,” International Journal of Pharmaceutics 477 (2014 ), 650-654, which is incorporated herein by reference.

(Example 6 Oral transmucosal delivery)
Porcine oral mucosal tissue has histological features similar to human oral mucosal tissue (Heaney TG, Jones RS, Histological investigation of the influence of adult porcine alveolar mucosal connective tissue on epithelial differentiation. of the influence of adult porcine alveolar mucosal connective tissues on epithelial differentiation)', Arch Oral Biol 23 (1978) 713-717; Squier CA and Collins P, 'Soft tissue attachment, epithelial downgrowth and surface porosity 'The relationship between soft tissue attachment, epithelial downgrowth and surface porosity', Journal of Periodontal Research 16 (1981) 434-440). Lesch et al., "The Permeability of Human Oral Mucosa and Skin to Water," J Dent Res 68 (9), 1345-1349, 1989) reported that although mucosal water permeability is not significantly different from human buccal mucosa, the floor of the oral cavity is more permeable in human tissue than in pig tissue. A comparison between fresh porcine tissue specimens and specimens stored at -80°C revealed no significant effect on permeability as a result of freezing. Buccal mucosal absorption in pigs has been tested for a wide range of drug molecules both in vitro and in vivo (see, for example, M. Sattar, "Oral Transmucosal Drugs," incorporated herein by reference. Oral transmucosal drug delivery - current status and future prospects', International Journal of Pharmaceutics 471 (2014) 498-506). Typically, in vitro testing involves mounting excised porcine buccal tissue in an Ussing chamber, Franz cell or similar diffusion device. The in vivo test described in this document involves application of the drug as a solution, gel or composition to the buccal mucosa of a pig, followed by plasma sampling.

Nicolazzo et al. (“The Effect of Various in Vitro Conditions on the Permeability Characteristics of the Buccal Mucosa”, Journal of Pharmaceutical Sciences 92(12) (2002) 2399 -2410) investigated the effect of various in vitro conditions on the permeability of porcine buccal tissues using caffeine and estradiol as model hydrophilic and lipophilic molecules. Drug permeation in the buccal mucosa was tested using a modified Ussing chamber. Comparative permeation studies were performed through full thickness epithelial tissue, fresh tissue, and frozen tissue. Tissue integrity was monitored by uptake of fluorescein isothiocyanate (FITC)-labeled dextran 20kDa (FD20) and tissue viability was determined by absorption of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 -diphenyltetrazolium bromide) biochemical assays and histological evaluation. Permeability through the buccal epithelium was 1.8 times greater for caffeine and 16.7 times greater for estradiol compared to full thickness buccal tissue. Although flux values for both compounds were comparable for fresh and frozen buccal epithelium, histological evaluation revealed signs of cell death in the frozen tissue. The tissue appeared to remain viable for up to 12 hours post-mortem using the MTT viability assay, which was also confirmed by histological evaluation.

Kulkarni et al. investigated the relative contributions of epithelial and connective tissue to the barrier properties of buccal tissues in pigs. In vitro permeation studies were performed using antipyrine, buspirone, bupivacaine and caffeine as model permeants. The permeability of a model diffusant across buccal mucosa of 250, 400, 500, 600, and 700 μm thickness was determined. A bilayer membrane model was developed to delineate the relative contributions of epithelium and connective tissue to barrier function. The relative contribution of the connective tissue area as a permeability barrier increased significantly with increasing mucosal tissue thickness. A mucosal tissue thickness of approximately 500 μm was recommended by the authors for in vitro transbuccal permeation studies. This is because the epithelium represented the major permeability barrier for all diffusers at this thickness. The authors also investigated the effect of several biological and experimental variables on the permeability of the same group of model permeates in the porcine buccal mucosa (pig buccal mucosa as an in vitro model: Effect of scientific and experimental variables, Kulkarni et al., J Pharm Sci. 2010 99(3):1265-77). Significantly, higher permeability of permeate was observed for the thinner area of the back of the lips (170-220 μm) compared to the thicker cheek area (250-280 μm). Porcine buccal mucosa maintained its integrity in Krebs bicarbonate Ringer's solution for 24 hours at 4°C. Heat treatment to separate the epithelium from the underlying connective tissue did not adversely affect its permeability and integrity characteristics compared to surgical separation.

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

(Example 7 Cryopreservation of buccal mucosa)
Different regions of the pig buccal mucosa have different patterns of permeability, and there is a significantly higher permeability in the back-lip region compared to the buccal region; This is because the epithelium acts as a permeability barrier and the thickness of the buccal epithelium is greater than the thickness of the back area of the lips (Harris and Robinson, 1992). In an exemplary permeation study, fresh or frozen porcine buccal mucosa from the same region, which contributes to the diffusion barrier (Sudhakar et al., 2006), was cut into sheets 500 ± 50 μm thick and electrolyzed. They were obtained using a skin harvester (model GA 630, Aesculap, Tuttlingen, Germany) and trimmed into appropriate pieces with surgical scissors. All equipment utilized was previously sterilized. Most of the lower connective tissue was removed with a scalpel. The membrane was then mounted in a specially designed membrane holder with a transmission orifice diameter of 9 mm (diffusion area 0.63 cm ² ). Using a membrane holder, the buccal membrane of each pig was attached between the donor compartment (1.5 mL) and the receptor compartment (6 mL), where the epithelial side was placed in a static Franz-type diffusion cell (Vidra Foc Barcelona, Spain). ) facing the donor chamber and the connective tissue area facing the receiver to prevent bubble formation. The experiments were carried out using PP as a model drug, which has lipophilic characteristics (logP = 1.16; n-octanol/PBS, pH 7.4), is ionizable (pKa = 9.50), and has a MW = 259.3 g/mol. (Modamio et al., 2000).

Infinite dose conditions were applied in the receptor chamber with 300 μL of PP saturated solution (CO = 588005 ± 5852 μg/mL, n = 6 at 37 °C ± 1 °C) in PBS (pH 7.4) as the donor solution. , and immediately sealed with parafilm to prevent water evaporation.

Before carrying out this experiment, the diffusion cells were incubated in a water bath for 1 hour so that the temperature in all cells was equilibrated (37°C ± 1°C). Each cell contained a small Teflon-coated magnetic stir bar, which was used to ensure that the fluid within the receptor compartment remained homogeneous during the experiment. Sink conditions were ensured in all experiments after first testing the PP saturation concentration in the receptor medium.

Samples (300 μL) were withdrawn via syringe from the center of the receptor compartment at the following time intervals: 0.25, 0.5, 1, 2, 3, 4, 5 and 6 hours. The removed sample volume was immediately replaced with the same volume of fresh receptor medium (PBS; pH 7.4), taking great care to avoid trapping air under the dermis. The cumulative amount of drug (μg) permeating unit surface area (cm ² ) of mucosa was corrected for removed sample and plotted against time (h). This diffusion experiment was performed 27 times on fresh buccal mucosa and 22 times on frozen buccal mucosa.

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

(Example 8 Penetration of quinine across the sublingual mucosal compartment)
The porcine oral mucosa is a suitable model for the human oral mucosa since the oral membranes of pigs and humans are similar in composition, structure and permeability measurements. Permeability across the porcine oral mucosa is not metabolically related and therefore it is not important that the tissue is viable.

To prepare porcine membranes, the porcine oral floor and ventral (lower) tongue mucosa were excised by blunt dissection using a scalpel. The excised mucosa was cut into approximately 1 cm squares and frozen on aluminum foil at -20°C until use (<2 weeks). For the unfrozen ventral surface of the pig tongue, this mucosa was used in permeation studies within 3 hours of removal.

The permeability of the membrane to quinine was determined using an all-glass Franz diffusion cell with a nominal receptor volume of 3.6 mL and a diffusion area of 0.2 cm ² . The flange of the cell was coated with high performance vacuum grease and the membrane was attached between the receptor and donor compartments, with the mucosal surface on top. A clamp was used to hold the membrane in place and the receptor compartment was then filled with degassed phosphate buffered saline (PBS) pH 7.4. A micromagnetic stirrer was added to the receptor compartment and the complete cell was placed in a 37°C water bath. The membrane was equilibrated for 20 minutes with PBS applied to the donor compartment and then aspirated with a pipette. Aliquots of 5 μL of quinine solution or 100 μL of saturated solution of Q/2-HP-β-CD complex in various vehicles were applied to each donor compartment. In tests to determine the effect of saliva on the permeation of quinine across the ventral surface of the tongue, 100 μL of sterile saliva was added to the donor compartment followed by 5 μL of quinine solution.

At 2, 4, 6, 8, 10 and 12 hours, the receptor phase was withdrawn from the sampling port and a 1 mL aliquot of sample was transferred to an HPLC autosampler vial and replaced with fresh PBS, which was then stored at 37°C. Apart from tests involving Q/2-HP-β-CD saturated solutions (an infinite dose is applied at the beginning of the experiment), 5 μL of each quinine solution was applied again to the donor phase for up to 10 hours. . The purpose of this was to represent a hypothetical use-time finite dosing regimen based on a 2 hour interval between doses. At least three replicates were performed for each test.

Additional details can be found in C. Ong, “Permeation of quinine across sublingual mucosa, in vitro,” International Journal of Pharmaceutics 366 (2009) 58-64. can.

(Example 9 Ex vivo initial test - Form of API)
In this example, the permeation of solubilized epinephrine base versus essentially soluble epinephrine bitartrate was tested in situ and no differences were observed. Epinephrine bitartrate was selected for further development based on ease of processing. Flux is induced as a gradient in permeation as a function of time. Steady state flux was extrapolated from the plateau of the flux versus time curve multiplied by the volume of the receiver medium. The graph in Figure 2A shows the average permeation versus time with 8.00 mg/mL epinephrine bitartrate and 4.4 mg/mL solubilized epinephrine base. The graph in Figure 2B shows the average flux versus time with 8.00 mg/mL epinephrine bitartrate and 4.4 mg/mL solubilized epinephrine base.

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

(Example 11 Effect of pH)
In this example, the permeation of epinephrine bitartrate as a function of solution pH was tested. In this example, acidic conditions were examined for their ability to promote stability. The results showed that pH5 was slightly preferred compared to pH3. The specific pH of epinephrine bitartrate in solution in the concentration range investigated is 4.5-5. No pH adjustment with buffers was necessary.

Figure 4 shows the permeation of epinephrine bitartrate as a function of solution pH. Acidic conditions were investigated to promote stability. The results compared epinephrine bitartrate pH 3 buffer and epinephrine bitartrate pH 5 buffer and found that the epinephrine bitartrate pH 5 buffer was slightly preferred.

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

Enhancers were selected and designed to have functionality that affects various barriers in the mucosa. All tested enhancers improved permeation over time, but clove oil and labrasol in particular showed significant and unexpectedly high permeation enhancement.

(Example 13 Effect of enhancer on epinephrine release)
The release profile of epinephrine was tested to determine the effect of enhancers (Labrasol and clove oil) on epinephrine release. Figure 6A shows epinephrine release from different polymer platforms. Figure 6B shows the effect of enhancers on epinephrine release. These results showed that the amount permeated leveled off at approximately between 3250 and 4250 μg after about 40 minutes. The enhancers tested were shown not to limit the release of epinephrine from the matrix.

(Example 14 Acceleration stability)
Different loadings of stabilizer were tested.

(Example 15 Effect of enhancer)
A pharmacokinetic model in male Yucatan minipigs was tested. The graph in Figure 7 shows the results of the pharmacokinetic model in male Yucatan minipigs. This study compares 0.3 mg EpiPen, 0.12 mg epinephrine IV, and placebo.

The effect of no enhancer on the concentration profile of 0.3 mg EpiPen and 40 mg epinephrine films without enhancer is shown in Figure 8.

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

In addition, the effect of film size and the effect of clove oil (3%) are also shown in Figure 11. This study was performed comparing 0.30 mg EpiPen (n = 4), 40 mg epinephrine film (10-1-1) (n = 5) and 40 mg epinephrine film (11-1-1) (n = 5). . This concentration vs. time profile follows sublingual or intramuscular epinephrine administration to male minipigs.

Experiments were conducted to vary the ratio of epinephrine to enhancer. These studies were also concentration versus time profiles following sublingual or intramuscular epinephrine administration to male minipigs. By varying the ratio of epinephrine to clove oil (Enhancer L), the results shown in Figure 12 were obtained. This study was performed comparing 0.30 mg EpiPen (n = 4), 40 mg epinephrine film (12-1-1) (n = 5) and 20 mg epinephrine film (13-1-1) (n = 5). Ta.

(Example 16)
Variable doses were performed in a constant matrix with enhancer Labrasol (3%) and clove oil (3%) and are shown in Figures 13 and 14, respectively. The test in Figure 13 compared 0.30 mg EpiPen (n = 4), 40 mg epinephrine film (18-1-1) (n = 5) and 30 mg epinephrine film (20-1-1) (n = 5). went. The test in Figure 14 compared 0.30 mg EpiPen (n = 4), 40 mg epinephrine film (19-1-1) (n = 5) and 30 mg epinephrine film (21-1-1) (n = 5). went. These studies were also concentration versus time profiles following sublingual or intramuscular epinephrine administration to male minipigs.

(Example 17)
A pharmacokinetic model in male minipigs was tested to determine the effect of an enhancer (farnesol) on epinephrine concentrations over time. The graph in Figure 17 shows epinephrine plasma concentration (ng/mL) as a function of time (minutes) after sublingual or intramuscular administration of farnesol permeation enhancer. This study compared 0.3 mg EpiPen (n = 3), 30 mg epinephrine film 31-1-1 (n = 5), and 30 mg epinephrine film 32-1-1 (n = 5); each epinephrine film Formulated with enhancers. As shown in this figure, the 31-1-1 film exhibits enhanced stability of epinephrine concentration starting at about 30-40 minutes until approximately 130 minutes.

The graph in Figure 18 was obtained from the same study as Figure 17, but exclusively shows data points comparing 0.3 mg EpiPen to 30 mg Epinephrine Flume 31-1-1 (n=5).

The graph in Figure 19 was obtained from the same study as Figure 17, but exclusively shows data points comparing 0.3 mg EpiPen to 30 mg Epinephrine Film 32-1-1 (n=5).

(Example 18)
Referring to FIG. 20, this graph shows a pharmacokinetic model in male minipigs tested to determine the effect of an enhancer (farnesol) on epinephrine concentrations over time after sublingual or intramuscular administration. Epinephrine plasma concentration (ng/mL) is shown as a function of time (minutes) after sublingual or intramuscular administration of farnesol permeation enhancer in epinephrine film. This study compared data from three 0.3 mg Epipens against five 30 mg epinephrine films (32-1-1). This data shows an epinephrine film with enhanced stability of epinephrine concentration starting at about 20-30 minutes until approximately 130 minutes.

(Example 19)
In one embodiment, an epinephrine pharmaceutical composition film can be manufactured with the following formulation:

(Example 20)
An epinephrine pharmaceutical composition film was prepared with the following formulation:

(Example 21)
In another embodiment, a pharmaceutical film composition was made with the following formulation:

(Example 22)
In another embodiment, a pharmaceutical film composition was made with the following formulation:

(Example 23)
Referring to Figure 21, this graph shows the pharmacokinetics in male minipigs tested to determine the effect of enhancers (6% clove oil and 6% Labrasol) on epinephrine plasma concentrations over time after sublingual or intramuscular administration. The model (logarithmic scale) is shown. Epinephrine plasma concentration (ng/mL) is shown as a function of time (minutes) after sublingual or intramuscular administration of farnesol permeation enhancer in epinephrine film. This data shows an epinephrine film with enhanced stability of epinephrine concentration starting just after the 10 minute mark starting at about 30 minutes until approximately 100 minutes.

Referring to FIG. 22, this graph shows a pharmacokinetic model of epinephrine film formulation in male minipigs as mentioned in FIG. 21 compared to average data collected from 0.3 mg EpiPen (represented by diamond data points). As this data shows, the mean plasma concentration of 0.3 mg EpiPen peaked between 0.5 and 1 ng/mL. In contrast, the epinephrine film formulation peaked between 4 and 4.5 ng/mL.

(Example 24)
With respect to Figure 23, this graph shows that male A pharmacokinetic model in minipigs is shown. General peak concentrations were reached between 10 and 30 minutes.

(alprazolam data)
(Example 25)
24A, 24B, and 24B, these graphs compare alprazolam plasma concentrations over time (in hours) upon sublingual administration of oral alprazolam disintegrating tablets (ODT) and alprazolam pharmaceutical composition films. , represents data from a male minipig study.

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

Figure 24B shows average data from alprazolam pharmaceutical composition films (Group 2). More than 5ng/mL, more than 10ng/mL, more than 12ng/mL, more than 15ng/mL, more than 17ng/mL, less than 17ng/mL, less than 15ng/mL, less than 12ng/mL, less than 10ng/mL, less than 5ng/mL Contains peak concentrations between 5 and 17 ng/mL for >10 minutes, >20 minutes, >30 minutes, >45 minutes, >1 hour, >1.5 hours, >2 hours, >2.5 hours, >3 hours, 3.5 more than or including about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes , reached within 10 minutes to 4 hours.

Figure 24C shows average data from alprazolam pharmaceutical composition films from another group of male minipigs (Group 3). More than 5ng/mL, more than 10ng/mL, more than 12ng/mL, more than 15ng/mL, more than 17ng/mL, less than 17ng/mL, less than 15ng/mL, less than 12ng/mL, less than 10ng/mL, less than 5ng/mL Contains peak concentrations of 5 to 17 ng/mL for >10 minutes, >20 minutes, >30 minutes, >45 minutes, >1 hour, >1.5 hours, >2 hours, >2.5 hours, >3 hours, 3.5 hours. more than, and including about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes; It took 10 minutes to 4 hours to reach it.

(Example 26)
With respect to Figure 25A, this graph shows that after sublingual administration of oral alprazolam disintegrating tablets (ODT) (indicated by circular data points) and two groups (indicated by square and triangular data points) with alprazolam pharmaceutical composition film. Figure 2 shows data from a male minipig study comparing alprazolam plasma concentrations over time (in hours).

As this graph shows, the data from the alprazolam pharmaceutical composition films (both groups) are more than 10 minutes, more than 20 minutes, about 30 minutes, more than 30 minutes, less than 30 minutes, less than 20 minutes, less than 15 minutes, or Relatively high alprazolam plasma concentrations of up to approximately 15-25 mg/mL were obtained in treatment windows of approximately 30 minutes or less, including less than 10 minutes.

With respect to FIG. 25B, this graph shows individual data points from the study mentioned in FIG. 25A.

With respect to FIG. 25C, this graph shows the individual data points from the test mentioned in FIG. 25A from 0 to 1 hour.

With respect to Figure 26A, this graph shows the individual data points for alprazolam ODT mentioned in Figure 25C.

With respect to FIG. 26B, this graph shows individual data points for the alprazolam pharmaceutical film mentioned in FIG. 25C.

With respect to Figure 26C, this graph shows the individual data points for the alprazolam pharmaceutical film (Group 2) mentioned in Figure 25C.

The data from the previously mentioned graphs are also summarized in the table below.

(Example 27)
With respect to Figure 27A, this figure shows that after sublingual administration of oral alprazolam disintegrating tablets (ODT) (indicated by circular data points) and two groups of alprazolam pharmaceutical composition films (indicated by square and triangular data points). Figure 2 shows average data from a male minipig study comparing alprazolam plasma concentrations over time. Data show that 0.5mg alprazolam ODT is effective for >10 minutes, >20 minutes, >30 minutes, >45 minutes, >1 hour, >1.5 hours, >2 hours, >2.5 hours, >3 hours, and 3.5 hours. more than or including about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes; A peak concentration range of approximately 5-6 ng/mL was reached between 0 and 4 hours. The 0.5 mg alprazolam pharmaceutical composition film is more than 10 minutes, more than 20 minutes, more than 30 minutes, more than 45 minutes, more than 1 hour, more than 1.5 hours, more than 2 hours, more than 2.5 hours, more than 3 hours, more than 3.5 hours, or 0 to 4, including about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes Over time, peak concentrations of approximately 7-8 ng/mL and 6-7 ng/mL, respectively, were reached.

With respect to Figure 27B, this graph shows oral alprazolam disintegrating tablets (ODT) (indicated by circular data points) and two groups of alprazolam pharmaceutical composition films (indicated by square and triangular data points) between 0 and 2 hours. Figure 2 shows the average data of alprazolam plasma concentration over time after sublingual administration of (indicated). Unlike ODT, the therapeutic window of the alprazolam pharmaceutical composition film began at 10-15 minutes, whereas ODT began at approximately 17-20 minutes.

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

The data from the graphs mentioned earlier are summarized in the table below:

(Example 28)
In one study, the usefulness of diazepam buccal soluble film as an oral treatment in adult epileptic patients was tested. Diazepam buccal soluble film (DBSF) is an exemplary embodiment of the claimed subject matter. DBSF is a novel dosage form of diazepam being developed for the management of selected patients with refractory epilepsy who require intermittent use of diazepam to control episodes of increased seizure activity. DBSF has the potential to be the first orally administered treatment for this indication and may provide an alternative to rectal diazepam gel. DBSF is administered by placing the film against the inner surface of the cheek, where it adheres and dissolves, releasing the drug onto the buccal mucosa. This DBSF dosage form is expected to be accepted by a wide range of epilepsy patients. A phase 2 pharmacokinetic study in the Epilepsy Monitoring Unit (EMU) evaluated the safety, pharmacokinetics, and efficacy of DBSF.

A phase 2, multicenter, open-label, crossover study in adults was conducted between two treatment visits at least 3 weeks apart. The study enrolled male and female subjects aged 17 to 65 years with a clinical diagnosis of epilepsy (tonic-clonic or focal seizures with impaired consciousness) who required EMU evaluation. Subjects received DBSF administered at 12.5 mg during the interictal state (Treatment A) and during the ictal/periictal state (during the seizure or within 5 minutes of the seizure; Treatment B). Investigators' DBSF placement utility endpoints included: (1) whether placement was successful, (2) number of attempts required to successfully insert the film, and (3) whether the subject Included were whether the film was spat out or squirted and (4) whether the DBSF was swallowed.

The results were as follows: A total of 35 subjects received at least one dose of DBSF. Of these subjects, utility data was collected during Treatment A from 33 subjects and utility data was collected during Treatment B from 33 subjects. There were no DBSF insertion failures during both Treatment A and Treatment B. Two subjects (6.1%) during Treatment A and one subject (3.0%) during Treatment B were recorded as having swallowed DBSF during dosing. An additional 3 subjects (9.1%) swallowed the DBSF following a protocol that instructed all subjects to swallow the film if it did not completely dissolve 15 minutes after placement. During Procedure A, no patients spit or squirted DBSF after initial placement on the buccal mucosa, whereas during Procedure B, 3 subjects (9.1%) experienced DBSF after initial placement. The film was spit out or blown out. DBSF is generally safe and well tolerated. The most common adverse event possibly related to the drug was somnolence, reported by 2 of 35 subjects (5.7%). There were no serious adverse events related to the study drug, and no subjects withdrew due to adverse events.

This allowed the investigators to conclude that, surprisingly, in the EMU setting, DBSF was successfully administered in both interictal and intraictal/periictal states. did. This study data supports the safe and effective use of DBSF for the management of selected patients with refractory epilepsy who require intermittent use of diazepam to control episodes of increased seizure activity. This may also support possible utility in the domestic setting.

(Example 29)
Another study evaluated the pharmacokinetics of diazepam buccal soluble film in adult patients with epilepsy. Comparative bioavailability of periictal and interictal administration was evaluated.

As indicated above, a dibuccal soluble film (DBSF) is an exemplary embodiment of the claimed subject matter. This is a novel dosage form of diazepam being developed for the management of selected patients with refractory epilepsy who require intermittent use of diazepam to control episodes of increased seizure activity. In this study, the investigators sought to assess pharmacokinetic (PK) performance during or immediately after an attack. Subjects were studied while undergoing clinical epilepsy monitoring unit (EMU) evaluation and at separate PK-only visits, with visits approximately 3 weeks apart. This study investigated the maximum plasma concentrations of diazepam (C _max ), time to maximum concentration (T _max ), and and the partial area under the curve (partial AUC) at 2 or 4 hours were investigated.

In this study, adult men and women (N=35) aged 17 to 65 years with poorly controlled, unconsciously impaired tonic-clonic or focal seizures were treated in a clinical EMU setting under interictal conditions (Treatment A) and seizures. Patients were enrolled in a single-dose crossover where both were administered DBSF 12.5 mg under intermediate/periictal conditions (Treatment B). Plasma samples for analysis of diazepam were obtained before dosing and at intervals up to 2 or 4 hours after dosing. Administration was classified as interictal if no seizure activity was observed in the preceding 4 hours, and if DBSF occurred during clinically observed seizure activity or within 5 minutes after seizure activity subsided. If administered, the patient was classified as periictal/periictal. Subjects were monitored for adverse events (AEs) throughout the study.

The results were as follows: Valid pharmacokinetic (PK) profiles for analysis of both treatment conditions were available for 21 subjects. Most of these subjects were sampled for up to 4 hours, but 3 subjects were sampled for only up to 2 hours. Subjects were excluded from pre-dose diazepam concentrations if they failed to complete both treatments (N=4), if they missed critical PK time points (N=3) as judged by experts blinded to concentration data. was excluded from the analysis if it was >5% of C _max (N=2) or if DBSF was administered in a manner contrary to instructions (N=5). The table shows the values of C _max , AUC _(0-2h) and AUC _(0-4h) (geometric mean) and the ratio of the geometric means (Treatment B/Treatment A) with 90% CI. Surprisingly, the values of C _max , AUC _(0-2h) , and AUC _(0-4h) were similar in interictal and intraictal/periictal states, with median T _max There was no significant difference (Table). DBSF 12.5 mg was shown to be effective, safe, and well tolerated. The most common adverse event possibly related to the drug was somnolence, reported in 2 of 35 subjects (5.7%). There were no serious adverse events related to the study drug, and no subjects withdrew due to adverse events.

Remarkably, these results show that a single dose of 12.5 mg of DBSF administered to adults with epilepsy is comparable to that obtained under interictal conditions, both during/periictal conditions. was shown to provide exposure to diazepam.
(Table of pharmacokinetic parameters after 12.5 mg of DBSF in interictal and intraictal/periictal states)

All references cited herein are incorporated by reference in their entirety. Other implementations are within the scope of the following claims.
The present application provides the following aspects of the invention.
(Aspect 1)
polymer matrix;
a pharmaceutically active ingredient in the polymer matrix; and
adrenergic receptor interactor
A pharmaceutical composition comprising.
(Aspect 2)
The pharmaceutical composition according to embodiment 1, further comprising a permeation enhancer.
(Aspect 3)
2. The pharmaceutical composition of embodiment 1, wherein the adrenergic receptor interacting substance comprises a terpenoid, a terpene, or a sesquiterpene.
(Aspect 4)
3. The pharmaceutical composition according to embodiment 2, wherein the permeation enhancer comprises farnesol or labrasol.
(Aspect 5)
3. The pharmaceutical composition according to embodiment 2, wherein the permeation enhancer comprises linoleic acid.
(Aspect 6)
A pharmaceutical composition according to embodiment 1, which is a film further comprising a polymer matrix, wherein the pharmaceutically active ingredient is contained in the polymer matrix.
(Aspect 7)
2. The pharmaceutical composition according to embodiment 1, wherein the adrenergic receptor interacting substance comprises a phenylpropanoid.
(Aspect 8)
8. The pharmaceutical composition according to aspect 7, wherein the phenylpropanoid is eugenol or eugenol acetate.
(Aspect 9)
8. The pharmaceutical composition according to aspect 7, wherein the phenylpropanoid is cinnamic acid, cinnamic acid ester, cinnamaldehyde, or hydrocinnamic acid.
(Aspect 10)
8. The pharmaceutical composition according to aspect 7, wherein the phenylpropanoid is cavicol.
(Aspect 11)
8. The pharmaceutical composition according to aspect 7, wherein the phenylpropanoid is safrole.
(Aspect 12)
The pharmaceutical composition according to aspect 1, wherein the adrenergic receptor interacting substance is a plant extract.
(Aspect 13)
13. The pharmaceutical composition according to embodiment 12, wherein the plant extract further comprises an essential oil extract of a clove plant.
(Aspect 14)
13. The pharmaceutical composition according to embodiment 12, wherein the plant extract further comprises an essential oil extract of leaves of a clove plant.
(Aspect 15)
13. The pharmaceutical composition according to embodiment 12, wherein the plant extract further comprises an essential oil extract of flower buds of a clove plant.
(Aspect 16)
13. The pharmaceutical composition according to embodiment 12, wherein the plant extract further comprises an essential oil extract of clove plant stems.
(Aspect 17)
13. The pharmaceutical composition according to embodiment 12, wherein the plant extract is synthetic or biosynthetic.
(Aspect 18)
13. The pharmaceutical composition according to embodiment 12, wherein the plant extract further comprises 40-95% eugenol.
(Aspect 19)
The pharmaceutical composition according to aspect 1, wherein the pharmaceutically active ingredient is epinephrine, diazepam, or alprazolam.
(Aspect 20)
A pharmaceutical composition according to embodiment 1, wherein the polymer matrix comprises a polymer.
(Aspect 21)
21. The pharmaceutical composition of embodiment 20, wherein the polymer comprises a water-soluble polymer.
(Aspect 22)
21. The pharmaceutical composition of embodiment 20, wherein the polymer comprises a cellulosic polymer selected from the following group: hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose.
(Aspect 23)
21. The pharmaceutical composition according to embodiment 20, which is a chewable or gelatin-based dosage form, spray, gum, gel, cream, tablet, solution, or film.
(Aspect 24)
The polymer matrix comprises polyethylene oxide, a cellulosic polymer, polyethylene oxide, and polyvinylpyrrolidone, polyethylene oxide and a polysaccharide, polyethylene oxide, hydroxypropyl methylcellulose, and a polysaccharide, or polyethylene oxide, hydroxypropyl methylcellulose, a polysaccharide, and polyvinylpyrrolidone. Pharmaceutical composition according to embodiment 20.
(Aspect 25)
The polymer matrix is of the following group: pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, gum tragacanth, guar gum, gum acacia, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin. , ethylene oxide, propylene oxide copolymers, collagen, albumin, polyamino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof.
(Aspect 26)
The pharmaceutical composition according to embodiment 1, further comprising a stabilizer.
(Aspect 27)
A pharmaceutical composition according to embodiment 1, wherein the polymer matrix comprises a dendritic polymer or a hyperbranched polymer.
(Aspect 28)
combining the adrenergic receptor interacting substance with a pharmaceutically active ingredient; and
forming a pharmaceutical composition comprising the adrenergic receptor interacting substance and the pharmaceutically active ingredient;
A method of manufacturing a pharmaceutical composition comprising:
(Aspect 29)
A housing for holding an amount of a pharmaceutical composition, the pharmaceutical composition comprising:
polymer matrix;
a pharmaceutically active ingredient in the polymer matrix, and
adrenergic receptor interactor
said housing; and
an opening for dispensing a predetermined amount of the pharmaceutical composition;
A device comprising:
(Aspect 30)
polymer matrix;
a pharmaceutically active ingredient in the polymer matrix; and
Aporphine alkaloid interactor
A pharmaceutical composition comprising.
(Aspect 31)
polymer matrix;
a pharmaceutically active ingredient in the polymer matrix; and
Vasodilator interactors
A pharmaceutical composition comprising.
(Aspect 32)
polymer matrix;
a pharmaceutically active ingredient in the polymer matrix; and
An interacting agent that alters the transmucosal uptake of the pharmaceutically active ingredient by producing increased blood flow or allowing tissue flushing.
A pharmaceutical composition comprising.
(Aspect 33)
polymer matrix;
a pharmaceutically active ingredient in the polymer matrix; and
Interacting substances that have a positive or negative heat of solution and are used as adjuvants to alter transmucosal uptake
A pharmaceutical composition comprising.
(Aspect 34)
polymer matrix;
a pharmaceutically active ingredient in the polymer matrix; and
interacting substances
A pharmaceutical composition comprising:
Said pharmaceutical composition contained in a multilayer film having at least one side bordered by edges.
(Aspect 35)
A method of treating a medical condition, the method comprising:
polymer matrix;
a pharmaceutically active ingredient in the polymer matrix; and
adrenergic receptor interactor
said method comprising administering an effective amount of a pharmaceutical composition comprising:
(Aspect 36)
36. The method of embodiment 35, wherein the pharmaceutically active ingredient is epinephrine, diazepam, or alprazolam.
(Aspect 37)
36. The method of embodiment 35, wherein the medical condition includes symptoms of epilepsy.
(Aspect 38)
36. The method of embodiment 35, wherein the composition comprises diazepam administered during an interictal state.
(Aspect 39)
36. The method of embodiment 35, wherein the composition comprises diazepam administered during an ictal state.
(Aspect 40)
36. The method of embodiment 35, wherein the composition comprises diazepam administered during a periictal state.
(Aspect 41)
36. The method of embodiment 35, wherein the medical condition comprises anxiety, drug withdrawal, parasomnia, alcohol withdrawal, muscle spasms, or seizure disorders.
(Aspect 42)
36. The method of embodiment 35, wherein the medical condition comprises treatment as a sedative.
(Aspect 43)
36. The method of embodiment 35, wherein the medical condition comprises sedation for a medical procedure.

Claims (9)

polymer matrix;
a pharmaceutically active ingredient in the polymer matrix; and a permeation enhancer.
A pharmaceutical composition comprising:
the composition is contained in a multilayer film having at least one side whose edges completely overlap each other;
the pharmaceutically active ingredient is diazepam ;
The permeation enhancer is eugenol , eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamaldehyde , clove oil, an essential oil extract of clove plants, an essential oil extract of leaves of clove plants, an essential oil extract of flower buds of clove plants, or Clove plant stem essential oil extract , Labrasol containing caprylocaproyl polyoxyl-8 glyceride, β-caryophyllene, phenol, linoleic acid, oleic acid, PEG 200, benzyl alcohol, propylene glycol monocaprylate, polyglyceryl-3 olein Said pharmaceutical composition selected from the group consisting of acid ester, lauroylpolyoxyl-32 glyceride, Capriol 90, plurol oleique, TDM, and Gelucire 44/14 . 2. The pharmaceutical composition of claim 1, wherein the polymer matrix comprises a polymer. 3. The pharmaceutical composition of claim 2, wherein the polymer comprises a water-soluble polymer. 3. The pharmaceutical composition of claim 2, wherein the polymer comprises a cellulosic polymer selected from the following group: hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose. 3. A pharmaceutical composition according to claim 2, which is in a chewable or gelatin-based dosage form. 2. The polymer matrix comprises polyethylene oxide, a cellulosic polymer, polyethylene oxide and polyvinylpyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide, hydroxypropyl methylcellulose and polysaccharide, or polyethylene oxide, hydroxypropyl methylcellulose, polysaccharide and polyvinylpyrrolidone. Pharmaceutical compositions as described. The polymer matrix is of the following group: pullulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, gum tragacanth, guar gum, gum acacia, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin. 3. The pharmaceutical composition of claim 2, comprising at least one polymer selected from , ethylene oxide-propylene oxide copolymers, collagen, albumin, polyamino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof. The pharmaceutical composition according to claim 1, further comprising a stabilizer. 2. The pharmaceutical composition of claim 1, wherein the polymer matrix comprises a dendritic polymer or a hyperbranched polymer.

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