SUBLINGUAL ONDANSETRON SPRAY

FIELD OF THE INVENTION

[0001] The invention is directed to sublingual spray formulations containing ondansetron, or a pharmaceutically acceptable salt thereof; and a solvent consisting of ethanol and glycerin, suitable for administration to humans, and methods for treatment with sublingual formulations.

BACKGROUND OF THE INVENTION

[0002] Ondansetron is a serotonin 5-HT3 receptor antagonist with the following structure:

[0003] 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.

[0004] 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.

[0005] US Patent No. 6,998,110 discloses a method for administering a composition, such as ondansetron, to a requied through the oral mucosa. This patent teaches mat a polar solvent and a propellent are required. Although US Patent No. 6,676,931 teaches a propellent 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.

[0006] US Patent No. 5,854,270 is directed to a liquid ondansetron formulation that includes a sorintol-containing sweetener and has a pH of from 2 to 5. US Patent 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.

[0007] "Sublingual" means 'hinder the tongue" and refers to admimstration of a substance via the mouth in such a way that the substance is rapidly absorbed via the blood vessels under the tongue. A subungual 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.

[0008] While there are various ondansetron formulations currently available, there is still a need in the art for a rapid onset, storage stable, sublingual spray formulation containing ondansetron, or a phannaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

[0009] In one aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof; and a solvent consisting of ethanol and glycerin.

[0010] In another aspect, the formulation of the invention is a liquid, preferably a simple solution.

[0011] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof, and a solvent consisting of ethanol and glycerin, wherein the formulation is substantially free ofpropellant

[0012] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof, and a solvent consisting of ethanol and glycerin, wherein the formulation is substantially free of water. [0013] In another aspect, the present invention is directed to sublingual spray fbnnulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof a solvent consisting of ethanol and glycerin, and water.

[0014] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1% to about 15¾ w/w ondansetron or a pharmaceutically acceptable salt thereof and a solvent comprising ethanol and propylene glycol, caprylic acid and menthol, wherein %w/w is of the total formulation.

[0015] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof, a solvent consisting of ethanol and glycerin, and a permeation enhancer, preferably selected from the group consisting of menthol, caprylic acid and a combination thereof.

[0016] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof, a solvent consisting of ethanol and glycerin, and a pharmaceutically acceptable sweetener.

[0017] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof, a solvent consisting of ethanol and glycerin, and sucralose.

[0018] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof, and a solvent consisting of ethanol and glycerin, wherein the formulation is substantially free of water and wherein the formulation is capable of producing a droplet size distribution wherein the mean Dv(10) is from about 10 to about 35 microns during administration.

[0019] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof, and a solvent consisting of ethanol and glycerin, wherein the formulation is substantially free of water and wherein the formulation is capable of producing a droplet size distribution wherein the mean Dv(50) is from about 40 to about 200 microns during administration.

[0020] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a phiirmaceutically acceptable salt thereof, and a solvent oonsistixig of ctfaanol and glycerin, wherein the mean Dv(90) is fiom about ISO to about 700 microns during administration.

[0021] In another aspect, the present invention is directed to sublingual spray formulations comprising tram about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof, and a solvent consisting of ethanol and glycerin, and wherein the formulation is capable of producing a spray plume wherein a mean ovality ratio is from about 1.0 to about 2.0.

[0022] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or aphannaceutically acceptable salt thereof, and a solvent consisting of ethanol and glycerin, and wherein the formulation is capable of producing a spray plume wherein a mean width is from about 20 to about 40 millimeters.

[0023] In another aspect, the present invention is directed to sublingual spray formulations comprising from about 1 to about 15% w/w ondansetron or a pharmaceutically acceptable salt thereof, wherein the formulation is capable of producing a spray plume wherein a mean angle is from about 25 to about 65 degrees.

[0024] In a preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration from about 1% to about 15% w/w, and

a solvent conmrising, consisting of, or consisting essentially of ethanol at a concentration from about 10% to about 80% w/w and glycerin at a concentration from about 10% to about 80% w/w.

[0025] In a preferred aspect, the present invention is directed to sublingual spray formulations conmrising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration from about 1% to about 15% w/w,

a solvent consisting of ethanol at a concentration from about 10% to about 80% w/w and glycerin at a concentration fiom about 10% to about 80% w/w, and

a permeation enhancer selected from the group consisting of menthol at a∞ru%ntration from about 0.01% to about 8% w/w, caprylic acid at a concentration fiom about 0.1% to about 10% w/w or a combination thereof. [0026] In a preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration from about 1% to about 15% w/w,

a solvent consisting of ethanol at a concentration from about 10% to about 80% w/w and glycerin at a concentration from about 10% to about 80% w/w, and

a permeation enhancer selected from the group consisting of menthol at a concentration from about 0.01% to about 8% w/w, caprylic acid at a concentration from about 0.1% to about 10% w/w or a combination thereof,

wherein the formulation is substantially free of water.

[0027] ma preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration from about 1% to about 15% w/w,

a solvent consisting of ethanol at a concentration from about 10% to about 80% w/w and glycerin at a concentration from about 10% to about 80% w/w,

a permeation enhancer selected from the group consisting of menthol at a concentration from about 0.01% to about 8% w/w, caprylic acid at a concentration from about 0.1% to about 10% w/w or a combination thereof; and

water at a concentration from about 1% to about 50% w/w.

[0028] In a more preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concemtotion from about

3% to about 11% w/w,

a solvent consisting of ethanol at a concentration from about 30% to about 60% w/w and glycerin at a concentration from about 30% to about 48% w/w, and

a permeation enhancer selected from the group consisting of menthol at a concentration from about 0.05% to about 5% w/w, caprylic acid at a concentration of about 2% w/w and a combination thereof.

[0029] In a more preferred aspect, the present invention is directed to sublingual spray formulations comprising: ondansetron or a pharmaceutically acceptable salt thereof at a concentration from about 3% to about 11% w/w,

a solvent consisting of ethanol at a∞ncentration from about 30% to about 60% w/w and glycerin at a concentration from about 30% to about 48% w/w; and

a permeation enhancer selected from the group consisting of menthol at a concentration from about 0.05% to about 5% w/w, caprylic acid at a concentration of about 2% w/w and a combination thereof,

wherein the formulation is substantially free of water.

[0030] In a more preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a phannaceutically acceptable salt thereof at a concentration from about

3% to about 11% w/w,

a solvent consisting of etnanol at a concentration from about 30% to about 60% w/w and glycerin at a concentration from about 30% to about 48% w/w,

a permeation enhancer selected from the group consisting of menthol at a concentration from about 0.05% to about 5% w/w, caprylic acid at a concentration of about 2% w/w and a combination thereof; and

from about 1% to about 50% water.

[0031] In yet another preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron at a concentration from about 3% to about 11% w/w;

etnanol at a concentration from about 40% to about 60% w/w,

propylene glycol at a concentration from about 1% to about 10% w/w,

menthol at a concentration from about 0.05% to about 5% w/w, and

caprylic acid at a concentration from about 0.5% to about 5% w/w.

[0032] In yet another preferred aspect, the present invention is directed to sublingual spray formulations comprising: ondansetron at a concentration from about 3% to about 5% w/w,

ethanol at a concentration of about 50% w/w,

propylene glycol at a concentration of about 5% w/w, menthol at a concentration of about 0.5% w/w, and

caprylic acid at a concentration of about 2% w/w.

[0033] In a yet more preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration of about

4.24% w/w,

a solvent consisting of emanol at a concentration of about S0%and glycerin at a concentration of about 30% w/w, and

a permeation enhancer consisting of menthol at a concentration of about 0.5% w/w and caprylic acid at a concentration of about 2% w/w.

[0034] In a yet more preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration of about

424% w/w,

a solvent consisting of emanol at a concentration of about 50%, glycerin at a concentration of about 30% w/w, and

a permeation enhancer consisting of menthol at a concentration of about 0.5% w/w, caprylic acid at a concentration of about 2% w/w,

a pharmaceutically acceptable sweetener consisting of sucralose at a concentration of about 0.6% w/w,

a preservative consisting about 0.001% w/w edetate disodium dihydrate and about 0.01% w/w benzalkonium chloride; and

about 0.08% w/w of strawberry flavor.

[0035] In another aspect, the present invention is directed to a method for treating or preventing nausea and emesis in humans associated with chemotherapy, radiation or surgery for cancer treatment comprising administering a sublingual spray formulation of the present invention to a patient in need thereof.

[0036] In another aspect, the present invention is directed to a method for treating or preventing nausea and emesis in humans associated with chemotherapy, radiation or surgery for cancer treatment comprising administering about 50 to about 400 uL of a sublingual spray formulation of the present invention to a patient in need thereof [0037] In another aspect, the present invention is directed to a method for treating or preventing nausea and emesis in humans associated with chemotherapy, radiation or surgery for cancer treatment comprising administering about 100 to about 200 uL of a sublingual spray formulation of the present invention to a patient in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1. shows pharmacokinetic profiles of ondansetron sublingual formulation administered to Yucatan mini-pigs and illustrates superior performance of formulations containing caprylic acid.

DETAILED DESCRIPTION OF THE INVENTION

[0039] Applicants unexpectedly discovered a sublingual ondansetron spray formulation, which has improved storage stability and excellent spray characteristics.

Definitions

[0040] As used herein, "ondansetron" refers to the base or a pharmaceutically acceptable salt, ester, derivative, or prodrug thereof.

[0041] Pharmaceutically acceptable salts mat 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.

[0042] As used herein, "nausea" refers to the sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit

[0043] As used herein, "emesis" refers to the action of vomiting.

[0044] As used herein, "chemotherapy" refers to administering one or more cytotoxic antineoplastic drugs to a cancer patient as part of a standardized treatment regimen.

[0045] As used herein, "free of propellent" refers to a sublingually administered formulation that is not administered using compressed gas.

[0046] As used herein, "substantially free of water" refers to a sublingual spray which contains less than 0.5% w/w water.

[0047] As used herein the term "patient" refers, but is not limited to, a person that is being treated for nausea and emesis.

[0048] As used herein the term "pharmaceutically acceptable" refers to ingredients that are not biologically or otherwise undesirable in a sublingual dosage form. [0049] As used herein the term "effective amount" refers to the amount necessary to treat a patient in need thereof

[0050] As used herein "% w/w" and "percent w/w" refer to the percent weight of the total formulation.

[0051] As used herein, all numerical values relating to amounts, weights, and the like, mat 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.

Compositions of the Invention

[0052] In a preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration from about 1% to about 15% w/w,

a solvent consisting of ethanol at a concentration from about 10% to about 80% w/w and glycerin at a concentration from about 10% to about 80% w/w; and

a permeation enhancer selected from the group consisting of menthol at a concentration from about 0.01% to about 8% w/w, caprylic acid at a concentration from about 1% to about 10% w/w or a combination thereof.

[0053] In a more preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration from about 8% to about 11% w/w,

a solvent consisting of ethanol at a concentration from about 40% to about 48% w/w and glycerin at a concentration from about 40% to about 48% w/w, and

menthol at a concentration from about 2% to about 5% w/w.

[0054] In a yet more preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration from about

3% to about 11% w/w,

a solvent consisting of ethanol at a concentration from about 30% to about 50% w/w and glycerin at a concentration from about 30% to about 48% w/w, and a penncation enhancer selected from the group consisting of menthol at a concentration from about 0.05% to about 5% w/w, caprylic acid at a concentration of about 2% w/w and a combination thereof.

[0055] In a yet more preferred aspect, the present invention is directed to sublingual spray formulations comprising:

ondansetron or a pharmaceutically acceptable salt thereof at a concentration of about

4.24% w/w,

a solvent consisting of ethanol at a conceiitration of about 50% and glycerin at a concentration of about 30% w/w, and

a permeation enhancer consisting of menthol at a concentration of about 0.5% w/w and caprylic acid at a concentration of about 2% w/w;

a pharmaceutically acceptable sweetener consisting of sucralose at a concentration of about 0.6% w/w, and

a preservative consisting about 0.001% w/w edetate disodium dihydrate and about 0.01% w/w benzalkonium chloride.

[0056] In some embodiments, the formulations of the present invention may contain a preservative. Preservatives include, but are not limited to, methyl paraben, ethyl paraben, butyl paraben, propyl paraben, sodium benzoate, benzoic acid, edetate disodium dihydrate, benzalkonium chloride ("BKC) or a mixture thereof. Preferred preservatives are edetate disodium dihydrate and BKC.

[0057] When a preservative is used, the effective amount of the preservative is from about 0.01% to about 0.S % w/w of the formulation.

[0058] In some embodiments, the formulations of the present invention may also contain a permeation enhancer. Permeation enhancers include, but are not limited to, menthol, menthol, limonene, carvone, transcutol, oleic acid, triacetin, polysorbate 80, polyoxyl 35 hydrogenated castor oil, polyvinylpyrrolidone, caprylocaproyl, fatty acids including caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, oleic acid, stearic acid, nonadecylic acid, linoleic acid, arachidic acid and arachidonic acid, medium chain glycerides, decanoyl glycerides, octanoyl glycerides, caprylic/capric triglyceride, capryUc/capric/linoleic triglyceride, macrogol-8 glyceride, sodium glycocholate, sodium lauryl sulphate, sodium taurocholate, triethyl citrate, mannitol, disodium lauretfa sulfosuccinate, N- [8-(2-hydroxybcnzoyl) amino]caprylate, n-dodccyi β-D- mahoside, glyceryl monosterate, sodium caprate, and dodecyl dimethyl amino propionate. One presently preferred permeation enhancer is menthol and caprylic acid

[0059] When a permeation enhancer is used, the effective amount of the permeation enhancer is from about 0.01% to about 10.0 % w/w of the formulation, preferably from about 0.05% to about 5.0% w/w.

[0060] In some embodiments, the formulations of the present invention may also contain a flavoring agent Flavoring agents include, but are not limited to, 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.

[0061] 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.

[0062] When menthol is used in a formulation of the present invention in amounts of 0.5% w/w or more the menthol is both a flavoring agent and a permeation enhancer.

[0063] In some embodiments, 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.

[0064] 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.

[0065] The following preferred embodiments and 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.

EXAMPLES

Method of Making the Formulations

[0066] Excipients were first dissolved in either the ethanol or the purified water based on their solubilhy by mixing. Water and alcohol phase were men combined together and mixed to make homogenous solution. Ondansetron hydrochloride dihydrate was men added to the excipients solution and mixed until dissolved.

Example 1 : Stable Ondansetron Formulations

Stability Data

[006η Formulations #l-#3 of Table 1 were subjected to stability test at 40°C ± 2°C/75% ± 5% RH and 25°C ± 2 ^o C/60%± 5% RH. At predetermined time points samples were pulled and analyzed for stability. Assay and impurities were detected using high performance liquid chromatography with an ultraviolet detector. The assay was performed at 216 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 216 nm and expressed as a % area. Stability data of these formulations are summarized in Tables 3-8.

Table 3: Stability Data for Sublingual Ondansetron Spray Formulation #1 stored at 40° C ± 2°C under 75% ± 5% Relative Humidity

Assay (% of initial concentration)

% impurity D

% Impurity F

Total Impurities (% Area)

Table 4: Stability Data for Sublingual Ondansetron Spray Formulation #2 stored at 40° C under 75% ± 5% Relative Humidity

40°C

Assay (% of inmal concentration)

% Impurity D

% Impurity F

Total Impurities (% Area)

Table 5: Stability Data for Sublingual Ondansetron Spray Formulation #3 stored at 40° C ± 2°C under 75% ± 5% Relative Humidity

40°C

Assay (% of initial concentration)

% Impurity D

% Impurity F

Total Impurities (% Area) 0.03% 0.04% 0.04% 0.05%

Table 6: Stability Data for Sublingual Ondansetron Spray Formulation #1 stored at 25° C ± 2°C under 60% ± 5% Relative Humidit

25°C

Assay (% of initial concentration)

% Impurity D

% Impurity F

Total Impurities (% Area)

Table 7: Stability Data for Sublingual Ondansetron Spray Formulation #2 stored at 25° C ± 2°C under 60% ± 5% Relative Humidity

25°C

Assay (% of initial concentration)

% Impurity D

% Impurity F

Total Impurities (% Area)

Table 8: Stability Data for Sublingual Ondansetron Spray Formulation #3 stored at 25° C ± 2°C under 60% ± 5% Relative Humidity

25°C

Assay (% of initial concentration)

% Impurity D

% Impurity F

Total Impurities (% Area)

Results

[0068] Each formulation showed unexpected stability. After 3 months, formulation #1 had 0.07% w/w and 0.03% w/w total irnpurities at 40°C ± 2°C/75% ± 5% relative humidity ("RIF) and 25°C ± 2°C/60% ± 5% RH, respectively; formulation #2 had 0.07% w/w and 0.03% w/w, and formulation #3 had 0.05% w/w and 0.03% w/w. Concentrations of any excipient used in formulations did not exceed maximum allowable daily dose recommended in FDA's inactive ingredient list The stability of each formulation showed that all the excipients used in the formulations were compatible with Ondansetron.

Example 2: Spray Characteristics of Sublingual Ondansetron Formulations

[0069] Formulations #4 and #5 of Table lwere used to evaluate spray characteristics of an ondansetron sublingual spray. The data for droplet size distribution and spray pattern are provided in Tables 9 -20. All data was collected while formulations were at 25° C.

Table 9. Droplet Size Distribution of Formulation #4 at 3 cm

Max 28.8 μπι 82.8 μπι 605.3 μιη 8.7

[0070] A challenge of creating an ondansetron sublingual spray formulation is mat it must be capable of producing spray droplets that are over 10 microns in diameter. Spray droplets 10 microns or smaller could be inhaled into the lungs. Sublingual formulations should be able to maintain a consistent droplet size throughout its shelf life.

[0071] Formulations #4 and #5 yielded excellent droplet sizes and spray patterns for sublingual administration. The testing also revealed that the formulation dose remained consistent when administered with a spray pump.

Example 3 Phanriacokinetics of Ondansetron Sublingual Spray Formulations in Mini-Pigs Study design

[0072] Protocol design was a single dose crossover study. Four or five healthy male Yucatan mini-pigs weighing approximately forty kilograms each were sublingually administered the ondansetron formulations. The rnini-pigs were fasted overnight till four hours post administration. Each dosing was followed by a one-week washout period Blood samples were taken prior to administration and 3, 5, 10, 15, 20, 30 min, 1, 2, 4, 8 and 24 hours post administration. Iviini-pig plasma samples were measured for ondansetron concentrations via liquid chromatography-tandem mass spectrometry. [0073] The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmn), time to reach Cmn (Tnw), and area under the concentration-time curve from time-zero to 24 hours post-dose (AUCo-24h).

Table 21. Pharmacokinetic parameters of ondansetron sublingual spray in mini-pigs

Tmn: median value

Cmn and AUQv24h: geometric mean ± geometric SD

Results

[0074] Phannaookinetic profiles of ondansetron formulations tested in mini-pigs are showed in Figure 1. The summary of ondansetron pharmacokinetic parameters after single-dose sublingual administration of ondansetron formulations to Yucatan mini-pigs under fasted conditions are summarized in Table 21. As shown, Formulations #9-12, which include caprylic acid and replaced parabens with edetate disodium dihydrate and benzalkonium chloride showed better pharmacolcinetic performance, compared to Formulations #7 and #8. Specifically, Formulations #9-12 reached peak plasma concentration at least 7 times faster; achieved a much greater peak plasma concentration and achieved a greater area under the curve than Formulations #7 and #8. Notably, Formulation #12 reached maximum plasma concentration of 8.9 in only 3 rninutes. Example 4. Ondansetron Sublingual Spray characterization

[0075] Formulations #12 Table 2 was used to evaluate spray characteristics of an ondansetron sublingual spray. The data for droplet size distribution and spray pattern are provided in Tables 22 -25. All data was collected while formulations were at 25° C.

Table 22: Spray Pattern of Ondansetron Sublingual Spray at 3cm

Table 23: Spray Pattern of Ondansetron Sublingual Spray at 6cm

Table 24: Droplet Size Distribution of Ondansetron Sublingual Spray at 3cm

Table 25: Droplet Size Distribution of Ondansetron Sublingual Spray at 6cm

[0076] A challenge of creating an ondansetron sublingual spray formulation is mat it must be capable of producing spray droplets mat are over 10 niicrons in diameter. Spray droplets 10 microns or smaller could be inhaled into the lungs. Sublingual formulations should be able to maintain a consistent droplet size throughout its shelf life.

[0077] Formulation #3 yielded excellent droplet sizes and spray patterns for sublingual administration. The testing also revealed that the formulation dose remained consistent when administered with a spray pump.

Example 5. Stability of Ondansetron Sublingual Spray Formulations

[0078] Formulations #7-#12 of Table 2 were subjected to stability test at various temperatures including 55°C ± 2, 40°C ± 2°C/75% ± 5% RH and 25°C ± 2°C/60%t 5% RH. At predeterrmned time points samples were pulled and analyzed for stability. Assay and impurities were detected using high performance liquid chromatography with an ultraviolet detector. The assay was performed at 216 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 216 nm and expressed as a % area. Stability data of these formulations are summarized in Tables 25-29. Table 26: Stability data for ondansetron sublingual spray formulation# 7 stored at 40°C ± 2°C under 75% ± 5% relative humidity

Table 27: Stability data for ondansetron sublingual spray formulation* 8 stored at 40°C ± 2°C under 75% ± 5% relative humidity and at 25°C ± 2°C under 60% ± 5% relative humidity

Table 28: Stability data for ondansetron sublingual spray formulau'on# 10 stored at 55°C, at 40°C ± 2°C under 75% ± 5% relative humidity and at 25°C ± 2°C under 60% ± 5% relative humidity

Table 29: Stability data for ondansetron sublingual spray formulatiori# 11 stored at 55°C

Results

[0079] Each formulation showed unexpected stability. After 2 months at 40°C ± 2°C/75% ± 5% relative humidity ("RH"), Formulation #7 had 0.1% total impurities. After 6 months at°C± 2°C/75% ± 5% RH and 25°C ± 2°C under 60% ± 5% RH, Formulation #8 had 0.11% and 0.07% total impurities, respectively. After 1 month at 55 °C ± 2°C, 40°C ± 2°C under 75% ± 5% RH and at 25°C ± 2°C under 60% ± 5% RH, Formulation #10 had 0.18%, 0.08% and 0.08% total imrjurities, respectively. After 2 weeks at 55 °C ± 2°C and 40°C ± 2°C under 75% ± 5% RH, Formulation #11 had 0.12% and 0.03% total impurities, respectively. Finally, after 2 week at 55 °C ± 2°C and 40°C ± 2°C under 75% ± 5% RH, Formulation #12 had 0.08% and 0.02% total impurities, respectively. Concentrations of any excipient used in formulations did not exceed maximum allowable dairy dose recommended in FDA's inactive ingredient list The stability of each formulation showed that all the excipients used in the formulations were compatible with Ondansetron. Example 6: Invitro permeability of Ondansetronacrossporcine bucal andcoss

Method

[0080] In vitro perrmeability of Ondansetron formulations across porcine buccal mucosa was evaluated to identify the formulations with better permeability and flux. A Franz diffusion apparatus and epithelial layers of porcine buccal mucosa were used to evaluate permeability. Heat separation method was used to collect the epithelia from the connective tissue and basal membrane of the mucosa. Specifically, a previously cut (1 inch x 1 inch) mucosal membrane piece was placed into 65 °C phosphate buffered saline (PBS, pH 7.34) for two minutes, and then promptly removed and placed in a clear petri dish with a minimal amount of PBS. Afterwards, the connective tissue underneath was firmly held in place with a spatula and gently picked at the upper epithelia until it began to separate. Upon noticeable separation, the full edge was separated with a gentle practice across the tissue. Finally, the entire epithelia were pulled up and away from the lower dermis in small increments. Each epithelial membrane was placed between the 5 mm donor chamber and the receptor cell, and secured with clamps.

[0081] At the beginning of the study (i.e., time zero), S mL PBS was used as a receiver media and 0.5 mL of test formulation was loaded to the donor chamber. The membrane integrity was evaluated by the handheld Keysight LCR meter U1731C.

[0082] Subsequently, 02 mL of the sample was collected from the receptor cell at predetermined time intervals and immediately replaced with 02 mL of fresh PBS. Collected samples were filtered with a OAS urn Nylon membrane and then analyzed using an HPLC method.

Results

[0083] Permeability coefficient of Ondansetron HC1 Dihydrate from formulations #012 and #013 (no permeability enhancer) was negligible, with a value of 1.13 and 0.13 X 10 ^-7 cm/sec, respectively. See Table 33. Surprisingly 2% caprylic acid in the formulation (#014) improved the permeability coefficient to S.32 X 10 ^*7 cm/sec. Inclusion of 1% cetylpyridinium chloride to the formulations did not make any difference in the permeability coefficients (#03: 1.37 and #04: 2.2 X 10 ^-7 cm/sec). See Table 31. A combination of 0.01% BAK and 2% caprylic add improved the permeability coefficient of Ondansetron HC1 Dihydrate by 13-fold (13.1 X 10 ^-7 cm/sec), compared to the control #012 and by 6 fold over #08 which has the same formulation except that #02 contains BKC. Use of 30% glycerol (#010) gave similar results as #02.

Furthermore, addition of 3% caprylic acid and no glycerol increased the permeability coefficient approximately 17-fold (17.8 X 10 ^-7 cm/sec), compared to the control (#012). The combination of 0.5% menthol, 15% propylene glycol, 0.01% BKC, 2-3% caprylic acid and 40-41% alcohol improved the permeability coefficient of Ondansetron HC1 Dihydrate at least 13 fold (#01: 17.8, #02: 13.1 X 10~ ⁷ cm/sec). Hence, the results conclude that combination of 0.01% BKC, 0.5% Menthol and 2% caprylic acid is likely to enhance the permeability of Ondansetron HQ Dihydrate across the sublingual mucosa.

Table 31. In vitro permeability of Ondansetron sublingual spray formulations across the porcine buccal mucosa.

Components: %w/w

QS: quantity sufficient

Permeability coefficient: mean ± standard deviation

Table 32. In vitro permeability of Ondansetron sublingual spray formulations across the porcine buccal mucosa.

Components: %w/w

QS: quantity sufficient

Penneability coefficient: mean ± standard deviation

Table 33. In vitro penneability of Ondansetron sublingual spray formulations across the porcine buccal mucosa.

Cornponent8: %w/w

QS: quantity sufficient

Penneability coefficient: mean± standard deviation

Method

[0084] Protocol design was a single dose crossover study. Four or five healthy male Yucatan mini-pigs weighing approximately forty kilograms each were sublingually administered the Ondansetron formulations. The mini-pigs were fasted overnight until four hours post adrninistration. Each dosing was followed by a one-week washout period Blood samples were taken pre-dose and 3, 5, 10, 15, 20, 30 min, 1, 2, 4, 8 and 24 hours post dose. Mini-pig plasma samples were measured for Ondansetron concentrations via liquid chromatography-tandem mass spectrometry.

[0085] The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cum), time to reach Cmn (Tmn), and area under the concentration-time curve from time- zero to 24 hours post-dose (AUCo44h).

Results

[0086] The surnmary of Ondansetron pharmacokinetic parameters after single-dose sublingual administration of Ondansetron formulations to Yucatan mini-pigs under fasted conditions are summarized in Table 34. As shown, Formulations #02M, #04M, #05M and #06M, which include caprylic acid and replaced parabens with edetate disodium dihydrate and benzalkonium chloride (BKC) showed better pharinacokinetic perfonnance, compared to Formulations #01M and#03M Surprisingly, these formulations reached peak plasma concentration at least 7 times faster, achieved a much greater peak plasma concentration and achieved a greater area under the curve man Formulations #01M and #03M. Notably, Formulation #05M reached geo-mean maximum plasma concentration of 8.9 ng/mL in only 3 minutes. See Table 35.

Table 34: Sublingual Ondansetron Formulations for Mini-pig Dosing

Components: %w/w

QS: quantity sufficient Permeability coefficient: mean ± standard deviation

Table 35: Geometric mean plasma concentrations for Ondansetron after sublingual administration of Ondansetron formulations to Yucatan mini-pigs under tasted conditions.

NC: blood sample not collected

Tm: median value

Cum and AUCoam: geometric mean ± geometric SD