JP2020535176A - Pharmaceutical composition with enhanced permeation - Google Patents

Abstract

Pharmaceutical compositions with enhanced active ingredient permeation properties are described. [Selection diagram] FIG. 1A

Description

(Priority claim)
This application is a partial continuation of U.S. Patent Application No. 15 / 724,234 filed October 3, 2017, and U.S. Patent Application No. 62 / 331,993 filed May 5, 2016. In contrast, US Patent Law Section 119 (e) has priority over US Patent Application No. 62 / 735,822 filed on September 24, 2018, claiming priority under US Patent Law Section 119 (e). Part of U.S. Patent Application No. 15 / 587,376 filed on May 4, 2017, which claims rights Part of U.S. Patent Application No. 15 / 717,856 filed on September 27, 2017, which is a continuation application. It is a continuation application, each of which is incorporated herein by reference in its entirety.

(Technical field)
The present invention relates to pharmaceutical compositions.

(background)
The active ingredient, such as a drug or drug, is delivered to the patient in a planned manner. Delivery of a percutaneous or transmucosal drug or drug using film requires the drug or drug to permeate or otherwise traverse the biological membrane in an effective and efficient manner. I have something to do.

(Overview)
In general, a pharmaceutical composition can contain a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and an adrenergic receptor interacting substance. In certain embodiments, the pharmaceutical composition may further comprise a permeation enhancer. The adrenergic receptor interacting substance can be an adrenergic receptor blocker. The permeation enhancer can also be flavonoids or used in combination with flavonoids.

In certain embodiments, the adrenergic receptor interacting material can be a terpenoid, terpene or C3-C22 alcohol or acid. The adrenergic receptor interacting substance can be a sesquiterpene. In certain embodiments, the adrenergic receptor interacting material can include farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, or docosapentaenoic acid, or a combination thereof.

In certain embodiments, the pharmaceutical composition can comprise a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and an aporphin alkaloid interacting substance.

In another embodiment, the pharmaceutical composition can comprise a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and a vasodilator interacting substance.

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

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

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

In certain embodiments, the permeation enhancer can include phenylpropanoids.

In another embodiment, the phenylpropanoid can be eugenol.

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

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

In certain embodiments, the alcohol can be a benzyl alcohol.

In some cases, the flavonoids, plant extracts, phenylpropanoids, eugenols, or fungal extracts can be used as solubilizers.

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

In another embodiment, the phenylpropanoid can be hydrocinnamic acid. In certain embodiments, the phenylpropanoid can be chavicol. In another embodiment, the phenylpropanoid can be safrole.

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

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 active ingredient of the present invention can be diazepam.

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

In certain embodiments, the polymer matrix can include polymers. In certain 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 hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose and / or sodium carboxymethyl cellulose.

In certain embodiments, the polymer can include hydroxypropyl methylcellulose.

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

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

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

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

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: purulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic rubber, 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, polyphosphazene, polysaccharides, chitin, chitosan, and derivatives thereof.

In certain embodiments, the pharmaceutical composition may further comprise a stabilizer. Stabilizers form a chelate complex, an antioxidant that can prevent unwanted oxidation of a substance, or block metal ions that can inactivate trace amounts of metal ions that would otherwise act as catalysts. Agents, emulsifiers and radicals that can stabilize emulsions, UV stabilizers that can protect substances from the harmful effects of UV rays, chemicals that absorb UV rays and prevent them from entering the composition. UV absorbers, scavengers capable of dissipating radiated energy as heat without breaking chemical bonds, or scavengers capable of removing free radicals formed by ultraviolet light can be included.

In yet another embodiment, the pharmaceutical composition comprises a suitable non-toxic nonionic alkyl glycoside having a hydrophobic alkyl group linked by binding to a hydrophilic saccharide: (a) Aggregation inhibitor. (B) Charge modifier; (c) pH adjuster; (d) Degrading enzyme inhibitor; (e) Mucilalytic or mucilage remover; (f) Ciliostatic agent; (g) The following: (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) nitrogen monoxide donating compounds (Vi) Long-chain amphoteric molecule; (vii) Low molecular weight hydrophobic permeation enhancer; (viii) Sodium or salicylic acid derivative; (ix) Glycoester of acetacetic acid; (x) Cyclodextrin or β-cyclodextrin derivative; (xi) Medium chain fatty acids; (xii) chelating agents; (xiii) amino acids or salts thereof; (xiv) N-acetyl amino acids or salts thereof; (xv) enzymes degradable to selected membrane components; ( ix) Inhibitors of fatty acid synthesis; (x) Inhibitors of cholesterol synthesis; and membrane permeation enhancers selected from any combination of the membrane permeation enhancers according to (xi) (i)-(x); ( h) Regulators of epithelial junction physiology; (i) Vascular dilators; (j) Selective transport promoters; and (k) Stabilized delivery vehicles, carriers, mucosal adherents, supports, or complex-forming species The stabilized delivery vehicle, wherein, together with which the compound is effectively compounded, associated, contained, encapsulated or bound to provide stabilization of the compound for enhanced mucosal delivery. , Carriers, Mucoadhesive Substances, Supports, or Complexes-Formulations of this compound having in combination with a mucosal delivery promoter selected from the forming species, wherein the transmucosal delivery promoters are included. It provides an increased bioavailability of the compound in plasma.

In general, a method for producing a pharmaceutical composition comprises blending an adrenergic receptor interacting substance with a pharmaceutically active ingredient and forming a pharmaceutical composition containing the adrenergic receptor interacting substance 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.

In general, the pharmaceutical composition can be dispensed from the device. The device can dispense the pharmaceutical composition in a predetermined dose as a chewable or gelatin-based dosage form, spray, gum, gel, cream, tablet, liquid or film. The device comprises a polymer matrix; a pharmaceutically active ingredient in the polymer matrix; and a housing that holds an amount of the adrenergic receptor interacting substance, and an opening that distributes a predetermined amount of the pharmaceutical composition. Can be provided. The device can also dispense pharmaceutical compositions containing permeation enhancers containing phenylpropanoids and / or plant extracts.

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

In certain embodiments, the pharmaceutical composition is a polymer matrix; a pharmaceutically active ingredient in the polymer matrix; and transmucosal uptake of the pharmaceutically active ingredient by causing increased blood flow or allowing tissue flushing. Can include interacting substances that alter.

In certain embodiments, the pharmaceutical composition has a polymer matrix; a pharmaceutically active ingredient in the polymer matrix; and a positive or negative heat of solution and is used as an adjunct to alter (increase or decrease) transmucosal uptake. Can include interacting substances that are

In another embodiment, the pharmaceutical composition comprises a polymer matrix, a pharmaceutically active ingredient in the polymer matrix, and an interacting substance, the composition having at least one surface with edges that are bordered together. It is contained in the multilayer film.

In general, 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 interacting substance. The pharmaceutically active ingredient may be epinephrine, diazepam, or alprazolam. Medical conditions can include symptoms of epilepsy such as seizures. In certain embodiments, the method comprises administering the pharmaceutical composition comprising diazepam during a seizure state. In certain embodiments, the method comprises administering the pharmaceutical composition comprising diazepam during the peri-seizure state. In certain embodiments, the method comprises administering the pharmaceutical composition comprising diazepam during an intermittent seizure state. This medical condition can also include anxiety, drug withdrawal, parasomnia, alcohol withdrawal, muscle cramps, or paroxysmal illness. This medical condition can include treatment as a sedative. The medical condition can also include sedation for medical treatment.

Other aspects, embodiments, and features will become apparent from the following description, drawings, and claims.

(A brief description of the 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, stir bar 106, and heater / circulator 107. With respect to FIG. 1B, the pharmaceutical composition is film 100 containing a polymer matrix 200, and the pharmaceutically active ingredient 300 is contained in this polymer matrix. This film can include a transmission enhancer 400. For FIGS. 2A and 2B, the graph shows the permeation of the active substance from the composition. With respect to FIG. 2A, this graph shows the average amount of permeated active material versus time with 8.00 mg / mL epinephrine hydrogen tartrate and 4.4 mg / mL solubilized epinephrine base. For FIG. 2B, this graph shows the average flux vs. time with 8.00 mg / mL hydrogen tartrate and 4.4 mg / mL solubilized epinephrine base. With respect to FIG. 3, this graph shows the exvivo permeation of epinephrine hydrogen tartrate as a function of concentration. With respect to FIG. 4, this graph shows the permeation of epinephrine hydrogen tartrate as a function of the pH of the solution. With respect to FIG. 5, this graph shows the effect of the enhancer on the permeation of epinephrine, shown as the amount permeated, as a function of time. For FIGS. 6A and 6B, these graphs show the release of epinephrine on the polymer platform (6A) and the effect of the enhancer on that release (6B), shown as permeation (μg) vs. time. With respect to FIG. 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. With respect to FIG. 8, this graph shows the effect of the absence of enhancers on the concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen. With respect to FIG. 9, this graph shows the effect of enhancer A (labrasol) on the concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen. With respect to FIG. 10, this graph shows the effect of enhancer L (clove oil) on the concentration profiles of two 40 mg epinephrine films (10-1-1) and (11-1-1) vs. 0.3 mg epipen. With respect to FIG. 11, this graph shows the effect of enhancer L (clove oil) and film dimensions (10-1-1 thin and large film and 11-1-1 thick and small film) on the concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen. Shown. With respect to FIG. 12, this graph shows the concentration profile for variable doses of epinephrine film in a constant matrix for enhancer L (clove oil) for 0.3 mg epipen. With respect to FIG. 13, this graph shows the concentration profile for variable doses of epinephrine film in a constant matrix for enhancer L (clove oil) relative to 0.3 mg epipen. With respect to FIG. 14, this graph shows the concentration profile for variable doses of epinephrine film in a constant matrix for enhancer A (labrasol) for 0.3 mg epipen. With respect to FIG. 15, this graph shows the effect of the enhancer on the permeation of diazepam, shown as the amount permeated, as a function of time. With respect to FIG. 16, this graph shows the average flux as a function of time (diazepam + enhancer). With respect to FIG. 17, this graph shows the effect of farnesol and farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen. With respect to FIG. 18, this graph shows the effect of farnesol on the plasma concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen. With respect 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 vs. 0.3 mg epipen. With respect to FIG. 20, this graph shows the effect of farnesol and farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen. With respect to FIG. 21, this graph shows the effect of enhancer A (labrasol) in combination with enhancer L (clove oil) on the concentration profile of 40 mg epinephrine film (also shown in FIG. 22) in logarithmic representation. With respect to FIG. 22, this graph shows the effect of enhancer A (labrasol) in combination with enhancer L (clove oil) on the concentration profile of the 40 mg epinephrine film compared to the mean data collected from 0.3 mg epipen. With respect to FIG. 23, this graph shows the effect of enhancer A (labrasol) in combination with enhancer L (clove oil) on the concentration profile of the 40 mg epinephrine film shown for individual animal subjects. With respect to FIG. 24A, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of alprazolam oral disintegrating tablets (ODT). With respect to FIG. 24B, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of the alprazolam pharmaceutical composition film. With respect to FIG. 24C, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of the alprazolam pharmaceutical composition film. With respect to FIG. 25A, this graph shows the average alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT and alprazolam pharmaceutical composition film. With respect to FIG. 25B, this graph shows alprazolam plasma concentration as a function of time after sublingual administration. For FIG. 25C, this graph shows alprazolam plasma concentration as a function of time after sublingual administration. With respect to FIG. 26A, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT. With respect to FIG. 26B, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of the alprazolam pharmaceutical composition film. With respect to FIG. 26C, this graph shows alprazolam plasma concentration as a function of time after sublingual administration of the alprazolam pharmaceutical composition film. With respect to FIG. 27A, this graph shows the average alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT and pharmaceutical composition film. With respect to FIG. 27B, this graph shows the average alprazolam plasma concentration as a function of time after sublingual administration of alprazolam ODT and pharmaceutical composition film. With respect to FIG. 27C, this graph shows alprazolam plasma concentration 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 angioplasted and permeable and do not pass through the digestive system, thereby avoiding first-pass metabolism, resulting in increased bioavailability and action. Due to the fact that it provides a rapid onset of, the mucosal surface is a convenient route for drug delivery to the body. In particular, the buccal and sublingual tissues are highly permeable areas of the oral mucosa, allowing the drug to spread through the oral mucosa to have direct access to systemic circulation. , Provides an advantageous site for drug delivery. This also results in increased convenience and thus increased patient compliance. For certain drugs or pharmaceutically active ingredients, permeation enhancers can help overcome mucosal barriers and improve permeability. Permeation enhancers reversibly adjust the permeability of the barrier layer in favor of drug absorption. Permeation enhancers facilitate the transport of molecules through the epithelium. Absorption profiles and their rates can be controlled and adjusted, but not limited to, by various parameters such as film size, drug loading, enhancer type / loading, polymer matrix release rate and mucosal residence time.

The pharmaceutical composition can be designed to deliver the pharmaceutically active ingredient in a planned and tailored manner. However, the solubility and permeability of the pharmaceutically active ingredient in vivo, especially in the mouth of the subject, can vary considerably. Certain classes of permeation enhancers can improve the in vivo uptake and bioavailability of pharmaceutically active ingredients. In particular, when delivered to the mouth via a film, the permeation enhancer can improve the permeability of the pharmaceutically active ingredient that enters the bloodstream through the mucosa of interest. 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%, Only 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 can be improved.

In certain embodiments, the pharmaceutical composition comprises a suitable non-toxic nonionic alkyl glycoside having a hydrophobic alkyl group linked by binding to a hydrophilic saccharide: (a) aggregation inhibitor; b) Charge modifiers; (c) pH adjusters; (d) degrading enzyme inhibitors; (e) mucolytic agents or mucosal removers; (f) hair dyskinesias; (g) and below: (i) interfaces Activators; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamines; (v) NO donor compounds; (vi) long chain parents Sex molecules; (vii) low molecular weight hydrophobic permeation enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerol esters of acetacetic acid; (x) cyclodextrin or β-cyclodextrin derivatives; (xi) medium chain fatty acids; (xi) xii) chelating agent; (xiii) amino acid or salt thereof; (xiv) N-acetyl amino acid or salt thereof; (xv) enzyme degradable to selected membrane components; (ix) inhibitor of fatty acid synthesis; (x) Inhibitor of cholesterol synthesis; and (xi) Membrane permeation enhancer selected from any combination of membrane permeation enhancers according to (i) to (x); (h) Adjustment of epithelial junction physiological function Agents; (i) Vascular dilators; (j) Selective transport promoters; and (k) Stabilized delivery vehicles, carriers, mucoadhesives, supports, or complex-forming species, along with The stabilized delivery vehicle, carrier, mucoadhesive substance, wherein the compound is effectively compounded, associated, contained, encapsulated or combined to provide stabilization of the compound for enhanced mucosal delivery. , Supports, or complex-formations of this compound in combination with a mucosal delivery promoter selected from the forming species, wherein the formulation of the compound comprising a transmucosal delivery promoter is the organism of the compound in the plasma of interest. Provides increased scholarly availability. Penetration enhancers are described in J. Nicolazzo et al., J. of Controlled Disease, 105 (2005) 1-15, which are 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 intestine can be avoided. The first pass effect can be a major reason for poor bioavailability of some compounds when administered orally. In addition, the mucosa covering the oral cavity is readily accessible, which ensures that the dosage form is applied where it is needed and can be easily removed in an emergency. However, like the skin, the buccal mucosa acts as a barrier to the absorption of foreign bodies, which can block the permeation of compounds beyond this tissue. As a result, the determination of safe and effective osmotic enhancers has become a major goal in the quest for improved oral mucosal drug delivery.

A chemical penetration enhancer is a substance that controls the permeation rate of a drug co-administered through a biological membrane. Large studies have focused on gaining a better understanding of how osmotic enhancers alter intestinal and transdermal permeability, but are involved in buccal and sublingual osmotic enhancement. Little is known about the introduction.

The buccal mucosa outlines the inner lining of the cheek, as well as the area between the gums and the upper and lower lips, which has an average surface area of 100 cm ² . The surface of the buccal mucosa consists of stratified squamous epithelium separated from the inferior connective tissue (lamina propria and submucosa) by a wavy basement membrane (a continuous layer of extracellular material approximately 1-2 μm thick). This stratified squamous epithelium consists of a differentiated layer of cells that changes in size, shape, and inclusions as it moves from the basal region to the superficial region where cells shed. There are approximately 40-50 cell layers, resulting in a buccal mucosa with a thickness of 500-600 μm.

Structurally, the sublingual mucosa is comparable to the buccal mucosa, but the thickness of this epithelium is 100-200 μm. This membrane is also not keratinized and is relatively thin, which has been shown to be more permeable than the buccal mucosa. Blood flow to the sublingual mucosa is slower than that of the buccal mucosa, in 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 tissues. The absence of organized lipid lamellas 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, increased thickness and tight junctions. The lack results in the buccal mucosa becoming 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 permeable barrier of the non-keratinized oral mucosa beyond the surface epithelium is also attributed to the content extruded from the membrane-coated granules into the epithelial cell space.

Intercellular lipids in the non-keratinized areas of the oral cavity are more polar than epidermal, palate, and gingival lipids, and differences in the chemical properties of these lipids are observed between these tissues. It contributes to the difference in permeability. As a result, this is not only due to the greater degree of intercellular lipid filling in the stratum corneum of the keratinized epithelium, which creates a more effective barrier, but also due to the chemistry of the lipids present within that barrier. It is clear that there is.

The presence of hydrophilic and lipophilic regions within the oral mucosa tells researchers the presence of two drug transport pathways through the buccal mucosa-paracells (intercellular) and transcells (beyond cells). I made you assume.

Since drug delivery through the buccal mucosa is limited by the nature of the barriers in the epithelium and areas available for absorption, various augmentation strategies are available to deliver therapeutically appropriate amounts of drug to the systemic circulation. is necessary. Various methods can be utilized to overcome the barrier properties of the buccal mucosa, including the use of chemical osmotic enhancers, prodrugs, and physical methods.

A chemical penetration enhancer, or absorption promoter, is a substance added to a pharmaceutical formulation to increase the rate of membrane permeation or absorption of co-administered drugs without causing membrane damage and / or toxicity. is there. There are many studies investigating the effects of chemical osmotic enhancers on the delivery of compounds across the skin, nasal mucosa, and intestines. In recent years, more attention has been paid to the action of these substances on the permeability of the buccal mucosa. Permeability beyond the buccal mucosa is considered to be a passive diffusion process, so steady-state flux (Jss) should increase with increasing donor chamber concentration (CD) according to Fick's first diffusion law.

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

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

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

Oral transmucosal drug delivery (OTDD) is the administration of a pharmaceutically active substance through the oral mucosa to achieve systemic effects. Permeation pathways and predictive models of OTDD are described, for example, in M. Sattar's article "Oral transmucosal drug delivery-Current status and future prospects", Int'l. Journal of It is described in Pharmaceutics, 47 (2014) 498-506, and this document is incorporated herein by reference. OTDD continues to draw the attention of scientists in academia and industry. Despite the limited characterization of intraoral permeation pathways compared to skin and nasal delivery pathways, recent advances in researchers' understanding of the extent to which ionized molecules permeate the buccal epithelium, as well as studying the oral cavity. The emergence of new analytical techniques for, as well as the ongoing development of incilico models that predict buccal and sublingual permeation; the outlook is bright.

In order to deliver a broader class of drugs across the buccal mucosa, reversible methods of reducing the barrier capacity of this tissue should be utilized. This requirement encourages the study of osmotic enhancers that safely alter buccal mucosal permeability constraints. Buccal penetration is improved by the use of various classes of transmucosal and percutaneous permeation enhancers such as bile salts, detergents, fatty acids and their derivatives, chelating agents, cyclodextrin and chitosan. It has been shown to get. Of these chemicals used to enhance drug permeation, bile salts are the most common.

An in vitro study on the enhancing effect of bile salts on buccal permeation is described in Sevda Senel's article, Drug permeation enhancement via buccal route: possibilities and limitations, Journal of Considered in Controlled Release 72 (2001) 133-144, this document is incorporated herein by reference. The article also includes dihydroxybile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC) and tri-hydroxybile salts, sodium glycocholate (GC) and sodium taurocholate (TC). The latest study on the permeable effects of the buccal epithelium at a concentration of 100 mM is also considered, including changes in permeable effects associated with histological effects. Fluorescein isothiocyanate (FITC) and morphine sulfate were used as model compounds, respectively.

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

The permeation enhancer can be a plant extract. The plant extract can be an essential oil extracted by distillation of the plant material or a composition containing the essential oil. In certain situations, plant extracts can include synthetic analogs of compounds extracted from plant materials (ie, compounds produced by organic synthesis). Plant extracts can include phenylpropanoids such as phenylalanine, eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamic aldehyde, hydrocinnamic acid, chavicol, or safrole, or a combination thereof. The plant extract can be an essential oil extract of a clove plant, eg, a leaf, stem, or flower bud of a clove plant. The clove plant is Syzygium aromaticum. This botanical extract may contain 20-95% eugenol, 40-95% eugenol and 60-95% eugenol, eg 80-95% eugenol. The extract can also contain 5% to 15% eugenol acetate. This extract can also contain caryophyllene. The extract can also contain up to 2.1% α-humulene. Other volatile compounds contained in lower concentrations in clove essential oil can be β-pinene, limonene, farnesol, benzaldehyde, 2-heptanone or ethyl hexanoate. Another permeation enhancer may be added to the composition to improve drug absorption. Suitable permeation enhancers are natural or synthetic bile acids such as sodium citrate; glycocholic acid or deoxycholic acid and salts thereof; fatty acids and derivatives such as sodium laurate, oleic acid, oleyl alcohol, monoolein, etc. Or palmitoyl carnitine, etc .; chelating agents such as EDTA disodium, sodium citrate and sodium lauryl sulfate, azone, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth- 9. Includes polysorbate, sterol, or glycerides such as caprilocaproyl polyoxyl glyceride, such as labrasol. Permeation enhancers can include derivatives of plant extracts and / or monolignol. The permeation enhancer can also be a fungal extract.

Some natural products of plant origin have been shown to have vasodilatory effects. There are several mechanisms or modes by 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 effect of eugenol has been reported in several animal studies. For example, Lahlou, S. et al., J. Cardiovasc. Pharmacol. 43: 250-57 (2004), Damiani, CEN et al., Vascular Pharmacol. 40, each incorporated herein by reference. : 59-66 (2003), Nishijima, H. et al., Japanese J. Pharmacol. 79: 327-334 (1998), and Hume WR, J. Dent Res. 62 (9): 1013-15 ( 1983). It has been suggested that calcium channel blockade is a major cause of vascular relaxation induced by plant essential oils or their main component, eugenol. See Interaminense L.R.L. et al., Fundamental & Clin. Pharmacol. 21: 497-506 (2007), 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 ingredients in formulations due to their certain functional effects and their biocompatibility properties. Fatty acids, both free lipids and some of the complex lipids, are essential components of major metabolic fuels (storage and transport energy), all membranes and gene regulators. For review articles, see the Rustan AC and Drevon, CA references incorporated herein by reference, "Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences" (Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences). Please refer to 2005). There are two families of essential fatty acids that are metabolized in the human body: ω-3 and ω-6 polyunsaturated fatty acids (PUFAs). If the first double bond is found between the third and fourth carbon atoms from the ω carbon, these are referred to as omega-3 fatty acids. If the first double bond is found between the 6th and 7th carbon atoms, they are referred to as omega-6 fatty acids. PUFAs are further metabolized in the body by the addition and desaturation of carbon atoms (removal of hydrogen). Linoleic acid, an omega-6 fatty acid, is metabolized to γ-linolenic acid, dihomo-γ-linolenic acid, arachidonic acid, adrenoic acid, tetracosapentaenoic acid, tetracosapentaenoic acid, and docosapentaenoic acid. The omega-3 fatty acids α-linolenic acid include octadecatetraenoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, tetracosapentaenoic acid, tetracosapentaenoic acid, and docosahexaenoic acid. It is metabolized to acid (DHA).

Fatty acids such as palmitic acid, oleic acid, linoleic acid, and eicosapentaenoic acid induce relaxation and hyperpolarization of porcine coronary smooth muscle cells through mechanisms involved in the activation of the Na ⁺ K ⁺ -APTase pump. It has been reported that fatty acids became more potent as cis-unsaturation increased. See the literature of 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, is vasoconstrictive or dilatable, depending on the dose, animal species, mode of arachidonic acid administration, and tone of 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., each incorporated herein by reference. See Appl. Physiol. 44: 397-495 (1978) and the literature of Wicks, TC et al., Circ. Res. 38: 167-71 (1976).

Many studies have reported the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on vascular reactivity after administration in oral ingestible form. Several studies have found that EPA-DHA or EPA alone suppressed the vasoconstrictive effect of norepinephrine or enhanced the vasoconstrictor response to acetylcholine in the forearm microcirculation. The literature of Chin, JPF et al., Hypertension 21: 22-8 (1993), and the literature of Tagawa, H. et al., J Cardiovasc Pharmacol 33: 633-40 (1999), each incorporated herein by reference. ). Another study found that both EPA and DHA tend to increase systemic arterial compliance and reduce pulse pressure and total vascular resistance. See Am J. Clin. Nutr. 76: 326-30 (2002), Nestel, P. et al., Incorporated herein by reference. On the other hand, studies have found that DHA, but not EPA, enhanced the vasodilatory mechanism and attenuated the contractile response in the forearm microcirculation of hyperlipidemic overweight men. See the reference of Mori, T.A. et al., Circulation 102: 1264-69 (2000), incorporated herein by reference. Another study found the vasodilatory effect of DHA on the rhythmic contraction 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.

Adrenaline receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenergic). Epinephrine (adrenaline) interacts with both α- and β-adrenoreceptors, causing vasoconstriction and vasodilation, respectively. Alpha receptors are less sensitive to epinephrine, but peripheral α1 receptors are more abundant than β-adrenoceptors, so when activated, they negate β-adrenoreceptor-mediated vasodilation. To. As a result, high levels of circulating epinephrine cause vasoconstriction. At relatively low levels of circulating epinephrine, β-adrenoreceptor stimulation predominates, resulting in vasodilation followed by a decrease in peripheral vascular resistance. Alpha-1 adrenergic receptors are known for smooth muscle contraction, mydriasis, vasoconstriction in the skin, mucous membranes and abdominal organs, and sphincter muscle contraction in the gastrointestinal (GI) tract and bladder. The α1-adrenergic receptor is a member 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 and alters intracellular calcium content. For a review, see the article by Smith RS et al., Journal of Neurophysiology 102 (2): 1103-14 (2009), which is incorporated herein by reference. Many cells have these receptors.

The α1-adrenergic receptor can be the major receptor for fatty acids. For example, saw palmetto extract (SPE), which is widely used in the treatment of benign prostatic hyperplasia (BPH), is α1-adrenalinergic, muscarinergic, and 1,4-dihydropyridine (1,4-DHP) -based calcium channel antagonist. It has been reported to bind to sex receptors. The references of 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. See: 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 non-competitively to α1-adrenergic, muscarinic, and 1,4-DHP calcium channel antagonistic receptors.

In certain embodiments, the permeation enhancer can be an adrenergic receptor interacting agent. An adrenergic receptor interacting substance refers to a compound or substance that modifies and / or otherwise alters the action of an adrenergic receptor. For example, adrenergic receptor interacting substances can prevent receptor stimulation by increasing or decreasing their binding capacity. Such interacting materials can be provided in either short-acting or long-acting forms. Some short-acting interacting substances can act rapidly, but their action only lasts for several hours. Some long-acting interacting substances take a long time to act, but their action can last longer. The interacting material shall 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 condition to be treated. Can be done. The adrenergic receptor interacting substance can be an adrenergic receptor blocker. Adrenergic receptor interactants can be terpenes (eg, volatile unsaturated hydrocarbons found in plant essential oils derived from isoprene units), or C3-C22 alcohols or acids, preferably C7-C18 alcohols or acids. There can be. In certain embodiments, the adrenergic receptor interacting substance can include farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, and / or docosapentaenoic acid. The acid can be a carboxylic acid, a phosphoric acid, a sulfuric acid, a hydroxamic acid, or a derivative thereof. This derivative can be an ester or an amide. For example, the adrenergic receptor interacting substance can be a fatty acid or an aliphatic alcohol.

The C3-C22 alcohol or acid is a linear C3-C22 hydrocarbon, eg, a C3-C22 hydrocarbon comprising 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 acid with a hydrogen chain; the hydrocarbon chain can optionally be C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, hydroxyl, halo, amino. , Nitro, cyano, C _3-5 cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C _1-4 alkylcarbonyloxy, C _1-4 alkyloxycarbonyl, Substituted with C _1-4 alkylcarbonyl, or formyl; and optionally -O-, -N (R ^a )-, -N (R ^a ) -C (O) -O-, -OC (O) -N (R ^a )-, -N (R ^a ) -C (O) -N (R ^b )-, or -OC (O) -O- is sandwiched between them. 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 good candidates for enhancing drug permeation. Unsaturated fatty acids showed higher enhancement than saturated fatty acids, and the enhancement increased with the number of double bonds. Incorporated herein by reference, A. Mittal et al., "Status of Fatty Acids as Skin Penetration Enhancers-A Review," Current Drug Delivery, 2009. , 6, pp. 274-279. The position of the double bond also affects the enhancement of fatty acid activity. Differences in the physicochemical properties of fatty acids due to differences in double bond positions are most likely to determine the efficacy of these compounds as skin penetration enhancers. The skin distribution increases as the position of the double bond shifts to the hydrophilic end. It has also been reported that fatty acids with double bonds at even positions act more rapidly on the structural perturbation of both the stratum corneum and the dermis than fatty acids with double bonds at odd positions. .. Intrachain cis-unsaturation tends to increase activity.

The adrenergic receptor interacting substance can be a terpene. The hypotensive activity of terpenes in essential oils has been reported. See the reference to Menezes IA et al., Z. Naturforsch. 65c: 652-66 (2010), which is incorporated herein by reference. In certain embodiments, the transmission enhancer can be a sesquiterpene. Sesquiterpenes are a class of terpenes consisting of three isoprene units and having 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 the associated sesquiterpenoids.

The adrenergic receptor interacting substance can be an unsaturated fatty acid, such as linoleic acid. In certain embodiments, the transmission enhancer can be farnesol. Farnesol is a 15-carbon organic compound, an acyclic sesquiterpene alcohol, which is a naturally dephosphorylated form of farnesyl pyrophosphate. Under standard conditions, this 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 tuberose. This is an intermediate step in the biosynthesis of cholesterol from mevalonic acid in vertebrates. It has a delicate floral scent or a weak citrus-lime scent and is used in perfumes and fragrances. Farnesol has been reported to selectively kill acute myeloid leukemia blasts and leukocyte cell lines in preference to primary hematopoietic cells. See Rioja A. et al., FEBS Lett 467 (2-3): 291-5 (2000), which is incorporated herein by reference. The vasoactive properties of farnesyl analog 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), and synthetic mimics of the carboxyl ends of the farnesylated protein inhibited vasoconstriction in the rat vascular ring.

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

In general, the interacting agent can also be a vasodilator or a therapeutic vasodilator. Vasodilators are drugs that open or dilate blood vessels. Vasodilators are usually used to treat hypertension, heart failure, and angina, but can also be used to treat other conditions, including, for example, glaucoma. Some vasodilators (arterial dilators) that act primarily on resistant blood vessels are used for hypertension, heart failure, and angina; however, reflex cardiac stimulation is present in some arteries. Make dilators unsuitable for angina. Venous dilators are very effective in angina and are sometimes used for heart failure, but not as a first-line therapy for hypertension. Vasodilators can be mixed (or balanced) vasodilators in that they dilate both arteries and veins, and are therefore widely applicable in hypertension, heart failure, and angina. Some vasodilators may, in some cases, enhance their therapeutic utility or provide some additional therapeutic benefit because of their mechanism of action. It also has an important effect of. For example, some calcium channel blockers not only dilate blood vessels, but also reduce the mechanical and electrical function of the heart, which can enhance their antihypertensive effects and cause arrhythmias. Additional therapeutic benefits such as blocking can be provided.

Vasodilators can be classified based on their site of action (arterial vs. vein) or by mechanism of action. Some drugs predominantly dilate resistant blood vessels (arterial dilators; eg hydralazine), while others predominantly affect venous volume vessels (venous dilators; eg nitroglycerin). Many vasodilators, such as phentolamine, have mixed arterial and venous dilatability (mixed dilators; eg, α-adrenergic receptor antagonists, angiotensin converting enzyme inhibitors).

However, it is more common to classify vasodilators based on their primary mechanism of action. The figure on the right represents a class of important mechanisms of vasodilators. Classes of these drugs, and others that cause vasodilation: α-adrenergic receptor antagonists (α-blockers); angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor antagonists (ARBs); β ₂ -Adrenergic receptor agonist (β ₂ -agonist); Calcium channel blocker (CCB); Central action type sympathetic blocker; Direct action type vasodilator; Endoserin receptor antagonist; ganglion blocker; Nitro dilator; Includes phosphodiesterase inhibitors; potassium channel opening agents; renin inhibitors.

In general, active or inactive ingredients or materials cause increased blood flow or tissue flushing, allowing changes or differences (increases or decreases) in transmucosal uptake of APIs, and / Alternatively, it can be a substance or compound that has positive or negative heat of solution and is used as an adjunct to alter (increase or decrease) transmucosal uptake.

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

For example, permeation enhancers can be used as pretreatment alone or in combination with at least one API to precondition the mucosa for further absorption of the API. This procedure can be followed by another procedure with a neat permeation enhancer, followed by the mucosal application of at least one of the APIs. This 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, this pretreatment is contained within a separate domain of a single film designed to dissolve and release into the mucosa prior to the release of a second domain with or without a permeation enhancer or API. May be good. The active ingredient can then be delivered from the second treatment alone or in combination with an additional permeation enhancer. Even if there is a third treatment or domain that delivers additional transmission enhancers and / or at least one API or prodrug, either at different ratios to each other or at different ratios compared to the total load of other treatments. Good. This makes it possible to obtain a custom pharmacokinetic profile. Thus, the product may differ in mucosal application order, composition, concentration, or total load leading to the desired absorption and / or absorption rate to achieve the intended pharmacokinetic profile and / or pharmacodynamic effects. It may have a single or multiple domains containing transparent enhancers and APIs that can be made.

The film format is such that there is no clear surface, or the film has at least one multilayer film with co-terminated edges (having or contacting a shared border or limit). It can be oriented so that it has a face.

The pharmaceutical composition can be a chewable or gelatin-based dosage form, spray, gum, gel, cream, tablet, solution or film. The composition can include textures, such as surface microneedles or microprojections. Recently, the use of micron-scale needles in increasing skin permeability has been shown to significantly increase transdermal delivery, including macromolecules, especially with respect to macromolecules. Most drug delivery studies emphasize solid microneedles, which have been shown to increase skin permeability to a wide range of molecules and nanoparticles in vitro. In vivo studies have revealed the delivery of oligonucleotides, the reduction of blood glucose levels by insulin, and the induction of immune responses from protein and DNA vaccines. For such studies, needle arrays have been used to puncture the skin to increase diffusion or iontophoresis transport, or as a drug carrier to release the drug from the microneedle surface coating into the skin. Hollow microneedles have also been developed and have been shown to microinject insulin into diabetic rats. To address the practical application of microneedle, the ratio of microneedle crushing strength to skin insertion force (ie, safety margin) was found to be optimal for needles with small tip radii and large wall thickness. A microneedle inserted into the skin of a human subject was reported as painless. Taken together, these results suggest that ultrafine needles are a promising technique for delivering therapeutic compounds to the skin for a wide range of potential applications. Using the tools of the microelectronics industry, microneedles are made in a wide range of sizes, shapes and materials. The microneedle can be, for example, a polymer microscopic needle that delivers the encapsulated drug in a minimally invasive manner, but other suitable materials can be used.

Applicants have found that ultrafine needles can be used to enhance the delivery of the drug through the oral mucosa, especially with the claimed composition. The microneedles create micron-sized pores in the oral mucosa, which can enhance the delivery of the drug beyond the mucosa. Solid, hollow, or soluble microneedles can be made of suitable materials, including, but not limited to, metals, polymers, glass and ceramics. Microfabrication processes can include photolithography, silicon etching, laser cutting, metal electroplating, metal electropolishing and molding. The microneedles can be solids that are used to pretreat the tissue and are removed prior to application of the film. The drug-loaded polymer film described in this application can be used as a matrix material for the microneedle itself. These films can have microneedles or microprojections made on their surface, which will dissolve after forming microchannels in the mucosa through which the drug 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 a preferred embodiment, the film can have a thickness and size such that it can be administered to the user, eg, placed in 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 be even relatively large, i.e. greater than about 1.0 mm, or relatively thin, i.e. less than about 0.0025 mm. The film can be a single layer, or the film can be a multi-layer, including a laminated film or a multi-cast film. Permeation enhancers and pharmaceutically active ingredients are combined in a single layer, each contained in a separate layer, or otherwise each contained in a separate region of the same dosage form. Can be In certain embodiments, the pharmaceutically active ingredient contained in the polymer matrix can be dispersed in the matrix. In certain embodiments, the permeation enhancers contained in the polymer matrix can be dispersed in the matrix.

Orally soluble films can be divided into three major classes: immediate solubility, moderate solubility and slow solubility. Orally soluble films can also include combinations of any of the above categories. The instantly soluble film can be dissolved in the mouth in about 1 to about 30 seconds, including greater than 1 second, greater than 5 seconds, greater than 10 seconds, greater than 20 seconds, and less than 30 seconds. Moderately soluble films can be dissolved in the mouth in about 1 to about 30 minutes, including greater than 1 minute, greater than 5 minutes, greater than 10 minutes, greater than 20 minutes or less than 30 minutes, slow soluble films. Can be dissolved in the mouth over 30 minutes. As a general trend, instantly soluble films can include (or consist of) low molecular weight hydrophilic polymers (eg, polymers with a molecular weight of about 1,000-9,000 daltons, or polymers with a molecular weight of up to 200,000 daltons). In contrast, slowly soluble films generally contain high molecular weight polymers (eg, having a molecular weight of millions). Moderately soluble films tend to fit between immediate and slowly soluble 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 mucosal adhesion. Moderately soluble films are also flexible, can be quickly moistened, and are typically non-irritating to the user. Such moderately soluble films can provide a sufficiently rapid, most preferably about 1 to about 20 minute dissolution rate, while once placed in the user's oral cavity, once placed. It provides an acceptable level of mucosal adhesion so that the film is not easily removed. This can ensure delivery of the pharmaceutically active ingredient to the user.

The pharmaceutical composition can contain one or more pharmaceutically active ingredients. This pharmaceutically active ingredient can be a single pharmaceutical ingredient or a combination of pharmaceutical ingredients. Pharmaceutically active ingredients are anti-inflammatory analgesics, steroidal anti-inflammatory drugs, antihistamines, local anesthetics, bactericides, disinfectants, vasoconstrictors, hemostats, chemotherapeutic agents, antibiotics, keratolytic agents, cautery. It can be a drug, an antiviral drug, an antirheumatic drug, an antihypertensive drug, a bronchodilator, an anticholinergic drug, an anti-anxiety drug, an antiemetic compound, a hormone, a peptide, a protein or a vaccine. The active ingredient of the present invention can be a compound, a pharmaceutically acceptable salt of a drug, a prodrug, a derivative, a drug complex or an analog of a drug. The term "prodrug" refers to a biologically inactive compound that can be metabolized in the body to produce a biologically active drug.

In some embodiments, the film may contain two or more pharmaceutically active ingredients. This medicinal active ingredient is an ACE inhibitor, a angina drug, an anti-arrhythmic drug, an anti-asthma drug, an anti-cholesterolemia drug, an analgesic, an anesthetic, an anticonvulant drug, an antipsychotic drug, a diabetic drug. , Anti-diarrhea preparations, anti-toxic drugs, anti-histamine drugs, anti-hypertensive drugs, anti-inflammatory drugs, anti-lipid drugs, anti-manic drugs, antipsychotic drugs, anti-stroke drugs, anti-thyroid preparations, amphetamine, anti-tumor Drugs, antiviral drugs, acne remedies, alkaloids, amino acid preparations, antitussives, anti-urinary tract stones, anti-viral drugs, anabolic preparations, systemic and non-systemic infections, anti- Neobiogenic agents, Parkinson's remedies, anti-rheumatic agents, appetite enhancers, 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 disorder treatment, fertility drugs, gastrointestinal drugs, homeopathic remedies, hormones, hypercalcemia and hypocalcemia control drugs, immunomodulators, immunity Inhibitors, migraine preparations, anti-sickness drugs, muscle relaxants, obesity control drugs, osteoporosis preparations, uterine contractile drugs, parasympathomimetics, parasympathomimetics, prostaglandins, psychotic drugs, respiratory organs Antipsychotics, sedatives, cessation aids, sympathomimetics, tremor treatment preparations, urinary tract drugs, vasodilators, relaxants, anti-inflammatory drugs, ion exchange resins, hypothermia, appetite suppressants, sputum Drugs, anti-anxiety drugs, anti-ulcer drugs, anti-inflammatory substances, coronary vasodilators, cerebral dilators, peripheral vasodilators, antipsychotics, stimulants, hypertension remedies, Vascular contractors, migraine drugs, antibiotics, tranquilizers, antipsychotics, anti-tumor drugs, anticoagulants, antithrombotic drugs, hypnotics, antiemetics, anti-psychotics, anticonvulants, neuromuscular agents , Hypoglycemic and depressant, thyroid and anti-thyroid preparations, diuretics, antispasmodics, uterine relaxants, anti-obesitants, erythropoiesis, anti-asthma, antitussives, mucolytics, DNA and genes It can be a modifier, a diagnostic agent, a contrast agent, a dye, or a tracer, or a combination thereof.

For example, the active ingredients of this drug are buprenorfin, naloxone, acetaminophen, lysole, clavazam, lizatriptan, propofol, methyl salicylate, monoglycol salicylate, aspirin, mephenamic acid, flufenamic acid, indomethacin, diclofenac, alcrofenac, diclofenac sodium, ibprofen , Ketoprofen, naproxen, planoprofen, phenoprofen, slindac, phenclofenac, cridanac, furrubiprofen, fentiazac, bufexamac, pyroxicum, phenylbutazone, oxyphenbutazone, clofezone, pentazocin, mepyrizol, thialamide hydrochloride , Hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluosinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumethasone, fluorometholone, dipropionate bechrometazone , Esomeprazole, lumateperone, naldemedin, doxylamine, pyridoxin, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate, isothipendyl hydrochloride, tryperenamine hydrochloride, procaine hydrochloride, dicaine hydrochloride , Diclofen, 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, dicronin, diclonin hydrochloride, timerosal, phenol, timol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone iodine, cetylpyridinium chloride, eugenol, trimethylammonium bromide, nafazoline nitrate, tetrahydrozoline hydrochloride, oxymethazoline hydrochloride, Phenilefurin hydrochloride, tramazoline hydrochloride, trombine, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, sodium carbazochrome sulfonate, rutin, hesperidin, sulfamine, sulfathiazole, sulfaziazine , Homo sulfamine, sulfisoxazole, sulfisomidin, sulfamethizole, nitrofrazone, penicillin, methicillin, oxacillin, cephalotin, cefalordin, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, Ramphenicol, canamycin, streptomycin, gentamycin, bacitracine, cycloserine, salicylic acid, podophilum resin, podolifox, cantalidine, chloroacetic acid, silver nitrate, protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors , Structural protein synthesis inhibitors, adhesion and adsorption inhibitors, and nucleoside analogs such as acyclovir, pencyclovir, baracyclovir, and gancyclovir, heparin, insulin, LHRH, TRH, interferon, oligonuclides, calcitonin, octreotide, omeprazone, fluoroxetine. , Etynyl estradiol, amiodipine, paroxetin, enalapril, lisinopril, leuprolide, prevastatin, robastatin, noruetindron, risperidone, olanzapine, albuterol, hydrochlorothiazide, pseudoephedrin, walpryazide Methylphenidet, levothyroxine, solpidem, levonorgestrel, glybrid, benazepril, medroxyprogesterone, clonazepam, ondansetron, rosartan, quinapril, nitroglycerine, midazolamversedo, cetilidine, doxazosin, glypidide, hepatitis B vaccine, salmerol Sumatriptan, triamsinolone acetonide, goseleline, bechrometazone, granisteron, desogestrel, alprazolam, estradiol, nicotine, interferon β1A, chromoline, hosinopril, digoxin, fluticazone, bisoprolol, calciumtril, captopril, butorupril, captopril Tryptan, crotrimazole, bisacodil, dextromethorphan, nitroglycerin, na It can be farerin, dinoproston, nicotine, bisacodyl, goserelin, or granisetron. In certain embodiments, the pharmaceutical active ingredient is a benzodiazepine, such as epinephrine, diazepam or lorazepam, or alprazolam.

(Examples of epinephrine, diazepam and alprazolam)
In one example, a composition containing epinephrine or a salt or ester thereof may have a biodelivery profile similar to the biodelivery profile of epinephrine administered by injection, eg, using epipen. Epinephrine can be present in doses of about 0.01 mg to about 100 mg / dose, eg, 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 doses. More than 0.1 mg, more than 5 mg, more than 20 mg, more than 30 mg, more than 40 mg, more than 50 mg, more than 60 mg, more than 70 mg, more than 80 mg, more than 90 mg, or less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg , Less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg or less than 5 mg, or any combination thereof. In another example, a composition containing diazepam can have a biodelivery profile that is similar to or better than the biodelivery profile of diazepam tablets or gels. Diazepam or a salt thereof is present in an amount of about 0.5 mg to about 100 mg / dose, for example, in a dose of 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg. Can be over 1 mg, over 5 mg, over 20 mg, over 30 mg, over 40 mg, over 50 mg, over 60 mg, over 70 mg, over 80 mg, over 90 mg, or less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, 60 mg Includes less than, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg, or any combination thereof.

In another example, the composition (eg, one containing alprazolam, diazepam or epinephrine) comprises a suitable non-toxic nonionic alkyl glycoside having a hydrophobic alkyl group linked by binding to a hydrophilic saccharide. , And below: (a) aggregation inhibitors; (b) charge modifiers; (c) pH regulators; (d) degrading enzyme inhibitors; (e) mucolytic agents or mucilage removers; (f) hair dyskinesia Agents; (g) or less: (i) surfactants; (ii) bile salts; (ii) phospholipid additives, mixed micelles, liposomes, or carriers; (iii) alcohols; (iv) enamin; (v) NO donor compounds; (vi) long-chain amphoteric molecules; (vii) hydrophobic permeation enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerol esters of acetacetic acid; (x) cyclodextrin or β-cyclodextrin derivatives (Xi) Medium chain fatty acids; (xii) chelating agents; (xiii) amino acids or salts thereof; (xiv) N-acetyl amino acids or salts thereof; (xv) enzymes degradable to selected membrane components; (ix) Inhibitor of fatty acid synthesis; (x) Inhibitor of cholesterol synthesis; and (xi) Membrane permeation enhancer selected from any combination of membrane permeation enhancers according to (i) to (x); (h) Regulators of epithelial junction physiological functions; (i) Vascular dilators; (j) Selective transport-promoters; or (k) Stabilized delivery vehicles, carriers, mucosal adherents, supports or complexes- The stabilizer, said stable, which is a form of the compound, together with which the compound is effectively compounded, associated, contained, encapsulated or combined to result in stabilization of the compound for enhanced mucosal delivery. Can be carried in combination with a mucosal delivery promoter selected from chemical delivery vehicles, carriers, mucoadhesives, supports or complexes-forming species, wherein the compound comprises a transmucosal delivery-promoter. The formulation provides increased bioavailability of the compound in the plasma of the subject. This formulation can contain approximately the same active pharmaceutical ingredient (API): enhancer ratio as in other examples of diazepam and alprazolam.

(Treatment or adjunctive treatment)
Status epilepticus (SE) is a seizure with seizures longer than 5 minutes or two or more seizures within 5 minutes that do not return to normal between seizures. Another previous definition used a time limit of 30 minutes. Benzodiazepines are some of the most effective drugs in the treatment of acute seizures and status epilepticus. The most commonly used benzodiazepines in the treatment of status epilepticus include diazepam (Valium), lorazepam (Ativan), or midazolam (Versed). The pharmaceutically active ingredients in the pharmaceutical composition (eg, pharmaceutical composition film) include Angelmann syndrome (AS), pediatric benign Roland epilepsy (BREC) and benign Roland epilepsy with central temporal spine (BECTS), CDKL5 Disorder, Childhood Epilepsy (CAE), Myokronus-Inverted Epilepsy or Douse Syndrome, Drabe Syndrome, Early Myokronus Encephalopathy (EME), Epilepsy with General Tonic Epilepsy Only (EGTCS), Tonic Epilepsy During Awakening Epilepsy with seizures, myocrony epilepsy, frontal lobe epilepsy, glucose transporter 1 deficiency syndrome, hypothalamic erroneous tumor (HH), drip epilepsy (also known as IS) or West syndrome, juvenile epilepsy (JAE) , Juvenile myoclonus epilepsy (JME), Lafora progressive myocronus epilepsy (Lafora disease), Landor-Kleffner syndrome, Lenox-Gasteau syndrome (LGS), Otawara syndrome (OS), Panayiotopoulos syndrome (PS), PCDH19 epilepsy, progressive myoclonus Epilepsy, Rasmussen Syndrome Circular Chromium 20 Syndrome (RC20), Reflex Epilepsy, TBCK-Related Intellectual Disorder Syndrome, Neurocutaneous Syndrome May Associated with Attacks Including Temporal Epilepsy and Pigment Discoloration, Type 1 Neurofibromatosis , Sturge-Weber syndrome (cerebral trigeminal epilepsy), and nodular sclerosis can be therapeutic or adjunct treatment.

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 is insoluble in an aqueous solvent, including, but not limited to, water. Solvents may include water or other solvents (preferably polar solvents) either alone or in combination with water.

The composition can include a polymer matrix. Any desired polymer matrix may be used as long as it is orally soluble or erosible. This dosage form must be bioadhesive enough to not be easily removed and form a gel-like structure when administered. These are moderately soluble in the oral cavity and are particularly suitable for delivery of pharmaceutically active ingredients, but all of the immediate, delayed, controlled and sustained release compositions are also available. It is among the various intended embodiments.

(Branched polymer)
The pharmaceutical composition film can include dendritic polymers that can contain highly branched macromolecules with various structural architectures. Dendritic polymers can include dendrimers, dendritic polymers (dendritic grafted polymers), linear dendritic hybrids, multi-armed star polymers, or highly branched polymers.

Highly branched 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 mass utilization. Apart from their spherical structure, the properties of these polymers are abundant functional groups, intramolecular cavities, low viscosity and high solubility. Dendritic polymers are used in several drug delivery applications. 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.

The dendritic polymer can have an internal cavity in which the drug can be encapsulated. Steric hindrance caused by high density polymer chains can prevent drug crystallization. Thus, the branched polymer can provide the additional advantage of formulating the crystalline drug in the polymer matrix.

Examples of suitable dendritic polymers are poly (ether) based dendrons, dendrimers, and highly branched polymers, poly (ester) based dendrons, dendrimers and highly branched polymers, poly (thioether) based dendrons, dendrimers and highly branched. Polymers, poly (amino acid) based dendrons, dendrimers and highly branched polymers, poly (arylalkylene ether) based dendrons, dendrimers and highly branched polymers, poly (alkyleneimine) based dendrons, dendrimers and highly branched polymers, poly (amide amines) ) Includes base dendron, dendrimer or highly branched polymer.

Other examples of hyperbranched polymers are poly (amine), polycarbonate, poly (etherketone), polyurethane, polycarbosilane, polysiloxane, poly (esteramine), poly (sulfonamine), poly (urethane urea) or poly. Includes ether polyols such as polyglycerin.

The film can be made from a combination of at least one polymer and optionally a solvent containing other components. The solvent may be water, a polar organic solvent containing, but not limited to, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride. The film can be prepared by utilizing a selected casting or deposition method and a controlled drying process. For example, the film may be prepared through a controlled drying process that involves the application of heat and / or radiation energy to a moist film matrix to form a viscoelastic structure, thereby making the contents of the film uniform. Gender is controlled. The controlled drying process is in contact with the top or bottom of the film, or the substrate supporting the cast or deposited or extruded film, or at the same time or at different times during the drying process. It may contain air only, heat only, or heat and air in contact with one or more surfaces. Part of such a process is 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 incorporated herein by reference.

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

As used herein, the term "water-soluble polymer" and its variants refer to a polymer that is at least partially soluble in water, preferably completely or partially soluble in water, or absorbs water. Polymers that absorb water are often referred to as water-swellable polymers. Substances useful in the present invention may be water-soluble or water-swellable at room temperature and other temperatures, eg, at temperatures above room temperature. In addition, these materials may be water soluble or water swellable at pressures below atmospheric pressure. In some embodiments, the film formed from such a water-soluble polymer may be sufficiently water-soluble to be soluble on contact with body fluids.

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

A variety of different polymers may be used, but it is desirable to select a polymer that provides mucosal adhesion properties to the film as well as the desired dissolution and / or disintegration rate. In particular, the time it is desirable to maintain contact of the film with the mucosal tissue depends on the type of pharmaceutically active ingredient contained in the composition. Some pharmaceutically active ingredients may require only a few minutes for delivery through the mucosal tissue, whereas other pharmaceutically active ingredients require up to several hours and even longer. Sometimes. Therefore, 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 a water-soluble polymer and a water-swellable, water-insoluble and / or biodegradable polymer as previously provided. Inclusion of one or more polymers that are water swellable, water insoluble and / or biodegradable provides a film with a slower dissolution or disintegration rate than a film formed entirely of water soluble polymers. Can be done. Therefore, the film adheres to the mucosal tissue for a relatively long time, such as up to several hours, which is desirable for the delivery of certain pharmaceutically active ingredients.

Desirably, the individual dosage forms of the pharmaceutical film can have a suitable thickness and small size, which is about 0.0625 to 3 inches (1.5875 mm x 76.2 mm) x about 0.0625 to 3 inches. Between. The film size is also 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 approximately 3 inches (76.2 mm), or 3 in at least one embodiment. More than 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 other embodiments, more than 0.0625 inches, more than 0.5 inches, more than 1 inch, more than 2 inches, or 3 It can be more than an inch, about 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, or less than 0.0625 inches. Aspect ratios, including thickness, length and width, are based on the chemical and physical properties of the polymer matrix, active pharmaceutical ingredients, dosages, enhancers, and other additives involved, as well as the desired distribution unit dimensions. It can be optimized by the vendor. This film dosage form must have good adhesion when placed in the buccal or sublingual region of the user. In addition, the film dosage form must disperse and dissolve at a moderate rate, most preferably within about 1 minute and dissolve within about 3 minutes. In some embodiments, the film dosage form takes 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 More than 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 It is possible to disperse and dissolve. 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 polymer component. The second polymer may be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer, or any combination thereof. Suitable water-soluble polymers include, but are not limited to, those provided above. In some embodiments, the water-soluble polymer comprises a hydrophilic cellulosic polymer, such as hydroxypropyl cellulose and / or hydroxypropyl methylcellulose. In some embodiments, one or more water swellable, water insoluble and / or biodegradable polymers may also be included in the polyethylene oxide-based film. Any of the previously provided water swellable, water insoluble or biodegradable polymers may be utilized. The second polymer component is in an amount of about 0% to about 80% by weight, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight. May be utilized in quantities of over 5%, over 10%, over 15%, over 20%, over 30%, over 40%, over 50%, over 60%, and over 70%, about Includes 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, foaming agents, pigments, colorants, fillers, bulking agents, sweeteners, flavoring agents, Fragrances, release modifiers, adjuvants, plasticizers, flow promoters, mold release agents, polyols, granulators, diluents, binders, buffers, absorbents, lubricants, adhesives, anti-adhesives, acidulants, softening Includes agents, resins, lubricants, solvents, surfactants, emulsifiers, elastomers, anti-adhesives, anti-static agents and mixtures thereof. These additives may be added together with the pharmaceutically active ingredient (s).

The term "stabilizer" as used herein is capable of preventing aggregation or other physical decomposition, as well as chemical decomposition, of active pharmaceutical ingredients, other excipients, or combinations thereof. Means an excipient.

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

Antioxidants (ie, pharmaceutically compatible compounds (s) or compositions (s) that slow down, inhibit, interrupt and / or stop the oxidation process) are in particular the following substances: tocopherols and theirs. Esters, sesamole of sesame oil, coniferyl benzoate of benzoin resin, nordihydroguaiaretinic acid resin and nordihydroguayretoic acid (NDGA), caric acid salts (especially methyl, ethyl, propyl, amyl, butyl, lauryl ), Butylated hydroxyanisole (BHA / BHT, both butyl-p-cresol); ascorbic acid and its salts and esters (eg, ascorbyl palmitate), erythorbic acid (isoascorbic acid) and its salts and esters, monothioglycerol. , Sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium hydrogen sulfite, sodium sulfite, potassium metabisulfite, butylated hydroxytoluene, butylated hydroxytoluene (BHT), propionic acid. Representative antioxidants are tocopherols, such as α-tocopherol and its esters, butylated hydroxytoluene and butylated hydroxyanisole. The term "tocopherol" also includes esters of tocopherol. A known tocopherol is α-tocopherol. The term "α-tocopherol" includes an ester of α-tocopherol (eg, α-tocopherol acetate).

Sequestrants (ie, any compound that can be added during host-guest complex formation with another compound, such as an active ingredient or another excipient; also referred to as a sequestering agent) are calcium chloride, ethylenediamine. Includes calcium tetraacetate disodium, gluconodelta-lactone, sodium gluconate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate, and combinations thereof. Metal ion blockers are also cyclic oligosaccharides such as cyclodextrin, cyclomannin (5 or more α-D-mannopyranose units linked at positions 1, 4 by α-bond), cyclogalactin (by β-bond). 5 or more β-D-galactopyranose units linked at 1,4 positions), cycloaltrin (5 or more α-D-altropyranose units linked at 1,4 positions by α binding) , And combinations thereof.

pH adjusters include acids (eg, tartrate, citric acid, lactic acid, fumaric acid, phosphoric acid, ascorbic acid, acetic acid, succinic acid, adipic acid and maleic acid), acidic amino acids (eg, glutamate, aspartic acid, etc.) Inorganic salts of such acidic substances (alkali metal salts, alkaline earth metal salts, ammonium salts, etc.), organic bases of such acidic substances (eg, basic amino acids such as lysine, arginine, etc. and the like, meglumine and the like. Includes salts with (similar) and their solvates (eg, hydrates). Other examples of pH adjusters include silicified microcrystalline cellulose, magnesium aluminometasilicate, calcium salts of phosphate (eg, anhydrides or hydrates of calcium hydrogen phosphate, carbonic acid or calcium hydrogencarbonate, sodium or potassium. , And calcium lactate or a mixture thereof), sodium and / or calcium salt of carboxymethyl cellulose, crosslinked carboxymethyl cellulose (eg, croscarmellose sodium and / or calcium), potassium polaricrine, sodium alginate and / or calcium, Doc. Includes sodium salt, magnesium stearate, calcium, aluminum, or zinc, magnesium palmitate, and magnesium oleate, sodium stearyl fumarate, and combinations thereof.

Examples of emulsifiers and / or surfactants are poroxamer or pluronic, polyethylene glycol, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylated and hydrided castor oil, alkylpolyosides, on hydrophobic main chains. Water-soluble proteins graft-polymerized to, lecithin, glyceryl monosteert, glyceryl monosteert / polyoxyethylene stealert, ketostearyl alcohol / sodium lauryl sulphate, carbomer, phospholipids, (C _10- C ₂₀ ) -alkyl and Alkylene carboxylate, alkyl carboxylic acid ether, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, alkylamide sulfate and sulfonate, fatty acid alkylamide polyglycol ether sulfate, alkane sulfonate and hydroxyalcan sulfonate , Olefin sulphonate, acyl ester of isethionic acid, α-sulfo fatty acid ester, alkylbenzene sulfonate, alkylphenol glycol ether sulfonate, sulfosuccinate, monoester and diester of sulfosuccinic acid, aliphatic alcohol ether phosphate, Protein / fatty acid condensation products, alkyl monoglycerides sulfates and sulfonates, alkyl glyceride ether sulfonates, fatty acid methyl tauride, fatty acid sarcosinates, sulfolicinolates, and acyl glutamates, quaternary ammonium salts (eg, di- (C) _10- C ₂₄ )-alkyl-dimethylammonium chloride or bromide), (C _10- C ₂₄ ) -alkyl-dimethylethylammonium chloride or bromide, (C _10- C ₂₄ ) -alkyl-trimethylammonium chloride or bromide (eg, _10- C ₂₄ )-alkyl-trimethylammonium chloride or bromide Cetyltrimethylammonium chloride or bromide), (C _10- C ₂₄ ) -alkyl-dimethylbenzylammonium chloride or bromide (eg, (C _12- C ₁₈ ) -alkyl-dimethylbenzylammonium chloride), N- (C ₁₀ -C) ₁₈ )-Alkyl-pyridinium chloride or bromide (eg 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 - poly Oil amino formyl methyl pyridinium _{chloride, N- (C 12 -C 18)} - alkyl -N- methyl morpholinium chloride, bromide or monoalkyl sulfate, N- (C ₁₂ -C ₁₈ )-Alkyl-N-ethylmorpholinium chloride, bromide or monoalkyl sulfate, (C _16- C ₁₈ )-alkyl-pentaoxytylammonium chloride, diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride, N, N-di Salts of -ethylaminoethylstearylamide and -oleylamide with hydrochloric acid, acetic acid, lactic acid, citric acid, phosphoric acid, N-acylaminoethyl-N, N-diethyl-N-methylammonium chloride, bromide or monoalkyl sulfate , And N-acylaminoethyl-N, N-diethyl-N-benzylammonium chloride, bromide or monoalkyl sulfate (in the above, "acyl" stands for, for example, stearyl or oleyl), and combinations thereof. ..

Examples of UV stabilizers are UV absorbers (eg, benzophenones), UV extinguishers (ie, any compound that dissipates UV energy as heat rather than degrading it), scavengers (ie). That is, any compound that removes free radicals resulting from exposure to UV radiation), and combinations thereof.

In other embodiments, the stabilizers are 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 hydrogen sulfite, propyl citrate, glutathione, thioglycerol, monooxygen scavenger, hydroxyl radical scavenger, hydroperoxide remover, reducing agent, metal chelating agent, cleaning Includes agents, chaotropes, and combinations thereof. "Single-term oxygen solubilizers" include alkylimidazoles (eg, histidine, L-camosin, histamine, imidazole 4-acetic acid), indols (eg, tryptophan and its derivatives, such as N-acetyl-5-methoxytryptamine, N-acetyl). Serotonin, 6-methoxy-1,2,3,4-tetrahydro-beta-carbolin), sulfur-containing amino acids (eg, methionine, ethionine, diencoric acid, lanthionin, N-formylmethionine, ferrinin, S-allylcysteine, S- Aminoethyl-L-cysteine), phenolic compounds (eg, tyrosine and its derivatives), aromatic acids (eg, ascorbate, salicylic acid, and their derivatives), azide (eg, sodium azide), tocopherols and related Includes, but is not limited to, vitamin E derivatives, as well as carotene and related vitamin A derivatives. "Hydroxyl radical scavenger" includes, but is not limited to, azide, dimethyl sulfoxide, histidine, mannitol, sucrose, glucose, salicylate, and L-cysteine. "Hydroperoxidase removers" include, but are not limited to, catalase, pyruvate, glutathione, and glutathione peroxidase. "Reducing agents" include, but are not limited to, cysteine and mercaptoethylene. "Metal chelating agents" include, but are not limited to, EDTA, EGTA, o-phenanthroline, and citrate. "Cleaning agents" include, but are not limited to, SDS and sodium lauroyl sarcosine. "Chaotrope" includes, but is not limited to, guanidium hydrochloride, isothiocyanate, urea, and formamide. As discussed herein, stabilizers can be present in 0.0001% to 50% by weight, which by weight are 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. Water-soluble derivatives of cellulose such as acrylicized proteins, water-soluble polysaccharides such as alginate, caragenan, guar gum, agar, xanthan gum, gellan gum, arabic gum and related gums (gatti gum, karaya gum, tragacanth gum), pectin: alkyl cellulose, hydroxyalkyl cellulose And hydroxyalkylalkyl celluloses such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose and the like, cellulose esters and hydroxyalkyl cellulose esters such as cellulose phthalate acetate (CAP), hydroxy Propropylmethyl Cellulose (HPMC); Carboxyalkyl Cellulose, Carboxyalkylalkyl Cellulose, Carboxyalkyl Cellulose Estel, eg, Carboxymethyl Cellulose and Alkali Metal Salts thereof; It can contain methacrylic acid ester, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVA / vinyl acetate copolymer, or polycrotonic acid; also gelatin phthalate, gelatin succinate, crosslinked gelatin. , Shelac, water-soluble chemical derivatives of cellulose, such as cationically modified acrylates and methacrylates having a tertiary or quaternary amino group, such as, if desired, a quaternized diethylaminoethyl group; or other Similar polymers are also suitable.

The additional ingredients can range from up to about 80%, preferably from about 0.005% to 50%, more preferably from 1% to 20%, based on the weight of all composition ingredients. Is over 1%, over 5%, over 10%, over 20%, over 30%, over 40%, over 50%, over 60%, over 70%, about 80%, over 80%, less than 80%, 70 Includes less than%, 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 include anti-adhesives, fluidizers and emulsions such as magnesium, aluminum, silicon and titanium oxides, preferably in a concentration range of about 0.005% to based on the weight of all film components. It can be included in about 5% by weight, and preferably from about 0.02% to about 2% by weight, which is greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, greater than 1.5%, greater 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 can include a plasticizer, which is a low molecular weight organic plasticizer such as polyalkylene oxide, such as polyethylene glycol, polypropylene glycol, polyethylene-propylene glycol, such as glycerol, glycerol mono. Acetate, diacetate or triacetate, 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. Can be added at concentrations in the range of about 0.1% to about 40%, preferably in the range of 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% Includes less than, less than 4%, less than 2%, less than 1%, or less than 0.5%. Compounds that improve the texture properties of the film material, such as animal or vegetable fats, may be further added, preferably in their hydrogenated form. The composition can also contain compounds that improve the texture properties of the product. Other ingredients include binders that contribute to the easy formation of the film and overall quality. Non-limiting examples of binders include starch, natural rubber, pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxazolidone, or polyvinyl alcohol.

Further potential 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. In general, these materials are donut-shaped molecules with hydrophobic internal cavities and hydrophilic externals. The insoluble and / or unstable pharmaceutically active ingredient fits into the hydrophobic cavity, which results in an encapsulating complex, which is soluble in water. Therefore, the formation of the encapsulated complex allows the highly insoluble and / or unstable pharmaceutically active ingredient to dissolve in water. A particularly desirable example of such a substance is cyclodextrin, which is a cyclic carbohydrate derived from starch. However, other similar substances are believed to fall within the scope of the present invention.

Suitable colorants include food, pharmaceutical and cosmetic colorants (FD & C), pharmaceutical and cosmetic colorants (D & C), or external drug and cosmetic colorants (Ext. D & C). These colorants are pigments, their corresponding lakes, and certain natural and derived colorants. A rake is a dye absorbed on 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 at concentrations in the range of about 0.001 to about 10%, preferably about 0.5 to about 3%, based on the weight of all components. This is over 0.001%, over 0.01%, over 0.1%, over 0.5%, over 1%, over 2%, over 5%, about 10%, over 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%.

The fragrance may be selected from natural and synthetic flavored liquids. An exemplary list of such substances was derived from volatile oils, synthetic flavor oils, savory aromatics, oils, liquids, oil-containing resins, or plants, leaves, flowers, fruits, stems, and combinations thereof. Contains extract. A non-limiting representative list of examples is 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. Contains fruit essences, or other fruit fragrances. Other useful flavoring agents are aldehydes and esters such as benzaldehyde (sakurambo, almond), citral, ie alpha citral (lemon, lime), neral, ie beta-citral (lemon, lime), decanal (orange, lemon). , Aldehyde C-8 (Citral Fruit), Aldehyde C-9 (Citral Fruit), Aldehyde C-12 (Citral Fruit), Truylaldehyde (Citral, Almond), 2,6-Dimethyloctanol (Green Fruit), Or 2-dodecenal (citral, mandarin), combinations thereof, etc. are included.

Sweeteners include the following non-limiting list: glucose (corn syrup), dextrose, converted sugars, fructose, and combinations thereof; saccharin and various salts thereof, such as sodium salts; dipeptide-based sweeteners, such as aspartame, neotheme. , Advantame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (stebioside); chlorine derivatives of saccharin, such as sclarose; sugar alcohols, such as sorbitol, mannitol, xylitol, and the like. Also, hydrolyzed starch hydrolysates and synthetic sweeteners 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazine-4-one-2,2-dioxides, especially potassium salts. (Acesulfame-K), as well as their sodium and calcium salts, as well as natural intensive sweeteners such as Lo Han Kuo. Other sweeteners may also be used.

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

Any other component described in US Pat. Nos. 7,425,292 and 8,765,167, as mentioned above, assigned to the assignee of the invention may also be included in the films described herein.

The film composition should further contain a buffer 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 as the pharmaceutically active ingredient is released from the composition. The buffer is preferably 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, hydrogen tartrate 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, the film dosage form composition is formed by first preparing a wet composition, which comprises a polymeric carrier matrix and a therapeutically effective amount of the pharmaceutically active ingredient. The wet composition is cast to form a film and then sufficiently dried to form a self-supporting film composition. The wet composition is cast into individual dosage forms, or it is cast into sheets, which are then cut into individual dosage forms.

The pharmaceutical composition can adhere to the mucosal surface. The present invention is particularly used for the topical treatment of body tissues, affected areas, or wounds that have a moist surface and are susceptible to body fluids, such as the mouth, vagina, organs, or other types of mucosal surfaces. .. The composition carries the drug and, upon application and attachment to the mucosal surface, provides a protective layer and delivers the drug to the treatment site, surrounding tissues, and other body fluids. Given the control of erosion in body fluids such as aqueous solutions or saliva, and the slow and natural erosion of the film at the same time as or after delivery, this composition provides a suitable residence time for effective drug delivery at the treatment site. provide.

The residence time of the composition depends on the erosion rate of the water erosive polymers used in the formulation and their respective concentrations. The erosion rate is different for the same polymer, for example by mixing components with different dissolving properties or chemically different polymers, such as hydroxyethyl cellulose and hydroxypropyl cellulose; a mixture of low and medium molecular weight hydroxyethyl cellulose. By using molecular weight grades; by using excipients or plasticizers with various lipophilic or water solubility properties (including essentially insoluble components); by using water-soluble organic and inorganic salts By using a polymer such as hydroxyethyl cellulose and a cross-linking agent such as glyoxal for partial cross-linking; or, once obtained, the physical state of the film, including its crystallinity or phase transition. Can be modified by post-treatment irradiation or curing. These strategies may be used alone or in combination to alter the erosive dynamics of the film. Upon application, the pharmaceutical composition film adheres to the mucosal surface and is retained in place. Absorption of water softens the composition, thereby reducing the foreign body sensation. Delivery of the drug occurs while the composition is placed on the mucosal surface. The residence time can be extensively adjusted depending on the desired timing of delivery of the selected drug and the desired lifetime of the carrier. However, in general, the residence time is adjusted between about a few seconds and about a few days. Preferably, the residence time of most medications 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 has adhered to the mucosal surface, it also provides protection for the treatment site and acts as an erosible bandage. Lipophilic substances can be designed to delay erosion in order to reduce disintegration and dissolution.

The erosive kinetics of the composition can also be regulated 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 chlorides, carbonates, bicarbonates, citrates, trifluoroacetates, benzoates, phosphates, fluorides, sulfates, or sodium and potassium salts of tartrates. May include. The amount added may vary depending on how much the erosive dynamics are altered and the amount and nature of the other components in the composition.

The emulsifiers typically used in the water-based emulsions described above are preferably linoleic acid, palmitic acid, myristoleic acid, lauric acid, stearic acid, setreic acid or oleic acid and sodium hydroxide or water. Obtained in-situ when selected from potassium oxide, or lauric acid ester, palmitic acid ester, stearic acid ester, or oleic acid ester, monooleate, monostearate, monopalmitate, monolaurate of sorbitol and anhydrous sorbitol. It is either selected from polyoxyethylene derivatives containing rates, aliphatic alcohols, alkylphenols, allyl ethers, alkylaryl ethers, sorbitan monostearate, sorbitan monooleate and / or sorbitan monopalmitate.

The amount of pharmaceutically active ingredient used depends on the desired therapeutic intensity and the composition of these layers, but preferably the pharmaceutical ingredient is from about 0.001% to about 99% of the composition, more preferably from about 0.003 to about 75. %, And most preferably about 0.005% to about 50% by weight, which is greater than 0.005%, greater than 0.05%, greater than 0.5%, greater than 1%, greater than 5%, greater than 10%, greater than 15%, 20%. Super, over 30%, about 50%, over 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 includes less than 0.005%. The amount of other ingredients may vary depending on the drug or other ingredients, but typically these ingredients do not exceed 50%, preferably not more than 30%, by total weight of the composition. , And most preferably not to exceed 15%.

The thickness of the film may vary depending on the thickness of each layer and the number of layers. As mentioned above, both the thickness and amount of the layer may be adjusted to alter the erosive dynamics. Preferably, if the composition has only two layers, the thickness is in the range of 0.005 mm to 2 mm, preferably 0.01 to 1 mm, more preferably 0.1 to 0.5 mm, which is greater than 0.1 mm, greater than 0.2 mm. Includes 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 stratified composition, preferably from 30 to 60%, which is greater than 10%, greater than 20%, 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. Therefore, the preferred thickness of each layer may vary from 0.01 mm to 0.9 mm or 0.03 mm to 0.5 mm.

As will be appreciated by those skilled in the art, if systemic delivery, such as transmucosal or transdermal delivery, is desired, the treatment site will allow the film to deliver and / or maintain the desired level of medication in blood, lymph, or other body fluids. It may include any region that can be. Typically, such treatment sites include mucosal tissues of the mouth, esophagus, ears, eyes, anus, nose, and vagina, as well as skin. When the skin is used as a therapeutic site, usually a relatively large area of skin, such as the upper arm or thigh, where movement does not interfere with film adhesion is preferred.

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 away, the film not only protects the wound, but also heals, aseptically, scars ( Drugs can also be delivered to promote scarification), to relieve pain, or to improve the overall condition of the affected person. Some of the examples provided below are well suited for application to the skin or wounds. As will be appreciated by those skilled in the art, the formulation requires the incorporation of specific hydrophilic / hygroscopic excipients that will help maintain good adhesion on dry skin over time. Would be. Another advantage of the present invention when used in this manner is that the use of pigments or colorings is unnecessary if the film does not want to stand out on the skin. On the other hand, if it is desirable for the film to stand out, a dye or colorant can be utilized.

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

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, for example separated by a membrane of 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 permeating 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, stir bar 106, and heater / circulator 107.

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

For FIGS. 2A and 2B, the graph shows the permeation of the active substance from the composition. This graph shows that there was no significant difference between the epinephrine base pair solubilized in situ and the essentially soluble epinephrine hydrogen tartrate. Epinephrine hydrogen tartrate was selected for further development due to its ease of processing. The flux is derived as a gradient of permeation as a function of time. The steady-state flux is obtained from a plateau of flux vs. time curves, multiplied by the volume of the receiver medium and standardized for permeation area.

With respect to FIG. 2A, this graph shows the average amount of permeated active material versus time with 8.00 mg / mL epinephrine hydrogen tartrate and 4.4 mg / mL solubilized epinephrine base.

With respect to FIG. 2B, this graph shows the average flux vs. time with 8.00 mg / mL epinephrine hydrogen tartrate and 4.4 mg / mL solubilized epinephrine base.

With respect to FIG. 3, this graph shows the exvivo permeation of epinephrine hydrogen tartrate 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 increasing concentration showed increased permeation, and the level of enhancement decreased with higher loading.

With respect to FIG. 4, this graph shows the permeation of epinephrine hydrogen tartrate as a function of solution pH. It was investigated whether acidic conditions promote stability. The results compared the hydrogen tartrate epinephrine pH3 buffer and the hydrogen tartrate epinephrine pH5 buffer, and found that the hydrogen tartrate epinephrine pH5 buffer was slightly preferred.

With respect to FIG. 5, this graph shows the effect of the enhancer on the permeation of epinephrine, shown 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 start-up time and steady-state flux were achieved, and surprisingly enhanced permeation was achieved for clove oil and labrasol.

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

With respect to FIG. 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.

With respect to FIG. 8, this graph shows the effect of no enhancer on the concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen.

With respect to FIG. 9, this graph shows the effect of enhancer A (labrasol) on the concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen.

With respect to FIG. 10, this graph shows the effect of enhancer L (clove oil) on the concentration profiles of two 40 mg epinephrine films (10-1-1) and (11-1-1) vs. 0.3 mg epipen.

With respect to FIG. 11, this graph shows the effect of enhancer L (clove oil) and film dimensions (10-1-1 thin and large film and 11-1-1 thick and small film) on the concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen. Is shown.

With respect to FIG. 12, this graph shows a concentration profile of changes in the dose of epinephrine film in a given matrix for enhancer L (clove oil) relative to 0.3 mg epipen.

With respect to FIG. 13, this graph shows the concentration profile for variations in the dose of epinephrine film in a given matrix for enhancer L (clove oil) relative to 0.3 mg epipen.

With respect to FIG. 14, this graph shows the concentration profile for changes in the dose of epinephrine film in a given matrix for enhancer A (labrasol) relative to 0.3 mg epipen.

With respect 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.

With respect to FIG. 16, this graph shows the average flux as a function of time (diazepam + enhancer).

With respect to FIG. 17, this graph shows the effect of farnesol and farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen.

With respect to FIG. 18, this graph shows the effect of farnesol and farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen.

With respect 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 vs. 0.3 mg epipen.

With respect to FIG. 20, this graph shows the effect of farnesol and farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen.

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

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 Permeation enhancer-epinephrine)
Permeation enhancement was tested at a hydrogen tartrate epinephrine concentration of 16.00 mg / mL using several permeation enhancers. The results show the flux enhancements shown 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 increased flux enhancement rate (%).

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

For these examples, clove oil was obtained from clove leaves. Similar results would be obtained from clove oil from clove buds and / or clove stalks. Based on this data, results of similar permeability enhancement can be predicted from pharmaceutical compounds structurally similar to epinephrine.

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

The following excipients have also been tested to improve solubility.

Excipients below: Cinnamon leaf, basil, laurier, nutmeg, Kolliphor® TPGS, vitamin E PEG succinate, Kolliphor® EL, polyoxyl 35 cod liver oil USP / NF, menthol, N-methyl-2 -Pyrrolidone, SLS (SDS), SDBS, dimethyl phthalate, sucrose palmitate (Sisterna PS750-C), sucrose stearate (Sisterna SP70-C), CHAPS, octylglucoside, Triton X 100 (octoxinol) -9), Ethylmaltol (powdered flavor), Brij 58 (Ceteth-20), Vitamin E tocopherol, tocopherol acetate or tocopherol succinate, sterol, plant extracts, essential oils or cod liver oil also due to similar enhancing properties 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-Exvivo permeation test protocol)
In one example, the transparency technique is performed as follows. The hot bath is set to 37 ° C., the receiver medium is placed in the water bath to control the temperature and degassing is initiated. Obtain and prepare a Franz diffusion cell. The Franz diffusion cell comprises a donor compound, a donor chamber, a membrane, a sampling port, a receptor chamber, a stir bar, and a heater / circulator. The stir bar is inserted into the Franz diffusion cell. Place the tissue on the Franz diffusion cell and ensure that the tissue covers the entire surface with overlap on the glass joint. The top of the diffusion cell is placed on top of the tissue and the top of the cell is clamped to the bottom. Approximately 5 mL of receptor medium is loaded into the receiver area to ensure that air bubbles are not trapped in the receiving portion of the cell. This ensures that all 5 mL can fit in the receiver area. Start stirring and allow the temperature to equilibrate for about 20 minutes. On the other hand, high performance liquid chromatography (HPLC) vials are labeled by number of cells and time point. The bubbles must then be checked again as the gas escapes from the solution during heating.

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

For the solution test, the following steps: (1) Distribute 500 μL of the solution to each donor cell using a micropipette and start the timer; (2) Time = 0 minutes, 20 minutes, 40 minutes, 60 Minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, 360 minutes), 200 μL was sampled and placed in a labeled HPLC vial and tapped on the sealed vial to allow air to reach the bottom of the vial. Steps to ensure non-capture; (3) Replace with 200 μL of receptor medium at each sampling time (to maintain 5 mL); (4) When all time points are complete, disassemble the cell and all The process of properly disposing of the substance can be carried out.

(Example 4 Exvibo transparency evaluation)
An example of an Exvivo transparency evaluation is:
1. Tissue is freshly removed and delivered at 4 ° C (eg overnight).
2. Tissues are treated and frozen 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 sync conditions.
5. Place the tissue in a Franz diffusion cell equipped with a 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 round film with 500 μL of PBS buffer.
7. Samples are taken from the receiver chamber at predetermined intervals and replaced with fresh media.

(Example 5 Transbuccal delivery of doxepin)
The following is an exemplary permeation test for transbuccal delivery of doxepin. The study was conducted under a protocol approved by the Animal Care and Ethics Committee of the University of Barcelona (Spain) and the Animal Care and Use Committee of the Catalan Regional Autonomous Government (Spain). Sows aged 3-4 months were used. At the animal facility of Bellvitge Campus (University of Barcelona, Spain), the buccal mucosa from the buccal region of the pig was immediately removed after slaughtering the pig using overdose of sodium thiopental anesthesia. Fresh buccal tissue was placed in a container filled with Hanks 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 cryoprotectant.

Contributes to the diffusion barrier for permeation testing (Sudhakar et al., "Buccal bioadhesive drug delivery-A promising option for orally less efficient drugs" ) ”, Journal of Controlled Release, 114 (2006) 15-40) Cut the buccal mucosa of a pig into a sheet with a thickness of 500 ± 50 μm using an electric skin sword (GA 630, Aesculap, Tuttlingen, Germany). Then, it was cut into appropriate pieces with surgical scissors. Most of the inferior connective tissue was removed with a scalpel.

The membrane was then attached to 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 a static Franz-type diffusion cell (Vidra Foc Barcelona, Spain). The connective tissue region faces the donor chamber of the donor chamber and faces the receiver to prevent the formation of bubbles.

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 evaporation of water. Prior to performing this experiment, the diffusion cells were incubated for 1 hour in a water bath so that the temperatures in all cells were equal (37 ° C ± ° C). Each cell contained a small Teflon 1 coated magnetic stir bar, which was used during the experiment to ensure that the fluid in the receptor compartment remained homogeneous.

Sink conditions were ensured in all experiments by first testing the doxepin saturation concentration in the receptor medium. Samples (300 μL) were syringed 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 sample volume removed was immediately replaced with the same volume of fresh receptor medium (PBS; pH 7.4), taking great care to avoid trapping air under the membrane.

For additional details, see 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)
Pig oral mucosal tissue has histological characteristics similar to human oral mucosal tissue (Heaney TG, Jones RS literature, "Histological investigation of the effect 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 literature," Between soft tissue attachment, subepithelial growth and surface porosity. The relationship between soft tissue attachment, epithelial downgrowth and surface porosity ”, Journal of Periodontal Research 16 (1981) 434-440). The literature by Lesch et al., "The Permeability of Human Oral Mucosa and Skin to Water," J Dent Res 68 (9), 1345-1349, 1989) describes the buccal side of pigs. Although the water permeability of the mucosa is not significantly different from that of the human buccal mucosa, the oral floor was reported to be 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 (eg, incorporated herein by reference, M. Sattar's literature, "Oral Transmucosal Drugs". See Table 1 of Oral transmucosal drug delivery-current status and future prospects, International Journal of Pharmaceutics 471 (2014) 498-506). Typically, the in vitro test involves attaching the buccal tissue of the removed pig in a washing chamber, Franz cell or similar diffuser. The in vivo tests described in this document include the application of the drug as a solution, gel or composition to the buccal mucosa of pigs, 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 effects 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 washing chamber. Comparative permeation tests were performed through full-thickness epithelial tissue, fresh tissue and frozen tissue. Tissue integrity is monitored by absorption of fluorescein isothiocyanate (FITC) -labeled dextran 20 kDa (FD20) and tissue viability is monitored by MTT (3- [4,5-dimethylthiazole-2-yl] -2,5. -Diphenyltetrazolium bromide) Evaluated using biochemical assay and histological evaluation. Permeability through the buccal epithelium was 1.8-fold greater for caffeine and 16.7-fold greater for estradiol compared to full-thick buccal tissue. Flux values for both compounds were comparable for fresh and frozen buccal epithelium, but histological evaluation revealed signs of cell death in frozen tissue. The tissue appeared to survive up to 12 hours after death using the MTT viability assay, which was also confirmed by histological evaluation.

Kulkarni et al. Investigated the relative contribution of epithelium and connective tissue to the barrier properties of porcine buccal tissue. In vitro permeation tests were performed with antipyrine, buspirone, bupivacaine and caffeine as model permeants. Permeability of the model diffuser over the buccal mucosa of thicknesses 250, 400, 500, 600, and 700 μm was determined. A bilayer model was developed to delineate the relative contribution of epithelial and connective tissue to barrier function. The relative contribution of the connective tissue region as a permeable barrier increased significantly with increasing mucosal tissue thickness. A mucosal tissue thickness of approximately 500 μm was recommended by the authors for the in vitro transbuccal permeation test. This is because the epithelium, at this thickness, represented a major permeation barrier for all diffusers. The authors also investigated the effects of several biological and experimental variables on the permeability of the same group of model permeates in the buccal mucosa of pigs (porcine buccal mucosa as an in vitro model: organisms). Actions of Scientific and Experimental Variables, Kulkarni et al., J Pharm Sci. 2010 99 (3): 1265-77). Remarkably, higher permeability of the permeate was observed in the thinner area (170-220 μm) on the back of the lip compared to the thicker cheek area (250-280 μm). The buccal mucosa of pigs maintained its integrity in Krebs hydrogen carbonate Ringer's solution at 4 ° C. for 24 hours. Heat treatment to separate the epithelium from the underlying connective tissue did not adversely affect its permeability and integrity characteristics compared to surgical separation.

For additional details, see M. Sattar's literature, "Oral transmucosal drug delivery-current status and future prospects," International Journal of Pharmaceutics 471 (2014) 498- It can be found in 506, which is incorporated herein by reference.

(Example 7 Cryopreservation of buccal mucosa)
Different regions of the porcine buccal mucosa have different patterns of permeability, with significantly higher permeability in the back region of the lips compared to the buccal region, because in the porcine buccal mucosa. This is because the epithelium acts as a permeable barrier and the thickness of the buccal epithelium is greater than the thickness of the dorsal region of the lips (Harris and Robinson literature, 1992). In an exemplary permeation test, fresh or frozen porcine buccal mucosa from the same region, which contributes to the diffusion barrier (Sudhakar et al., 2006), was cut into 500 ± 50 μm thick sheets and electrocuted. Obtained using a sword (model GA 630, Aesculap, Tuttlingen, Germany) and cut into suitable pieces with surgical scissors. All equipment used was sterilized in advance. Most of the inferior connective tissue was removed with a scalpel. The membrane was then attached to 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 a static Franz-type diffusion cell (Vidra Foc Barcelona, Spain). ) Facing the donor chamber and the connective tissue region facing its receiver to prevent the formation of bubbles. Using the experiment as a model drug, PP having lipophilic characteristics (logP = 1.16; n-octanol / PBS, pH7.4), ionizable (pKa = 9.50), and MW = 259.3 g / mol was used. Performed using (Modamio et al., 2000).

The infinite dose condition was applied into the receptor chamber using 300 μL of a saturated PP solution (C0 = 588005 ± 5852 μg / mL, n = 6) in PBS (pH 7.4) as a donor solution at 37 ° C ± 1 ° C. And it was ensured by immediate sealing with parafilm to prevent evaporation of water.

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

Samples (300 μL) were withdrawn from the center of the receptor compartment by syringe at the following time intervals: 0.25, 0.5, 1, 2, 3, 4, 5 and 6 hours. The sample volume removed 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) penetrating the unit surface area (cm ² ) of the mucosa was corrected for the removed sample and plotted against time (h). This diffusion experiment was performed 27 times for fresh buccal mucosa and 22 times for frozen buccal mucosa.

For additional details, see S. Amores's literature, "An improved cryopreservation method for porcine buccal mucosa in ex vivo drug permeation studies in an ex vivo drug permeation test using Franz diffusion cells. using Franz diffusion cells) ”, European Journal of Pharmaceutical Sciences 60 (2014) 49-54.

(Example 8 Permeation of quinine beyond the sublingual mucosal compartment)
The porcine oral mucosa is a good model of the human oral mucosa because the porcine and human oral membranes are similar in composition, structure and permeability measurements. Permeability beyond the porcine oral mucosa is not associated with metabolism, so it is not important that the tissue be viable.

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

Membrane permeability 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 this cell was coated with high performance vacuum grease, a membrane was attached between the receptor compartment and the donor compartment, with the mucosal surface on top. Membranes were held in place using clamps and then the receptor compartment was filled with degassed phosphate buffered saline (PBS) pH 7.4. A micromagnetic stir bar was added to the receptor compartment and the complete cell was placed in a 37 ° C. water bath. The membrane was equilibrated with PBS applied to the donor compartment for 20 minutes and then pipette aspirated. An aliquot of 5 μL of quinine solution in various vehicles or 100 μL of saturated solution of Q / 2-HP-β-CD complex was applied to each donor compartment. In a test to determine the effect of saliva on the permeation of quinine over 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 removed from the sampling port and a 1 mL aliquot of the sample was transferred to an HPLC automatic sampler vial and then replaced with fresh PBS stored at 37 ° C. Apart from studies involving Q / 2-HP-β-CD saturated solutions (infinite doses are applied at the beginning of the experiment), 5 μL of each quinine solution was reapplied to the donor phase for up to 10 hours. .. The purpose of this was to represent a hypothetical finite dosing regimen based on a 2-hour interval between doses. At least 3 iterations were performed for each test.

Additional details can be found in C. Ong's literature, "Permeation of quinine across sublingual mucosa, in vitro," International Journal of Pharmaceutics 366 (2009) 58-64. it can.

(Example 9 Exvivo initial test-API form)
In this example, permeation of solubilized epinephrine base pair essentially soluble epinephrine hydrogen tartrate was tested in situ and no difference was observed. Epinephrine hydrogen tartrate was selected for further development based on its ease of processing. The flux is derived as a gradient of permeation as a function of time. Steady-state flux was extrapolated from the flux-to-time curve plateau multiplied by the volume of the receiver medium. The graph in FIG. 2A shows the average permeation vs. time with 8.00 mg / mL epinephrine hydrogen tartrate and 4.4 mg / mL solubilized epinephrine base. The graph in Figure 2B shows the average flux vs. time with 8.00 mg / mL epinephrine hydrogen tartrate and 4.4 mg / mL solubilized epinephrine base.

(Example 10 Concentration dependence on permeation / flux)
In this test, the exvivo permeation of epinephrine hydrogen tartrate as a function of concentration was tested. FIG. 3 shows the exvivo permeation of epinephrine hydrogen tartrate 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 increased permeation, 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.

(Effect of Example 11 pH)
In this example, permeation of epinephrine hydrogen tartrate 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 pH 5 was slightly preferred over pH 3. The inherent pH of epinephrine hydrogen tartrate in solutions in the investigated concentration range is 4.5-5. No pH adjustment with buffer was required.

FIG. 4 shows the permeation of epinephrine hydrogen tartrate as a function of solution pH. Acidic conditions were investigated to promote stability. The results compared the hydrogen tartrate epinephrine pH3 buffer and the hydrogen tartrate epinephrine pH5 buffer, and found that the hydrogen tartrate epinephrine pH5 buffer was slightly preferred.

(Example 12 Effect of enhancer on epinephrine permeation)
In this example, the permeation of epinephrine to test transmucosal delivery was tested as permeation (μg) vs. time (minutes). 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 have been selected and designed to have functionality that affects various barriers in the mucosa. All tested enhancers improved permeation over time, with clove oil and labrasol in particular showing significant and unexpectedly high permeation enhancements.

(Example 13 Effect of enhancer on epinephrine release)
Epinephrine release profiles were tested to determine the effect of enhancers (labrasol and clove oil) on epinephrine release. FIG. 6A shows epinephrine release from different polymer platforms. Figure 6B shows the effect of enhancers on epinephrine release. These results showed that the permeation level leveled off between approximately 3250 and 4250 μg after about 40 minutes. The enhancers tested did not limit the release of epinephrine from the matrix.

(Example 14 Acceleration stability)
Differences in stabilizer loading were tested.

(Effect of Example 15 Enhancer)
A pharmacokinetic model was tested in male Yucatan minipigs. The graph in Figure 7 shows the results of a 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 profiles of the 0.3 mg epipen and 40 mg epinephrine films without enhancers is shown in FIG.

The effect of enhancer 3% labrasol is shown in FIG. 9, which shows the effect of enhancer A (labrasol) on the concentration profile of 40 mg epinephrine film vs. 0.3 mg epipen. FIG. 10 shows the effect of enhancer L (clove oil) on the concentration profiles of two 40 mg epinephrine films (10-1-1) and (11-1-1) vs. 0.3 mg epipen.

In addition, the effect of film size and the effect of clove oil (3%) are also shown in FIG. 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-to-time profile is after sublingual or intramuscular epinephrine administration to male miniature pigs.

Tests were performed to vary the ratio of epinephrine to enhancers. These studies were also concentration-to-time profiles after sublingual or intramuscular epinephrine administration to male miniature pigs. By varying the ratio of epinephrine to clove oil (enhancer L), the results shown in FIG. 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). It was.

(Example 16)
Variable doses were run on a constant matrix with enhancer labrasol (3%) and clove oil (3%), shown in FIGS. 13 and 14, respectively. The study 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 study 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-to-time profiles after sublingual or intramuscular epinephrine administration to male miniature pigs.

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

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

The graph in FIG. 19 was taken from the same test as in FIG. 17, but shows exclusively data points comparing 0.3 mg epipen to 30 mg epinephrine film 32-1-1 (n = 5).

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

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

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

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

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

(Example 23)
With respect to FIG. 21, this graph was tested to determine the effect of enhancers (6% clove oil and 6% labrazole) on epinephrine plasma concentration over time after sublingual or intramuscular administration, pharmacokinetics in male miniature pigs. 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 the farnesol permeation enhancer in epinephrine film. This data shows an epinephrine film with enhanced stability of epinephrine concentration starting immediately after 10 minutes and starting from about 30 minutes to about 100 minutes.

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

(Example 24)
With respect to FIG. 23, this graph was tested to determine the effect of enhancers (9% clove + 3% labrazole) on epinephrine concentration over time after sublingual or intramuscular administration across 7 animal models, males. A pharmacokinetic model in miniature pigs is shown. The general peak concentration was reached within 10-30 minutes.

(Alprazolam data)
(Example 25)
With respect to FIGS. 24A, 24B, and 24B, these graphs compare alprazolam plasma concentrations over time (in hours) during sublingual administration of oral alprazolam disintegrating tablets (ODT) and alprazolam pharmaceutical composition films. , Represents data from the male miniature pig test.

Figure 24A shows the mean data from the Alprazolam ODT (Group 1). Peak concentrations between 7-12 ng / mL were reached in approximately 1-8 hours.

FIG. 24B shows average data from alprazolam pharmaceutical composition film (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 Including, peak concentration between 5 and 17 ng / mL, over 10 minutes, over 20 minutes, over 30 minutes, over 45 minutes, over 1 hour, over 1.5 hours, over 2 hours, over 2.5 hours, over 3 hours, 3.5 Including more than hours, or about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes Reached in 10 minutes to 4 hours.

FIG. 24C shows average data from the alprazolam pharmaceutical composition film from another group of male miniature pigs (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 Including, peak concentration of 5 to 17 ng / mL, over 10 minutes, over 20 minutes, over 30 minutes, over 45 minutes, over 1 hour, over 1.5 hours, over 2 hours, over 2.5 hours, over 3 hours, 3.5 hours Including super and less than 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 arrived in 10 minutes to 4 hours.

(Example 26)
For FIG. 25A, this graph shows 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. Shows data from a male mini-pig study comparing alprazolam plasma concentrations over time (in hours).

As this graph shows, data from alprazolam pharmaceutical composition films (both groups) are over 10 minutes, over 20 minutes, about 30 minutes, over 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 less than about 30 minutes, including less than 10 minutes.

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

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

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

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

For FIG. 26C, this graph shows the individual data points for the alprazolam pharmaceutical film (Group 2) mentioned in FIG. 25C.

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

(Example 27)
With respect to FIG. 27A, this figure shows after sublingual administration of two groups of oral alprazolam disintegrating tablets (ODT) (indicated by circular data points) and alprazolam pharmaceutical composition film (indicated by square and triangular data points). Shows average data from a male mini-pig study comparing alprazolam plasma concentrations over time. As the data show, 0.5 mg alprazolam ODT is over 10 minutes, over 20 minutes, over 30 minutes, over 45 minutes, over 1 hour, over 1.5 hours, over 2 hours, over 2.5 hours, over 3 hours, 3.5 hours Including super or less than 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, Between 0 and 4 hours, a peak concentration range of about 5 to 6 ng / mL was reached. 0.5 mg Alprazolam pharmaceutical composition film is over 10 minutes, over 20 minutes, over 30 minutes, over 45 minutes, over 1 hour, over 1.5 hours, over 2 hours, over 2.5 hours, over 3 hours, over 3.5 hours, or Approximately 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes, 0-4 Over time, peak concentrations of about 7-8 ng / mL and 6-7 ng / mL were reached, respectively.

With respect to FIG. 27B, this graph shows two groups of oral alprazolam disintegrating tablets (ODT) (shown with circular data points) and alprazolam pharmaceutical composition film (square and triangular data points) between 0 and 2 hours. The average data of alprazolam plasma concentration over time after sublingual administration (shown) is shown. Unlike ODT, the treatment window for alprazolam pharmaceutical composition films started in 10-15 minutes, while ODT started in approximately 17-20 minutes.

For 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). ), The complete data mentioned in Figure 27B is shown.

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

(Example 28)
In one study, the usefulness of diazepam buccal soluble film as an oral treatment in adult epilepsy 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 under development for the management of selected refractory epilepsy patients who require intermittent use of diazepam to control episodes of increased seizure activity. DBSF is likely 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 the film attaches, dissolves and releases 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 usefulness of DBSF.

A phase 2, multicenter, open-label, crossover study in adults was conducted between two treatment visits, at least three weeks apart. The study enrolled male and female subjects aged 17-65 years who had a clinical diagnosis of epilepsy (unconscious tonic-clonic seizure or focal seizure) that required EMU assessment. Subjects received DBSF administered at 12.5 mg during intermittent seizure states (Treatment A) and during seizure / peri-seizure states (during seizures or within 5 minutes of seizures; Treatment B). Usefulness of Investigator DBSF Deployment Endpoints include: (1) Successful deployment, (2) Number of trials required for successful film insertion, and (3) Target. It included whether the film was spit out or blown out, and (4) whether DBSF was swallowed.

The results were as follows: A total of 35 subjects received at least one dose of DBSF. Of these subjects, 33 subjects collected usefulness data during treatment A and 33 subjects collected usefulness data during treatment B. There were no DBSF insertion failures between treatment A and treatment B. Two subjects (6.1%) during treatment A and one subject (3.0%) during treatment B were recorded to have swallowed DBSF during dosing. An additional 3 subjects (9.1%) swallowed DBSF according to a protocol instructing all subjects to swallow if the film did not completely dissolve 15 minutes after placement. During procedure A, no patients exhaled or exhaled DBSF after initial attachment to the buccal mucosa, but during procedure B, 3 subjects (9.1%) had 3 subjects (9.1%) after the initial placement. The film was spit out or blown out. DBSF is generally safe and exhibits good tolerability. Perhaps the most common adverse event associated with the drug was somnolence reported in 2 of 35 subjects (5.7%). There were no serious adverse events associated with the study drug, and no subjects withdrew due to adverse events.

This allows investigators to surprisingly conclude that DBSF was successfully administered in both interictal and intra-seizure / peri-seizure conditions in the EMU setting. did. This study data supports the safe and effective use of DBSF for the management of selected refractory epilepsy patients who require the use of intermittent diazepam to control episodes of increased seizure activity. This may also support the potential for usefulness in the home.

(Example 29)
Another study evaluated the pharmacokinetics of diazepam buccal soluble film in adult epilepsy patients. A comparison of bioavailability between peri-seizure and intermittent seizure administration was evaluated.

As shown above, the buccal soluble film (DBSF) is an exemplary embodiment of the claimed subject matter. This is a novel dosage form of diazepam under development for the management of selected refractory epilepsy patients who require the use of intermittent diazepam to control episodes of increased seizure activity. In this trial, investigators sought to assess pharmacokinetic (PK) performance during or immediately after a seizure. Subjects were investigated while undergoing a clinical epilepsy monitoring unit (EMU) evaluation and with another PK-only visit, with consultations approximately three weeks apart. In this study, diazepam maximal plasma concentration (C _max ) and time to maximal concentration (T _max ) in adults with epilepsy after a single dose of DBSF under intermittent seizure and intra-seizure / peri-seizure conditions, And the area under the partial curve (partial AUC) at 2 or 4 hours was investigated.

In this study, adult males and females (N = 35) aged 17-65 years with tonic-clonic seizures or focal seizures who lost consciousness of uncontrolled seizures in the clinical EMU setting had intermittent seizure conditions (treatment A) and seizures They were enrolled in a single-dose crossover in which DBSF 12.5 mg was administered both under moderate / peripheral seizure conditions (Treatment B). Plasma samples for analysis of diazepam were obtained before administration and at intervals of 2 hours or 4 hours after administration. Dosing is classified as intermittent seizures if no seizure activity was observed in the previous 4 hours, and DBSF was given during clinically observed seizure activity or within 5 minutes of subsidence of seizure activity. When administered, it was classified as in the mid-seizure / peri-seizure stage. Subjects were monitored for adverse events (AEs) from beginning to end of the study.

The results were as follows: Pharmacokinetic (PK) profiles useful for the analysis of both treatment conditions were available for 21 subjects. Most of these subjects were sampled for up to 4 hours, while 3 subjects were sampled for up to 2 hours. Subjects should have pre-dose diazepam levels if both treatments were not completed (N = 4), or if an expert who was not informed of the concentration data determined that a significant PK time point was missed (N = 3). Was excluded from the analysis if it was greater than 5% of C _max (N = 2) or if DBSF was administered in a manner contrary to the instructions (N = 5). The table shows the _{values of} C _max , AUC _(0-2h) , and AUC _(0-4h) (geometric mean), and the ratio of geometric mean (treatment B / treatment A) in 90% CI. Surprisingly, the values of C _max , AUC _(0-2h) , and AUC _(0-4h) are similar in the _interictal and _intra- seizure / _peri- seizure states, _reaching the median T _max. There was no significant difference (table). DBSF 12.5 mg has been shown to be effective, safe and well tolerated. Perhaps the most common adverse event associated with 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.

Surprisingly, these results are comparable to that of a single dose of DBSF 12.5 mg given to adults with epilepsy obtained under intermittent seizure conditions, both during and peri-seizure conditions. It has been shown to provide exposure to diazepam.
(Table of pharmacokinetic parameters after 12.5 mg of DBSF in intermittent seizure and intra-seizure / peri-seizure states)

All references cited herein are incorporated herein by reference in their entirety. Other embodiments are within the scope of the following claims.

Claims (43)

Polymer matrix;
A pharmaceutical composition comprising a pharmaceutically active ingredient in the polymer matrix; and an adrenergic receptor interacting substance. The pharmaceutical composition according to claim 1, further comprising a permeation enhancer. The pharmaceutical composition according to claim 1, wherein the adrenergic receptor interacting substance comprises a terpenoid, a terpene, or a sesquiterpene. The pharmaceutical composition according to claim 2, wherein the permeation enhancer comprises farnesol or labrasol. The pharmaceutical composition according to claim 2, wherein the permeation enhancer contains linoleic acid. The pharmaceutical composition according to claim 1, which is a film further containing a polymer matrix, wherein the pharmaceutically active ingredient is contained in the polymer matrix. The pharmaceutical composition according to claim 1, wherein the adrenergic receptor interacting substance contains a phenylpropanoid. The pharmaceutical composition according to claim 7, wherein the phenylpropanoid is eugenol or eugenol acetate. The pharmaceutical composition according to claim 7, wherein the phenylpropanoid is cinnamic acid, cinnamic acid ester, cinnamaldehyde, or hydrocinnamic acid. The pharmaceutical composition according to claim 7, wherein the phenylpropanoid is chavicol. The pharmaceutical composition according to claim 7, wherein the phenylpropanoid is safrole. The pharmaceutical composition according to claim 1, wherein the adrenergic receptor interacting substance is a plant extract. The pharmaceutical composition according to claim 12, wherein the plant extract further comprises an essential oil extract of a clove plant. The pharmaceutical composition according to claim 12, wherein the plant extract further comprises an essential oil extract of leaves of a clove plant. The pharmaceutical composition according to claim 12, wherein the plant extract further comprises an essential oil extract of flower buds of a clove plant. The pharmaceutical composition according to claim 12, wherein the plant extract further comprises an essential oil extract of a clove plant stem. The pharmaceutical composition according to claim 12, wherein the plant extract is synthetic or biosynthetic. The pharmaceutical composition according to claim 12, wherein the plant extract further comprises 40-95% eugenol. The pharmaceutical composition according to claim 1, wherein the pharmaceutically active ingredient is epinephrine, diazepam, or alprazolam. The pharmaceutical composition according to claim 1, wherein the polymer matrix contains a polymer. The pharmaceutical composition according to claim 20, wherein the polymer comprises a water-soluble polymer. The pharmaceutical composition according to claim 20, wherein the polymer comprises a cellulosic polymer selected from the following groups: hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and carboxymethyl cellulose. The pharmaceutical composition according to claim 20, which is a chewable or gelatin-based dosage form, spray, gum, gel, cream, tablet, solution, or film. The polymer matrix comprises polyethylene oxide, cellulosic polymers, polyethylene oxide, and polyvinylpyrrolidone, polyethylene oxide and polysaccharides, polyethylene oxide, hydroxypropylmethylcellulose, and polysaccharides, or polyethylene oxide, hydroxypropylmethylcellulose, polysaccharides, and polyvinylpyrrolidone. The pharmaceutical composition according to claim 20. The polymer matrix consists of the following groups: purulan, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragant gum, guar gum, acacia rubber, arabic rubber, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin. The pharmaceutical composition according to claim 20, which comprises at least one polymer selected from, ethylene oxide, propylene oxide copolymer, collagen, albumin, polyamino acid, polyphosphazene, polysaccharide, chitin, chitosan, and derivatives thereof. The pharmaceutical composition according to claim 1, further comprising a stabilizer. The pharmaceutical composition according to claim 1, wherein the polymer matrix comprises a dendritic polymer or a highly branched polymer. A method for producing a pharmaceutical composition comprising blending an adrenergic receptor interacting substance with a pharmaceutically active ingredient; and forming a pharmaceutical composition containing the adrenergic receptor interacting substance and the pharmaceutically active ingredient. A housing that holds an amount of a pharmaceutical composition, wherein the pharmaceutical composition is:
Polymer matrix;
A device comprising said housing; comprising a pharmaceutically active ingredient in the polymer matrix and an adrenergic receptor interacting substance; and an opening for distributing a predetermined amount of the pharmaceutical composition. Polymer matrix;
A pharmaceutical composition comprising a pharmaceutically active ingredient in the polymer matrix; and an aporphin alkaloid interacting substance. Polymer matrix;
A pharmaceutical composition comprising a pharmaceutically active ingredient in the polymer matrix; and a vasodilator interacting substance. Polymer matrix;
A pharmaceutical composition comprising a pharmaceutically active ingredient in the polymer matrix; and an interacting substance that causes increased blood flow or allows tissue flushing to alter transmucosal uptake of the pharmaceutically active ingredient. Polymer matrix;
A pharmaceutical composition comprising a pharmaceutically active ingredient in the polymer matrix; and an interacting substance having a positive or negative heat of solution and used as an adjunct to alter transmucosal uptake. Polymer matrix;
A pharmaceutical composition comprising a pharmaceutically active ingredient; and an interacting substance in the polymer matrix.
The pharmaceutical composition, which is contained in a multilayer film having at least one surface whose edges share a border. A way to treat a medical condition
Polymer matrix;
The method comprising administering an effective amount of a pharmaceutical composition comprising a pharmaceutically active ingredient in the polymer matrix; and an adrenergic receptor interacting substance. 35. The method of claim 35, wherein the pharmaceutically active ingredient is epinephrine, diazepam, or alprazolam. 35. The method of claim 35, wherein the medical condition comprises symptoms of epilepsy. 35. The method of claim 35, wherein the composition comprises diazepam administered during an intermittent seizure condition. 35. The method of claim 35, wherein the composition comprises diazepam administered during a seizure state. 35. The method of claim 35, wherein the composition comprises diazepam administered during the peri-seizure phase. 35. The method of claim 35, wherein the medical condition comprises anxiety, drug withdrawal, parasomnia, alcohol withdrawal, muscle cramps, or paroxysmal illness. 35. The method of claim 35, wherein the medical condition comprises treatment as a sedative. 35. The method of claim 35, wherein the medical condition comprises sedation for medical treatment.

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