Ondansetron sublingual spray formulation

The invention is directed to sublingual spray formulations containing ondansetron or a pharmaceutically acceptable salt thereof. The invention is further directed to method for treating or preventing nausea and emesis associated with cancer treatments by administering sublingual spray formulations containing ondansetron or a pharmaceutically acceptable salt thereof to a patient in need thereof.

Ondansetron is a serotonin 5-HT3 receptor antagonist with the following structure:

Ondansetron's primary use is as an antiemetic (to treat nausea and vomiting) following cancer treatments such as chemotherapy, surgery and/or radiation. Ondansetron works by reducing the activity of the vagus nerve which then deactivates the vomiting center in the medulla oblongata. Ondansetron also blocks serotonin receptors in the chemoreceptor trigger zone.

Ondansetron is currently available from GlaxoSmithKline as a film coated tablet, an oral solution, as an injection (Zofran®), and an orally disintegrating tablet (Zofran ODT®). Ondansetron is also available as an oral soluble film (Zuplenz®) from Vestiq Pharmaceuticals.

U.S. Pat. No. 6,998,110 discloses a method for administering a composition, such as ondansetron, to a mammal through the oral mucosa. This patent teaches that a polar solvent and a propellant are required. Although U.S. Pat. No. 6,676,931 teaches a propellant free ondansetron composition, this patent requires the use of a pharmacologically acceptable polar solvent in an amount of 19 to 90 weight percent and flavoring agent in an amount of 0.1 to 10 weight percent of the total composition.

U.S. Pat. No. 5,854,270 is directed to a liquid ondansetron formulation that includes a sorbitol-containing sweetener and has a pH of from 2 to 5. U.S. Pat. No. 6,555,546 discloses a formulation which may contain ondansetron and polyethylene glycol (PEG)-electrolyte solution for use in treating constipation or for accelerating intestinal lavage. However, these formulations fail to provide a sublingual formulation that has quick-onset and is storage stable.

“Sublingual” means “under the tongue” and refers to administration of a substance via the mouth in such a way that the substance is rapidly absorbed via the blood vessels under the tongue. A sublingual formulation is desirable because it bypasses hepatic first pass metabolic processes which provide better bioavailability, rapid onset of action, and higher patient compliance. Dysphagia (difficulty in swallowing) is common among in all ages of people and more in pediatric, geriatric, and psychiatric patients. In terms of permeability, the sublingual area of oral cavity is more permeable than buccal area. Sublingual drug administration is applied in field of cardiovascular drugs, steroids, enzymes and barbiturates.

While there are various ondansetron formulations currently available, there is still a need in the art for a quick-onset sublingual spray formulation containing ondansetron, or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a salt thereof and purified water.

In a further aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a salt thereof, from about 10 to about 95% w/w purified water, and from about 2 to about 80% w/w cosolvent, wherein the % w/w is of the total formulation.

In another aspect, the present invention is directed to methods for treating or preventing nausea and emesis in humans associated with cancer therapies such as surgery, chemotherapy and/or radiation comprising administering the formulations of the present invention to a patient.

Applicants unexpectedly discovered a sublingual ondansetron formulation which has improved bioavailability, has a more rapid onset of action, has improved storage stability, and has excellent spray characteristics.

In one embodiment, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a salt thereof and purified water. Preferably, this formulation is propellant free.

Preferably, all of the formulations of the present invention are propellant free.

As used herein, “ondansetron” refers to the base or a pharmaceutically acceptable salt, ester, derivative, or prodrug thereof.

Pharmaceutically acceptable salts that can be used in accordance with the current invention include but are not limited to hydrochloride salts. In preferred embodiments the pharmaceutically acceptable salt is hydrochloride.

In another embodiment, the formulations of the present invention contain from about 10 to about 95% w/w purified water.

In a further embodiment, the formulations of the present invention contain a cosolvent selected from the group consisting of purified water, an alcohol, a glycol, and a mixture thereof. Preferably, the cosolvent is a mixture of an alcohol and a glycol.

In a preferred embodiment, from about 2 to about 80% w/w of the formulation is cosolvent. More preferably, from about 10 to about 60% w/w of the formulation is cosolvent.

In preferred embodiments, the formulations may contain from about from about 15 to about 60% w/w ethanol and/or from about 5 to about 25% w/w propylene glycol as cosolvents. In a more preferred embodiment, the formulations may contain about 31.5% w/w ethanol and about 15% w/w propylene glycol as cosolvents.

In some embodiments, the formulations of the present invention may also contain an effective amount of a pharmaceutically acceptable solubilizer. Suitable solubilizers include polysorbate, sorbitan, polyvinylpyrrolidine, sodium lauryl sulfate, cyclodextrin, or a mixture thereof. One presently preferred solubilizer is cyclodextrin.

When a solubilizer is used, the effective amount of the solubilizer is from about 0.01 to about 30% w/w of the formulation.

In another preferred embodiment, the formulations of the present invention contain a preservative. Preservatives include methyl paraben, ethyl paraben, butyl paraben, propyl paraben, sodium benzoate, benzoic acid, or a mixture thereof. Preferred preservatives are methyl paraben and propyl paraben.

When a preservative is used, the effective amount of the preservative is from about 0.01 to about 0.5% w/w of the formulation.

The formulations of the present invention may also contain a flavoring agent. Flavoring agents include menthol, fruit punch flavor, strawberry flavor, cherry flavor, raspberry flavor, mint flavor, orange oil, spearmint oil, citrus oil, peppermint oil, cinnamon oil, anise oil, or a mixture thereof. Preferred flavoring agents are menthol and fruit punch flavor.

When a flavoring agent is used, the effective amount of the flavoring agent is from about 0.01 to about 0.5% w/w of the formulation.

The formulations of the present invention may also contain a sweetener. Sweeteners include sucralose, sucrose, aspartame, neotame, saccharin, dextrose, mannitol, glycerin, xylitol, or a combination thereof. A preferred sweetener is sucralose.

When a sweetener is used, the effective amount of the sweetener is from about 0.01 to about 0.5% w/w of the formulation.

In a preferred embodiment, the sublingual spray formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(10) is from about 10 to about 30 microns during administration.

In a preferred embodiment, the sublingual spray formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(50) is from about 15 to about 80 microns during administration.

In yet another preferred embodiment, the sublingual spray formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv(90) is from about 40 to about 200 microns during administration.

In a further embodiment, the sublingual spray formulations of the present invention are capable of producing a spray plume that has an ovality ratio of from about 1.1 to 2.8.

In another preferred embodiment, the sublingual spray formulations of the present invention are capable of producing a spray plume width that is from about 15 to about 45 millimeters during administration.

In an embodiment of the present invention, the sublingual spray formulations comprise from about 1 to about 15% w/w ondansetron or a salt thereof, from about 10 to about 95% w/w purified water, and from about 2 to about 80% w/w cosolvent.

In another embodiment of the present invention, the sublingual spray formulations comprise from about 1 to about 15% w/w ondansetron or a salt thereof, from about 10 to about 95% w/w purified water, from about 2 to about 80% w/w cosolvent, from about 0.01 to about 0.5% w/w antimicrobial preservative, from about 0.01 to about 0.5% w/w sweetener, and from about 0.01 to about 0.5% w/w flavoring agent.

In a preferred embodiment, the sublingual spray formulations comprise from about 2 to about 10% w/w ondansetron or a salt thereof, from about 15 to about 70% w/w purified water, and from about 15 to about 60% w/w ethanol and from about 5 to about 25% w/w propylene glycol as cosolvents.

In a preferred embodiment, the sublingual spray formulations comprise from about 2 to about 10% w/w ondansetron or a salt thereof, from about 15 to about 70% w/w purified water, from about 15 to about 60% w/w ethanol, from about 5 to about 25% w/w propylene glycol as cosolvents, from about 0.01 to about 0.5% w/w antimicrobial preservative, from about 0.01 to about 0.5% w/w sweetener, and from about 0.01 to about 0.5% w/w flavoring agent.

In yet another preferred embodiment, the sublingual spray formulations of the present invention comprise about 3.93% w/w ondansetron hydrochloride dihydrate, about 48.73% w/w purified water, and about 31.5% w/w ethanol and about 15% w/w propylene glycol as cosolvents.

In yet another preferred embodiment, the sublingual spray formulations of the present invention comprise about 3.93% w/w ondansetron hydrochloride dehydrate, about 48.73% w/w purified water, about 31.5% ethanol and about 15% w/w propylene glycol as cosolvents, from about 0.01 to about 0.5% w/w antimicrobial preservative, from about 0.01 to about 0.5% w/w sweetener, and from about 0.01 to about 0.5% w/w flavoring agent.

In another embodiment, the present invention is directed to methods for treating or preventing nausea and emesis in humans associated with chemotherapy, radiation or surgery comprising administering the formulation of claim 1 to a patient in need thereof.

In a preferred embodiment, from about 50 to about 400 μL of the formulation of claim 1 is administered to a patient.

As used herein, “nausea” refers to the sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit.

As used herein, “emesis” refers to the action of vomiting.

As used herein, “chemotherapy” refers to administering one or more cytotoxic anti-neoplastic drugs to a cancer patient as part of a standardized treatment regimen.

As used herein, “propellant free” refers to a sublingually administered formulation that is not administered using compressed gas.

As used herein the term “patient” refers, but is not limited to, a person that is being treated for nausea and emesis.

As used herein the term “pharmaceutically acceptable” refers to ingredients that are not biologically or otherwise undesirable in a sublingual dosage form.

As used herein the term “effective amount” refers to the amount necessary to treat a patient in need thereof.

As used herein “% w/w” and “percent w/w” refer to the percent weight of the total formulation.

As used herein, all numerical values relating to amounts, weights, and the like, that are defined as “about” each particular value is plus or minus 10%. For example, the phrase “about 10% w/w” is to be understood as “9% to 11% w/w.” Therefore, amounts within 10% of the claimed value are encompassed by the scope of the claims.

The disclosed embodiments are simply exemplary embodiments of the inventive concepts disclosed herein and should not be considered as limiting, unless the claims expressly state otherwise.

The following examples are intended to illustrate the present invention and to teach one of ordinary skill in the art how to use the formulations of the invention. They are not intended to be limiting in any way.