The present invention provides a novel method for treating oral conditions and upper gastrointestinal conditions in a subject by providing an inventive oral dosage form of a pharmaceutical composition comprising an effective amount of at least one antifungal and optionally a flavor modifier and/or salivation component such as an herbal component. In the present invention, the subjects have either not been diagnosed or do not have active or recurrent fungal infections. Specifically, the present invention is directed to chewable dosage forms.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides a method for treating upper gastrointestinal conditions in a subject, which method includes administering to the subject in need thereof a solid oral dosage form of a pharmaceutical composition containing an effective amount of an antifungal and, wherein the subject has not been diagnosed with a gastric or esophogeal fungal infection. In certain embodiments of the invention, the pharmaceutical composition further comprises a flavor modifier and/or one or more herbal component and/or a vitamin component. In particular embodiments, the oral dosage form comprises a component that induces salivation, including for example an herbal component.

In one embodiment, at least one antifungal is selected from the group consisting of nystatin, nystatin dehydrate, nystop, mycostatin, bio-statin, mykinac, nilstat, nystex, o-v statin, amphotericin, amphotericin B, amphotec, fungizone, undecyne, undecylenic acid, zinc undecylenate, gentian, amphocin, gentian root, gentian violet, and combinations thereof. In a preferred embodiment, the antifungal is nystatin.

In certain embodiments, the effective amount of nystatin ranges from about from about 10,000 units to about 1,000,000 units in powder form. More particularly, the amount ranges from about 50,000 units to about 500,000 units, even more particularly from about 80,000 to about 200,000 units. The oral dosage form is administered at least once a day.

In a specific embodiment, the oral dosage form is a solid oral controlled release form; in particular, it can be selected from a group consisting of a tablet, capsule, particle, powder, sachet, a wafer, a chewable tablet, a buccal tablet, a sublingual tablet, a quick-dissolve tablet, an effervescent tablet, a granule, a pellet, a bead, a pill, a troche, a sprinkle, a film, a dry syrup, a reconstitutable solid, a suspension, pastille, lozenge, gum, lollipop, chewing gum or chewable candies, pouch or plugs (similar to chew/dip strands), caplet, or a strip. In a specific embodiment, the oral dosage form is a pastille, lozenge, chewing gum, chewable candy, pouch or plug.

According to the invention, the upper gastrointestinal condition is selected from the group consisting of active benign gastric ulcer, gastroesophageal reflux disease (GERD), Zollinger-Ellison syndrome, erosive esophagitis, indigestion gastric reflux, dyspepsia, reflux disease, or nausea associated with morning sickness.

The present invention also provides for the treatment of oral conditions including halitosis, dental plaque, gingivitis, xerostomia, dry mouth, oral malodor and combinations thereof.

In one specific embodiment, the compositions are used in the evening or at night before sleep to aid in controlling or preventing snoring, night coughing, aspirations (and therefore aspirational pneumonia).

The invention also provides for the oral dosage form containing a pharmaceutical composition, which includes an effective amount of an antifungal; preferably a flavor modifier; and a carrier. In certain embodiments, the solid oral dosage form further contains at least one additive selected from the group consisting of: an excipient, a diluent, a disintegrant, a lubricant, a plasticizer, a colorant, a dosing vehicle, and any combination thereof.

The compositions of the present invention may also contain one or more additives selected from the group consisting of betaine hydrochloride, betaine beta carotene, vitamin E, selenium, vitamin B-6, folic acid, vitamin C, magnesium, vitamin B-1, vitamin B-2, niacinamide, vitamin B-12, zinc, copper, biotin, pantothenic acid, dandelion root, acidophilus dairy free, bifidus dairy free, FOS powder, chromium polynicotinate, betaine HCl, pancreatin, papain, and pepsin.

DETAILED DESCRIPTION

It has now been discovered that antifungal compounds, such as nystatin, can be effectively used to achieve the desired symptomatic relief of upper gastrointestinal conditions. The invention is based in part on the unexpected discovery that sustained release of nystatin is capable of resolving gastroesophageal reflux disease (GERD) in otherwise healthy adults.

The subject invention advantageously provides a dosage form for oral administration containing an antifungal medicament to treat symptoms of upper gastrointestinal conditions. The treatable symptoms include but are not limited to heartburn, indigestion, acid reflux, reflux esophagitis, gastroesophogeal reflux disease, gastritis, dyspepsia and other acid-related upper GI conditions. In a further embodiment, treatable symptoms include nausea associated with pregnancy, e.g., morning sickness. It has been discovered that the oral dosage form is beneficial in the treatment of upper GI conditions in individuals not diagnosed with or does not have a gastric fungal infection. The antifungal oral dosage form provides sustained relief of discomforting symptoms and lasting therapeutic effect.

Pharmaceutical Formulation

The pharmaceutical formulations of the present invention are directed to use of oral dosage forms comprising at least one antifungal active ingredient to treat upper GI conditions; in some cases, without testing for a fungal infection. In specific embodiments, the oral dosage form includes at least one flavor modifier, and additives as necessary including, for example, bases, stabilizers, and/or fillers.

As used herein, the term "active ingredient" or "active agent" refers to one or more compounds that have some antifungal property. Accordingly, more than one type of antifungal compound may be added to the formulation of the invention. The formulation of the invention may comprise any pharmaceutically acceptable antifungal that may be orally administered to a subject. Formulations including active ingredients in amounts appropriate for the desired pharmacological properties at the dosage administration can be prepared. An "active ingredient" of the present invention can be any non-active compound, including but not limited to antifungals, H.sub.2-blockers, and proton pump inhibitors.

Antifungals

The pharmaceutical compositions of the present invention include at least one active ingredient that is a pharmaceutically acceptable antifungal agent. Exemplary antifungal agents include, but are not limited to, at least on of the following: nystatin, amphotericin B, natamycin, miconazole, ketoconazole, clotrimazole, econazole, mebendazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, thiabendazole, tiaconazole, fluconazole, itraconazole, ravuconazole, posaconazole, voriconazole, terbinafine, amorolfine, naftifine, butenafine, caspofungin, micafungin, flucytosine, undycene, undecylenic acid, zinc undecylenate, gentian, griseofulvin, gentian root, gentian violet, and combinations thereof. Examples of imidazole antifungals are disclosed in U.S. Pat. No. 6,656,928 (to McAdden), which is incorporated herein by reference.

In a specific embodiment of the invention, the antifungal is nystatin. Nystatin is disclosed, for example, in U.S. Pat. No. 4,006,222 (to Metzger), which is incorporated herein by reference in its entirety. In another embodiment, the antifungal is amphoteracin B, as disclosed for example in U.S. Pat. No. 4,902,789 (to Michel, et al.), also incorporated herein by reference in its entirety.

The antifungal is present in each dosage form in amounts ranging from about 5,000 units to about 1,000,000 units in powder form. Preferably, the amount ranges from about 50,000 units to about 500,000 units, more preferably from about 80,000 to about 200,000 units.

In certain embodiments, the dosage form may include a combination therapy with one or more active ingredients, including but not limited to antacids or H-blockers. For example, an embodiment may contain an antifungal and a histamine H.sub.2-receptor antagonist. Examples of H.sub.2-receptor antagonists include cimetidine (TAGAMET.RTM.), nizatidine (AXID.RTM.), ranitidine hydrochloride (ZANTAC.RTM.), rabeprazole (ACIPHEX.RTM.), and famotidine. U.S. Pat. No. 5,667,794 (to Simon et al.), incorporated herein by reference, discloses famotidine, an exemplary H.sub.2-receptor antagonist used for the treatment of upper GI conditions.

Alternatively, embodiments may contain an antifungal and a proton pump inhibitor. Examples of PPIs include but are not limited to lansoprazole (PREVACID.RTM.), esomeprazole (NEXIUM.RTM.), omeprazole (PRILOSEC.RTM.), pantoprazole (PROTONIX.RTM.), and omeprazole IR (ZEGERID.RTM.). Various proton pump inhibitors are disclosed in U.S. Pat. No. 6,132,770 (to Lundberg); U.S. Pat. No. 6,869,615 (to Chen, et al.); and U.S. Pat. No. 4,786,505 (to Lovgren, et al.), all of which are incorporated herein by reference in their entirety.

Flavor Modifiers

In certain embodiments, the pharmaceutical composition of the present invention also preferably includes at least one flavor modifier. The flavor modifiers, or taste masking components, are components to mask or lessen the unpleasant tastes commonly known to be associated with antifungal compounds. Inclusion of taste masking components is particularly desirable when administration is prolonged in the oral cavity, such as compositions in the form of lozenges. Non-limiting examples of taste masking components include fruit flavorings, mint flavorings, salt, or sweeteners.

Examples of sweeteners include, but are not limited to, stevia (stevioside), Nutrasweet, and Splenda, as well as any non-nutritive sweeteners, also called sugar substitutes or artificial sweeteners, including but not limited to saccharin, cyclamate, aspartame, sucralose, and acesulfame potassium. Additionally, sugar alcohols or other nutritive sweeteners derived from fruits or produced commercially from dextrose may be used. The most common include: sorbitol, mannitol, xylitol, maltitol, sorbitol, and mannitol. In some embodiments, the flavor modifiers do not contain sugar and the dosage form is sugar-free. In a specific embodiment, the sweetener is stevia.

U.S. Pat. No. 5,972,374 (to Theisen), U.S. Pat. No. 5,523,105 (to Ishikawa, et al.), and U.S. Pat. No. 5,425,962 (to Johnson, et al.) disclose mint oils and flavorants and their uses in various products such as gum and medications. Other exemplary flavor modifiers and/or flavorants include, but are not limited to fruit flavorings such as grape, cherry, lemon, or other citrus flavors; other acceptable nonfood flavorings such as tutti frutti flavor; and herbal flavorings. Flavor modifiers may be artificial or juice extracts.

The flavor modifiers may be present in varying amounts, depending on the particular antifungal used. In certain embodiments, the flavor modifiers are present in amounts ranging from about 5 mg to about 100 mg per dosage form, preferably from about 20 mg to about 50 mg per dosage form.

Herbal Components

The pharmaceutical composition of the present invention may also includes at least one component that induces salivation. In particular, the pharmaceutical composition includes an herbal component that induces salivation. Inducing salivation in a subject improves the efficacy of the composition and ultimately enhances treatment of the gastrointestinal conditions.

Any components which will promote salivation may be used in the present invention. In particular, bitter herbs are used to promote salivation. Herbal component(s) of the present invention can be selected from a group consisting of, but not limited to, ginger, senega root, gentian, motherwort, hops, dandelion, papaya, dock or sorrel, sunflower, calendula, nasturtium, mallow, chicory, corn silk, clover and mixtures thereof. In other embodiments, nonherbal salivation enhancing components are also contemplated.

The salivation inducing components may be present in varying amounts, depending on the particular antifungal used and depending on what particular dosage form is used.

Vitamins or Food Additives

The therapeutic composition of the present invention may also contain vitamins or food additives that deliver or increase hydrochloric acid, gastric juices, and enzymes. Such additives include but are not limited to an effective amount of betaine hydrochloride, betaine beta carotene, vitamin E, selenium, vitamin B-6, folic acid, vitamin C, magnesium, vitamin B-1, vitamin B-2, niacinamide, vitamin B-12, zinc, copper, biotin, pantothenic acid, dandelion root, acidophilus dairy free, bifidus dairy free, FOS powder, chromium polynicotinate, betaine HCl, pancreatin, papain, and pepsin.

Dandelion Root supports the digestive tract. It primarily works with the liver and gallbladder by stimulating digestive enzymes produced by each organ. It also stimulates digestion and can help with those who suffer from constipation and acid reflux. This herb is also high in many vitamins and minerals. Vitamins found in food are better absorbed and retained by the body. These types of additive ingredients not only giving the digestive system support, but also by giving a natural source of vitamins and minerals. Other additives such as kelp, sea vegetation, alfalfa, trace minerals, and molybdenum, which also have high concentrations of minerals, could be substituted. As for digestive support, other items such as juniper, aloe vera, burdock, ginger root, and artichoke also have potent effects on supporting the digestive tract and could be substituted.

Probiotic (acidophilus dairy free/bifidus dairy free) bacteria favorably alter the intestinal micro-flora balance, inhibit the growth of harmful bacteria, promote good digestion, boost immune function, and increase resistance to infection. Individuals with flourishing intestinal colonies of beneficial bacteria are better equipped to fight the growth of disease-causing bacteria. Probiotics are important in finishing the digestive process and therefore can increase the absorption of nutrients.

Fructo-oligosaccharides (FOS) are naturally occurring carbohydrates that cannot be digested or absorbed by humans but support the growth of bifidobacteria, one of the beneficial bacterial strains. Friendly bacteria support digestion, elimination and the absorption of nutrients in the body.

Betaine (hcl/gastric acid) may also be added to the compositions of the present invention. One of the most important parts of digestion occurs in the stomach, where gastric (stomach) acid helps break down proteins for further digestion in the small intestine. This increased digestion aids in the absorption of nutrients that support the nervous system.

Papain/Pancreatin/Pepsin are digestive enzymes (also called pancreatic enzymes) include three classes of enzymes: proteolytic enzymes needed to digest protein, lipases needed to digest fat, and amylases needed to digest carbohydrates. Pancreatic enzymes should be used with to support the digestive process. Allergies are triggered by partially undigested protein, while protoolytic enzymes reduce allergy symptoms. Proteolytic enzymes such as trypsin, chymotrypsin, and bromelain are partially absorbed by the body. Proteolytic enzymes may improve immune system function, a common problem with people with allergies and nervous system weakness. Papain, pancreatin and, pepsin are contemplated in the compositions of the present invention, however other items such as papaya, and pineapple also have high concentrations of these digestive enzymes could be substituted.

Any suitable medicament for oral cleansing, breath freshening or the like can be added to the film formulation. The medicaments can include, for example, a pH control agent, such as urea and buffers, inorganic components for tartar or caries control, such as phosphates and fluorides, a breath freshening agent, such as zinc gluconate, an anti-plaque/anti-gingivitis agent, such as chlorohexidene, CPC, and triclosan, a saliva stimulating agent including, for example, food acids such as citric, lactic, maleic, succinic, ascorbic, adipic, fumaric and tartaric acids, a pharmaceutical agent, a nutraceutical agent, a vitamin, a mineral, other like medicaments or combinations thereof.

Additional Additives

The therapeutic composition of the present invention may also contain additional additives, including polymer or therapeutic agent stabilizers, such as but not limited to sucrose, salts, and pH adjusting agents; and preservatives including antioxidants such as butylated hydroxytoluene, and antibacterials. Alternative additives are disclosed in detail below.

Thus, the pharmaceutical composition may include one or more additives, depending on the pharmaceutically acceptable carrier, a base, a preservative, a dye, a binder, a suspending agent, a dispersing agent, a stabilizer, a colorant, a disintegrant, an excipient, a diluent, a lubricant, a plasticizer, an oil or any combination of any of the foregoing. Suitable pharmaceutically acceptable additives include, but are not limited to, ethanol; water; glycerol; aloe vera gel; allantoin; glycerin; vitamin A and E oils, citric acid; mineral oil; PPG2 myristyl propionate; vegetable oils and solketal. Examples of additional additives include, but are not limited to, sorbitol; talc; stearic acid; and dicalcium phosphate.

Suitable binders, fillers and/or bases include, but are not limited to, starch; gelatin; natural sugars, such as glucose, sucrose and lactose; corn sweeteners; natural and synthetic gums, such as acacia, tragacanth, vegetable gum, and sodium alginate; carboxymethylcellulose; polyethylene glycol; waxes; and the like.

Suitable disintegrators include, but are not limited to, starch such as corn starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Suitable lubricants include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium acetate, and the like.

The composition may also include suitable preservatives, e.g., sodium benzoate, and other additives the may render the composition more suitable for application, e.g., sodium chloride, which affects the osmolarity of the preparation.

Suitable dispersing and suspending agents include, but are not limited to, synthetic and natural gums, such as bentoite, vegetable gum, tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone and gelatin.

A suitable pharmaceutical diluent is, but is not limited to, water.

Under ordinary conditions of storage and use, the preparations of the present invention can also contain a preservative to prevent the growth of microorganisms. The therapeutic composition can be stable under the conditions of manufacture and storage and preferably preserved against the contaminating action of microorganisms such as bacteria and fungi. A carrier liquid can be a solvent of dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, benzoic acid, alcohol, benzalkonium chloride and the like. In many cases, it will be preferable to include isotonic agents, e.g., sugars, phosphate buffers, sodium benzoate, sodium chloride, or mixtures thereof.

Modes of Administration

The therapeutic composition can be administered in a variety of oral dosage forms adapted to the chosen route of administration. Administration in this situation can include, for example, use of a tablet, capsule, particle, powder, sachet, pastille (e.g., as disclosed in U.S. Pat. No. 4,725,440), lozenge, chewing gum, chewable candies (i.e. gummy type or taffy) pouch or plugs (similar to chew/dip strands), lollipop, caplet, coated or encapsulated chewable capsules, or other solid oral dosage form of the formulation. In particular, the solid oral dosage form is a chewing gum or chewable candy, which while being sustained in the mouth, the nystatin is slowly dissolved and mixed with saliva. The saliva is then swallowed thereby coating mucosal surfaces in the esophagus, esophagogastric (EG) junction, and stomach, particularly the antrum of the stomach.

In a specific embodiment, the solid oral dosage form may be in the form of an edible wax. The dosage form is made according to known methods in the art, including for example, heating an edible wax at a temperature above its melting point; heating an edible oil at a temperature above the melting point of the edible wax; mixing the melted wax with the oil along with the pharmaceutical formulation, and homogenizing the mixture.

In yet another embodiment, the antifungal agent can be formulated for sublingual and/or oral pharyngeal administration. For example, nystatin can be incorporated in a chewable "candy" matrix, such as that described in U.S. Pat. No. 4,671,953 (to Stanley, et al.), or in a gum base.

The oral dosage forms of the present invention provide the advantage of a sustained-release system, whereby effective amounts of antifungal are released over time. Various types of sustained-release materials have been established and are well known by those skilled in the art.

Methods of Treatment

The therapeutic composition of the present invention may be administered to a host subject (patient) to achieve any desired effect in the clinical outcome of the targeted upper gastrointestinal condition. Preferably the subject is a mammal, and more preferably a human. The human may be from an adult or pediatric population.

Specifically, in the present invention, the subject is one who has either not been diagnosed with a fungal infection or who has not been diagnosed with recurrent fungal infections. The present invention is directed to subjects needing relief and treatment of upper gastrointestinal diseases, independent of any fungal infection (i.e., candida).

The terms "upper gastrointestinal condition" refers to symptoms affecting the proximal part of the gastrointestinal tract, which consists of the mouth, pharynx, esophagus, and stomach (including the antrum, pylorus and pyloric sphincter proximal to the pylorus valve).

The compositions of the invention may be used for the treatment or prevention of gastrointestinal conditions. Such conditions include, but are not limited to: gastritis; peptic ulcer; reflux esophagitis; dyspepsia; gastric ulcers; gastroesophageal reflux disease (GERD); severe erosive esophagitis; and pathological hypersecretory conditions such as Zollinger Ellison Syndrome. The methods and composition of the present invention may also be useful in the treatment of H. pylori infection and conditions associated with H. pylori infection (e.g., ulcers, gastric carcinoma, non-ulcer dyspepsia, gastritis, and esophageal lesions associated with gastro-esophageal reflux disease). Other examples of the gastrointestinal disorder include, but are not limited to, gastrointestinal diseases, such as acute gastritis, chronic superficial gastritis, atrophic gastritis, antral gastritis, senile gastritis, bile-regurgitational gastritis, esophagitis, gastric neurosis, as well as various consequent conditions including gastric hyperacidity, hypochlorhydria, gastrointestinal discomfort after meals, gastritis caused by taking acidic drugs such as salicylates (e.g., aspirin), gastric discomfort after drinking, and gastric discomfort due to fasting. Symptoms often associated with these conditions include indigestion, heartburn, burping, coughing, wheezing, chest pain, stomach pain, feeling bloated, emesis, and hematemesis. U.S. Pat. Nos. 5,601,848 and 5,256,684 (to Marshall), and U.S. Pat. No. 5,977,159 (to Fandriks, et al.) disclose treatment of a variety of these upper GI disorders, and are incorporated herein by reference in their entirety. The present invention also provides the benefit of reducing or eliminating the use of H.sub.2-receptor antagonists or PPIs, thereby reducing the incidence of hip fractures.

In another embodiment of the present invention, the pharmaceutical compositions are used to treat morning sickness in pregnant women. In particular embodiments, the classic nausea and vomiting in early pregnancy is treated. Cases can range in degree from mild to severe, and symptoms usually begin soon after the first missed period. Morning sickness, i.e., nausea and vomiting experienced during the first and second trimesters of pregnancy, is experienced by approximately half of all pregnant women, however it is particularly common in cases of multiple pregnancy and hydatidiform mole. (Kousen, M., "Treatment of nausea and vomiting in pregnancy", Am Fam Physician, 48:1279 (1993)). These symptoms appear to be related to hormonal issues in early pregnancy. These women may or may not have heartburn or signs of GERD and are previously not symptomatic people who have a self limiting disease. In another embodiment, the pregnant women may have preexisting disease (although may not be symptomatic) such as GERD or dyspepsia who develop those GI symptoms during the pregnancy that appear related to the preexisting condition with exacerbation due to anatomical changes or other pregnancy issues. This development may occur at any time during pregnancy. Hyperemesis gravidarum, i.e., persistent nausea and vomiting during pregnancy, can lead to a reduction in fluid and electrolyte levels, as well as a jeopardized nutritional status if the condition is not treated. The condition is characterized by prolonged and severe nausea and vomiting, dehydration, ketosis, and body weight loss. Other complications may include hyponatraemia, hypokalaemia, a low serum level, metabolic hypochloraemic alkalosis, ketonuria, liver function test abnormalities, abnormal thyroid function tests, and suppressed thyroid-stimulating hormone levels. Nelson-Piercy, C., "Treatment of nausea and vomiting in pregnancy. When should it be treated and what can be safely taken?", Drug Saf, 19(2):155-64 (1998).

In another embodiment of the present invention, the pharmaceutical compositions of the present invention may be used to treat oral conditions. The oral conditions include but are not limited to halitosis, dental plaque, gingivitis, xerostomia, dry mouth, oral malodor or combinations thereof. Halitosis is produced by the production and liberation of volatile compounds, mainly volatile derivatives of sulphur, such as hydrogen sulphide and methyl-mercaptane. According to the localization of the origin of the unpleasant odour, it can be classified as oral (localised in lips, tongue, teeth, dental prosthetic elements, periodontal tissues, oropharynx) or non-oral [caused by diseases of the respiratory tract, systemic diseases (hepatic dysfunction, cirrhosis, diabetic ketoacidosis, carcinomas and certain metabolic diseases in which an enzymatic anomaly occurs), diseases of the gastrointestinal tract and certain foods, drinks, tobacco and medicaments].

Treatment of these conditions is accomplished by administering to a patient an effective amount of the pharmaceutical composition according to the present invention. The effective amount may be administered once or multiple times daily, as necessary. Alternatively, the dosage form may be taken once every other day, or once or twice weekly.

Treatment duration can be short-term, e.g., several hours (for example 8-14 hours), or long-term, e.g., a number of days or indefinitely until the attending physician deems further administration no longer is necessary.
 

Claim 1 of 11 Claims

1. A method for treating GERD in a subject, which comprises administering to the subject in need thereof a solid oral dosage form of a pharmaceutical composition consisting essentially of an effective amount of at least one antifungal, wherein the antifungal is selected from the group consisting of nystatin and nystatin dehydrate, and a flavor modifier.

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