KR102845228B1 - Pharmacological compositions having enhanced penetration - Google Patents

Abstract

Pharmaceutical compositions having enhanced active ingredient penetration properties are described.

Description

Pharmacological compositions having enhanced penetration

Claim of priority

This application is a continuation-in-part of U.S. patent application Ser. No. 15/724,234, filed Oct. 3, 2017, which is a continuation-in-part of U.S. patent application Ser. No. 15/717,856, filed Sep. 27, 2017, which is a continuation-in-part of U.S. patent application Ser. No. 15/587,376, filed May 4, 2017, which claims priority under 35 U.S.C. ξ119(e) to U.S. patent application Ser. No. 62/331,993, filed May 5, 2016, and which claims priority under 35 U.S.C. ξ119(e) to U.S. patent application Ser. No. 62/735,822, filed Sep. 24, 2018, each of which is incorporated herein by reference.

Technology field

The present invention relates to a pharmaceutical composition.

Active ingredients, such as pharmaceuticals or drugs, are delivered to the patient in a deliberate manner.

J Nicoiazzo, et al, J of Controlled Disease, 105, (2005) 1-15

Transdermal or transmucosal drug or medicine delivery using films may require the drug or medicine to penetrate or otherwise cross a biological membrane in an effective and efficient manner.

summation

Generally, a pharmaceutical composition may comprise a polymeric matrix, a pharmacologically active ingredient within the polymeric matrix, and an adrenergic receptor interactor. In certain embodiments, the pharmaceutical composition may further comprise a penetration enhancer. The adrenergic receptor interactor may be an adrenergic receptor blocker. The penetration enhancer may be a flavonoid, or may be used in combination with a flavonoid.

In certain embodiments, the adrenergic receptor interactor can be a terpenoid, a terpene, or a C3-C22 alcohol or acid. The adrenergic receptor interactor can be a sesquiterpene. In certain embodiments, the adrenergic receptor interactor can comprise farnesol, linoleic acid, arachidonic acid, docosahexanoic acid, eicosapentanoic acid, or tocosapentanoic acid, or a combination thereof.

In certain embodiments, the pharmaceutical composition may comprise a polymer matrix, a pharmacologically active ingredient within the polymer matrix, and an aporphine alkaloid interactor.

In certain embodiments, the pharmaceutical composition may comprise a polymer matrix, a pharmacologically active ingredient within the polymer matrix, and a vasodilator interactor.

In certain embodiments, the pharmaceutical composition may be a film further comprising a polymer matrix, wherein the pharmacologically active ingredient may be contained in the polymer matrix.

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

In certain embodiments, the penetration enhancer may be a plant extract.

In certain embodiments, the penetration enhancer may be a phenylpropanoid.

In certain embodiments, the phenylpropanoid can be eugenol.

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

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

In certain embodiments, the alcohol may be benzyl alcohol.

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

In another embodiment, the phenylpropanoid may be eugenol. In a particular embodiment, the phenylpropanoid may be eugenol acetate. In a particular embodiment, the phenylpropanoid may be cinnamic acid. In another specific embodiment, the phenylpropanoid may be a cinnamic acid ester. In another specific embodiment, the phenylpropanoid may be cinnamic aldehyde.

In another specific example, the phenylpropanoid may be a hydrocinnamic acid. In a specific embodiment, the phenylpropanoid may be chavicol. In another specific example, the phenylpropanoid may be safrole.

In a specific embodiment, the plant extract may be an essential oil extract of a clove plant. In another embodiment, the plant extract may be an essential oil extract of a clove plant leaf. In another embodiment, the plant extract may be an essential oil extract of a clove plant flower bud. In another embodiment, the plant extract may be an essential oil extract of a clove plant stem.

In certain embodiments, the plant extract may be a synthetic material. In certain embodiments, the plant extract may comprise 20-95% eugenol, 40-95% eugenol, or 60-95% eugenol. In certain embodiments, the plant extract may comprise 80-95% eugenol.

In another embodiment, the pharmacologically active ingredient may be epinephrine.

In certain embodiments, the pharmacologically active ingredient may be diazepam.

In certain embodiments, the pharmacologically active ingredient may be alprazolam.

In certain embodiments, the polymer matrix may comprise a polymer. In certain embodiments, the polymer may comprise a water-soluble polymer.

In certain embodiments, the polymer may be polyethylene oxide.

In certain embodiments, the polymer may be a cellulosic polymer. In certain embodiments, the cellulosic polymer may be hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, and/or sodium carboxymethyl cellulose.

In certain embodiments, the polymer may comprise hydroxypropylmethyl cellulose.

In certain embodiments, the polymer may comprise polyethylene oxide and hydroxypropyl methylcellulose.

In certain embodiments, the polymer may comprise polyethylene oxide and/or polyvinyl pyrrolidone.

In certain embodiments, the polymer matrix may comprise polyethylene oxide and/or polysaccharide.

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

In certain embodiments, the polymer matrix may comprise polyethylene oxide, a cellulosic polymer, a polysaccharide, and/or polyvinyl pyrrolidone.

In certain embodiments, the polymer matrix may comprise at least one selected from the group of pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tranganth gum, guar gum, acacia gum, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide, propylene oxide copolymer, collagen, albumin, poly-amino acid, polyphosphazene, polysaccharide, chitin, chitosan and derivatives thereof.

In certain embodiments, the pharmaceutical composition may further comprise a stabilizer. The stabilizer may include an antioxidant capable of preventing unwanted oxidation of the substance, a separating agent capable of forming a chelating complex and deactivating traces of metal ions that might otherwise act as catalysts, an emulsifier and a surfactant capable of stabilizing the emulsion, a UV stabilizer capable of protecting the substance from the harmful effects of ultraviolet light, a UV absorber, which is a chemical that absorbs ultraviolet radiation and prevents it from penetrating the composition, a quencher capable of dissipating the radiant energy as heat instead of breaking chemical bonds, or a scavenger capable of removing free radicals formed by ultraviolet light.

In another aspect, the pharmaceutical composition comprises:

(a) aggregation inhibitor; (b) a charge-modifying agent; (c) a pH adjusting agent; (d) a degrading enzyme inhibitor; (e) a mucolytic or mucosal cleansing agent; (f) a ciliostatic agent; (g) (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome or carrier; (iii) an alcohol; (iv) an enamine; (v) a nitric oxide donor compound; (vi) a long-chain amphiphilic molecule; (vii) a small hydrophobic penetration enhancer; (viii) a sodium or salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or a beta-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) an N-acetyl amino acid or a salt thereof; (xv) a membrane permeability-enhancing agent selected from the group consisting of: (ix) a fatty acid synthesis inhibitor; (x) a cholesterol synthesis inhibitor; and (xi) any combination of the membrane permeability-enhancing agents mentioned in (i) to (x); (h) an epithelial junction physiology modulator; (i) a vasodilator; (j) a selective transport enhancer; and (k) a mucosal delivery-enhancing agent selected from a stabilizing delivery vehicle, carrier, mucoadhesive, scaffold or complex forming agent; wherein the compound is effectively combined, associated, contained, encapsulated or bound to a mucosal delivery-enhancing agent, wherein the compound has a suitable non-toxic, non-ionic alkyl glycoside having a hydrophobic alkyl group bound by linkage to a hydrophilic saccharide, wherein the formulation of the compound with the mucosal delivery-enhancing agent increases the bioavailability of the compound in the plasma of a subject.

In general, a method of preparing a pharmaceutical composition may comprise mixing an adrenergic receptor interactor with a pharmacologically active ingredient and forming a pharmaceutical composition comprising the adrenergic receptor interactor and the pharmacologically active ingredient.

The pharmacologically active ingredient may be in the form of chewable or gelatinous dosing, spray, gum, gel, cream, tablet, liquid or film.

In general, a pharmaceutical composition can be dispensed from a device. The device can dispense a pharmacologically active ingredient in a predetermined dose form, such as a chewable or gelatin-based dosing foam, spray, gum, gel, cream, tablet, liquid, or film. The device comprises a polymer matrix; a housing containing a quantity of a pharmacological composition comprising a pharmacologically active ingredient within the polymer matrix; and an adrenergic receptor interactor; and an opening for dispensing the pharmacological composition in a predetermined amount. The device can also dispense a pharmacological composition comprising a penetration enhancer comprising a phenylpropanoid and/or a phytoextract.

In certain embodiments, the pharmaceutical composition may comprise a polymer matrix, a pharmacologically active ingredient within the polymer matrix, and a penetration enhancer comprising a phenylpropanoid and/or a plant extract.

In certain embodiments, the pharmaceutical composition may comprise a polymer matrix; a pharmacologically active ingredient within the polymer matrix; and an interactor that creates increased blood flow or flushing of the tissue to improve mucosal absorption of the pharmacologically active ingredient.

In certain embodiments, the pharmaceutical composition may comprise a polymer matrix; a pharmacologically active ingredient within the polymer matrix; and an interactor having a positive or negative heat of solution that may be used as an adjuvant to modify (increase or decrease) absorption in the case of mucosal absorption.

In another embodiment, the pharmaceutical composition comprises a polymer matrix, a pharmacologically active ingredient within the polymer matrix, and an interactor, wherein the composition is contained in a multilayer film having at least one side where the boundaries of the edges are shared.

In general, a method for treating a medical condition may comprise administering an effective amount of a pharmaceutical composition comprising a polymer matrix, a pharmacologically active ingredient within the polymer matrix, and an adrenergic receptor interactor. The pharmacologically active ingredient may be epinephrine, diazepam, or alprazolam. The medical condition may include an epileptic syndrome, such as a seizure. In a specific embodiment, the method comprises administering a pharmaceutical composition comprising diazepam during a seizure. In a specific embodiment, the method comprises administering a pharmaceutical composition comprising diazepam during a periictal state. In a specific embodiment, the method comprises administering a pharmaceutical composition comprising diazepam during an interictal state. The medical condition may also include anxiety, drug withdrawal, parasomnia, alcohol withdrawal, muscle spasms, or a seizure disorder. The medical condition may also include treatment with a sedative. The medical condition may also include sedation for a medical procedure.

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

Referring to FIG. 1A, the Franz diffusion cell (100) includes a donor compound (101), a donor chamber (102), a membrane (103), a sampling port (104), a receptor chamber (105), a stirring bar (106), and a heater/circulator (107).
Referring to FIG. 1B, the pharmaceutical composition is a film (100) comprising a polymer matrix (200) and a pharmacologically active ingredient (300) contained in the polymer matrix. The film may include a penetration enhancer (400).
Referring to FIGS. 2a and 2b, the graphs show the permeation of the active material from the composition.
Referring to Figure 2a, this graph shows the average permeation of active substance versus time for 8.00 mg/mL of epinephrine bitartrate and 4.4 mg/mL of dissolved epinephrine base.
Referring to Figure 2B, this graph shows the average flux versus time for 8.00 mg/mL bitartrate and 4.4 mg/mL dissolved epinephrine base.
Referring to Figure 3, this graph shows the in vitro permeation of epinephrine bitartrate as a function of concentration.
Referring to Figure 4, this graph shows the permeation of epinephrine bitartrate as a function of solution pH.
Referring to Figure 5, this graph shows the effect of enhancers on epinephrine penetration, expressed as the amount penetrated as a function of time.
Referring to FIGS. 6A and 6B, these graphs show the release of epinephrine (6A) and the effect of an enhancer on its release (6B) on the polymer platform, plotted as amount permeated (μg) versus time.
Referring to Figure 7, this graph represents a pharmacokinetic model in male Yucatan miniature pigs. This study compares a 0.3 mg EpiPen, 0.12 mg epinephrine IV, and a placebo film.
Referring to Figure 8, this graph shows the effect of no enhancer on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.
Referring to Figure 9, this graph depicts the effect of potentiator A (Labrazol) on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.
Referring to Figure 10, this graph depicts the effect of potentiator L (clove oil) on the concentration profiles of two 40 mg epinephrine films (10-1-1) and (11-1-1) versus a 0.3 mg EpiPen.
Referring to Figure 11, this graph illustrates the effect of enhancer L (clove oil) and film dimensions (10-1-1 thinner, larger and 11-1-1 thicker, smaller films) on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.
Referring to Figure 12, this graph depicts the concentration profiles for various doses of epinephrine film in a constant matrix for potentiator L (clove oil) versus 0.3 mg EpiPen.
Referring to Figure 13, this graph depicts the concentration profiles for various doses of epinephrine film in a constant matrix for 0.3 mg EpiPen versus Enhancer L (clove oil).
Referring to Figure 14, this graph shows the concentration profiles for various doses of epinephrine film in a constant matrix for potentiator A (Labrasol) versus 0.3 mg of EpiPen.
Referring to Figure 15, this graph shows the amount permeated as a function of time and shows the effect of a potentiator on the permeation of diazepam.
Referring to Figure 16, this graph shows the average flux (diazepam + potentiator) as a function of time.
Referring to Figure 17, this graph shows the effect of farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.
Referring to Figure 18, this graph shows the effect of farnesol on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.
Referring to Figure 19, this graph shows the effect of farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.
Referring to Figure 20, this graph shows the effect of farnesol in combination with linoleic acid on the plasma concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen.
Referring to Figure 21, this graph shows the effect of potentiator A (labrazol) combined with potentiator L (clove oil) on the concentration profile of a 40 mg epinephrine film (also shown in Figure 22) in logarithmic form.
Referring to Figure 22, this graph shows the effect of potentiator A (labrazol) combined with potentiator L (clove oil) on the concentration profile of mean data collected from 40 mg epinephrine film versus 0.3 mg epinephrine.
Referring to Figure 23, this graph shows the effect of potentiator A (labrazol) combined with potentiator L (clove oil) on the concentration profile of a 40 mg epinephrine film, shown as a separate animal test subject.
Referring to Figure 24A, this graph shows alprazolam plasma concentrations as a function of time following sublingual administration of alprazolam orally disintegrating tablets (ODT).
Referring to Figure 24B, this graph shows alprazolam plasma concentration as a function of time following sublingual administration of the alprazolam pharmacological composition film.
Referring to Figure 24C, this graph shows alprazolam plasma concentration as a function of time following sublingual administration of the alprazolam pharmacological composition film.
Referring to Figure 25A, this graph shows the mean alprazolam plasma concentration as a function of time following sublingual administration of alprazolam ODT and alprazolam pharmacological composition film.
Referring to Figure 25B, this graph shows alprazolam plasma concentrations as a function of time following sublingual administration.
Referring to Figure 25C, this graph shows alprazolam plasma concentration as a function of time following sublingual administration.
Referring to Figure 26A, this graph shows alprazolam plasma concentrations as a function of time following sublingual administration of alprazolam ODT.
Referring to Figure 26B, this graph shows alprazolam plasma concentration as a function of time following sublingual administration of the alprazolam pharmacological composition film.
Referring to Figure 26C, this graph shows alprazolam plasma concentration as a function of time following sublingual administration of an alprazolam pharmacological composition film.
Referring to Figure 27A, this graph shows the mean alprazolam plasma concentration as a function of time following sublingual administration of alprazolam ODTs and pharmacological composition films.
Referring to Figure 27B, this graph shows the mean alprazolam plasma concentration as a function of time following sublingual administration of alprazolam ODTs and pharmacological composition films.
Referring to Figure 27C, this graph shows the mean alprazolam plasma concentration as a function of time following sublingual administration of alprazolam ODTs and pharmacological composition films.

Detailed description

Mucosal surfaces, such as the oral mucosa, provide a convenient route for drug delivery into the body. This is due to their high vascularity and permeability, as they bypass the digestive system and thus first-pass metabolism, resulting in increased bioavailability and a rapid onset of action. In particular, the buccal and sublingual tissues, which are highly permeable regions of the oral mucosa, provide favorable sites for drug delivery, allowing drug diffusion from the oral mucosa directly into the systemic circulation. This also enhances patient convenience and, therefore, compliance. For certain drugs or pharmacologically active ingredients, penetration enhancers can help overcome the mucosal barrier and improve permeability. Penetration enhancers reversibly modulate the permeability of the barrier layer, favoring drug absorption. Penetration enhancers facilitate the transport of molecules across the epithelium. The absorption profile and rate can be controlled and modulated by various factors, including, but not limited to, film size, drug loading, enhancer type/loading, polymer matrix release rate, and mucosal residence time.

Pharmaceutical compositions can be designed to deliver pharmacologically active ingredients in a targeted and customized manner. However, the solubility and permeability of pharmacologically active ingredients in vivo, particularly within a subject's mouth, can vary widely. Certain types of penetration enhancers can enhance the absorption and bioavailability of pharmacologically active ingredients in vivo. In particular, when delivered orally via a film, penetration enhancers can enhance the permeability of the pharmacologically active ingredient through the mucosa into the subject's bloodstream. A penetration enhancer can enhance the rate and amount of absorption of a pharmacologically active ingredient by greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 100%, greater than 150%, about 200% or more, or by less than 200%, less than 150%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, or a combination of these ranges, depending on the other ingredients in the composition.

In certain embodiments, the pharmaceutical composition comprises (a) an aggregation inhibitor; (b) a charge-modifying agent; (c) a pH adjusting agent; (d) a degradative enzyme inhibitor; (e) a mucolytic or mucosal cleansing agent; (f) a ciliostatic agent; (g) (i) a surfactant; (ii) a bile salt; (ii) a phospholipid excipient, mixed micelle, liposome or carrier; (iii) an alcohol; (iv) an enamine; (v) an NO donor compound; (vi) a long-chain amphiphilic molecule; (vii) a small hydrophobic permeation enhancer; (viii) a sodium or salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or a beta-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) an N-acetyl amino acid or a salt thereof; (xv) a membrane penetration enhancer selected from: (ix) a fatty acid synthesis inhibitor; (x) a cholesterol synthesis inhibitor; (xi) any combination of the membrane penetration enhancers mentioned in (i) to (x); (h) a modulator of epithelial junction physiology; (i) a vasodilator; (j) a selective transport enhancer; and (k) a stabilizing delivery vehicle, carrier, mucoadhesive, scaffold or complex forming agent in which the compound is effectively combined, associated, contained, encapsulated or bound to stabilize the compound for enhanced mucosal delivery; wherein the compound with the mucosal penetration enhancer increases the bioavailability of the compound in the plasma of a subject. The penetration enhancer is described in J. Nicolazzo, et al., J. of Controlled Disease , 105 (2005) 1-15, which is incorporated herein by reference. There are many reasons why the oral mucosa may be an attractive location for delivering therapeutic agents into the systemic circulation. Direct blood drainage from the buccal epithelium into the internal jugular vein avoids first-pass metabolism in the liver and intestines. This first-pass effect may be a major reason for the low bioavailability of some compounds when administered orally. Furthermore, the easily accessible mucosa lining the oral cavity ensures that dosage forms can be applied to the required area and easily removed in case of emergency. However, like the skin, the buccal mucosa acts as a barrier to the absorption of xenobiotics, which can impede the penetration of compounds across the tissue. Consequently, the identification of safe and effective penetration enhancers is a key goal in the search for improved oral mucosal drug delivery.

Chemical permeation enhancers are substances that modulate the rate of drug permeation through biological membranes. While extensive research has focused on improving understanding of how permeation enhancers can alter intestinal and transdermal permeability, little is known about the mechanisms involved in enhancing buccal and sublingual permeation.

The buccal mucosa (buccal musosa) describes the area between the gums and the upper and lower lips, as well as the inner lining of the cheek, and has an average surface area of 100 cm2. The surface of the buccal mucosa is composed of stratified squamous epithelium, separated from the underlying connective tissue (lamina propria and submucosa) by a wavy basement membrane (a continuous layer of extracellular material approximately 1–2 µm thick). This stratified squamous epithelium consists of differentiated layers of cells that change in size, shape, and content as they migrate from the basal region to the superficial region, where they shed. Approximately 40–50 cell layers exist, resulting in a buccal mucosa thickness of 500–600 µm.

Structurally, the sublingual mucosa is comparable to the buccal mucosa, but its epithelium is 100-200 µm thicker. This membrane is also devoid of keratin, and its relatively thinner structure has been shown to be more permeable than the buccal mucosa. Blood flow to the sublingual mucosa is slower than that to the buccal mucosa, on the order of 1.0 ml/min ^-1 /cm ^-2 .

The permeability of the buccal mucosa is greater than that of the skin but less than that of the intestine. This difference in permeability is a result of structural differences between the tissues. The absence of organized lipid lamellae in the intercellular spaces of the buccal mucosa results in greater permeability to exogenous compounds compared to the keratinized epithelial cells of the skin; conversely, the increased thickness and lack of tight junctions result in the buccal mucosa being less permeable than intestinal tissue.

The primary barrier properties of the buccal mucosa are attributed to the upper third to fourth of the buccal epithelium. Researchers have discovered that, beyond the surface epithelium, the permeability barrier of the non-keratinized oral mucosa may also be due to contents released from membrane-coating granules into the intercellular space.

Intercellular lipids in non-keratinized areas of the oral cavity are more polar than those in the epidermis, palate, and gingiva, and differences in lipid chemical properties may contribute to the observed differences in permeability between these tissues. Consequently, it appears that not only does the greater degree of intercellular lipid packing in the stratum corneum of keratinized epithelium create a more effective barrier, but also that the chemical properties of the lipids within that barrier are crucial.

The presence of hydrophilic and lipophilic regions in the oral mucosa has led researchers to hypothesize the existence of two routes of drug transport through the buccal mucosa—intercellular (between cells) and transcellular (across cells).

Because drug delivery through the buccal mucosa is limited by the barrier properties and absorbable area of the epithelium, various strategies are needed to deliver therapeutically relevant doses of drugs into the systemic circulation. Various methods, including the use of chemical permeation enhancers, prodrugs, and physical methods, can be used to overcome the barrier properties of the buccal mucosa.

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

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

Fatty acids have been shown to enhance the permeation of many drugs through the skin, and this has been shown by differential scanning calorimetry and Fourier transform infrared spectroscopy to be related to increased interstitial lipid fluidity.

Furthermore, ethanol pretreatment has been shown to enhance the permeability of tritiated water and albumin across the abdominal lingual mucosa, and caffeine across the porcine buccal mucosa. Several reports have demonstrated the enhancing effect of azone on the permeability of compounds across the oral mucosa. Furthermore, chitosan, a biocompatible and biodegradable polymer, has been shown to enhance drug delivery across various tissues, including the intestinal and nasal mucosa.

Oral transmucosal drug delivery (OTDD) is the administration of pharmacologically active agents through the oral mucosa to achieve systemic effects. The permeation pathways and predictive models for OTDD are described in M. Sattar, Oral Transmucosal Drug Delivery - Current Status and Future Prospects, Int'l. Journal of Pharmaceutics, 47 (2014) 498-506, which is incorporated herein by reference. OTDD continues to attract the attention of scientists in both academia and industry. Despite the limited nature of the oral permeation route compared to the skin and nasal delivery routes, the outlook is encouraging due to advances in our understanding of how ionized molecules permeate the buccal epithelium, the advent of new analytical techniques for oral studies, and the development of in silico models to predict buccal and sublingual permeation.

To deliver a wider range of drugs across the buccal mucosa, reversible methods to lower the barrier potential of this tissue are necessary. This requirement has prompted research into permeation enhancers that can safely alter the permeability limitations of the buccal mucosa. It has been shown that buccal permeation can be improved by the use of various transmucosal and transdermal permeation enhancers, such as bile salts, surfactants, fatty acids and their derivatives, chelating agents, cyclodextrins, and chitosan. Among these chemicals used to enhance drug permeation, bile salts are the most common.

In vitro studies on the enhancing effect of bile salts on buccal permeation of compounds are discussed in Sevda Senel, Drug permeation enhancement via buccal route: possibilities and limitations, Journal of Controlled Release 72 (2001) 133-144, which is incorporated herein by reference. This paper also discusses recent studies on the effects of dihydroxy bile salts, sodium glycodeoxycholate (SGDC) and sodium taurodeoxycholate (TDC), and trihydroxy bile salts, sodium glycocholate (GC) and sodium taurocholate (TC), at 100 mM concentrations on buccal epithelial permeability, including changes in permeability associated with histological effects. Fluorescein isothiocyanate (FITC) and morphine sulfate were used as model compounds, respectively.

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

The penetration enhancer may be a plant extract. The plant extract may be a composition comprising an essential oil or essential oil extracted by distillation of plant material. In certain circumstances, the plant extract may include a synthetic analogue (i.e., a compound made by organic synthesis) of a compound extracted from the plant material. The plant extract may include a phenylpropanoid, 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 may be an essential oil extract of a clove plant, such as the leaves, stems, or flower buds of the clove plant. The clove plant may be Syzygium aromaticum . The plant extract may include 20-95% eugenol, 40-95% eugenol, 60-95% eugenol, for example, 80-95% eugenol. The extract may also contain 5% to 15% eugenol acetate. The extract may also contain caryophyllene. The extract may contain up to 2.1% α-humulen. Other volatile compounds present in low concentrations in clove essential oil may be beta-pinene, limonene, farnesol, benzaldehyde, 2-heptanone, or ethyl hexanoate. To enhance drug absorption, other penetration enhancers may be added to the composition. Suitable penetration enhancers include natural or synthetic bile salts such as sodium fusidate; glycocholate or deoxycholate and their salts; fatty acids and derivatives such as sodium laurate, oleic acid, oleyl alcohol, monoolein, or palmitoylcarnitine; Chelating agents such as disodium EDTA, sodium citrate and sodium lauryl sulfate, azone, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurylate, octoxynoyl-9, laureth-9, polysorbates, sterols or glycerides such as caprylocaproyl polyoxylglyceride, for example, labrazol. Penetration enhancers may include plant extract derivatives and/or monolignols. Penetration enhancers may also be fungal extracts.

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

Fatty acids can be used as inactive ingredients in drug formulations or drug vehicles. Furthermore, fatty acids can be used as formulation ingredients due to their specific functional effects and biocompatibility properties. Fatty acids, either as part of complex lipids or alone, are a major metabolic fuel (storage and transport energy) and essential components of all membranes and gene regulators. For a review, see Rustan A.C. and Drevon C.A., Fatty Acids: Structures and Properties, Encyclopedia of Life Sciences (2005), incorporated herein by reference. There are two families of essential fatty acids metabolized in the human body: ω-3 and ω-6 polyunsaturated fatty acids (PUFAs). If the first double bond is found between the third and fourth carbon atoms from the ω carbon, they are called ω-3 fatty acids. If the first double bond is between the sixth and seventh carbon atoms, they are called ω-6 fatty acids. PUFAs are further metabolized in the body by the addition of carbon atoms and desaturation (abstraction of hydrogen). Linoleic acid is an ω-6 fatty acid and is metabolized to gamma-linolenic acid, dihomo-gamma-linolinic acid, arachidonic acid, adrenic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, and docosapentaenoic acid. α-Linoleic acid is an ω-3 fatty acid and is metabolized to octadecatetranoic acid, eicosatetraenoic acid, eicosapetaenoic acid (EPA), docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenic acid, and docosahexaenoic acid (DHA).

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

Many studies have reported the effects of eicosapentaenoic acid (EPA) and decosahexaenoic acid (DHA) on vascular responses after administration in ingestible forms. Some studies have reported that administration of EPA-DHA or EPA alone inhibits the hypotensive effects of norepinephrine or enhances the vasodilatory response to acetylcholine in the forearm microcirculation. See Chin, J.P.F., et al., Hypertension 21:22-8 (1993), and Tagawa, H. et al., J Cardiovasc Pharmacol 33:633-40 (1999), which are incorporated herein by reference. Another study found that both EPA and DHA tend to increase systemic arterial compliance and decrease pulse pressure and total vascular resistance. See Nestel, P. et al., Am J. Clin. Nutr. 76:326-30 (2002), incorporated herein by reference. Meanwhile, one study found that DHA, but not EPA, enhanced the dilatatory vasodilation mechanism and attenuated the flexural response in forearm microcirculation in hyperlipidemic men. See Mori, T.A., et al., Circulation 102:1264-69 (2000), incorporated herein by reference. Another study found a vasodilatory effect of DHA on rhythmic contractions in isolated human coronary arteries in vitro. See Wu, K.-T. et al., Chinese J. Physiol. 50(4):164-70 (2007), incorporated herein by reference.

Adrenergic receptors (or adrenoceptors) are a class of G-protein-coupled receptors that are targets of catecholamines, particularly norepinephrine (noradrenaline) and epinephrine (adrenaline). Epinephrine (adrenaline) interacts with both α- and β-adrenoceptors, causing vasoconstriction and vasodilation, respectively. Although α-receptors are less sensitive to epinephrine, when activated, they abrogate vasodilation mediated by β-adrenoceptors because there are more peripheral α1-receptors than β-adrenoceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. At low levels of circulating epinephrine, β-adrenoceptor stimulation predominates, producing vasodilation with subsequent decrease in peripheral vascular resistance. α1-adrenoceptors stimulate smooth muscle cells. It is known to induce contraction, mydriasis, vasoconstriction in the skin, mucosa, and abdominal villi, and sphincter contraction in the gastrointestinal (GI) tract and bladder. The α1-adrenergic receptor is a member of the Gq protein-coupled receptor superfamily. Upon activation, the heterotrimeric G protein, Gq, activates phospholipase C (PLC). The mechanism of action involves interaction with calcium channels and changes in intracellular calcium content. For a review, see Smith R. S. et al., Journal of Neurophysiology 102(2): 1103-14 (2009), which is incorporated herein by reference. Many cells contain this receptor.

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

In certain embodiments, the penetration enhancer may be an adrenergic receptor interactor. An adrenergic receptor interactor is a compound or substance that modifies and/or otherwise alters the action of an adrenergic receptor. For example, an adrenergic receptor interactor may prevent stimulation of the receptor by increasing or decreasing its binding capacity. Such interactors may be provided in short-acting or long-acting forms. Certain short-acting interactors may act quickly, but their effects may last only a few hours. Certain long-acting interactors may take longer to act, but their effects may last longer. The interactor may be selected and/or designed based on, for example, one or more of the desired delivery and dosage, the active pharmacological ingredient, the penetration modifier, the penetration enhancer, the matrix, and the condition being treated. The adrenergic receptor interactor may be an adrenergic receptor blocker. The adrenergic receptor interactor may be a terpene (e.g., a volatile unsaturated hydrocarbon found in essential oils of plants, derived from isoprene units) or a C3-C22 alcohol or acid, preferably a C7-C18 alcohol or acid. In certain embodiments, the adrenergic receptor interactor may comprise farnesol, linoleic acid, arachidonic acid, docosahexanoic acid, eicosapentanoic acid, and/or docosapentanoic acid. The acid may be a carboxylic acid, phosphoric acid, sulfuric acid, hydroxamic acid, or a derivative thereof. The derivative may be an ester or an amide. For example, the adrenergic receptor interactor may be a fatty acid or a fatty alcohol.

The C3-C22 alcohol or acid may be an alcohol or acid having a straight C3-C22 hydrocarbon chain, for example a C3-C22 hydrocarbon chain optionally comprising at least one double bond, at least one triple bond, or at least one double bond and one triple bond; wherein the hydrocarbon chain is optionally substituted with 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, C _1-4 alkylcarbonyl, or formyl; And -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- are optionally additionally inserted. R ^a and R ^b are each, independently, hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, hydroxyl, or haloalkyl.

Fatty acids with a high degree of unsaturation are effective candidates for enhancing drug penetration. Unsaturated fatty acids showed higher potentiation than saturated fatty acids, and the potentiation increased with the number of double bonds. (See A. Mittal, et al., Status of Fatty Acids as Skin Penetration Enhancers - A Review, Current Drug Delivery , 2009, 6, pp. 274-279, incorporated herein by reference.) Furthermore, the position of the double bond affects the potentiation activity of fatty acids. Differences in the physicochemical properties of fatty acids due to differences in double bond position likely determine the efficacy of these compounds as skin penetration enhancers. As the double bond position moves toward the hydrophilic end, skin distribution increases. Fatty acids with even-numbered double bonds have been reported to more rapidly affect the structural perturbation of both the stratum corneum and the skin than those with odd-numbered double bonds. Cis-unsaturation within the chain tends to enhance activity.

Adrenergic receptor interactors may be terpenes. The hypotensive activity of terpenes in essential oils has been reported. See Menezes IA et al., Z. Naturforsch. 65c:652-66 (2010), incorporated herein by reference. In certain embodiments, the penetration enhancer may be a sesquiterpene. Sesquiterpenes are terpenes composed of three isoprene units and have the empirical formula C ₁₅ H ₂₄ . Like monoterpenes, sesquiterpenes can be acyclic or ring-containing, and include many unique combinations. Biochemical transformations, such as oxidation or rearrangement, produce related sesquiterpenoids.

The adrenergic receptor interactor may be an unsaturated fatty acid, such as linoleic acid. In certain embodiments, the penetration enhancer may be farnesol. Farnesol is a 15-carbon organic compound that is an acyclic sesquiterpene alcohol, and is the naturally occurring dephosphorylated form of farnesyl pyrophosphate. Under standard conditions, it is a colorless liquid. It is hydrophobic and insoluble in water, but miscible with oils. Farnesol can be extracted from plant oils such as citronella, neroli, cyclamen, and tuberose. It is an intermediate in the biological synthesis of cholesterol from mevalonate in vertebrates. It has a young floral or faint citrus-lime odor and is used in perfumes and fragrances. Farnesol has been reported to selectively kill acute myeloid leukemia embryonic cells and leukemia cell lines more selectively than primary hematopoietic stem cells. Here, see Rioja A. et al., FEBS Lett 467 (2-3): 291-5 (2000), incorporated herein by reference. The vasoactive properties of farnesyl analogues have been reported. Roullet, J.B., et al., J. Clin. Invest., 1996, 97: 2384-2390]. Both farnesol and N-acetyl-S-trans, trans-farnesyl-L-cysteine (AFC) inhibited vasoconstriction in rat aortic rings.

In some embodiments, the interactor may be an aporine alkaloid. For example, the interactor may be dicentrin.

In general, interactors can also be vasodilators or therapeutic vasodilators. Vasodilators are drugs that dilate or open blood vessels. They are typically used to treat hypertension, heart failure, and angina, but can also be used to treat other conditions, including glaucoma. Some vasodilators act primarily on resistance vessels (arteriolar dilators) and are used for hypertension, heart failure, and angina. However, reflex cardiac stimulation makes some arteriolar dilators inappropriate for angina. Venodilators are highly effective for angina and are sometimes used for heart failure, but are not used as a first-line treatment for hypertension. Vasodilator drugs can be mixed (or balanced) vasodilators, as they dilate both arteries and veins, making them widely applicable to hypertension, heart failure, and angina. Some vasodilators, due to their mechanism of action, also have other important actions that may enhance their therapeutic utility or provide additional therapeutic benefits. For example, some calcium channel blockers not only dilate blood vessels but also depress the mechanical and electrical function of the heart, which enhances their antihypertensive action and provides additional therapeutic effects such as blocking arrhythmias.

Vasodilator drugs can be classified by their site of action (arteries vs. veins) or mechanism of action. Some drugs primarily dilate resistance vessels (arteriodilators; e.g., hydralazine), while others primarily affect venous capacitance vessels (venodilators; e.g., nitroglycerin). Many vasodilator drugs have mixed arteriolar and venous dilator properties (mixed dilators; e.g., alpha-adrenergic receptor antagonists, angiotensin-converting enzyme inhibitors), such as phentolamine.

However, it is more common to classify vasodilator drugs according to their primary mechanism of action. The figure on the right shows an important mechanistic classification of vasodilator drugs. Drugs in these classes, as well as other classes that produce vasodilation, include: alpha-adrenergic receptor antagonists (alpha-blockers); angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); beta2-adrenergic receptor agonists (p2-agonists); calcium channel blockers (CCBs); centrally acting sympatholytics; direct-acting vasodilators; endothelin receptor antagonists; ganglion blockers; nitroglycerides; phosphodiesterase inhibitors; potassium channel openers; and renin inhibitors.

In general, the active or inactive ingredient or ingredients may be substances or compounds that produce increased blood flow or tissue flushing to enable a modification or difference (increase or decrease) in the transmucosal absorption of the API(s) and/or have a positive or negative heat of solution that serves as an aid to modify (increase or decrease) the transmucosal absorption.

Sequence of penetration enhancers and active pharmacological ingredients

The arrangement, order, and sequence of the penetration enhancer(s) and the active pharmaceutical ingredient(s) (API(s)) delivered to a given mucosal surface can be varied to deliver a desired pharmacokinetic profile. For example, the penetration enhancer(s) can be applied first by a film, swab, spray, gel, rinse, or as the first layer of a film, followed by the API(s) by a single film, swab, or second film layer. The order can be reversed or modified, for example, the API(s) can be applied first by a film, swab, or as the first layer of a film, followed by the penetration enhancer(s) by a film, swab, spray, gel, rinse, or second film layer. In another implementation, the penetration enhancer(s) can be applied by a film, followed by the drug by another film. For example, depending on the desired pharmacokinetic profile, a film of penetration enhancer(s) was positioned beneath a film containing the API(s) or a film containing the API(s) was positioned beneath a film containing the penetration enhancer(s).

For example, to precondition the mucosa for further absorption of the API(s), the penetration enhancer(s) may be used as a pretreatment alone or in combination with at least one API. This treatment may be followed by another treatment utilizing the pure penetration enhancer(s) following the mucosal application of at least one API. The pretreatment may be applied as a separate treatment (film, gel, solution, swab, etc.) or as a layer within a multilayer film structure comprising one or more layers. Similarly, the pretreatment(s) or API(s) may be incorporated into a separate domain of a single film designed to dissolve and release into the mucosa prior to release of the secondary domain, with or without the pretreatment(s) or API(s). The active ingredient may then be delivered from the secondary treatment, either alone or in combination with additional penetration enhancer(s). Additionally, there may be a tertiary treatment or domain that delivers additional penetration enhancer(s) and/or at least one API(s) or prodrug(s) in different proportions relative to each other or to the total loading of the other treatments. This allows for a customized pharmacodynamic profile to be achieved. In this manner, the product may have one or more domains with penetration enhancers and APIs that can modify the mucosal application sequence, composition, concentration, or overall loading to achieve a desired absorption amount and/or rate to achieve the intended pharmacodynamic profile and/or pharmacodynamic effect.

The film format may be oriented so that there are no distinct sides, or so that the film has one or more sides of a multilayer film whose edges are co-terminal (having or meeting at a shared boundary or limit).

Pharmaceutical compositions can be chewable or gelatin-based dosage forms, sprays, gums, gels, creams, tablets, liquids, or films. The compositions can include textures on their surfaces, such as microneedles or microprotrusions. Recently, in the pursuit of enhanced skin permeability, the use of micron-scale needles has been shown to significantly increase transdermal delivery, particularly for macromolecules. Most drug delivery studies have focused on rigid microneedles, which have demonstrated enhanced skin permeability for a wide range of molecules and nanoparticles in vitro. In vivo studies have demonstrated the delivery of oligonucleotides, insulin-induced reductions in blood glucose levels, and the induction of immune responses from protein and DNA vaccines. For such studies, needle arrays have been used to puncture the skin to enhance delivery by diffusion or iontophoresis, or as drug carriers to release drugs from the microneedle surface coating into the skin. Hollow microneedles have also been developed and demonstrated to microinject insulin into diabetic rats. To demonstrate the practical application of microneedles, the ratio of microneedle breaking force to skin insertion force (i.e., safety margin) was found to be optimal for needles with a small tip radius and large wall thickness. Microneedles inserted into the skin of human subjects were reported to be painless. Furthermore, these results suggest that microneedles are a promising technology for delivering therapeutic compounds into the skin, with a wide range of potential applications. Using tools from the microelectronics industry, microneedles have been fabricated into various sizes, shapes, and materials. For example, the microneedles can be polymeric microscopic needles that deliver encapsulated drugs in a minimally invasive manner, but other suitable materials can also be used.

Applicants have discovered that microneedles can be used to enhance drug delivery, particularly the claimed composition, through the oral mucosa. Microneedles create micron-sized pores in the oral mucosa, which can enhance drug delivery across the mucosa. Solid, hollow, or soluble microneedles can be fabricated from any suitable material, including but not limited to metals, polymers, glasses, and ceramics. Microfabrication processes can include photolithography, silicon etching, laser cutting, metal electroplating, metal electropolishing, and molding. The microneedles can be solid, used to pre-treat tissue, and are removed prior to film application. The drug-loaded polymer film described herein can be used as a matrix material for the microneedles themselves. This film can have microneedles or microprotrusions fabricated on its surface, which dissolve after forming microchannels in the mucosa through which the drug can penetrate.

The term "film" can include films and sheets of any shape, including rectangular, square, or other desired shapes. The film can have a desired thickness and size. In a preferred embodiment, the film can have a thickness and size that allows it to be administered to a user, for example, into the mouth of a user. The film can have a relatively thin thickness, such as from about 0.0025 mm to about 0.250 mm, or the film can have a somewhat thicker thickness, such as from about 0.250 mm to about 1.0 mm. For some films, the thickness can be greater, such as greater than about 1.0 mm, or thinner, such as less than about 0.0025 mm. The film can be a single layer, or the film can be multilayer, including a laminate or multicast film. The penetration enhancer and the pharmacologically active ingredient can be combined in a single layer, each contained in a separate layer, or each contained in discrete regions in the same dosage form. In certain embodiments, the pharmacologically active ingredient contained in the polymer matrix may be dispersed within the matrix. In certain embodiments, the penetration enhancer contained in the polymer matrix may be dispersed within the matrix.

Oral dissolving films can be classified into three main categories: fast dissolving, intermediate dissolving, and slow dissolving. Furthermore, oral dissolving films can include a combination of any of the above categories. Fast dissolving films can dissolve in the mouth within about 1 second to about 30 seconds, including at least 1 second, at least 5 seconds, at least 10 seconds, at least 20 seconds, and less than 30 seconds. Intermediate dissolving films can dissolve in the mouth within about 1 minute to about 30 minutes, including at least 1 minute, at least 5 minutes, at least 10 minutes, at least 20 minutes, or less than 30 minutes, and slow dissolving films can dissolve in the mouth within 30 minutes or more. Generally, fast dissolving films can be made of low molecular weight hydrophilic polymers (e.g., polymers having a molecular weight of about 1,000 to 9,000 daltons, or less than 200,000 daltons). In contrast, slow-dissolving films typically contain high-molecular-weight polymers (e.g., those with molecular weights in the millions). Intermediate-dissolving films tend to fall between fast-dissolving and slow-dissolving films.

The use of an intermediate dissolution film may be desirable. An intermediate dissolution film may dissolve relatively quickly while maintaining a good level of mucosal adhesion. An intermediate dissolution film is also flexible, quickly wettable, and typically non-irritating to the user. Such an intermediate dissolution film can provide a sufficiently rapid dissolution rate, most preferably within about 1 to about 20 minutes, while providing an acceptable level of mucosal adhesion once placed in the user's oral cavity, preventing the film from being easily removed. This ensures delivery of the pharmacologically active ingredient to the user.

A pharmaceutical composition may contain one or more pharmacologically active ingredients. The pharmacologically active ingredients may be a single pharmacological ingredient or a combination of pharmacological ingredients. The pharmacologically active ingredients may be anti-inflammatory analgesics, steroidal anti-inflammatory agents, antihistamines, local anesthetics, bactericidal agents, antiseptics, vasoconstrictors, hemostatic agents, chemotherapeutic agents, antibiotics, keratolytics, cauterizing agents, antiviral agents, antirheumatic agents, antihypertensives, bronchodilators, halalcholinergics, anxiolytics, antiemetics, hormones, peptides, proteins, or vaccines. The pharmacologically active ingredients may be compounds, pharmacologically acceptable salts of drugs, prodrugs, derivatives, drug complexes, or analogues of drugs. 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, one or more pharmacologically active ingredients may be included in the film. Pharmacologically active ingredients include ace inhibitors, anti-anginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, Amphetamines, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, antitussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplastics, anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants, blood modifiers, bone metabolism regulators, cardiovascular agents, central nervous system stimulates, cholinesterase inhibitors, Contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis management agents, enzymes, erectile dysfunction therapies, fertility agents, gastrointestinal agents, homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments, muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics, parasympathetic Parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives, smoking cessation aids, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, Peripheral vasodilators, psychotropics, stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, These may include, but are not limited to, uterine relaxants, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs, diagnostic agents, imaging agents, dyes, or tracers, and combinations thereof.

For example, pharmacologically active ingredients include buprenorphine, naloxone, acetaminophen, riluzole, clobazam, rizatriptan, propofol, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac, Fenclofenac, clidanac, flurbiprofen, fentiazac, bupexamac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, tiaramide hydrochloride, hydrocortisone, predonisolone, dexarnethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, predonisolone acetate Methyl predonisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumetasone, fluorometholone, beclomethasone diproprionate, fluocinonide, fluocinonide, edaravone, lurasidone, esomeprazole, lumateperone, naldmedine, doxylamine, pyridoxine, diphenhydramine hydrochloride, diphenhydramine salicylate Diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate isothipendyl hydrochloride, tripelennamine hydrochloride, promethazine hydrochloride, mesidilazine hydrochloride dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoic acid 2-(die-ethylamino) ethyl ester hydrochloride, procaine Procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dyclonine, dyclonine hydrochloride, thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone iodide, cetylpyridium cetylpyridinium chloride, eugenol, trimethylammonium bromide, naphazoline nitrate, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbazochrome sodium sulfanate, rutin, hesperidin, Sulfamine, sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole, sulfisomidine, sulfamethizole, nitrofurazone, penicillin, methicillin, oxacillin, cefalotin, cefalordin, erythromcycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, salicylic acid, podophyllum resin, podolipox, cantharidin, chloroacetic acids, silver nitrate, protease inhibitors, thymadine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, attachment and adsorption inhibitors, nucleoside analogues such as acyclovir, penciclovir, valacyclovir and ganciclovir, heparin, insulin, LHRH, TRH, interferons, Oligonucleides, calcitonin, octreotide, omeprazone, fluoxetine, ethinylestradiol, amiodipine, paroxetine, enalapril, linsinopril, leuprolide, prevastatin, lovastatin, norethindrone, risperidone, olanzapine, albuterol, hydrochlorothiazide, pseudoephridrine, warfarin, terazosin, cisapride, Ipratropium, busprione, methylphenidate, levothyroxine, zolpidem, levonorgestrel, glyburide, benazepril, medroxyprogesterone, clonazepam, ondansetron, losartan, quinapril, nitroglycerin, midazolam versed, cetirizine, doxazosin, glipizide, vaccine hepatitis B, salmeterol, sumatriptan, triamcinolone Acetonide (triamcinolone acetonide), goserelin, beclomethasone, granisteron, desogestrel, alprazolam, estradiol, nicotine, interferon beta 1A, cromolyn, fosinopril, digoxin, fluticasone, bisoprolol, calcitril, captorpril, butorphanol, clonidine, premarin, testosterone, sumatriptan, clotrimazole, bisacodyl, The pharmacologically active ingredient may be dextromethorphan, nitroglycerin, nafarelin, dinoprostone, nicotine, bisacodyl, goserelin, or granisetron. In certain embodiments, the pharmacologically active ingredient may be epinephrine and a benzodiazepine such as diazepam or lorazepam, or alprazolam.

epinephrine , diazepam and alprazolam Implementation yes

In one embodiment, a composition comprising epinephrine or a salt or ester thereof can have a biodelivery profile similar to that of epinephrine administered by injection, for example using an EpiPen. Epinephrine may be present in a dosage of about .01 mg to about 100 mg per dose, for example, a dosage of 0.1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, including greater than 0.1 mg, greater than 5 mg, greater than 20 mg, greater than 30 mg, greater than 40 mg, greater than 50 mg, greater than 60 mg, greater than 70 mg, greater than 80 mg, greater than 90 mg or less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg or less than 5 mg, or any combination thereof. In another example, a composition comprising diazepam may have a biodelivery profile similar to or better than that of diazepam tablets or gels.

The diazepine or its salts may be present in a range of about 0.5 mg to about 100 mg per dosage, for example, 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 per dosage, including greater than 1 mg, greater than 5 mg, greater than 20 mg, greater than 30 mg, greater than 40 mg, greater than 50 mg, greater than 60, greater than 70 mg, greater than 80 mg, greater than 90 mg, or less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg or less than 5 mg, or any combination thereof.

In another example, a composition (e.g., comprising alprazolam, diazepam, or epinephrine) comprises (a) an aggregation inhibitor; (b) a charge-modifying agent; (c) a pH adjusting agent; (d) a degradative enzyme inhibitor; (e) a mucolytic or mucopurifying agent; (f) a ciliary inhibitor; (g) (i) a surfactant; (ii) a bile salt; (ii) a phospholipid additive, mixed micelle, liposome, or carrier; (iii) an alcohol; (iv) an enamine; (v) an NO donor compound; (vi) a long-chain amphiphilic molecule; (vii) a small hydrophobic permeation enhancer; (viii) a sodium or salicylic acid derivative; (ix) a glycerol ester of acetoacetic acid; (x) a cyclodextrin or a beta-cyclodextrin derivative; (xi) a medium-chain fatty acid; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) an N-acetyl amino acid or a salt thereof; (xv) an enzyme capable of degrading a selected membrane component; (ix) a fatty acid synthesis inhibitor; (x) a cholesterol synthesis inhibitor; (xi) a membrane permeability enhancer selected from any combination of the membrane permeability enhancers mentioned in (i)-(x); (h) a modulator of epithelial junction physiology; (i) a vasodilator; (j) a selective transport enhancer; or (k) a stabilizing delivery vehicle, carrier, mucoadhesive, scaffold or complex forming agent in which the compound is effectively combined, associated, contained, encapsulated or bound to stabilize the compound for enhanced mucosal delivery, wherein the formulation of the compound with said mucosal delivery enhancing agent provides increased bioavailability of the compound in the plasma of a subject; and may have a suitable non-toxic, non-ionic alkyl glycoside having a hydrophobic alkyl group joined by a linkage to a hydrophilic saccharide, together with a mucosal delivery-enhancing agent selected from. As with other embodiments for diazepam and alprazolam, the formulation may comprise substantially the same active pharmaceutical ingredient (API): enhancing agent ratio.

Treatment or Adjunctive Treatment

Status epilepticus (SE) is an epileptic seizure that lasts longer than 5 minutes or occurs more than once within 5 minutes, during which the person does not return to normal. Other previous definitions used a 30-minute time limit. Benzodiazepines are some of the most effective medications for acute seizures and status epilepticus. The most commonly used benzodiazepines to treat status epilepticus include diazepam (Valium), lorazepam (Ativan), or midazolam (Versed). The pharmacologically active ingredient in a pharmacological composition (e.g., a pharmacological composition film) can be used to treat: Angelman syndrome (AS), benign rolandic epilepsy of childhood (BREC) and benign rolandic epilepsy with centro-temporal spikes (BECTS), CDKL5 disorder, childhood absence epilepsy (CAE), myoclonic-astatic epilepsy or Doose syndrome, Dravet syndrome, early myoclonic encephalopathy (EME), epilepsy with generalized tonic-clonic seizures alone (EGTCS) or epilepsy with tonic-clonic seizures on awakening, and myoclonus-absent frontal lobe epilepsy. Frontal lobe epilepsy with myoclonic-absences, Glut1 deficiency syndrome, hypothalamic hamartoma (HH), infantile spasms (also called IS) or West syndrome, juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), Lafora progressive myoclonus epilepsy (Lafora disease), Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), Ohtahara syndrome (OS), Panayiotopoulos syndrome (PS), PCDH19 epilepsy, progressive myoclonic epilepsies, Rasmussen's syndrome, Ring chromosome 20 syndrome (RC20), reflex epilepsies, TBCK-related intellectual disability syndrome, temporal lobe epilepsy, and seizure-related neurocutaneous syndromes including Incontinentia pigmenti, Neurofibromatosis Type 1, Sturge Weber Syndrome (Encephalotrigeminal Angiomatosis), and Tuberous Sclerosis Complex.

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

The composition may include a polymer matrix. Any polymer matrix can be used, as long as it is orally soluble or erodible. The dosage form must have sufficient bioadhesiveness to prevent easy removal and form a gel-like structure upon administration. Rapid-release, delayed-release, controlled-release, and sustained-release compositions are all considered embodiments, but they are capable of intermediate dissolution in the oral cavity and are particularly suitable for delivering pharmacologically active ingredients.

branched polymer

The pharmaceutical composition film may comprise a dendritic polymer, which may comprise highly branched macromolecules having various structural architectures. The dendritic polymer may comprise a dendrimer, a dendronized polymer (dendri-grafted polymer), a linear dendritic hybrid, a multi-arm star polymer, or a hyperbranched polymer.

Hyperbranched polymers are highly branched polymers with structural imperfections. However, they can be synthesized in a single step, which is advantageous over other dendritic structures, making them suitable for bulk applications. Other properties of these polymers, in addition to their globular structure, include abundant functional groups, intramolecular cavities, low viscosity, and high solubility. Dendritic polymers have been used in several drug delivery applications. For example, see Dendrimers as Drug Carriers: Applications in Different Routes of Drug Administration. J Pharm Sci, Vol. 97, 2008, 123-143, incorporated herein by reference.

Dendritic polymers can have internal cavities capable of encapsulating drugs. The steric hindrance caused by the dense polymer chains can prevent drug crystallization. Therefore, branched polymers can offer additional advantages in formulating drugs that can crystallize within a polymer matrix.

Examples of suitable dendritic polymers include poly(ether)-based dendrons, dendrimers and hyperbranched polymers, poly(ester)-based dendrons, dendrimers and hyperbranched polymers, poly(thioether)-based dendrons, dendrimers and hyperbranched polymers, poly(amino acid)-based dendrons, dendrimers and hyperbranched polymers, poly(arylalkylene ether)-based dendrons, dendrimers and hyperbranched polymers, poly(alkyleneimine)-based dendrons, dendrimers and hyperbranched polymers, poly(amidoamine)-based dendrons, dendrimers and hyperbranched polymers.

Other examples of hyperbranched polymers include poly(amines), polycarbonates, poly(ether ketones), polyurethanes, polycarbosilanes, polysiloxanes, poly(esteramines), poly(sulfone amines), poly(urea urethanes), or polyether polyols such as polyglycerols.

The film can be formed by combining at least one polymer and a solvent, optionally including other components. The solvent can be a polar organic solvent, including but not limited to water, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent can be a non-polar organic solvent, such as methylene chloride. The film can be formed using a selected casting or deposition method and a controlled drying process. For example, the film can be formed through a controlled drying process, which applies heat and/or radiation energy to a wet film matrix to form a viscoelastic structure, thereby controlling the uniformity of the film content. The controlled drying process includes contacting the film with air alone, heat alone, or heat and air together, with the film on top of the film, with the film underneath, or with a substrate supporting the cast, deposited, or extruded film, or with one or more surfaces simultaneously or at different times during the drying process. Some of these processes are described in more detail in U.S. Patent Nos. 8,765,167 and 8,652,378, which are incorporated herein by reference. Alternatively, the film may be extruded as described in U.S. Patent Publication No. 2005/0037055 A1, which is incorporated herein by reference.

The polymer included in the film can be water-soluble, water-swellable, water-insoluble or a combination of one or more water-soluble, water-swellable or water-insoluble polymers. The polymer can include cellulose, a cellulose derivative or a gum. Specific examples of useful water-soluble polymers can include, but are not limited to, the group consisting of polyethylene oxide, pullulan, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tranthan gum, guar gum, acacia gum, gum arabic, polyacrylic acid, methyl methacrylate copolymers, carboxy vinyl 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 acetate phthalate, hydroxypropyl methyl cellulose phthalate, and combinations thereof. For higher viscosity applications, it may be desirable to introduce polymers that provide higher viscosity levels than those for lower viscosity applications.

As used herein, the terms "water-soluble polymer" and variants thereof refer to polymers that are at least partially soluble in water, and preferably completely or overwhelmingly soluble in water, or that absorb water. Polymers that absorb water are often referred to as water-swellable polymers. Materials useful in the present invention may be water-soluble or water-swellable at room temperature and other temperatures, such as temperatures above room temperature. Additionally, the materials may be water-soluble or water-swellable at pressures below atmospheric pressure. In some embodiments, films formed from such water-soluble polymers may be sufficiently water-soluble that they dissolve upon contact with body fluids.

Other polymers useful for incorporation into the film include biodegradable polymers, copolymers, block polymers, or combinations thereof. The term "biodegradable" is understood to include materials that degrade chemically (i.e., bioerodible materials) as opposed to materials that degrade physically. The polymers incorporated into the film may also include a combination of biodegradable or bioerodible materials. Known useful polymers or classes of polymers that meet the above criteria include: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxane, polyoxalate, poly(alpha-ester), polyanhydride, polyacetate, polycaprolactone, poly(orthoester), polyamino acid, polyaminocarbonate, polyurethane, polycarbonate, polyamide, poly(alkyl cyanoacrylate), and mixtures and copolymers thereof. Additional useful polymers are stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propanoic acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid)/poly(glycolic acid)/polyethylene glycol copolymers, copolymers of polyurethane and poly(lactic acid), copolymers of alpha-amino acids and capronic acid, copolymers of alpha-benzyl glutamate and polyethylene glycol, copolymers of polysuccinates and poly(glycols), polyphosphazenes, polyhydroxy-alkanoates or mixtures thereof. The polymer matrix may comprise one, two, three, four or more components.

While a variety of different polymers may be used, it is desirable to select a polymer that provides the film with mucoadhesive properties, as well as the desired dissolution and/or degradation rate. In particular, the desired duration of time for the film to remain in contact with the mucosal tissue depends on the type of pharmacologically active ingredient contained in the composition. Some pharmacologically active ingredients may require only a few minutes to be transported through the mucosal tissue, while others may require hours or even longer. Therefore, in some embodiments, one or more water-soluble polymers, as described above, may be used to form the film. However, in other embodiments, it may be desirable to use a combination of water-swellable, water-insoluble, and/or biodegradable polymers and water-soluble polymers, as provided above. The inclusion of one or more water-swellable, water-insoluble, and/or biodegradable polymers may provide a film with a slower dissolution or degradation rate than a film formed solely with water-soluble polymers. In this way, the film can adhere to the mucosal tissue for a longer period of time, such as up to several hours, which may be desirable for the delivery of certain pharmacologically active ingredients.

Preferably, the individual film dossiers of the pharmacological film may have a suitable thickness and a small size, which is between about 0.0625 and 3 inches. The film size is greater than 0.0625 inches, greater than 0.5 inches, greater than 1 inch, greater than 2 inches, about 3 inches, or greater than 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, or less than 0.0625 inches on at least one side, and greater than 0.0625 inches, greater than 0.5 inches, greater than 1 inch, greater than 2 inches, or greater than 3 inches, less than 3 inches, less than 2 inches, less than 1 inch, less than 0.5 inches, or less than 0.0625 inches on at least one other side. The aspect ratios, including thickness, length, and width, can be optimized by those skilled in the art based on the chemical and physical properties of the polymer matrix, the active pharmaceutical ingredient, the dosimeter, reinforcing agents, and related additives, as well as the dimensions of a given dispensing unit. The film dosimeter should have good adhesion when placed in the oral cavity or sublingual area of the user. In addition, the film dosimeter should disperse and dissolve at a reasonable rate, most preferably within about 1 minute and dissolved within about 3 minutes. In some embodiments, the film dosimeter can disperse and dissolve at a rate of from about 1 to about 30 minutes, for example, from about 1 to about 20 minutes, or at least 1 minute, at least 5 minutes, at least 7 minutes, at least 10 minutes, at least 12 minutes, at least 15 minutes, at least 20 minutes, at least 30 minutes, at least about 30 minutes, or less than about 30 minutes, less than 20 minutes, less than 15 minutes, less than 12 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, or less than 1 minute. The sublingual dispersion velocity may be shorter than the buccal dispersion velocity.

For example, in some embodiments, the film may comprise 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, any of those provided above. In some embodiments, the water-soluble polymer may comprise a hydrophilic cellulosic polymer, such as hydroxypropyl cellulose and/or hydroxypropyl methyl cellulose. In some embodiments, at least one water-swellable, water-insoluble, and/or biodegradable polymer may also be included in the polyethylene oxide-based film. Any of the water-swellable, water-insoluble, or biodegradable polymers provided above may be used. The second polymer component can be used in an amount of from about 0 wt % to about 80 wt % of the polymer component, more specifically from about 30 wt % to about 70 wt %, and even more specifically from about 40 wt % to about 60 wt %, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, and greater than 70%, about 70%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%.

Additives may be included in the film. Examples of types of additives include preservatives, antimicrobials, excipients, lubricants, buffering agents, stabilizers, blowing agents, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, anti-adherents, Acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, anti-tacking agents, anti-static agents, and mixtures thereof. As used herein, the term "stabilizer" means an excipient capable of preventing aggregation or other physical degradation as well as chemical degradation of the active pharmaceutical ingredient, other excipients, or a combination thereof.

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

Antioxidants (i.e. pharmacologically compatible compounds or compositions which slow down, inhibit, stop and/or halt oxidation processes) include in particular the following substances: tocopherol and its esters, sesamol from sesame oil, coniferyl benzoate from benzoin resin, nordihydroguaietic resin and nordihydroguaiaretic acid (NDGA), gallates (e.g. methyl, ethyl, propyl, amyl, butyl, lauryl gallates), butylated hydroxyanisole (BHA/BHT, also butyl-p-cresol); Ascorbic acid and its salts and esters (e.g., acobyl palmitate), erythorbinic acid (isoascorbic acid) and its salts and esters, monothioglycerol, sodium formaldehyde sulfoxylate, sodium metabisulfate, sodium bisulfite, sodium sulfite, potassium metabisulfite, butylated hydroxy anisole, butylated hydroxy toluene (BHT), propionic acid. Typical antioxidants are tocopherols, e.g., α-tocopherol and its esters, butylated hydroxy toluene, and butylated hydroxy anisole. The term "tocopherol" also includes esters of tocopherol. A known tocopherol is α-tocopherol. The term "α-tocopherol" includes esters of α-tocopherol (e.g., α-tocopherol acetate).

Sequestering agents (i.e., any compound capable of engaging in host-guest complex formation with another compound, such as the active ingredient or other excipients, also referred to as a sequestering agent) include calcium chloride, calcium disodium ethylenediamine tetra-acetate, glucono delta-lactone, sodium gluconate, potassium gluconate, sodium tripolyphosphate, sodium hexametaphosphate, and combinations thereof. Sequestrants also include cyclic oligosaccharides, such as cyclodextrins, cyclomannins (five or more α-D-mannopyranose units linked at the 1,4 positions by α-linkages), cyclogalactins (five or more β-D-galactopyranose units linked at the 1,4 positions by β-linkages), cycloaltrins (five or more α-D-altropyranose units linked at the 1,4 positions by α-linkages), and combinations thereof.

pH adjusting agents include acids (e.g., tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, adipic acid, acetic acid, succinic acid, adipic acid, and maleic acid), acidic amino acids (e.g., glutamic acid, aspartic acid), inorganic salts of such acidic substances (e.g., alkali metal salts, alkaline earth metal salts, ammonium salts), salts of the acidic substances having organic bases (e.g., basic amino acids such as lysine, arginine, meglumine, etc.), and solvates (e.g., hydrates) thereof. Other examples of pH adjusting agents are silicated microcrystalline cellulose, magnesium aluminometasilicate, calcium phosphate salts (e.g., calcium hydrogen phosphate enhydroxide or hydrate, calcium, sodium, or potassium carbonate or hydrogen carbonate and calcium lactate or mixtures thereof), sodium and/or calcium salts of carboxymethyl cellulose and cross-linked carboxymethylcellulose (e.g., croscarmellose sodium and/or calcium), polacrilin potassium, sodium and/or calcium alginate, ducusate sodium, magnesium calcium, aluminum, or zinc stearate, magnesium palmitate, and magnesium oleate, sodium stearyl fumarate, and combinations thereof.

Examples of emulsifiers and/or surfactants include poloxamers or pluronics, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylates and hydrogenated castor oil, alkylpolyolsides, grafted water-soluble proteins on hydrophobic backbones, lecithin, glyceryl monostearate, glyceryl monostearate/polyoxyethylene stearate, ketostearyl alcohol/sodium lauryl sulfate, carbomers, phospholipids, (C ₁₀ -C ₂₀ )-alkyl and alkylene carboxylates, alkyl ether carboxylates, propyl alcohol sulfates, propyl alcohol ether sulfates, alkyl amide sulfates and sulfonates, acyl esters of fatty acid alkyl amide polyglycol ether sulfates, alkanesulfonates and hydroxyalkanesulfonates, olefinsulfonates, isethionates, α-Sulpho fatty acid esters, alkylbenzenesulfonates, alkylphenol glycol ether sulfonates, sulfosuccinates, sulfosuccinic monoesters and diesters, phenyl alcohol ether phosphates, protein/fatty acid condensation products, alkyl monoglyceride sulfates and sulfonates, alkyl glyceride ether sulfonates, fatty acid methyltaurides, fatty acid sarcosinates, sulforicinoleates and acyl glutamates, quaternary ammonium salts (e.g., di-(C ₁₀ -C ₂₄ )alkyl-dimethyl ammonium chloride or bromide), (C ₁₀ -C ₂₄ )alkyl-dimethylethylammonium chloride or bromide, (C ₁₀ -C ₂₄ )alkyl-trimethylammonium chloride or bromide (e.g., cetyltrimethylammonium chloride or bromide), (C ₁₀ -C ₂₄ )alkyl-dimethylbenzylammonium chloride or bromide)(e.g., (C ₁₂ -C ₁₈ )-alkyl-dimethylbenzylammonium chloride), N―(C ₁₀ -C ₁₈ )-alkyl-pyridinium chloride or bromide (e.g., N―(C ₁₂ -C ₁₆ )-alkyl-pyridinium chloride or bromide), N―(C ₁₀ -C ₁₈ )-alkyl-isoquinolium chloride, bromide or monoalkyl sulfate, N―(C ₁₂ -C ₁₈ )-alkyl-polyolaminoformylmethylpyridinium chloride, N―(C ₁₂ -C ₁₈ )-alkyl-N-methylmorpholinium chloride, bromide or monoalkyl sulfate, N―(C ₁₂ -C ₁₈ )-alkyl-N-ethylmorpholinium chloride, bromide or Monoalkyl sulfates, (C ₁₆ -C ₁₈ )-alkyl-pentaoxyethylammonium chloride, diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride, salts of N,N-di-ethylaminoethylstearylamide and oleylamide having hydrochloride acid, acetic acid, lactic acid, citric acid, phosphoric acid, N-acylaminoethyl-N,N-diethyl-N-methylammonium chloride, bromides or monoalkyl sulfates, and N-acylaminoethyl-N,N-diethyl-N-benzylammonium chloride, bromides or monoalkyl sulfates (wherein "acyl" is for example stearyl or oleyl), and combinations thereof.

Examples of UV stabilizers include UV absorbers (e.g., benzophenone), UV scavengers (i.e., any compound that dissipates UV energy as heat rather than having a decomposition effect), scavengers (i.e., any compound that removes free radicals resulting from UV radiation exposure), and combinations thereof.

In other specific examples, the stabilizer is ascorbyl palmitate, ascorbic acid, alpha tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, cysteine HC1, citric acid, ethylenediamine tetraacetic acid (EDTA), methionine, sodium citrate, sodium ascorbate, sodium thiosulfate, sodium metabisulfite, sodium bisulfite, propyl gallate, glutathione, thioglycerol, a singlet oxygen quencher, a hydroxyl radical scavenger, a hydroxide scavenger, a reducing agent, a metal chelating agent, a detergent, a carotropy, and combinations thereof. "Single oxygen quenchers" include, but are not limited to, alkyl imidazoles (e.g., histidine, L-carmocin, histamine, imidazole 4-acetic acid), indoles (e.g., tryptophan and its derivatives, e.g., N-acetyl-5-methoxytryptamine, N-acetylserotonin, 6-methoxy-1,2,3,4-tetrahydro-beta-carboline), sulfur-containing amino acids (e.g., methionine, ethionine, djenkolic acid, lanthionine, N-formyl methionine, felinine, S-allyl cysteine, S-aminoethyl-L-cysteine), phenolic compounds (e.g., tyrosine and its derivatives), aromatic acids (e.g., ascorbate, salicylic acid, and its derivatives), azides. (e.g., sodium azide), tocopherols and related vitamin E derivatives, carotene and related vitamin A derivatives. "Hydroxyl radical scavengers" include, but are not limited to, azides, dimethyl sulfoxide, histidine, mannitol, sucrose, glucose, salicylates, and L-cysteine. "Hydroperoxide scavengers" include, but are not limited to, catalase, pyruvate, glutathione, and glutathione peroxidase. "Reducing agents" include, but are not limited to, cysteine and mercaptoethylene. "Metal chelators" include, but are not limited to, EDTA, EGTA, o-phenanthroline, and citrate. "Detergents" include, but are not limited to, SDS and sodium lauroyl sarcosyl. "Chaotropes" include, but are not limited to, guaranidinium hydrochloride, isocyanates, urea, and formamide. As discussed herein, the stabilizers may be present in amounts from 0.0001% to 50% by weight, including greater than 0.0001%, greater than 0.001%, greater than 0.01%, greater than 0.1%, greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% by weight.

Useful additives may include, for example: plant proteins such as gelatin, sunflower protein, soy protein, cottonseed protein, peanut protein, grapeseed protein, whey protein, whey protein isolate, blood protein, egg protein, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar-agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragancanth), pectin, water-soluble derivatives of cellulose: alkyl celluloses hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, for example methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, Hydroxyalkyl cellulose esters such as hydroxybutyl methylcellulose, cellulose esters and cellulose acetate phthalate (CAP), hydroxypropyl methyl cellulose (HPMC); carboxyalkyl cellulose esters such as carboxyalkyl cellulose, carboxyalkylalkyl cellulose, carboxymethyl cellulose ester and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acid and polyacrylic acid esters, polymethacrylic acid and polymethacrylic acid esters, polyvinylacetate, polyvinyl alcohol, polyvinylacetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVA/vinylacetate copolymers, or polycrotonic acid; Also suitable are water-soluble chemical derivatives of phthalated gelatin, gelatin succinate, cross-linked gelatin, shellac, starch, cationically modified acrylates and methacrylates having tertiary or quaternary amino groups, such as diethylaminoethyl groups, which may be quaternized if desired; and other similar polymers.

The additional component may be present in an amount of up to about 80%, preferably from about 0.005% to 50%, and preferably from about 1% to 20%, based on the weight of all composition components, greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, about 80%, greater than 80%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, about 3%, or less than 1%. Other additives may include anti-tackifiers, fluidizing agents and opacifiers such as oxides of magnesium aluminum, silicon and titanium, and are present in an amount of from about 0.005% to about 5%, preferably from about 0.02% to 2%, greater than 0.02%, greater than 0.2%, greater than 0.5%, greater than 1%, greater than 1.5%, greater than 2%, greater than 4%, about 5%, greater than 5%, less than 4%, less than 2%, less than 1%, less than 0.5%, less than 0.2% or less than 0.02%, based on the weight of all film components.

In certain embodiments, the composition may include a plasticizer, which may include a low molecular weight organic plasticizer such as a polyalkylene oxide such as polyethylene glycol, polypropylene glycol, polyethylene-propylene glycol, glycerol, glycerol monoacetate, 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, etc., added in a concentration ranging from about 0.1% to about 40%, preferably from about 0.5% to about 20% by weight of the composition, greater than 0.5%, greater than 1%, greater than 1.5%, greater than 2%, greater than 4%, greater than 5%, greater than 10%, greater than 15%, about 20%, greater than 20%, less than 20%, less than 15%, Less than 10%, less than 5%, less than 4%, less than 2%, less than 1%, or less than 0.5%. Preferably, a compound for improving the textural properties of the film material, such as animal or vegetable fats, may be additionally added in a hydrogenated form. The composition may also include a compound for improving the textural properties of the product. Other components may include a binder that contributes to the easy formation and general quality of the film. Non-limiting examples of binders include starch, natural rubber, pregelatinized starch, gelatin, polyvinyl pyrrolidone, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyacrylamide, polyvinyl oxazolidone, or polyvinyl alcohol.

Additional potential additives include solubility enhancers, such as substances that form inclusion complexes with the active ingredient. These agents can be useful for improving the properties of highly insoluble and/or unstable active ingredients. Typically, these agents are doughnut-shaped molecules with a hydrophobic inner cavity and a hydrophilic outer cavity. The insoluble and/or unstable pharmacologically active ingredient can fit within the hydrophobic cavity, thereby forming a water-soluble inclusion complex that dissolves in water. Thus, the formation of the inclusion complex allows the highly insoluble and/or unstable pharmacologically active ingredient to dissolve in water. A particularly preferred example of such agents is cyclodextrin, a cyclic carbohydrate derived from starch. However, other similar materials are fully contemplated within the scope of the present invention.

Suitable colorants include food, drug, and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. E&C). These colors include dyes, their corresponding lakes, and certain natural and derived dyes. Lakes are dyes absorbed into aluminum hydroxide. Other examples of colorants include known azo dyes, organic or inorganic pigments, or colorants of natural origin. Inorganic pigments, for example oxides or iron or titanium, are preferred and are included in a concentration range of 0.001 to 10%, preferably 0.5 to 3%, based on the weight of all components, more than 0.001%, more than 0.01%, more than 0.1%, more than 0.5%, more than 1%, more than 2%, more than 5%, about 10%, more than 10%, less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01% or less than 0.001%.

The flavoring agent may be selected from natural and synthetic flavoring liquids. Exemplary examples of such agents include volatile oils, synthetic flavoring oils, flavoring agents, oils, liquids, oleoresins, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. A non-limiting representative list of examples includes mint oil, cocoa, and citrus oils such as lemon, orange, lime, and grapefruit, as well as fruit essences and other fruit flavors, including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, and apricot. Other useful flavoring agents include, but are not limited to, aldehydes and esters, such as benzaldehyde (cherry, almond), citral, i.e., alpha-citral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus), aldehyde C-9 (citrus), aldehyde C-12 (citrus), toyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), or 2-dodecenyl (citrus, mandarin), or combinations thereof.

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

Antifoaming and/or defoaming agents may also be used with the film. These agents assist in the removal of air, such as entrapped air, from the film-forming composition. This entrapped air can lead to an uneven film. Simethicone is a particularly useful antifoaming and/or defoaming agent. However, the present invention is not limited thereto, and other suitable antifoaming and/or defoaming agents may be used. Simethicone and related agents may be used for densification purposes. More specifically, these agents facilitate the removal of voids, air, moisture, and similar undesirable components, thereby providing a denser and more uniform film. Agents or components that perform this function may be referred to as densifying or compacting agents. As mentioned above, entrapped air or undesirable components can lead to an uneven film.

Any other optional components described in the previously assigned U.S. Patent Nos. 7,425,292 and 8,765,167 may also be included in the films described herein.

The film composition also preferably contains a buffer to control the pH of the film composition. A buffer of a predetermined level may be incorporated into the film composition to provide a desired pH level encountered when the pharmacologically active ingredient is released from the composition. The buffer is preferably provided in an amount sufficient to control the release from the film and/or absorption of the pharmacologically active ingredient into the body. In some embodiments, the buffer may include sodium citrate, citric acid, bitartrate salt, or combinations thereof.

The pharmaceutical film described herein can be formed by any desired method. Suitable methods are disclosed in U.S. Patent Nos. 8,652,378, 7,425,292, and 7,357,891, which are incorporated herein by reference. In one embodiment, the film-forming composition is formed by first preparing a wetting composition comprising a polymeric carrier matrix and a pharmacologically effective amount of a pharmacologically active ingredient. The wetting composition is cast into a film, which is then sufficiently dried to form a self-supporting film composition. The wetting composition can be cast into individual sheets, or can be cast into sheets, which are then cut into individual sheets.

The pharmaceutical composition can adhere to a mucosal surface. The present invention finds particular use in the localized treatment of fluid-sensitive body tissues, diseases, or wounds, such as the mouth, vagina, organs, or other types of mucosal surfaces, which may have moist surfaces. The composition carries a drug, and upon application and adherence to the mucosal surface, provides a protective layer and delivers the drug to the treatment site, surrounding tissues, and other body fluids. The composition provides an appropriate residence time for effective drug delivery at the treatment site, given controlled slow, natural erosion, either concurrent with or subsequent to erosion and delivery in body fluids such as aqueous solutions or saliva.

The residence time of the composition depends on the erosion rate and respective concentration of the water-erodible polymers used in the formulation. The erosion rate can be controlled, for example, by mixing together components with different solubility properties or chemically different polymers, such as hydroxyethylcellulose and hydroxypropylcellulose; by using different molecular weight grades of the same polymer, for example, by mixing low and medium molecular weight hydroxyethylcellulose; by using excipients or plasticizers with varying lipophilicity values or water solubility properties (including essentially insoluble components); by using water-soluble organic and inorganic salts; by using cross-linking agents, such as glyoxal, in conjunction with polymers such as hydroxyethyl cellulose for partial cross-linking; or by post-treatment radiation or curing, which can alter the physical state of the film, including crystallinity or phase transitions. These strategies can be used alone or in combination to modify the erosion kinetics of the film. Upon application, the pharmaceutical composition film adheres to the mucosal surface and is fixed in place. Moisture absorption softens the composition, reducing foreign body sensation. Once the composition is placed on the mucosal surface, drug delivery occurs. The residence time can be adjusted over a wide range, depending on the desired delivery time of the selected drug and the shelf life of the selected carrier. However, the residence time is generally adjusted between about a few seconds and about a few days. Preferably, the residence time for most pharmaceuticals is adjusted from about 5 seconds to about 24 hours. More preferably, the residence time is adjusted from about 5 seconds to about 30 minutes. In addition to providing drug delivery, once the composition adheres to the mucosal surface, it also acts as a corrosive bandage, providing protection to the treatment site. The lipophilic agent can be designed to have reduced erosion to reduce degradation and dissolution.

Additionally, the erosion kinetics of the composition can be controlled by adding excipients that are highly soluble in water, such as water-soluble organic and inorganic salts, and that are sensitive to enzymes such as amylase. Suitable excipients may include sodium and potassium salts of chloride, carbonate, bicarbonate, citrate, trifluoroacetate, benzoate, phosphate, fluoride, sulfate, or tartrate. The amount added will vary depending on the amount and nature of other components of the composition, as well as how much the erosion kinetics are to be altered.

The emulsifier typically used in the above aqueous emulsion is preferably selected from linoleic, palmitic, myristoleic, lauric, stearic, cetoleic, or oleic acid and sodium or calcium hydroxide, or is obtained by selecting from polyoxyethylene derivatives including laurate, palmitate, stearate, or oleate esters of sorbitol and sorbitol enhydride, monooleate, monostearate, monopalmitate, monolaurate, propyl alcohols, alkylphenols, alkyl ethers, alkylaryl ethers, sorbitan motostearate, sorbitan monooleate and/or sorbitan monopalmiate.

The amount of pharmacologically active ingredient used will depend on the desired therapeutic strength and the composition of the layers, and preferably the pharmacological ingredient is from about 0.001% to about 99%, more preferably from about 0.003% to about 75%, and most preferably from 0.005% to about 50%, by weight of the composition, greater than 0.005%, greater than 0.05%, greater than 0.5%, greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 30%, about 50%, greater than 50%, less than 50%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.05%, or less than 0.005%. The amount of other ingredients may vary depending on the drug or other ingredient, but typically these ingredients are within 50%, preferably within 30%, and most preferably within 15% of the total weight of the composition.

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

Those skilled in the art will recognize that when systemic delivery is desired, for example, when mucosal or transdermal delivery is desired, the treatment site includes any area where the film can deliver and/or maintain a desired level of agent within the blood, lymph, or other body fluid. Typically, such treatment sites include the mucosal tissues of the mouth, ears, eyes, anus, nose, and vagina, as well as the skin. If skin is to be used as the treatment site, a generally large area of skin, such as the upper arm or thigh, where movement does not interfere with skin adhesion is generally preferred.

Furthermore, the pharmaceutical composition can be used as a wound dressing. By providing a washable, physical, compatible, oxygen- and moisture-permeable, and flexible barrier, the film can not only protect the wound but also deliver medications to promote healing, asepsis, antipyresis, relieve pain, or improve the patient's overall condition. Some examples are suitable for use on the skin or wound site. As will be appreciated by those skilled in the art, the formulation may require the inclusion of specific hydrophilic/hygroscopic excipients to help maintain good adhesion to dry skin over an extended period of time. Another advantage of the present invention when used in this manner is that if the film is not desired to be noticeable on the skin, dyes or coloring agents are not required. Conversely, if the film is desired to be noticeable, dyes or coloring agents can be used.

The pharmaceutical composition can adhere to mucosal tissue, which is inherently moist tissue, but can also be applied to other surfaces, such as skin or wounds. The pharmaceutical film can adhere to the skin if the skin is wet with an aqueous fluid, such as water, saliva, wound drainage, or sweat, prior to application. The film can remain adhered to the skin until it is eroded by contact with water, for example, by rinsing, showering, bathing, or washing. The film can also be easily removed by peeling without causing significant tissue damage.

The Franz diffusion cell is an in vitro skin permeation assay used in formulation development. The Franz diffusion cell device (Figure 1A) consists of two chambers separated by a membrane, for example, made of animal or human tissue. The test product is applied to the membrane through the upper chamber. The lower chamber contains a fluid from which samples are periodically taken for analysis to determine the amount of active substance that has permeated the membrane. Referring to Figure 1A, the Franz diffusion cell (100) includes a donor compound (101), a donor chamber (102), a membrane (103), a sampling port (104), a receptor chamber (105), a stirrer (106), and a heater/circulator (107).

Referring to FIG. 1B, the pharmaceutical composition is a film (100) comprising a polymer matrix (200), and a pharmacologically active ingredient (300) is contained in the polymer matrix. The film may include a penetration enhancer (400).

Referring to Figures 2A and 2B, the graphs show the permeation of the active ingredient from the composition. The graphs show that no significant difference was observed for the in-situ dissolved epinephrine base versus the natively soluble epinephrine bitartrate. Epinephrine bitartrate was selected for further development based on its ease of processing. The flux is derived as the slope of the amount permeated as a function of time. The steady-state flux is obtained by multiplying the flux plateau versus time curve by the volume of the receptor medium and normalizing it for the permeation area.

Referring to Figure 2A, this graph shows the average permeation of active substance versus time with 8.00 mg/mL of epinephrine bitartrate and 4.4 mg/mL of dissolved epinephrine base.

Referring to Figure 2B, this graph shows the average flux versus time for 8.00 mg/mL of epinephrine bitartrate and 4.4 mg/mL of dissolved epinephrine base.

Referring to Figure 3, this graph shows the ex vivo permeation of epinephrine bitartrate as a function of concentration. This study compared concentrations of 4 mg/mL, 8 mg/mL, 16 mg/mL, and 100 mg/mL. The results show that permeation increases with increasing concentration, and the enhancement level decreases at high loadings.

Referring to Figure 4, this graph shows the permeation of epinephrine bitartrate as a function of solution pH. Acidic conditions were tested to improve stability. The results compared epinephrine bitartrate pH 3 buffer and epinephrine bitartrate pH 5 buffer, and the epinephrine bitartrate pH 5 buffer was found to have a slight advantage.

Referring to Figure 5, this graph shows the effect of enhancers on epinephrine permeation, expressed as the amount permeated as a function of time. Various enhancers were screened, including Labrasol, capryol 90, Plurol Oleique, Labrafil, TDM, SGDC, Gelucire 44/14, and clove oil. A significant effect of time on both the onset and steady-state fluxes was achieved, with significantly enhanced permeation achieved for clove oil and Labrasol.

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

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

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

Referring to Figure 9, this graph shows the effect of potentiator A (Labrasol) on the concentration profiles of a 40 mg epinephrine film versus a 0.3 mg EpiPen. Referring to Figure 10, this graph shows the effect of potentiator L (clove oil) on the concentration profiles of two 40 mg epinephrine films (10-1-1) and (11-1-1) versus a 0.3 mg EpiPen.

Referring to Figure 11, the effect of enhancer L (clove oil) and film dimensions (10-1-1 thinner and larger film and 11-1-1 thicker and smaller film) on the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen is shown.

Referring to Figure 12, this graph depicts the concentration profile for the change in the dosimetry of the epinephrine film in a constant matrix for the 0.3 mg EpiPen versus the enhancer L (clove oil).

Referring to Figure 13, this graph depicts the concentration profile for the change in the dosimetry of the epinephrine film in a constant matrix for the 0.3 mg EpiPen versus the enhancer L (clove oil).

Referring to Figure 14, this graph depicts the concentration profile for the change in the dosimetry of epinephrine film in a constant matrix for potentiator A (Labrasol) versus 0.3 mg of EpiPen.

Referring to Figure 15, this graph shows the amount permeated as a function of time and shows the effect of a potentiator on the permeation of diazepam.

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

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

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

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

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

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

Example

Example 1

Penetration enhancer - epinephrine

Flux enhancement was studied using several permeation enhancers, including epinephrine bitartrate at a concentration of 16.00 mg/mL. The results show flux enhancement, as shown in the data below. For 100% eugenol and 100% clove oil, the results show a significantly earlier steady-state flux, with an unexpectedly high % plus enhancement.

In these experiments, clove oil was obtained from clove leaves. Similar results were obtained from clove flower buds and/or clove stems. Based on these data, similar penetration-enhancing results can be expected from pharmacological compounds structurally similar to epinephrine.

Example 2

Diazepam solubility and permeability

Diazepam was applied to the buccal area (cheeks) to allow diazepam to diffuse through the oral mucosa and enter directly into the bloodstream. The solubility of diazepam was studied using various excipients. Figure 15 shows the effect of enhancers on the permeation of diazepam, expressed in μg as a function of time. Figure 16 shows the effect of enhancers on the permeation of diazepam solutions and certain selected enhancers. Shows the average flux expressed in μg/cm*min as a function of time in minutes in the solution.

The following excipients were studied to improve solubility.

The following excipients were studied for similar strengthening properties: cinnamon leaf, basil, bay leaf, nutmeg, Kolliphor ^R TPGS, Vit E PEG succinate, Kolliphor ^R EL, Polyoxyl 35 Castor Oil USP/NF, Menthol, N-Methyl-2-Pyrrolidone, SLS (SDS), SDBS, Dimethyl Phthalate, Sucrose Phthalate (Sisterna PS750-C), Sucrose Stearate (Sisterna SP70-C), CHAPS, Octyl Glucoside, Triton X 100 (Octoxynol-9), Ethyl Maltol (flavorant powder), Brij 58 (Ceteth-20), Vitamin E Tocopherol, Tocopherol Acetate or Tocopherol Succinate, Sterols, Phytoextracts, Essential Oils or Cod Liver Oil.

The following results were obtained from a diazepam solution having a concentration of 8.00 mg/mL.

Example 3

General Permeation Procedure - Ex Vivo Permeation Test Protocol

In one example, the permeation procedure is performed as follows. The temperature bath is set to 37°C, and the receiver is placed in the water bath to initiate temperature control and degassing. A Franz diffusion cell is obtained and prepared. The Franz diffusion cell contains a donor compound, a donor chamber, a membrane, a sampling port, a receiver chamber, a stir bar, and a heater/circulator. The stir bar is placed in the Franz diffusion cell. The tissue is placed over the Franz diffusion cell, ensuring that the tissue overlaps the glass joint and covers the entire area. The top of the diffusion cell is placed over the tissue, and the top of the cell is clamped to the bottom. Approximately 5 mL of receptor medium is loaded into the receiver compartment, ensuring that no air bubbles are trapped in the receiver compartment of the cell. This ensures that the entire 5 mL reaches the receiver compartment. Once stirring is initiated, the temperature is allowed to equilibrate for approximately 20 minutes. Meanwhile, high-performance liquid chromatography (HPLC) vials are labeled with the cell number and time. Since the solution degassed during heating, air bubbles should be checked again.

When testing the film, the following steps can be performed: (1) Weigh the film, punch it to match (or less) the diffusion area, reweigh it, and record the weight before and after punching; (2) Wet the donor area with approximately 100 μl of phosphate buffer; (3) Place the film on the donor surface, topped with 400 μl of phosphate buffer, and start the timer.

For solution studies, the following steps can be performed: (1) Using a micropipette, dispense 500 μL of solution into each donor cell and start the timer; (2) At the following time points (time = 0 min, 20 min, 40 min, 60 min, 120 min, 180 min, 240 min, 300 min, 360 min), sample 200 μL and place into labeled HPLC vials, tapping the sealed vials to ensure no air is trapped at the bottom of the vials; (3) Replace each sample time with 200 uL of acceptor medium (to maintain 5 mL); (4) Once all time points are completed, disassemble the cells and discard all material appropriately.

Example 4

In vitro permeation evaluation

Exemplary in vitro permeation assessments include:

1. The tissue is freshly cut and sent to 4℃ (e.g. overnight).

2. The tissues are processed and frozen at -20°C for up to 3 weeks before use.

3. The tissue is excised from the skin to an exact thickness.

4. Approximately 5 mL of receiving medium is added to the receiving chamber. The medium is selected to ensure sink conditions.

5. The tissue is placed in a Franz cell, which contains a donor compound, a donor chamber, a membrane, a sampling port, a receptor chamber, a stir bar, and a heater/circulator.

6. Approximately 0.5 mL of donor solution is applied or an 8 mm circular film, and moistened with 500 μL of PBS buffer.

7. Remove the sample from the storage chamber at given intervals and replace it with fresh medium.

Example 5

Transbuccal delivery of doxepin

The following is an exemplary permeation study of transbuccal delivery of doxepin. The study was conducted under a protocol approved by the Animal Experimentation Ethics Committee of the University of Barcelona (Spain) and the Animal Experimentation Committee of the Autonomous Government of Catalonia (Spain). Three- to four-month-old female pigs were used. Pigs were sacrificed in the animal facility at the Bellvitge Campus (University of Barcelona, Spain) using an overdose of sodium thiopental anesthesia. The buccal mucosa was immediately excised from the buccal region. Fresh buccal tissue was transported from the hospital to the laboratory in a container filled with Hank's solution. The remaining tissue specimens were stored at -80°C in a container containing a PBS mixture containing 4% albumin and 10% DMSO as a cryoprotectant.

For permeation studies, porcine buccal mucosa was incised into sheets 500 +/- 50 μm thick, which contribute to the diffusion barrier (Buccal bioadhesive drug delivery ― A promising option for orally less efficient drugs Sudhakar et al., Journal of Controlled Release 114 (2006) 15-40), using an electric dermatome (GA 630, Aesculap, Tuttlingen, Germany), and trimmed into appropriate pieces with surgical scissors. Most of the underlying connective tissue was removed with a scalpel.

The membranes were then mounted in a specially designed membrane holder with a permeation orifice diameter of 9 mm (diffusion area of 0.636 cm2). Using the membrane holder, each porcine buccal membrane was mounted between the donor (1.5 mL) and receptor (6 mL) compartments, with the epithelial side facing the donor chamber and the connective tissue area facing the receptor of a static Franz-type diffusion cell (Vidra Foe Barcelona, Spain), avoiding bubble formation.

Infinite dose conditions were ensured by applying 100 μL of saturated doxepin solution to the receptor chamber, which was immediately sealed with parafilm to prevent water evaporation. Prior to conducting the experiment, the diffusion cells were incubated in a water bath for 1 h to homogenize the temperature across all cells (37°+/-°C). Each cell contained a small Teflon-coated magnetic stirrer, which was used to ensure that the fluid in the receptor remained homogeneous throughout the experiment.

Sink conditions were ensured in all experiments by initial testing of saturating concentrations of doxepin in the receptor medium. Samples (300 μL) were withdrawn via syringe from the center of the receptor compartment at preselected time intervals (0.1, 0.2, 0.3, 0.7, 1, 2, 3, 4, 5, and 6 h). The withdrawn sample volume was immediately replaced with an equal volume of fresh receptor medium (PBS; pH 7.4), with extreme care to avoid trapping air beneath the membrane. Additional details can be found in A. Gimemo, et al., Transbuccal delivery of doxepin: Studies on permeation and histological evaluation , International Journal of Pharmaceutics 477 (2014), 650–654, incorporated herein by reference.

Example 6

Transmucosal oral delivery

Porcine oral mucosa has histological features similar to those of human oral mucosa (Heaney TG, Jones RS, Histological investigation of the influence of adult porcine alveolar mucosal connective tissues on epithelial differentiation. Arch Oral Biol 23 (1978) 713-717; Squier CA, and Collins P, The relationship between soft tissue attachment, epithelial downgrowth, and surface porosity. Journal of Periodontal Research 16 (1981) 434-440). Lesch et al. (The Permeability of Human Oral Mucosa and Skin to Water, J Dent Res 68 (9), 1345-1349, 1989) reported that the permeability of porcine buccal mucosa was not significantly different from that of human buccal mucosa, except that the floor of the mouth was more permeable in human tissue than in porcine tissue. A comparison between fresh porcine tissue samples and those stored at -80°C showed no significant effect on permeability as a result of freezing. Porcine buccal mucosal absorption has been studied for a wide range of drug molecules both in vivo and in vitro (see, e.g., Table 1 of M. Sattar, Oral transmucosal drug delivery - current status and future prospects, International Journal of Pharmaceutics 471 (2014) 498-506), which are incorporated herein by reference. In vitro studies typically involve mounting excised porcine buccal mucosal tissue in a Ussing chamber, Franz cell, or similar diffusion device. In vivo studies described in the literature involve application of drugs as solutions, gels, or compositions to the porcine buccal mucosa, 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 influence of various in vitro conditions on the permeability characteristics of porcine buccal tissue, using caffeine and estradiol as model hydrophilic and lipophilic molecules, respectively. Drug permeation in the buccal mucosa was studied using a modified Ussing chamber. Comparative permeation studies were performed across full thickness and epithelial tissue, fresh and frozen tissue. Tissue integrity was monitored by the uptake of fluorescein isothiocyanate (FITC)-labeled dextran 20 kDa (FD20), and tissue viability was assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) 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-thickness buccal tissue. Flux values for both compounds were comparable for fresh and frozen buccal epithelium, although histological evaluation showed signs of cell death in frozen tissue. The tissue appeared viable up to 12 hours postmortem using the MTT viability assay, which was confirmed by histological evaluation.

Kulkarni et al. investigated the relative contributions of epithelium and connective tissue to the barrier properties of porcine buccal tissue. In vitro permeation studies were performed using antipyrine, buspirone, bupivacaine, and caffeine as model permeants. The permeability of model diffusible agents across buccal mucosa with thicknesses of 250, 400, 500, 600, and 700 μm was determined. A double-membrane model was developed to describe the relative contributions of the epithelium and connective tissue to the barrier function. The relative contribution of the connective tissue region as a permeability barrier significantly increased with increasing mucosal thickness. A mucosal thickness of approximately 500 μm was recommended by the authors for in vitro mucosal permeation studies because, at this thickness, the epithelium represents the primary permeability barrier to all diffusible agents. The authors also studied the effect of several biological and experimental variables on the permeability of the same group of model penetrants in porcine buccal mucosa (Porcine buccal mucosa as in vitro model: effect of biological and experimental variables, Kulkarni et al., J Pharm Sci . 2010 99(3):1265-77). Significantly, higher permeability of the drug was observed in the thinner retrolabial region (170-220 μm) compared to the thicker buccal region (250-280 μm). Porcine buccal mucosa maintained its integrity in Kreb's bicarbonate Ringer's solution for 24 hours at 4°C. Heat treatment to separate the epithelium from the underlying connective tissue did not adversely affect the permeability and integrity properties compared to surgical separation. Additional details can be found in M. Sattar, Oral transmucosal drug delivery - current status and future prospects, International Journal of Pharmaceutics 471 (2014) 498-506, which is incorporated herein by reference.

Example 7

Cryopreservation of the buccal mucosa

Different regions of the porcine buccal mucosa have different permeabilities, with significantly higher permeability in the retrolabial region compared to the buccal region, likely due to the epithelium acting as a permeability barrier and the greater thickness of the buccal epithelium compared to the retrolabial region (Harris and Robinson, 1992). In a typical permeability study, fresh or frozen porcine buccal mucosa from the same region was sectioned into 500±50 μm thick sections, which contributed to the diffusion barrier (Sudhakar et al., 2006). The sections were obtained using a sheet electrodermatome (model GA 630, Aesculap, Tuttlingen, Germany), and trimmed into appropriate pieces with surgical scissors. All devices used were previously sterilized. Most of the underlying connective tissue was removed with a scalpel. The membranes were then mounted in a specially designed membrane holder with a permeable pore diameter of 9 mm (diffusion area of 0.63 cm2). Using a membrane holder, each porcine cheek membrane was placed between the receptor (6 mL) and donor (1.5 mL) compartments, with the epithelium facing the donor chamber and the connective tissue region facing the receptor, in a static Franz-type diffusion cell (Vidra, Foe, Barcelona, Spain), avoiding bubble formation. Experiments were performed using PP, which is a model drug (Modamio et al. 2000), has lipophilic properties (logP = 1.16; n-octanol/PBS, pH 7.4), is ionizable (pKa = 9.50), and has a MW of 259.3 g/mol.

Infinite dose conditions were ensured by applying 300 μL of donor solution of saturated PP (C0 = 588005±5852 μg/mL at 37°±1°C, n = 6) in PBS (pH 7.4) to the receptor chamber, which was immediately sealed with parafilm to prevent water evaporation.

Before conducting experiments, the diffusion cells were incubated in a water bath for 1 hour to ensure a uniform temperature across all cells (37°±1°C). Each cell contained a small Teflon-coated magnetic stir bar, which was used to ensure that the fluid in the receptor compartment remained homogeneous throughout the experiment. Sink conditions were ensured in all experiments, following initial testing of saturation concentrations of PP in the receptor medium.

Samples (300 μL) were withdrawn via syringe from the center of the receptor compartment at the following preselected time intervals (0.25, 0.5, 1, 2, 3, 4, 5, and 6 h). The withdrawn sample volume was immediately replaced with an equal volume of fresh receptor medium (PBS; pH 7.4) with extreme care to avoid entrapment of air under the skin. The cumulative amount of drug (μg) per unit surface area (cm2) of the mucosal membrane was corrected for sample withdrawal and plotted against time (h). Diffusion experiments were performed 27 times for fresh and 22 times for frozen buccal mucosa.

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

Example 8

Penetration of quinine across the sublingual mucosa

Because porcine and human oral mucosa share similar composition, structure, and permeability measurements, porcine oral mucosa is a suitable model for human oral mucosa. Because permeability across porcine oral mucosa is not metabolically linked, tissue survival is not critical.

To prepare the porcine tongue membrane, the mucosa membrane from the floor of the mouth and the ventral (inferior) tongue of the pig was excised using blunt dissection with a scalpel. The excised mucosa was cut into approximately 1 cm squares and frozen on aluminum foil at -20°C (<2 weeks) until use. For the unfrozen ventral surface of the porcine tongue, the mucosa was used for permeability testing within 3 hours of excision.

The permeability of the cell membrane to quinine was measured using an all-glass Franz diffusion cell with a diffusion area of 0.2 cm2 and a nominal receptor volume of 3.6 mL. The cell flanges were greased with high-performance vacuum grease, and the membranes were mounted between the receptor and donor compartments, with the membrane surface facing upward. Clamps were used to hold the membranes in place before the receptor compartment was filled with degassed phosphate-buffered saline (PBS), pH 7.4. A micro-stir bar was added to the receptor compartment, and the complete cell was placed in a water bath at 37 °C. The membranes were equilibrated with PBS applied to the donor compartment for 20 min before being aspirated with a pipette. 5 μL aliquots of quinine solution or 100 μL of a saturated solution of Q/2-HP-β-CD complexes were applied to each donor compartment with different vehicles. In a study to determine the effect of saliva on the penetration of quinine across the ventral surface of the tongue, 100 μl of sterile saliva was added to the donor compartment before the addition of 5 μl of quinine solution.

At 2, 4, 6, 8, 10, and 12 h, the donor phase was removed from the sampling port and aliquots of 1 mL sample were transferred to HPLC autosampler vials before being replaced with fresh PBS stored at 37°C. Apart from studies involving saturated Q/2-HP-β-CD solutions (where an infinite dose was applied at the beginning of the experiment), 5 μL of each quinine solution was reapplied to the donor phase for up to 10 h. The purpose of this was to represent a hypothetical finite-dose dosing regimen based on a 2-h interval between doses. At least three replicates were performed for each study.

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

Example 9

EX-Vivio Initial Study - API Form

In this example, the permeation of epinephrine base dissolved in situ versus natively soluble epinephrine bitartrate was tested, and no difference was found. Epinephrine bitartrate was selected for further development based on its ease of processing. Flux was derived as the slope of the amount permeated as a function of time. Steady-state flux was extrapolated as the product of the flux plateau versus time curve multiplied by the volume of the receptor medium. The graph in Figure 2A shows the average permeation versus time for 8.00 mg/mL epinephrine bitartrate and 4.4 mg/mL epinephrine base dissolved. The graph in Figure 2B shows the average flux versus time for 8.00 mg/mL epinephrine bitartrate and 4.4 mg/mL epinephrine base dissolved.

Example 10

Concentration dependence on permeation/flux

In this study, the in vitro permeation of epinephrine bitartrate as a function of concentration was studied. Figure 3 shows the in vitro permeation of epinephrine bitartrate as a function of concentration. The study compared concentrations of 4 mg/mL, 8 mg/mL, 16 mg/mL, and 100 mg/mL. The results showed that increasing the concentration increased permeation, and the level of enhancement decreased at higher loadings. The study compared concentrations of 4 mg/mL, 8 mg/mL, 16 mg/mL, and 100 mg/mL.

Example 11

Effect of pH

In this example, the permeation of epinephrine bitartrate as a function of solution pH was studied. In this example, acidic conditions were examined for their ability to enhance stability. The results showed that pH 5 was slightly more favorable than pH 3. The inherent pH of the epinephrine bitartrate solution over the concentration range studied was 4.5-5. No pH adjustment with buffers was required.

Figure 4 shows the permeation of epinephrine bitartrate as a function of solution pH. Acidic conditions were explored to enhance stability. The results were compared between epinephrine bitartrate pH 3 buffer and epinephrine bitartrate pH 5 buffer, and epinephrine bitartrate pH 5 buffer was found to be slightly advantageous.

Example 12

Effect of enhancers on epinephrine penetration

In this example, the permeation of epinephrine was studied as a function of time (minutes) versus permeation amount (μg) to test for transmucosal delivery. The following potentiators were screened for concentration effects in a solution containing 16.00 mg/mL of epinephrine. The graph in Figure 5 shows the results of these potentiators as a function of time.

The fortifiers were selected and designed to affect different barriers in the mucosa. All tested fortifiers improved penetration over time, but clove oil and labrazol showed particularly significant and unexpectedly high permeability enhancements.

Example 13

Effects of reinforcers on epinephrine release

The release profile of epinephrine was studied to determine the influence of enhancers (Labrasol and clove oil) on epinephrine release. Figure 6A depicts epinephrine release from different polymer platforms. Figure 6B shows the influence of enhancers on epinephrine release. The results showed that the permeated amount equalized to approximately 3250 to 4250 μg after approximately 40 minutes. The tested enhancers did not appear to limit the release of epinephrine from the matrix.

Example 14

Accelerated stability

Stabilizers loaded with the variant were tested.

Example 15

The effects of reinforcement

A pharmacokinetic model was studied in male Yucatan miniature pigs. The graph in Figure 7 presents the results of the pharmacokinetic model in male Yucatan miniature pigs. This study compares 0.3 mg EpiPen, 0.12 mg IV epinephrine, and placebo.

In the concentration profile of 40 mg epinephrine film versus 0.3 mg EpiPen, no effect of the potentiator is shown in Figure 8.

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

Additionally, the effect of film dimensions and clove oil (3%) are also shown in Figure 11. This study compared 0.3 mg EpiPen (n=4), 40 mg epinephrine film (10-1-1) (n=5), and 40 mg epinephrine film (11-1-1) (n=5). Concentration versus time profiles followed sublingual or intramuscular epinephrine administration to male miniature pigs.

A study was conducted to vary the ratio of epinephrine to the reinforcer. These studies examined the concentration versus time profiles following sublingual or intramuscular epinephrine administration to male miniature pigs. Varying the ratio of epinephrine to clove oil (reinforcer L) produced the results shown in Figure 12. The study compared a 0.30 mg EpiPen (n = 4), a 40 mg epinephrine film (12-1-1) (n = 5), and a 20 mg epinephrine film (13-1-1) (n = 5).

Example 16

Dose-varying studies were performed in a constant matrix with the fortifiers Labrasol (3%) and clove oil (3%) and are shown in Figures 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). 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). These studies were concentration versus time profiles after sublingual or intramuscular epinephrine administration to male miniature pigs.

Example 17

A pharmacokinetic model in male miniature pigs was studied to determine the effect of a potentiator (farnesol) on epinephrine concentrations over time. The graph in Figure 17 depicts epinephrine plasma concentrations (ng/mL) as a function of time (minutes) following sublingual, intramuscular, or intramuscular administration of the farnesol penetration enhancer. This study compares the 0.3 mg EpiPen (n=3), the 30 mg epinephrine Film 31-1-1 (n=5), and the 30 mg epinephrine Film 32-1-1 (n=5), each formulated with the farnesol potentiator. As depicted in this figure, the 31-1-1 Film exhibits enhanced epinephrine stability beginning at 30-40 minutes and lasting up to approximately 130 minutes.

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

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

Example 18

Referring to Figure 20, this graph shows a pharmacokinetic model study in male miniature pigs to determine the effect of a potentiator (farnesol) on epinephrine concentrations over time following sublingual or intramuscular administration. Epinephrine plasma concentrations (ng/mL) are plotted as a function of time (minutes) following sublingual or intramuscular administration of the farnesol permeation enhancer from epinephrine films. This study compared data from three 0.3 mg Epipens to five 30 mg epinephrine films (32-1-1). These data demonstrate that the epinephrine film exhibits enhanced stability of epinephrine concentrations, beginning at approximately 20-30 minutes and extending to approximately 130 minutes.

Example 19

In one specific example, the epinephrine pharmacological composition film may be prepared as follows:

Example 20

Epinephrine pharmacological composition films were prepared according to the following prescription:

Example 21

In another embodiment, a pharmaceutical film composition was prepared as follows:

Example 22

In another embodiment, a pharmaceutical film composition was prepared as follows:

Example 23

Referring to Figure 21, this graph represents a pharmacokinetic model (log scale) in male miniature pigs studied to determine the effect of potentiators (6% clove oil and 6% labrazol) on epinephrine plasma concentrations over time following sublingual or intramuscular administration. Epinephrine plasma concentrations (ng/mL) are plotted as a function of time (minutes) following sublingual or intramuscular administration of the farnesol permeation enhancer in the epinephrine film. The data demonstrate that the film exhibits enhanced stability of epinephrine concentrations, beginning immediately after the 10-minute time point, continuing through approximately 30 minutes and continuing to approximately 100 minutes.

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

Example 24

Referring to Figure 21, this graph represents a pharmacokinetic model in male miniature pigs studied to determine the effect of an intensifier (9% clove plus 3% labrazol) on epinephrine concentrations over time following sublingual or intramuscular administration across seven animal models. Typical peak concentrations were achieved between 10 and 30 minutes.

Alprazolam data

Example 25

Referring to Figures 24A, 24B, and 24C, these graphs represent data from a male miniature pig study comparing alprazolam plasma concentrations over time (hr) following sublingual administration of alprazolam pharmacological compound film and oral alprazolam disintegrating tablets (ODT).

Figure 24A shows the average data from alprazolam ODT (Group 1). Peak concentrations of 7-12 ng/mL were achieved at approximately 1-8 hours.

Figure 24B shows the average data from the alprazolam pharmacological composition film (Group 2). A peak concentration of between 5-17 ng/mL, greater than 5 ng/mL, greater than 10 ng/mL, greater than 12 ng/mL, greater than 15 ng/mL, greater than 17 ng/mL, less than 17 ng/mL, less than 15 ng/mL, less than 12 ng/mL, less than 10 ng/mL, less than 5 ng/mL is achieved at a time including between 10 minutes and 4 hours, greater than 10 minutes, greater than 20 minutes, greater than 30 minutes, greater than 45 minutes, greater than 1 hour, greater than 1.5 hours, greater than 2 hours, greater than 2.5 hours, greater than 3 hours, 3.5 hours or about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes or less than 20 minutes.

Figure 24C shows the average data from the alprazolam pharmacological composition film from another group of male miniature pigs (Group 3). A peak concentration of between 5-17 ng/mL, greater than 5 ng/mL, greater than 10 ng/mL, greater than 12 ng/mL, greater than 15 ng/mL, greater than 17 ng/mL, less than 17 ng/mL, less than 15 ng/mL, less than 12 ng/mL, less than 10 ng/mL, less than 5 ng/mL is achieved at a time including between 10 minutes and 4 hours, greater than 10 minutes, greater than 20 minutes, greater than 30 minutes, greater than 45 minutes, greater than 1 hour, greater than 1.5 hours, greater than 2 hours, greater than 2.5 hours, greater than 3 hours, greater than 3.5 hours, or about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes.

Example 26

Referring to Figure 25A, the graph depicts data from a male miniature pig study comparing alprazolam plasma concentrations over time following sublingual administration of oral alprazolam tablets (ODT) (circular data points) and two groups of alprazolam pharmacological composition films (square and triangular data points).

As the graph shows, data from the alprazolam pharmacological composition films (both groups) yielded higher alprazolam plasma concentrations of approximately 15 to 25 mg/mL in a therapeutic window of less than or equal to about 30 minutes, including greater than or equal to 10 minutes, greater than or equal to 20 minutes, less than about 30 minutes, less than 20 minutes, less than 15 minutes, and less than 10 minutes.

Referring to Figure 25B, this graph points to individual data points from the study referenced in Figure 25A.

Referring to Figure 25C, this graph points to individual data points from 0 to 1 hour from the study referenced in Figure 25A.

Referring to Figure 26A, this graph points to individual data points for the alprazolam ODT study referenced in Figure 25C.

Referring to Figure 26B, this graph points to individual data points for the alprazolam pharmacological film referenced in Figure 25C.

Referring to Figure 26C, this graph indicates individual data points for the alprazolam pharmacological film (second group) mentioned in Figure 25C.

Data from the above-mentioned graphs are summarized in the table below.

Example 27

Referring to Figure 27A, the graph depicts data from a male miniature pig study comparing alprazolam plasma concentrations over time following sublingual administration of oral alprazolam tablets (ODT) (represented by circular data points) and two groups of alprazolam pharmacological composition films (represented by square and triangular data points).

As the data indicate, 0.5 mg alprazolam ODT achieved peak concentrations of 5-6 ng/mL at times including 0 to 4 hours, >10 minutes, >20 minutes, >30 minutes, >45 minutes, >1 hour, >1.5 hours, >2 hours, >2.5 hours, >3 hours, >3.5 hours, or about 4 hours, <4 hours, <3.5 hours, <3 hours, <2.5 hours, <2 hours, <1.5 hours, <1 hour, <45 minutes, <30 minutes, or <20 minutes. The 0.5 mg alprazolam pharmacological composition film achieved peak concentrations of about 7 to 8 ng/mL and 6 to 7 ng/mL, respectively, at times including between 0 and 4 hours, greater than 10 minutes, greater than 20 minutes, greater than 30 minutes, greater than 45 minutes, greater than 1 hour, greater than 1.5 hours, greater than 2 hours, greater than 2.5 hours, greater than 3 hours, greater than 3.5 hours, or about 4 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 20 minutes.

Referring to Figure 27B, the graph depicts data from a male miniature pig study comparing alprazolam plasma concentrations over time from 0 to 2 hours after sublingual administration of oral alprazolam tablets (ODT) (represented by circular data points) and two groups of alprazolam pharmacological composition films (represented by square and triangular data points). Unlike ODT, the therapeutic window for alprazolam pharmacological composition films began at 10 to 15 minutes, whereas ODT began at approximately 17 to 20 minutes.

Referring to Figure 27C, this graph depicts the complete data referred to in Figure 27B for ODT (n=4), 0.5 mg alprazolam pharmaceutical composition film 14-1-1 (n=5), and 0.5 mg alprazolam pharmaceutical composition film 15-1-1 (=5).

Data from the above-mentioned graphs are also summarized in the table below.

Example 28

In one study, the utility of diazepam buccal dissolvable film was investigated as an oral treatment for adult patients with epilepsy. Diazepam buccal dissolvable film (DBSF) is an exemplary embodiment of the claimed subject matter. DBSF is a novel dosage form of diazepam currently being developed for selected patients with epilepsy who require intermittent diazepam use to control episodes of increased seizure activity. DBSF has the potential to be the first oral treatment for this condition and would provide an alternative to rectal diazepam gel. DBSF is administered by placing the film against the inner aspect of the cheek, where it adheres and dissolves, releasing the drug into the buccal mucosa. The DBSF dosage form is expected to be well-accepted by a wide range of patients with epilepsy. The safety, pharmacokinetics, and utility of DBSF were evaluated in a phase 2 pharmacokinetic study using an epilepsy monitoring unit (EMU).

This phase 2, multicenter, open-label, crossover study in adult subjects was conducted over two treatment visits separated by at least 3 weeks. The study enrolled male and female subjects aged 17 to 65 years with a clinical diagnosis of epilepsy (tonic-clonic seizures or focal seizure disorder) requiring EMU evaluation. Subjects received DBSF administered at a dose of 12.5 mg during status epilepticus (Treatment A) and during seizures/periictal status (during a seizure or within 5 minutes of a seizure; Treatment B). Usability endpoints for investigator-directed placement of DBSF included (1) whether successful placement was achieved, (2) the number of attempts required to successfully insert the film, (3) whether the subject spit out or extruded the film, and (4) whether the DBSF was swallowed.

Results were as follows: A total of 35 subjects received at least one dose of DBSF. Of these subjects, 33 had utility data collected during Treatment A, and 33 had utility data collected during Treatment B. There were no unsuccessful attempts to insert DBSF during Treatments A and B. During Treatment A, two subjects (6.1%) and one subject (3.0%) during Treatment B indicated swallowing DBSF during the ingestion. Three additional subjects (9.1%) swallowed DBSF, following a protocol instructing all subjects to swallow the film if it had not completely dissolved 15 minutes after placement. During Treatment A, no patient spit out or ejected DBSF after initial placement on the buccal mucosa, whereas three patients (9.1%) spit out or ejected the film during Treatment B after initial placement. DBSF was generally safe and well tolerated. The most common adverse event possibly related to the drug was drowsiness, reported by 2 of 35 subjects (5.7%). There were no serious adverse reactions related to the study drug, and no patients withdrew due to adverse reactions.

These findings allowed the researchers to conclude, surprisingly, that DBSF was successfully managed in the EMU environment in both cranial and ictal/peritoneal conditions. These study data support the safe and effective use of DBSF in the management of patients with refractory epilepsy who require intermittent diazepam use to control episodes of escalating seizures. This may also support its ease of use in the home setting.

Example 29

Another study evaluated the pharmacokinetics of diazepam buccal dissolvable film in adult patients with epilepsy. The bioavailability of perictal and interictal administration was compared.

As previously described, diazepam buccal soluble film (DBSF) is an exemplary embodiment of the claimed subject matter. DBSF is a novel dosage form of diazepam being developed for selected patients with epilepsy who require intermittent diazepam use to control episodes of increased seizure activity. In this study, the investigators sought to evaluate the pharmacokinetic (PK) performance during or immediately after a seizure. Subjects were examined at clinical epilepsy monitoring unit (EMU) assessments and other PK-only visits, separated by approximately three weeks. This study investigated the peak plasma concentration (Cmax), time to peak concentration (Tmax), and partial area under the curve (partial AUC) of diazepam at 2 or 4 hours after a single dose of DBSF under interictal, intraictal, and periictal conditions in adult patients with epilepsy.

In this study, adult men and women (N = 35) aged 17-65 years with impaired cognition and poorly controlled tonic-clonic or focal seizures were enrolled in a single-dose crossover to receive DBSF 12.5 mg interictal (Treatment A) and ictal/peritic (Treatment B) under clinical EMU settings. Plasma samples for diazepam analysis were obtained predose and at intervals of up to 2 or 4 hours postdose. Doses were classified as interictal if no seizure activity was observed in the preceding 4 hours, and as ictal/peritic if DBSF was given during clinically observed seizure activity or within 5 minutes after the cessation of seizure activity. Subjects were observed for adverse events (AEs) throughout the study.

Results were as follows: Pharmacokinetic (PK) profiles valid for the analysis of both treatment conditions were available for 21 subjects. Most of these subjects had samples collected up to 4 hours, but 3 subjects had samples collected up to 2 hours. Subjects were excluded from the analysis if both treatments were not completed (N=4), if critical PK time points were missing as judged by experts blinded to the concentration data (N=3), if predose diazepam concentrations were greater than 5% Cmax (N=2), or if DBSF was administered contrary to instructions (N=5). The table shows the geometric mean (Treatment B/Treatment A) ratios of Cmax, AUC(0-2 h), and AUC(0-4 h) (geometric mean) values and 90% CIs. The values for Cmax, AUC(0-2 h), and AUC(0-4 h) were strikingly similar in the intermittent and epileptic/perimittent conditions, and the median Tmax was not significantly different (Table). DBSF 12.5 mg was found to be effective, safe, and well-tolerated. The most common adverse event possibly related to the drug was drowsiness, reported by 2 of 35 subjects (5.7%). There were no serious adverse reactions related to the study drug, and no patient withdrew due to adverse reactions.

These results surprisingly demonstrate that a single dose of 12.5 mg of DBSF administered to adults with epilepsy provides exposure to diazepam under seizure/pericardial conditions comparable to that obtained under hepatic-filtration conditions.

All references cited herein are incorporated herein by reference in their entirety.

Other specific examples are within the scope of the claims below.

Claims (43)

As an oral pharmaceutical composition for oral delivery,
polymer matrix;
a pharmacologically active ingredient within the polymer matrix, wherein the pharmacologically active ingredient is diazepam; and
comprising an adrenergic receptor interactor within the polymer matrix;
The above composition is contained as an oral therapeutic agent in a diazepam buccal availability multilayer film,
Here, the adrenergic receptor interactors are eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamic aldehyde, clove oil, essential oil extract of a clove plant, essential oil extract of a leaf of a clove plant, essential oil extract of a flower bud of a clove plant, essential oil extract of a stem of a clove plant, Labrasol comprising caprylocaproyl polyoxyl-8 glycerides, β-caryophyllene, phenol, linoleic acid, A pharmaceutical composition selected from the group consisting of oleic acid, PEG 200, benzyl alcohol, propylene glycol monocaprylate, polyglyceryl-3 oleate, lauroyl polyoxyl-32 glycerides, capryol 90, plurol oleique, TDM, and Gelucire 44/14. delete In claim 1, the polymer matrix is a pharmaceutical composition comprising a polymer. In the third paragraph, the pharmaceutical composition comprises a water-soluble polymer. A pharmaceutical composition comprising a cellulose polymer selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose, in claim 3. In the third paragraph, the pharmaceutical composition is a pharmaceutical composition that is a chewable or gelatin-based dosimetric foam, spray, gum, gel, cream, tablet, liquid or film. A pharmaceutical composition in claim 3, wherein the polymer matrix comprises polyethylene oxide, a cellulose polymer, polyethylene oxide and polyvinyl pyrrolidone, polyethylene oxide and polysaccharide, polyethylene oxide, hydroxypropyl methylcellulose and polysaccharide, or polyethylene oxide, hydroxypropyl methylcellulose, polysaccharide and polyvinylpyrrolidone. A pharmaceutical composition according to claim 3, wherein the polymer matrix comprises at least one polymer selected from the group consisting of pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tranganth gum, guar gum, acacia gum, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide and propylene oxide copolymer, collagen, albumin, poly-amino acids, polyphosphazenes, polysaccharides, chitin, chitosan and derivatives thereof. A pharmaceutical composition further comprising a stabilizer in claim 1. In claim 1, a pharmaceutical composition comprising a polymer matrix comprising a dendritic polymer or a hyperbranched polymer. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete