WO2020030991A1

WO2020030991A1 - Dosage form for insertion into the mouth

Info

Publication number: WO2020030991A1
Application number: PCT/IB2019/054695
Authority: WO
Inventors: Chun Kwong Chu; Y. Joseph Mo
Original assignee: Nal Pharmaceutical Group Limited
Priority date: 2018-08-09
Filing date: 2019-06-05
Publication date: 2020-02-13
Also published as: TW202019394A

Abstract

A pharmaceutical composition for application to the oral mucosa comprising a water-soluble film matrix comprising an effective amount of a pharmaceutically active agent and an absorption enhancer. Provided the method of delivering the pharmaceutically active agent comprising administering the pharmaceutical composition. The water-soluble matrix can be incorporated into a solid, a film or a liquid oral dosage form for insertion into the mouth as a means for effectively delivering to and transporting pharmaceutical active agents selectively through the oral mucosal tissue into the patient. Said the water-soluble matrix system delivers the pharmaceutical active agent effectively and rapidly into the body through the mucous membranes in the mouth which is ideally suited for delivering pharmaceutically active agents which treat or prevent such as asthma, multiple sclerosis venous thromboembolism and angina.

Description

DOSAGE FORM FOR INSERTION INTO THE MOUTH

CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of priority from U.S. Provisional Application Serial No. 62/716,553 filed August 9, 2018, the contents of which are incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to oral dosage forms for insertion into the mouth for selective absorption by the mucosal tissue, particularly for administration of medicinal agents where fast onset of action is desirable for medicines such as but not limited to anti-asthmatic agents.

BACKGROUND OF THE INVENTION

Asthma is a widespread chronic respiratory disease affecting 1-18% of the population in different countries. Asthma is characterized by variable symptoms such as wheezing, coughing, chest tightness, shortness of breath, and airflow limitation. The episodes of symptoms many occur a few times a day or a week triggered by allergen, irritant exposure, exercise, change in weather, and so on. It could have a great impact on patient’s quality of life and sometimes life- threatening. Cure for asthma is yet to be invented. Episodes of symptoms can be prevented or treated by corticosteroids (ICS), beta-2 agonist or leukotriene receptor antagonists (LIRA).

Controller treatment with regular low dose ICS or leukotriene receptor antagonists are highly effective in long-term management of asthma. For severe asthma, long-acting beta-2 agonist

(LABA) can be administrated along with ICS or increasing dose of ICS. Short-acting beta-2 agonist (SABA) alone can be used as-needed to relieve symptoms rapidly.

Montelukast is a CysLTi antagonist, which inhibits the action of leukotriene D4 by binding on the cysteinyl leukotriene receptor CysLTi in the lungs and bronchial tubes, thereby smoothing airway muscles, reducing airway inflammation and alleviating symptoms of airway obstruction. Although ICS remains the first-line treatment for controlling persistent asthma,

LTRA is suitable to patents who are unable or unwilling to use ICS; for patients who experience intolerable side-effects from ICS; or for patients with concomitant allergic rhinitis; and recommended as an add-on therapy to ICS. LTRA was shown leading to a lower rate of exacerbations compared to ICS among children with no exacerbation requiring a health care utilization one year prior to treatment initiation. Montelukast is commercially available as

Singulair® marketed by Merck. It is available in form of tablet, chewable tablet, and granule taken once a day with or without food. The chewable tablet and oral granule are more adaptable and provide a better adherence to pediatric patients.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition for application to the oral mucosa comprising a water-soluble film matrix comprising an effective amount of a

pharmaceutically active agent and an absorption enhancer.

Another aspect of the present invention provides the method of delivering the pharmaceutically active agent comprising administering the pharmaceutical composition.

The water-soluble matrix of the present invention can be incorporated into a solid, a film or a liquid oral dosage form for insertion into the mouth as a means for effectively delivering to and transporting pharmaceutical active agents selectively through the oral mucosal tissue into the patient Said the water-soluble matrix system delivers the pharmaceutical active agent effectively and rapidly into the body through the mucous membranes in the mouth which is ideally suited for delivering pharmaceutically active agents which treat or prevent such as asthma, multiple sclerosis, venous thromboembolism, and angina.

The water-soluble matrix of this invention transports these pharmaceutically active agents selectively through the mucous membrane in the mouth bypassing the gastrointestinal ((H) system so as to avoid (H irritations and deactivation of the active agent in the (H track. Without (H inactivation, less active agent is needed to produce a therapeutic result In addition, the oral dosage matrix of this invention rapidly releases the pharmaceutically active agent for transport quickly into the blood stream of the patient Transport of the active agents selectively through the mucus membranes of the mouth is facilitated by incorporating one or more absorption enhancers having a combined hydrophilic lipophilic balance (HLB) of about 1 to about 16 with the active agent to form the matrix. The oral dosage matrix of this invention produces improved bioavailability and delivery of the pharmaceutical active agent with rapid onset of therapeutic effectiveness for the patient Rapid release and rapid and efficient absorption are particularly important for patients suffering from diseases such as asthma, multiple sclerosis, venous thromboembolism, and angina.

The water-soluble matrix further comprises additional ingredients to produce dosage forms such as a film, a rapid releasing solid such as a powder or granule, a tablet, and also a liquid which contain an effective amount of the pharmaceutically active agent to treat or prevent asthma, multiple sclerosis, venous thromboembolism and other diseases. In accordance with this invention, the water-soluble matrix when incorporated into a tablet, film or other solid dosage form or solid dosage unit may further comprise a polymeric mixture of polyvinylpyrrolidone, polymeric alginate and/or pullulan. This solid dosage form is of a size suitable for insertion into the mouth. The solid dosage form is advantageous for administration of pharmaceutical agents treating or preventing asthma, multiple sclerosis, venous thromboembolism, and angina. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates the oral dosage form comprising the water-soluble matrix comprising the effective amount of the pharmaceutically active agent and the absorption enhancer. This invention constitutes the matrix which can be incorporated into oral dosage forms such as the solid, film or liquid dosage form. The term oral dosage form shall include but not be limited to the oral disintegrating tablet, paste, gel, liquid, emulsion, film, lollipop, lozenge, buccal and gingival patch, granule and powdered dosage forms. The terms dosage form or dosage unit shall mean the combination of the matrix, which comprises the pharmaceutical active agent and the absorption enhancer having a combined HLB of about 1 to about 16, about 1 to about 8, or about 1 to about 7, with additional ingredients to form a film, tablet, paste, gel, liquid, emulsion, lollipop, lozenge, buccal and gingival patch, granule and powdered dosage form for insertion into the mouth of a patient The dosage forms are water soluble. The dosage form contains the effective amount of the pharmaceutically active agent distributed therein.

In addition, the present invention also presents method of delivering the pharmaceutically active agent comprising administering the pharmaceutical composition of the invention, wherein the first fraction of the drug is delivered to and absorbed by the oral mucosa and systemically which results in a rapid onset of action and improved bioavailability wherein the second fraction of the drag is delivered to and absorbed along the continuous length of the esophagus and gastrointestinal tract which results in a longer duration of action and improved bioavailability.

Pharmaceutically Active Agent

The pharmaceutically active agent is selected from anesthetic agents, antitussive agents, nonnarcotic analgesics such as the nonsteroidal anti-inflammatory agent (NSAIDS), erectile dysfunction agents, female sexual dysfunction agents, antihistamine, colds and allergy agents, cough agents, respiratory disorder agents, sore throat agents, respiratory disorder agents, heartburn and dyspepsia agents, antiemetic agents, sleep aids, diarrhea agents, oral hygiene agents, antagonists of CGRP receptors, drugs for hormone replacement, Alzheimer’s disease agent, caffeine, caffeine salt compounds, coagulation inhibitors, leukotriene receptors antagonists, immunomodulatory agents and vasodilators. For example, the anesthetic agent is lidocaine (xylocaine), procaine, or benzocaine; the antitussive agent is hexylresorcinol or dextromethorphan; the nonnarcotic analgesics such as the nonsteroidal anti-inflammatory agents

(NSAIDS) is acetaminophen, Ibuprofen, ketoprofen, indomethacin, aspirin (low dose for cardiovascular), naproxen sodium, ketorolac, diclofenac, meloxicam, or piroxicam; the erectile dysfunction agent is sildenafil, tadalafil, or vardenafil; the female sexual dysfunction agent is sildenafil, tadalafil, or vardenafil; the antihistamine, cold and allergy agent is cetirizine hydrochloride, loratadine, chlorcyclizine HC1, chlorpheniramine maleate,

dextrochlorpheniramine maleate, dexbrompheniramine maleate, diphenhydramine citrate, diphenhydramine HC1, doxylamine succinate, phenindamine tartrate, pheniramine, pyrilamine maleate, triprolidine HC1, thonzylamine HC1, or clemastine fumarate; the cough agent is menthol, camphor, dextromethorphan HBr, guaifenesin, codeine phosphate, or codeine; the respiratory disorder agent is pseudoephedrine HC1, phenylephrine HC1, guaifenesin,

dextromethorphan HBr, or ephedrine; the sore throat agent is benzocaine, menthol, dyclonine, or phenol; the heartburn and dyspepsia agent is cimetidine, nizatidine, famotidine, ranitidine, or omeprazole; the antiemetic agent is granisetron, ondansetron, etc. AZ-001, AZ-004, Levadex,

Zelrix, VR-147, ROX-828, COL-144, BF-1, diphenhydramine, or scopolamine; the sleep aid is zolpidem, Eszopiclone (Lunesta), Zaleplon (Sonata), diphenhydramine, doxylamine, benzodiazepines (such as: Estazolam (ProSom), Flurazepam (Dalmane), Temazepam (Restoril),

Triazolam (Halcion), or Ramelteon (Rozerem); the diarrhea agent is loperamide, digestive enzymes (lactase), or bismuth sub salicylate; the oral hygiene agent is cetylpyridinium chloride, domiphen, thymol, eucalyptol, methyl salicylate, menthol, stannous fluoride, sodium fluoride, benzocaine, phenol, or docosanol; the drug for hormone replacement is estradiol, or testosterone; the Alzheimer's agent is donepezil, galantamine, rivastigmine, tacrine, or memantine; the coagulation inhibitor is rivaroxaban, apixaban, edoxaban, or fondaparinux; the leukotriene receptor antagonists is montelukast, zafirlukast or zileuton; the immunomodulatory agents is flngolimod, teriflunomide, glatiramer or interferon beta; and the vasodilators is glyceryl trinitrate, isosorbide dinitrate, aminophylline or co-dergocrine mesylate. The preferred pharmaceutically active agent is sildenafil, tadalafil, vardenafil, cetirizine, donepezil, galantamine, rivastigmine, tacrine, memantine, rivaroxaban, montelukast, flngolimod, and isosorbide dinitrate.

By the terms "active agent" in the present invention refers to a compound that has a desired therapeutic or physiological effect once ingested and/or metabolized. These

pharmaceutically active agents are present in the oral dosage form in an amount effective for treating or preventing asthma, multiple sclerosis, venous thromboembolism, and angina.

Absorption Enhancer

The absorption enhancer is selected from the group comprising PEG-8 beeswax, PEG-75 stearate, pegoxol-7 stearate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol dioleate, 2-hydroxypropyl stearate, 2- hydroxypropyl laurate, propylene glycol oleate, propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dilaurate, polypropylene glycol (17) dioleate, propyleneglycol monolaurate, propylene glycol monomyristate, dipropylene glycol dipelargonate, polypropylene glycol monobutyl ether oleate, propylene glycol dipelargonate, propylene glycol didecanoate, dipropylene glycol dipelargonate, propylene glycol bis(9, 10-epoxystearate), propylene glycol monoisostearate, propylene glycol diundecanoate, glycol monoethyl ether, diethylene glycol monobutyl ether, oleoyl macrogolglycerides, lauroyl macrogolglycerides, stearoyl

macrogolglycerides, caprylocaproyl macrogolglycerides, triglycerides medium-chain, polyglyceryl-3 diisostearate, polyglyceryl oleate, ethylene glycol palmitostearate, diisopropyl adipate, di-n-butyl adipate, dimethyl adipate, dimethyl isosorbide, diethylene glycol monoethyl ether and sucrose fatty acid ester.

Said the sucrose fatty acid ester is a Cl 2 to C20 saturated fatty acid ester of sucrose, such as but not limited to sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate and sucrose eracate. The sucrose fatty acid esters have a monomer content of from about 20 percent to about 80 percent. The preferred sucrose fatty acid is the sucrose stearate.

One embodiment of the invention, the oral dosage form further comprises a secondary absorption enhancer such as but not limited to glycerol, ginger oil, cineole and terpenes. The terpines include limonene, cymene, pinene, pellandrene and the like.

The oral dosage matrix of the invention contains one or more absorption enhancers in an amount of about 0.1% to about 20%, about 0.1% to about 15% or about 1 % to about 10% by weight of the matrix. When one or more absorption enhancers is included in the matrix, the combined HLB is about 1 to about 16, about 1 to about 8 or about 1 to about 7. Surfactant

Other embodiment of the invention, the oral dosage form further comprises a nonionic surfactant wherein the combined nonionic surfactant and absorption enhancer have a combined

HLB of about 1 to about 16, about 1 to about 8 or about 1 to about 7. The nonionic surfactant is one or more of polysorbate and sorbitan fatty acid ester. For example, the polysorbate is selected from the group comprising polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan and Polyoxyethylene (20) sorbitan monooleate. The sorbitan fatty acid ester is selected from the group comprising sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate and sorbitan monooleate.

Water-soluble Film

In a preferred embodiment of the invention, the oral dosage matrix is the water-soluble film, wherein the oral dosage further comprises a film forming agent. The film forming agent is selected from pullulan or polymeric mixture of polyvinylpyrrolidone and a polymeric alginate, wherein the ratio of polyvinylpyrrolidone to polymeric alginate in the polymeric mixture is from about 5: 1 to about 1 :3. In a preferred embodiment, the polymeric mixture contains, from about

5% to about 95% by weight of polyvinylpyrrolidone and from about 5% to about 95% by weight of a polymeric alginate, both of said weights being based on the weight of said polymeric mixture.

The alginate salt can be any conventional pharmaceutically acceptable salt, preferably the alkali earth metal salts and more preferably sodium alginate. Both the polyvinyl pyrrolidone and the polymeric alginate utilized in forming this film are water soluble. Sufficient water is used in the formation of the aqueous mixture to dissolve the polyvinyl pyrrolidone and alginate salt.

The polyvinyl pyrrolidone which is utilized in forming the film has a molecular weight of from about 1 x 10³ to about 1 x 10⁸ daltons and the polymeric alginate has a molecular weight of from about 1 x 10³ to about 1 x 10⁷ daltons and a viscosity of from about 400 cps to about 900 cps measured in a 1% by weight aqueous solution. Pullulan typically has a molecular weight of about 5,000 to about 5,000,000 daltons and preferably pullulan has a molecular weight of about 10,000 to about 800,000 daltons.

The film has a surface area of from about 0.25 cm² to about 20 cm² and a weight of about 1 mg to about 200 mg, preferably from about 1 cm² to about 10 cm² and a weight of about 10 mg to about 200 mg.

The film has a thickness of between about 0.01 mm to about 5 mm, about 0.05 mm to about 2.5mm, or about 0.01 mm to about 2mm.

Flavoring Substances

Natural flavoring substances are flavoring substances obtained from plant or animal raw materials, by physical, microbiological or enzymatic processes. They can be either used in their natural state or processed for human consumption but cannot contain any nature-identical or artificial flavoring substances.

Nature-identical flavoring substances are flavoring substances that are obtained by synthesis or isolated through chemical processes, which are chemically identical to flavoring substances naturally present in products intended for human consumption. They cannot contain any artificial flavoring substances.

Artificial flavoring substances are flavoring substances not identified in a natural product intended for human consumption, whether or not the product is processed.

Method of Preparation

The oral dosage form composition of the present invention is prepared using the known methods or by adopting specific conditions suitable for the ingredients employed. Examples of The Oral Dosage Forms

Examples of the oral dosage forms are the amount of the ingredients which are listed below, but not limited:

Montelukast ODF

Rivaroxaban ODF

Administration

Administration of the oral dosage form of the invention preferably occurs by sublingual or buccal insertion which allows the pharmaceutical agent to be delivered to the patient selectively through the mucosa in the mouth thereby bypassing the GI system and allowing effective administration of pharmaceutical active agents that generally cause GI irritation or are rendered inactive in the GI system. In some instances, the dosage form is placed on to the tongue where absorption may also take place. The dosage forms of this invention act as a carrier device to transmit the pharmaceutically active agents to a patient in a fast and effective manner.

The oral dosage form of this invention can be utilized to transport any desired water- soluble pharmaceutically active agent As used herein, the term“effective amount” designates the amount of drug or pharmaceutical agent that produces the desired biological or medical response of a patient. In accordance with this invention depending upon the pharmaceutical agent that is administered, and the desired biological or medical response of a patient desired by the physician, the effective amount will vary. In general, the amount of a pharmaceutically active agent conventionally administered in other unit dosage forms can be used and administered by the unit dosage form of this invention. The dose of pharmaceutically active agent may be adjusted to take into account differences in absorption due to the different route of

administration. The term“selective” as used herein is means that a major portion of the pharmaceutical agent administered passes through the mucosal membranes of the mouth rather than through the GI tract

Absorption

One embodiment of the invention, when the oral dosage form of the invention is placed in the oral cavity, it dissolves in about 0.15 minutes to about 25 minutes, about 0.15 minutes to about 15 minutes, about 0.25 minutes to about 15 minutes, or about 0.20 minutes to about 18 minutes.

At least a fraction of 1% to 80% or greater of the oral dosage form (FI) is delivered to and absorbed by the oral mucosa and absorbed systemically and a second fraction of greater than

1% to 80% is delivered to and absorbed along the continuous length of the esophagus and gastrointestinal tract wherein the first fraction (FI) results in a rapid onset of action and improved bioavailability and wherein the second fraction (F2) results in a longer duration of action and improved bioavailability such that the combined FI and F2 results in improved bioavailability.

EXAMPLES

The following examples are merely exemplary in nature and is not intended to limit application and uses. The following examples further illustrate the present invention without, however, limiting the scope of the invention thereto. Various changes and modifications can be made by those skilled in the art on the basis of the description of the invention, and such changes and modifications are also included in the present invention.

Example 1: Montelukast ODF

Montelukast oral dosage forms were prepared according to the components and amounts shown in Table 1.

Example 2: Rivaroxaban ODF

Rivaroxaban oral dosage forms were prepared according to the components and amounts shown in Table 2.

Example 3. Isosorbide Dinitrate ODF

Isosorbide Dinitrate oral dosage forms were prepared according to the components and amounts shown in Table 3.

Example 4. Fingolimod ODF

Fingolimod oral dosage forms were prepared according to the components and amounts shown in Table 4.

Claims

CLAIMS We claim:

1. A pharmaceutical composition for application to the oral mucosa comprising:

a water-soluble matrix comprising an effective amount of a pharmaceutically active agent; and

an absorption enhancer having an HLB of about 1 to about 16,

wherein the absorption enhancers are selected from group consisting of PEG-8 beeswax, PEG-75 stearate, pegoxol-7 stearate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol dioleate, 2-hydroxypropyl stearate, 2-hydroxypropyl laurate, propylene glycol oleate, propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dilaurate, polypropylene glycol (17) dioleate, propyleneglycol monolaurate, propylene glycol monomyristate, dipropylene glycol

dipelargonate, polypropylene glycol monobutyl ether oleate, propylene glycol dipelargonate, propylene glycol didecanoate, dipropylene glycol dipelargonate, propylene glycol bis(9, 10- epoxystearate), propylene glycol monoisostearate, propylene glycol diundecanoate, glycol monoethyl ether, diethylene glycol monobutyl ether, oleoyl macrogolglycerides, lauroyl macrogolglycerides, stearoyl macrogolglycerides, caprylocaproyl macrogolglycerides, triglycerides medium-chain, polyglyceryl-3 diisostearate, polyglyceryl oleate, ethylene glycol palmitostearate, diisopropyl adipate, di-n-butyl adipate, dimethyl adipate, dimethyl isosorbide and diethylene glycol monoethyl ether; and

the matrix is a film.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical active agent is selected from the group consisting of anesthetic agents, antitussive agents, nonnarcotic analgesics such as the nonsteroidal anti-inflammatory agent (NSAIDS), erectile dysfunction agents, female sexual dysfunction agents, antihistamine, colds and allergy agents, cough agents, respiratory disorder agents, sore throat agents, respiratory disorder agents, heartburn and dyspepsia agents, antiemetic agents, sleep aids, diarrhea agents, oral hygiene agents, antagonists of CGRP receptors, drugs for hormone replacement, Alzheimer’s disease agent, caffeine, caffeine salt compounds, coagulation inhibitors, leukotriene receptors antagonists, immunomodulatory agents and vasodilators.

3. The pharmaceutical composition of claim 2, wherein

a. the anesthetic agent is lidocaine (xylocaine), procaine, or benzo caine;

b. the antitussive agent is hexylresorcinol or dextromethorphan;

c. the nonnarcotic analgesics such as the nonsteroidal anti-inflammatory agents (NSAIDS) is acetaminophen, Ibuprofen, ketoprofen, indomethacin, aspirin (low dose for cardiovascular), naproxen sodium, ketorolac, diclofenac, meloxicam, or piroxicam;

d. the erectile dysfunction agent is sildenafil, tadalafil, or vardenafil;

e. the female sexual dysfunction agent is sildenafil, tadalafil, or vardenafil;

f. the antihistamine, cold and allergy agent is cetirizine hydrochloride, loratadine, chlorcyclizine HC1, chlorpheniramine maleate, dextrochlorpheniramine maleate, dexbrompheniramine maleate, diphenhydramine citrate, diphenhydramine HC1, doxylamine succinate, phenindamine tartrate, pheniramine, pyrilamine maleate, triprolidine HC1, thonzylamine HC1, or clemastine fumarate;

g. the cough agent is menthol, camphor, dextromethorphan HBr, guaifenesin, codeine phosphate, or codeine;

h. the respiratory disorder agent is pseudoephedrine HC1, phenylephrine HC1, guaifenesin, dextromethorphan HBr, or ephedrine;

l. the sore throat agent is benzocaine, menthol, dyclonine, or phenol;

j. the heartburn and dyspepsia agent is cimetidine, nizatidine, famotidine, ranitidine, or omeprazole;

k. the antiemetic agent is granisetron, ondansetron, etc. AZ-001, AZ-004, Levadex, Zelrix, VR-147, ROX-828, COL-144, BF-1, diphenhydramine, or scopolamine;

l. the sleep aid is zolpidem, Eszopiclone (Lunesta), Zaleplon (Sonata),

diphenhydramine, doxylamine, benzodiazepines (such as: Estazolam (ProSom),

Flurazepam (Dalmane), Temazepam (Restoril), Triazolam (Halcion), or Ramelteon (Rozerem);

m. the diarrhea agent is loperamide, digestive enzymes (lactase), or bismuth sub salicylate;

n. the oral hygiene agent is cetylpyridinium chloride, domiphen, thymol, eucalyptol, methyl salicylate, menthol, stannous fluoride, sodium fluoride, benzocaine, phenol, or docosanol;

o. the drug for hormone replacement is estradiol, or testosterone;

P- the Alzheimer's agent is donepezil, galantamine, rivastigmine, tacrine, or memantine;

q. the coagulation inhibitor is rivaroxaban, apixaban, edoxaban, or fondaparinux; r. the leukotriene receptor antagonist is montelukast, zafirlukast or zileuton;

s. the immunomodulatory agent is fingolimod, teriflunomide, glatiramer or interferon beta; and

t the vasodilator is glyceryl trinitrate, isosorbide dinitrate, aminophylline or co- dergocrine mesylate.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutically active agent is selected from the group consisting of sildenafil, tadalafil, vardenafil, cetirizine, donepezil, galantamine, rivastigmine, tacrine, memantine, rivaroxaban, montelukast, fingolimod, and isosorbide dinitrate.

5. The pharmaceutical composition of claim 1, further comprising a secondary absorption enhancer, wherein the secondary absorption enhancer is selected from the group consisting of sucrose fatty acid esters, glycerol, ginger oil, cineole, terpenes and mixtures thereof.

6. A pharmaceutical composition for application to the oral mucosa comprising:

an absorption enhancer having an HLB of about 1 to about 16,

wherein the matrix is a film; and

the absorption enhancer is one or more sucrose fatty acid esters.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical active agent is selected from the group consisting of coagulation inhibitor, leukotriene receptor antagonists, immunomodulatory agents and vasodilators.

8. The pharmaceutical composition of claim 7, wherein

the coagulation inhibitor is rivaroxaban;

the leukotriene receptor antagonists is montelukast;

the immunomodulatory agents is fmgolimod; and

the vasodilators is isosorbide dinitrate.

9. The pharmaceutical composition of claims 1 or 6, further comprising a nonionic surfactant wherein the combined nonionic surfactant and the sucrose fatty acid ester have a combined HLB of about 1 to about 16.

10. The pharmaceutical composition of claim 9, wherein the nonionic surfactant is at least one or more of polysorbate and sorbitan fatty acid ester.

11. The pharmaceutical composition of claim 6, further comprising a secondary absorption enhancer, wherein the secondary absorption enhancer is selected from the group consisting of glycerol, ginger oil, cineole and terpenes.

12. The pharmaceutical composition of claims 5 or 6, wherein the sucrose fatty acid is a C12 to C20 saturated fatty acid ester of sucrose.

13. The pharmaceutical composition of claim 12, wherein the sucrose fatty acid is selected from the group consisting of sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate and sucrose erucate.

14. The pharmaceutical composition of claim 13, wherein the sucrose fatty acid ester is a sucrose stearate.

15. The pharmaceutical composition of claim 13, wherein the sucrose fatty acid ester has a monomer content of from about 20 percent to about 80 percent.

16. The pharmaceutical composition of claim 10, wherein the polysorbate is selected from the group consisting of polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan and Polyoxyethylene (20) sorbitan monooleate.

17. The pharmaceutical composition of claim 10, wherein the sorbitan fatty acid ester is selected from the group consisting of sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate and sorbitan monooleate.

18. The pharmaceutical composition of claims 1 or 6, further comprising a film forming agent selected from pullulan or a polymeric mixture of polyvinylpyrrolidone and a polymeric alginate.

19. The pharmaceutical composition of claim 18, wherein a ratio of polyvinylpyrrolidone to polymeric alginate in the polymeric mixture is from about 5: 1 to about 1:3.

20. The pharmaceutical composition of claim 18, wherein the polymeric mixture comprises, from about 5% to about 95% by weight of polyvinylpyrrolidone and from about 5% to about 95% by weight of a polymeric alginate, both of said weights being based on the weight of said polymeric mixture.

21. The pharmaceutical composition of claims 1 or 6, wherein the film has a surface area of from 0.25 cm² to 20 cm² and a weight of about 1 mg to about 200 mg or a surface area of from 1 cm² to 10 cm² and a weight of about 10 mg to 200 mg.

22. The pharmaceutical composition of claims 1 or 6, wherein the film comprises one or more absorption enhancers in an amount of from about 0.1% to about 20% by weight, about 0.1% to about 15% by weight, or about 1% to about 10% by weight of the film.

23. The pharmaceutical composition of claims 1 or 6, wherein the pharmaceutical composition dissolves in the oral cavity in about 0.25 minutes to about 15 minutes.

24. The pharmaceutical composition of claims 1 or 6, wherein the film has a thickness of about 0.01 mm to about 5 mm.

25. A method of delivering a pharmaceutically active agent comprising administering the pharmaceutical composition of claims 1 or 6.

26. The method of claim 25, wherein at least a fraction of 1% to 80% or greater of the drug (FI) is delivered to and absorbed by the oral mucosa and absorbed systemically and a second fraction of greater than 1% to 80% is delivered to and absorbed along the continuous length of the esophagus and gastrointestinal tract wherein the first fraction (FI) results in a rapid onset of action and improved bioavailability and wherein the second fraction (F2) results in a longer duration of action and improved bioavailability such that the combined FI and F2 results in improved bioavailability.