Stable liquid formulations of frovatriptan

Abstract

Liquid pharmaceutical formulations of frovatriptan, or a pharmaceutically acceptable salt thereof, intended for non-oral administration is disclosed. The formulations include frovatriptan, a liquid vehicle, and one or more optional pharmaceutically acceptable excipients, and demonstrate stability at room temperature for an extended period. The method of preparation for the liquid frovatriptan formulation as well as its therapeutic application in diseases treatable with frovatriptan are also described.

Description

TITLE OF THE INVENTIONSTABLE LIQUID FORMULATIONS OF FROVATRIPTANCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 689,763, filed on September 01, 2024, and U.S. Provisional Application No. 63 / 869,504 filed on August 25, 2025, the disclosure of which are hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present invention relates to stable liquid formulations of frovatriptan or its pharmaceutically acceptable salt suitable to be used in the pharmaceutical field.BACKGROUND OF THE INVENTION

[0003] Frovatriptan is currently indicated for the acute treatment of migraine with or without aura in adults. Frovatriptan succinate is marketed as FROVA® tablets for oral administration. Each FROVA® tablet for oral administration contains 3.91 mg frovatriptan succinate, equivalent to 2.5 mg of frovatriptan base.

[0004] Frovatriptan is currently available only as an oral tablet, a formulation that presents significant challenges. The onset of action is slow, often taking 2-3 hours to reach peak plasma levels, which is a major drawback for patients in acute pain. Furthermore, migraine-associated nausea and vomiting can make swallowing tablets difficult, and first-pass metabolism reduces the drug's bioavailability to a mere 20-30%.

[0005] Menstrual migraine is a type of migraine that is closely linked to the menstrual cycle in women. These migraines typically occur in the days leading up to, during, or immediately after menstruation. They are often more severe, last longer, and are more challenging to treat than migraines that occur at other times of the month. There are two types of menstrual migraine - (1) “Pure menstrual migraines” occur predominantly during the menstrual window, which is typically from two days before the period starts to the third day of the period. Women with pure menstrual migraine do not experience migraines at any other time of the month; (2) “Menstrually Related Migraine”, wherein women experience migraines not only during their menstrual period, but also at other times of the month. The primary trigger for menstrual migraines is the fluctuation of hormones, particularly the drop in estrogen levels that occurs just before the start of the menstrual period. Prostaglandins, the hormone-like substances that are released around the time of menstruation, have also been linked to these migraines. Currently used intranasal triptans, such as Sumatriptan and Zolmitriptan, have very short elimination half-life that is directly linked to duration of action. Frovatriptan has the longest elimination half-life that is suitable for menstrualmigraine where long lasting effect is desired. However, currently approved oral tablet of frovatriptan has delayed onset of action and lower bioavailability due to first pass metabolism.

[0006] To overcome these limitations, alternative delivery routes such as nasal, injectable, or sublingual administration are needed. These routes bypass the gastrointestinal tract, offering the potential for faster onset of action and improved bioavailability. US2007059254 discloses compositions for delivering 5-HT agonists across the oral mucosa, wherein the buffer system in the compositions raises the pH of saliva to a pH greater than about 9.9, thereby facilitating the substantially complete conversion of the 5-HT agonist from its ionized to its unionized form, leading to efficient and rapid absorption by the oral or buccal mucosa. While this reference refers to alternate routes of administration, nothing therein teaches successful stable liquid formulation of frovatriptan or its pharmaceutically acceptable salt.

[0007] CN111467303 discloses an injection formulation containing 3.91mg / ml of frovatriptan succinate, 10-100mg / ml of absolute ethyl alcohol, a pH regulator and water for injection, wherein the pH regulator is a sodium hydroxide solution / hydrochloric acid solution, present in an amount so as to provide a pH of 6.8-7. The disclosure does not provide details on stability and impurities, other than merely referring to it. Moreover, for some applications such as nasal spray or autoinjector, the volume for administration is very limited to administering the therapeutic dose (in most cases less than 1 mL), so higher concentration is required.

[0008] US 11135379 and US 11364225 disclosed a method for treating symptoms of migraine and cluster headaches that involves administering a serotonin receptor agonist (SRA) via pulmonary delivery by inhalation. Specifically, the patent teaches the preparation of a solution containing an SRA, which is aerosolized using an active mesh nebulizer to form a plume of fine particles. These particles are then inhaled by the patient, facilitating the delivery of the drug to the systemic circulation through the lungs. The invention further defines the characteristics of the aerosolized plume and specifies that delivery occurs during the patient’s inhalation process. Delivery of frovatriptan in lungs is not desirable as its site of action is in the brain. Moreover, nebulizers are not a convenient device to use and carry during travelling.

[0009] Therefore, there is a clear and unmet need for liquid formulations of frovatriptan that can provide rapid and reliable relief from acute migraine attacks, particularly in patients who cannot tolerate oral medications and need fast onset of action, such as in menstrual migraine.SUMMARY OF THE INVENTION

[0010] Disclosed herein are formulation compositions of frovatriptan or its pharmaceutically acceptable salt, such as frovatriptan succinate, method of preparation, and method of use thereof for treating migraine.

[0011] In one aspect of the present invention, described herein is a liquid formulation of frovatriptan suitable for intranasal administration in the form of nasal spray, comprising frovatriptan or its pharmaceutically acceptable salt at a concentration from about 0.5 mg / mL to about 100 mg / mL, with one or more optional ingredients, and a liquid vehicle.

[0012] In another aspect of the present invention, described herein is a liquid formulation of frovatriptan suitable for sublingual administration in the form of a sublingual spray, comprising frovatriptan or its pharmaceutically acceptable salt at a concentration from about 0.5 mg / mL to about 100 mg / mL, with one or more optional ingredient, and a liquid vehicle.

[0013] In yet another aspect of the present invention, described herein is a liquid formulation of frovatriptan suitable for intravenous or subcutaneous administration in the form of an injectable formulation, comprising frovatriptan or its pharmaceutically acceptable salt at a concentration from about 0.5 mg / mL to about 100 mg / mL, with one or more optional ingredient, and a liquid vehicle.

[0014] In an embodiment of the present invention, the liquid formulations of frovatriptan suitable for intranasal administration to patients in need thereof, comprises at least one or more pharmaceutically acceptable excipient selected from the group comprising vehicle, buffering agents, stabilizers, preservative, sweetening agent, flavoring agent, antioxidants, tonicity adjusting agent, chelating agent, pH adjusting agent, mucoadhesive agent, viscosity adjusting agent, permeation enhancer, and a combination thereof.

[0015] In an embodiment of the invention, the frovatriptan liquid formulation is a solution, suspension or emulsion. In a preferred embodiment, the frovatriptan liquid formulation is a solution.

[0016] In an embodiment of the invention, the frovatriptan liquid formulation comprises a vehicle, wherein the vehicle is water or water miscible liquid ingredient or a combination thereof. In some embodiments, the water miscible liquid ingredients are selected from the group consisting of propylene glycol, polyethylene glycol (such as PEG200, PEG300, PEG400, PEG600, PEG1000), alcohol, etc.

[0017] In yet another embodiment, the vehicle is nonaqueous liquid ingredient or mixture, such as, without limitation, tocopherol or Vitamin E, dehydrated alcohol, benzyl alcohol, propylene glycol, polyethylene glycol (such as 400).

[0018] In an embodiment, the liquid formulation of frovatriptan is suitable for the treatment of disease treatable by frovatriptan. In a preferred embodiment, the liquid formulation is intended for use in the treatment of migraine. In a more preferred embodiment, the liquid formulation is suitable for the treatment of menstrual migraine in women. In another embodiment, the liquid formulation is suitable for the treatment of migraine with aura. In yet another embodiment, the liquidformulation is suitable for the treatment of migraine without aura. In still another embodiment, the liquid formulation is suitable for the treatment of cluster headache.

[0019] In an embodiment of the present invention, the liquid formulation is prepared by solubilizing frovatriptan or its pharmaceutically acceptable salt in liquid vehicle, with one or more optional pharmaceutical excipients, filling the formulated frovatriptan liquid into primary packaging container and closing the container with suitable closure.BRIEF DESCRIPTION OF DRAWINGS

[0020] FIG. 1 is the graph representing solubility of frovatriptan succinate monohydrate in aqueous solution of sodium chloride. It was surprisingly found by the inventor that the solubility of frovatriptan succinate monohydrate (FSM) is inversely proportional to sodium chloride. The solubility of FSM reduced from about 67.5 mg / mL (in water) to 15.3 mg / mL in l%w / v sodium chloride in water.

[0021] FIG. 2 is the representation of process flow diagram for the preparation of liquid formulation of frovatriptan succinate suitable for intranasal or parenteral administration.

[0022] FIG. 3 is the representation or example of cross section of an assembled unit dose nasal spray device comprising USP type I glass vial, also known as microvial or capsule (301), filled with frovatriptan liquid formulation (302). The closure or plunger or piston (303) is placed using vacuum placement or tube insertion placement. The closed container is finally assembled into unit dose nasal spray device. The device has an actuator (304) that directs the spray in the nasal cavity. A stem (305) holds needle (308) and connects it with the actuator. The frovatriptan liquid (309) filled closed vial (306) with stopper (307) is placed in tube (311) that holds the vial and connect with the device body (310). During use of device by the patient, the actuator is placed in the nostril directing towards the nasal mucosa. Fingertips are placed on the shoulder of the device (310) and tube (311) is pressed with the thumb. The liquid filled vial (306) moves up, needle punctures the piston or plunger, and liquid is delivered as spray in the nasal cavity.DETAILED DESCRIPTION OF THE INVENTION

[0023] As used herein, the term “frovatriptan” refers to frovatriptan free base or its pharmaceutically acceptable salts (such as frovatriptan succinate), solvates, or hydrates thereof (such as frovatriptan succinate monohydrate or FSM). In principle, any crystalline or amorphous form of frovatriptan may be used to manufacture inventive pharmaceutical compositions of the present invention.

[0024] As used herein, the terms “impurity”, “degradation impurity” or “frovatriptan-related impurity” refer to any chemical compound that is undesired and generated from the degradation offrovatriptan during the formulation process or storage of the formulation. These compounds are reported as a percentage (%), representing the area percentage of the impurity peak with respect to active ingredient (frovatriptan) when separated from frovatriptan using HPLC method of analysis. Such impurities may be reported individually or in total. “Highest single impurity” or “maximum single impurity” or “maximum individual impurity” refers to any impurity (or mixture of impurities that may not be separated from each other but separated from parent peak of frovatriptan) with highest percent peak area when tested using HPLC method of analysis.

[0025] As used herein, the team “stable” refers to the invented composition that has less than 10% of the total degradation impurities after extended period of storage at room temperature (about 15- 25°C) or refrigerated condition, preferably at room temperature (about 15-25°C). In some embodiments of the invention, accelerated conditions such as about 40°C or even after terminal sterilization at about 121°C for about 5 to 15 minutes.

[0026] It should be noted that the unit of measurement for the quantity of any ingredients in this invention, such as "%", typically represents %w / w. In certain embodiments, this quantity may also be expressed using the unit %w / v. If the units are presented in %w / w in the present disclosure, it is also considered as %w / v, if the difference in concentration resulting from the conversion is less than 10%.

[0027] As used herein, the terms “vehicle”, “liquid vehicle”, “pharmaceutically acceptable liquid vehicle”, “solvent,” or “pharmaceutically acceptable solvent,” as used herein, is any liquid medium used for dilution or dissolution of frovatriptan.

[0028] As used herein, the term “shelf-life” refers to the time during which the pharmaceutical composition of the present invention remains stable.

[0029] As used herein, the term “step” is not particularly limiting. For example, each step as described herein may be a discrete step such that steps are performed sequentially upon completion of a preceding step. Alternatively, at least a portion of the method may be continuous, or the steps may be performed out of the order stated.

[0030] As used herein, the term “about” refers to within ±20% of the stated value, optionally within ±10%, optionally within ±5%, optionally within ±3%, optionally within ±2%, optionally within ±1%, optionally within ±0.5%, optionally within ±0.1%, and optionally within ±0.01%.

[0031] The terms “composition”, “formulation”, “dosage form” may be used interchangeably, and refer to the liquid pharmaceutical composition of the present invention.

[0032] The present invention relates to a liquid pharmaceutical composition of frovatriptan or its pharmaceutically acceptable salt such as frovatriptan succinate, wherein frovatriptan is present at a concentration of 0.1 mg / mL or more. In one aspect, the pharmaceutical composition of the present invention comprises frovatriptan wherein the concentration of frovatriptan in the composition isfrom about 0.1 mg / mL to about 200 mg / mL, preferably from about 5 mg / mL to about 100 mg / mL, preferably from about 10 mg / mL to about 50 mg / mL, preferably from about 20 mg / mL to about 30 mg / mL, preferably from about 22.5 mg / mL to about 27.5 mg / mL, preferably about 25 mg / mL.

[0033] In an embodiment, the concentration of frovatriptan in the presented liquid formulation may be about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 2.5 mg / mL, 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 39.1 mg / mL, about 40 mg / mL, about 50 mg / mL., about 60 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, or about 100 mg / mL. The concentration of frovatriptan may be from about 5 mg / mL to about 50 mg / mL.

[0034] In an embodiment of the present invention, the liquid formulation of frovatriptan may be suitable for intranasal, sublingual, oral or injectable route of administration, preferably for intranasal or injectable route of administration, more preferably for intranasal route of administration.

[0035] In an embodiment of the present invention, the liquid formulation of frovatriptan is in a dosage form selected from group of solution, suspension or emulsion, preferably in a solution dosage form.

[0036] In an embodiment of the present invention, the invention relates to the method of treatment for migraine in human or menstrual migraine in women by administering a therapeutic effective amount of frovatriptan in liquid dosage form via intranasal route of administration. In another embodiment, the invention relates to the method of treatment for migraine in human or menstrual migraine in women by administering a therapeutic effective amount of frovatriptan in liquid dosage form via injectable route, oral, sublingual or of administration.

[0037] In another aspect of the invention, the liquid formulation is stable for at least 1 week, preferably for at least 2 weeks, preferably for at least 1 month, preferably for at least 3 months, preferably for at least 6 months, preferably for at least 9 months, preferably for at least 12 months, preferably for at least 15 months, preferably for at least 18 months, preferably for at least 24 months, preferably for at least 30 months at room temperature (about 15 - 25°C).

[0038] According to some aspects, the pharmaceutical composition of the present invention may have initial total impurity concentration of not more than about 5%, more preferably not more than about 4.5%, more preferably not more than about 4%, more preferably not more than about 3.5%, more preferably not more than about 3%, more preferably not more than about 2.5%, more preferably not more than about 2%, more preferably not more than about 1.5%, more preferably not more than about 1%, and most preferably not more than about 0.5%.

[0039] According to some aspects, the pharmaceutical composition of the present invention may have initial total impurity concentration of less than about 2%, more preferably less than about 1%, more preferably less than about 0.99%, more preferably less than about 0.98%, more preferably less than about 0.97%, more preferably less than about 0.96%, more preferably less than about 0.95%, more preferably less than about 0.94%, more preferably less than about 0.93%, more preferably less than about 0.92%, more preferably less than about 0.91%, more preferably less than about 0.90%, more preferably less than about 0.89%, more preferably less than about 0.88%, more preferably less than about 0.87%, more preferably less than about 0.86%, more preferably less than about 0.85%, more preferably less than about 0.84%, more preferably less than about 0.83%, more preferably less than about 0.82%, more preferably less than about 0.81%, more preferably less than about 0.80%, more preferably less than about 0.79%, more preferably less than about 0.78%, more preferably less than about 0.77%, more preferably less than about 0.76%, more preferably less than about 0.75%, more preferably less than about 0.74%, more preferably less than about 0.73%, more preferably less than about 0.72%, more preferably less than about 0.71%, more preferably less than about 0.97%, more preferably less than about 0.69%, more preferably less than about 0.68%, more preferably less than about 0.67%, more preferably less than about 0.66%, more preferably less than about 0.65%, more preferably less than about 0.64%, more preferably less than about 0.63%, more preferably less than about 0.62%, more preferably less than about 0.61%, more preferably less than about 0.60%, more preferably less than about 0.59%, more preferably less than about 0.58%, more preferably less than about 0.57%, more preferably less than about 0.56%, more preferably less than about 0.55%, more preferably less than about 0.54%, more preferably less than about 0.53%, more preferably less than about 0.52%, more preferably less than about 0.51%, more preferably less than about 0.50%, more preferably less than about 0.49%, more preferably less than about 0.48%, more preferably less than about 0.47%, more preferably less than about 0.46%, more preferably less than about 0.45%, more preferably less than about 0.44%, more preferably less than about 0.43%, more preferably less than about 0.42%, more preferably less than about 0.41%, more preferably less than about 0.40%, more preferably less than about 0.39%, more preferably less than about 0.38%, more preferably less than about 0.37%, more preferably less than about 0.36%, more preferably less than about 0.35%, more preferably less than about 0.34%, more preferably less than about 0.33%, more preferably less than about 0.32%, more preferably less than about 0.31%, more preferably less than about 0.30%, more preferably less than about 0.29%, more preferably less than about 0.28%, more preferably less than about 0.27%, more preferably less than about 0.26%, more preferably less than about 0.25%, more preferably less than about 0.24%, more preferably less than about 0.23%, more preferably less than about 0.22%, more preferably less than about 0.21%, more preferably less than about 0.20%, more preferably less than about 0.19%, more preferably less than about 0.18%, morepreferably less than about 0.17%, more preferably less than about 0.16%, more preferably less than about 0.15%, more preferably less than about 0.14%, more preferably less than about 0.13%, more preferably less than about 0.12%, more preferably less than about 0.11%, and most preferably less than about 0.10%.

[0040] According to some aspects, the pharmaceutical composition of the present invention may have a total impurity concentration at the end of its shelf life of not more than about 5%, more preferably not more than about 4.5%, more preferably not more than about 4%, more preferably not more than about 3.5%, more preferably not more than about 3%, more preferably not more than about 2.5%, more preferably not more than about 2%, more preferably not more than about 1.5%, more preferably not more than about 1%, and most preferably not more than about 0.5%.

[0041] According to some aspects, the pharmaceutical composition of the present invention may have a total impurity concentration at the end of its shelf life of not more than about 1%, more preferably not more than about 0.99%, more preferably not more than about 0.98%, more preferably not more than about 0.97%, more preferably not more than about 0.96%, more preferably not more than about 0.95%, more preferably not more than about 0.94%, more preferably not more than about 0.93%, more preferably not more than about 0.92%, more preferably not more than about 0.91%, more preferably not more than about 0.90%, more preferably not more than about 0.89%, more preferably not more than about 0.88%, more preferably not more than about 0.87%, more preferably not more than about 0.86%, more preferably not more than about 0.85%, more preferably not more than about 0.84%, more preferably not more than about 0.83%, more preferably not more than about 0.82%, more preferably not more than about 0.81%, more preferably not more than about 0.80%, more preferably not more than about 0.79%, more preferably not more than about 0.78%, more preferably not more than about 0.77%, more preferably not more than about 0.76%, more preferably not more than about 0.75%, more preferably not more than about 0.74%, more preferably not more than about 0.73%, more preferably not more than about 0.72%, more preferably not more than about 0.71%, more preferably not more than about 0.97%, more preferably not more than about 0.69%, more preferably not more than about 0.68%, more preferably not more than about 0.67%, more preferably not more than about 0.66%, more preferably not more than about 0.65%, more preferably not more than about 0.64%, more preferably not more than about 0.63%, more preferably not more than about 0.62%, more preferably not more than about 0.61%, more preferably not more than about 0.60%, more preferably not more than about 0.59%, more preferably not more than about 0.58%, more preferably not more than about 0.57%, more preferably not more than about 0.56%, more preferably not more than about 0.55%, more preferably not more than about 0.54%, morepreferably not more than about 0.53%, more preferably not more than about 0.52%, more preferably not more than about 0.51%, more preferably not more than about 0.50%, more preferably not more than about 0.49%, more preferably not more than about 0.48%, more preferably not more than about 0.47%, more preferably not more than about 0.46%, more preferably not more than about 0.45%, more preferably not more than about 0.44%, more preferably not more than about 0.43%, more preferably not more than about 0.42%, more preferably not more than about 0.41%, more preferably not more than about 0.40%, more preferably not more than about 0.39%, more preferably not more than about 0.38%, more preferably not more than about 0.37%, more preferably not more than about 0.36%, more preferably not more than about 0.35%, more preferably not more than about 0.34%, more preferably not more than about 0.33%, more preferably not more than about 0.32%, more preferably not more than about 0.31%, more preferably not more than about 0.30%, more preferably not more than about 0.29%, more preferably not more than about 0.28%, more preferably not more than about 0.27%, more preferably not more than about 0.26%, more preferably not more than about 0.25%, more preferably not more than about 0.24%, more preferably not more than about 0.23%, more preferably not more than about 0.22%, more preferably not more than about 0.21%, more preferably not more than about 0.20%, more preferably not more than about 0.19%, more preferably not more than about 0.18%, more preferably not more than about 0.17%, more preferably not more than about 0.16%, more preferably not more than about 0.15%, more preferably not more than about 0.14%, more preferably not more than about 0.13%, more preferably not more than about 0.12%, more preferably not more than about 0.11%, and most preferably not more than about 0.10%.

[0042] According to some aspects, the liquid formulation of frovatriptan suitable for intranasal administration is filled in USP type I glass vial or plastic vial with fill volume of about 50pL to about 250pL, closed with polymeric plunger and assembled in unit dose nasal spray devices (as shown in FIG. 3). Upon actuation, such device will deliver the liquid formulation in the nasal cavity in the range from about 40pL to about 200pL in the form of spray.

[0043] In an embodiment, the present invention provides a liquid pharmaceutical formulation suitable for nasal or oral or sublingual or injectable administration, wherein the composition comprises (i) frovatriptan, (ii) liquid vehicle, and (iii) one or more optional pharmaceutically acceptable excipients.

[0044] In some embodiments, the nasal spray delivers, upon actuation, frovatriptan formulation in the form of spray, wherein less than 10% (D10) of the droplets have a size smaller than about 10pm, optionally smaller than about 5pm, and / or at least 50% (D50) of the droplets have a size from about 10pm to 150pm, preferably from about 40pm to about 80pm, and / or at least 90% (D90)of the droplet have a size smaller than 300pm, preferably smaller than 150pm, more preferably smaller than 120pm.

[0045] In some embodiments, the nasal spray delivers, upon actuation, frovatriptan formulation in the form of spray, wherein plume angle of the spray is from about 25° to about 75°, preferably from about 30° to about 60°.

[0046] In some embodiments, the frovatriptan liquid formulation of the present invention has water like viscosity such as about 1 cP. In some other embodiments, the viscosity of the formulation is higher than 1 cP, such as about 1 to 3 cP, about 3 to 10 cP, about 10 to 20 cP, about 20 to 30 cP, about 30 to 50 cP, about 50 to 100 cP, about 1 to 1000 cP. In some other embodiments, the viscosity of the formulation is from about 1 to 50 cP, preferably from about 5 to 50 cP. Higher than water viscosity may help increase residence time of the frovatriptan formulation on nasal mucosa for better absorption, while much higher viscosity such as gel (>3000 cP) may slow down the absorption, subtherapeutic plasma concentration and delayed onset of action. The viscosity range provided here is when tested using capillary viscometer, such as U-tube Ostwald capillary viscometer with ID of about 0.5 mm or about 1 mm, using water as reference.

[0047] In some embodiments, the frovatriptan liquid formulation has osmolality from about 100 mOsmol / kg to about 2000 mOsmol / kg, from about 200 mOsmol / Kg to about 1000 mOsmol / Kg, from about 250 mOsmol / Kg to about 800 mOsmol / Kg, from about 250 mOsmol / Kg to about 550 mOsmol / Kg, from about 250 mOsomol / Kg to about 350 mOsoml / Kg. In yet other embodiments, the osmolality of the frovatriptan liquid formulation is 280 to 320 mOsmol / Kg.

[0048] In some embodiments, the liquid formulation of frovatriptan is filled in USP type I glass vial and placed in unit dose nasal spray devices similar to that disclosed in US patent number 6708846 or similar devices suitable for nasal administration in the form of a spray. This nasal spray can be packaged in blister tray and placed in carton that protects the product from light.

[0049] As used herein, the term “vehicle” refers to any ingredient or mixture of ingredients, either in liquid form or solid form, that can be dissolved, homogenized or suspended, to increase the volume of the liquid composition of present invention. Non-limiting examples of vehicles are water, sorbitol, sucrose, sugar, mannitol, xylitol, propylene glycol, polyethylene glycol, glycerin, alcohol, lactose, cellulose, starch, triglycerides, or even oil. In an embodiment, the concentration of vehicles ranges from about 5% to about 99.9%, from about 10% to about 99.9%, from about 20% to about 99.9%, from about 30% to about 99.9%, from about 40% to about 99.9%, from about 50% to about 99.9%, from about 50% to about 99.9%, from about 60% to about 99.9%, from about 70% to about 99.9%, from about 80% to about 99.9%, from about 90% to about 99.9%, from about 95 to about 99.9% from about 97% to about 99.9% based on the total weight of the composition.

[0050] In some embodiments of the present invention, the vehicle suitable for the liquid pharmaceutical formulation of frovatriptan comprises organic solvent such as polyethylene glycol, propylene glycol, and glycerin at concentration from about 1 to about 80%v / v, preferably from about 5 to 50%v / v that may help achieving frovatriptan concentration in vehicle suitable for intended application. For example, intranasal administration requires higher concentration, but it was surprisingly discovered by the inventor that salts such as sodium chloride reduce the solubility of frovatriptan succinate in water (as shown in FIG. 1). In such cases, organic solvents may be used to improve the solubility in presence of such salt, and it is still within the scope of the present invention.

[0051] As used herein, the term “preservative” refers to an ingredient or group of ingredients that may be added to the liquid formulation of the present invention to protect it from microbial contamination or to prevent microbial growth. In one embodiment, the pharmaceutical composition of the liquid formulation of frovatriptan contains one or more preservatives selected from the group comprising benzoic acid and the sodium or potassium salts thereof, ethanol, isopropanol, methanol, butyl alcohol, benzalkonium chloride, benzyl alcohol, benzethonium chloride, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, propylparaben sodium, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol, and combinations thereof.

[0052] In some embodiments of the present invention, the concentration of preservatives ranges from about 0.001% to about 10%, preferably from about 0.01% to about 5%, preferably from about 0.01% about 2%, preferably from about 0.01% to about 1%, preferably from about 0.01% to about 0.5% based on the total weight of the composition. In some other embodiments of the present invention, the concentration of preservatives ranges from about 0.1% to about 10%, preferably from about 0.1% to about 5%, preferably from about 0.1% about 2%, preferably from about 0.1% to about 1%, preferably from about 0.1% to about 0.5% based on the total weight of the composition.

[0053] As used herein, the term “tonicity adjusting agent” refers to any ingredient or combination of ingredients added to the pharmaceutical formulation to adjust or contributing to its osmotic pressure, thereby ensuring that the formulation is isotonic or near-isotonic with physiological fluids, such as nasal mucosa, when administered intranasally, or to a soft tissue or muscle when administered by intramuscular route, or into the blood when administered intravenously. Tonicity adjusting agents contribute to patient comfort, prevent irritation, and help maintain the stability and efficacy of the formulation upon administration. Non-limiting examples of tonicity adjustingagents that may be used in the pharmaceutical compositions of the present invention include dextrose, mannitol, sorbitol, glycerin, glucose, propylene glycol, polyethylene glycol, sodium chloride, potassium chloride, calcium chloride, and magnesium sulfate, as well as mixtures thereof. In some other embodiments, the formulation of the present invention does not contain sodium chloride, potassium chloride, calcium chloride, magnesium sulfate or salt that may reduce the solubility of frovatriptan in vehicle or may be used with organic co-solvent or other ingredients that may help improve the solubility in presence of such salt. In some embodiments, the concentration of tonicity adjusting agents ranges from about 0.1% to about 10%, from about 0.2% to about 8%, from about 0.5% to about 5% by weight based on the total composition, with the precise amount selected to achieve the desired osmolality, for example, from about 100 mOsmol / Kg to about 1000 mOsmol / Kg, preferably from about 250 mOsmol / kg to about 350 mOsmol / kg. The specific selection, combination, and concentration of tonicity adjusting agents is tailored according to the overall composition and intended route of administration to ensure optimal therapeutic performance and patient tolerability. It is understood that frovatriptan succinate in dissolved form also contributes to the osmolality of the final formulation. At given concentration of frovatriptan succinate in water, it will also act as tonicity adjusting agent to achieve target osmolality.

[0054] As used herein, the term “pH adjusting agent” refers to both acidic and basic chemicals used for the adjustment of pH of the formulation of the present invention. Example of pH adjusting agents includes without limitation, hydrochloric acid, sodium hydroxide, benzoic acid, gluconic acid, formic acid, fumaric acid, lactic acid, isothionic acid, malic acid, maleic acid, mandelic acid, nitric acid, mucic acid, oxalic acid, pantothenic acid, p-toluenesulfonic acid, ascorbic acid, citric acid, tartaric acid, phosphoric acid, acetic acid, carbonic acid, phthalic acid, succinic acid, glutamic acid, methane sulfonic acid, sulfuric acid, potassium hydroxide, ammonia, or combination thereof.

[0055] In some embodiments of the present invention, the concentration of pH adjusting agent ranges up to about 10%, preferably up to about 8%, preferably up to about 5%, preferably up to about 2% based on total weight of the composition.

[0056] In some other embodiments of the present invention, the concentration of pH adjusting agent depends on the pH of formulation, and the quantity to be used is generally considered as “quantity sufficient (q.s.) to target pH”.

[0057] In some embodiments of the present invention, the pH of the liquid composition of present invention is between about 2 to about 10, optionally between about 3 to 9, optionally between about 3 to 7, optionally between about 3 and 6.5, optionally between about 3 and 6, optionally between about 3 and 5.5, optionally between about 4 and 5.5. In some other embodiments of the present invention, the pH of the liquid composition of present invention is between about 3 andabout 6.5, optionally between about 3 and about 6, optionally between about 3 and 5, optionally between about 4 and 5, optionally between about 4.5 to about 5.0, optionally about 4.7, optionally about 4.8, optionally about 4.9, optionally from 4.5 to 5.0.

[0058] As used herein, the term “permeation enhancer” refers to an ingredient or group of ingredients that are incorporated into the liquid formulation to increase the permeability of the active pharmaceutical ingredient across biological membranes. Permeation enhancers function by temporarily modifying the barrier properties of the membrane, facilitating improved absorption or bioavailability of the drug.

[0059] Examples of permeation enhancers include, without limitation: alcohol, arachidonic acid, benzethonium chloride, benzethonium bromide, benzalkonium chloride, capric acid, caproic acid, carvone, cetylpyridium chloride, chitosans, citric acid, 6-cyclohexyl-l-hexyl-P-D- maltopyranoside, n-decyl-P-D-maltopyranoside, dimethyl sulfoxide, dodecyl dimethyl aminopropionate, 1-O-n-Dodecyl-P-D-maltopyranoside, dodecylpolyethyleneglycol ether, edetate disodium dihydrate, enanthic acid, glyceryl monooleate, glyceryl monostearate, glycofurol, isopropyl myristate, isopropyl palmitate, pelargonic acid, lanolin, lauric acid, light mineral oil, limonene, linoleic acid, lysine, menthol, myristic acid, myristyl alcohol, oleic acid, oleyl alcohol, palmitic acid, peppermint oil, polyoxyethylene alkyl ethers, polyoxylglycerides, polysorbates, pyrrolidone, sodium caprate, sodium desoxycholate, sodium deoxyglycolate, sodium glycocholate, sodium hydroxybenzoyal amino caprylate, sodium lauryl sulfate, sodium taurocholate, stearic acid, thymol, tricaprylin, triolein, undecylenic acid, and combinations thereof.

[0060] In some embodiments of the present invention, the concentration of permeation enhancer ranges from about 0.001% to about 10%, preferably from about 0.001% to about 5%, preferably from about 0.001% to about 2%, or preferably from about 0.001% to about 1% based on the total weight of the composition. The precise concentration may be adjusted depending on desired permeability enhancement, physical properties of the formulation, and compatibility with other ingredients.

[0061] As used herein, the term “mucoadhesive agent” refers to an ingredient or group of ingredients that enhance the adhesion of the formulation to mucosal surfaces, thereby prolonging the residence time and improving the efficacy of the active pharmaceutical ingredient of the present invention. Mucoadhesive agents function by forming physical or chemical interactions with the mucin layer covering mucosal tissues. Examples of mucoadhesive agents include, without limitation, natural polymers such as chitosan, alginate, hyaluronic acid, gelatin, tragacanth, xanthan gum, guar gum, and pectin; synthetic and semi-synthetic polymers such as carbomers (Carbopol) of all grades (such as Carbopol 934, Carbopol 940, Carbopol 97 IP, and others), polyvinyl alcohol (including all pharmaceutical grades), polyvinylpyrrolidone (such as KI 2, K30, and K90 grades),polyethylene oxide (including Sentry Polyox grades such as WSR N10, N80, N750, and N205), polyacrylic acid (all USP and NF grades), hydroxypropyl methylcellulose (HPMC grades such as E3, E5, K4M, K15M, and K100M), methylcellulose (USP and food grades), carboxymethyl cellulose (including sodium carboxymethyl cellulose grades like low, medium, and high viscosity types), and pol oxamers (including grades such as Pol oxamer 188 and 407); as well as cellulose derivatives (all grades), sodium alginate, and acacia gum. In some embodiments of the present invention, the concentration of mucoadhesive agent ranges from about 0.001% to about 10%, preferably from about 0.01% to about 5%, preferably from about 0.1% to about 2%, preferably from about 0.1% to about 1%, and more preferably from about 0.1% to about 0.5% based on the total weight of the composition. The precise concentration may be adjusted depending on desired mucoadhesive strength, physical properties of the formulation, and compatibility with other ingredients.

[0062] As used herein, the term “stability enhancing agent” or “stabilizer” refers to ingredient or group of ingredients that inhibit, prevent, slow down, or reduce the degradation of frovatriptan or its pharmaceutically acceptable salt in the liquid formulation of the present invention. More specifically, stability-enhancing agents include amino acids such as alanine, glycine, glutamate, sodium glutamate, L-arginine, lysine, L-cysteine or methionine; sodium chloride or sodium sulfate salts; sodium hydroxide, potassium hydroxide, calcium hydroxide, lactic acid, glycolic acid, succinic acid, pyruvic acid, citric acid, ethylenediaminetetraacetic acid (EDTA), metal ions such as zinc, magnesium and calcium or mixtures thereof; natural or synthetic gums, cellulosic derivatives such as carboxy methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, hydroxyl propyl methylcellulose, methylcellulose, polyanionic cellulose; cyclodextrins; sugars; sugar alcohols; monosaccharides, disaccharides or polysaccharides and combinations thereof.

[0063] In some embodiments of the present invention, the concentration of the stabilizer ranges from 0.001% to 20%, preferably from about 0.001% to about 10%, preferably from about 0.01% to about 5%, preferably from about 0.1% to about 1%, preferably from about 0.15% to 0.5%, preferably from about 0.15% to 0.25% based on the total weight of the composition.

[0064] In some other embodiments of the present invention, the concentration of the stabilizer ranges from 0.1% to 20%, preferably from about 1% to about 20%, preferably from about 1% to about 10%, preferably from about 1% to about 5% based on the total weight of the composition.

[0065] In some other embodiments of the present invention, the concentration of the stabilizer is less than about 10%, less than about 5%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.25%, less than about 0.1%, less than about 0.05%, less than about 0.01%, less than about 0.001% based on the total weight of the composition.

[0066] As used herein, the terms “buffering agent”, “buffer” or “buffer system”, refers to ingredients that help in maintaining the pH of the formulation of the present invention. Examples of buffering agents include, without limitation, salts of citric acid, tartaric acid, ascorbic acid, phosphoric acid, acetic acid, carbonic acid, phthalic acid, succinic acid, glutamic acid, benzoic acid, gluconic acid, formic acid, fumaric acid, lactic acid, isothionic acid, malic acid, maleic acid, mandelic acid, nitric acid, mucic acid, oxalic acid, pantothenic acid, p-toluenesulfonic acid, methane sulfonic acid, sulfuric acid, hydrochloric acid, and combinations thereof. Additionally, pharmaceutically acceptable amino acids such as methionine, cysteine, glycine, etc. can also be used as buffering agents.

[0067] In some embodiments of the present invention, the concentration of buffering agent ranges from 0.0001% to 10%, preferably from about 0.0001% to about 5%, preferably from about 0.0001% to about 2%, preferably about 0.0001% to about 1%, preferably about 0.0001% to 0.5%, preferably about 0.0001% to about 0.25% based on the total weight of the composition.

[0068] In some other embodiments of the present invention, the concentration of buffering agent ranges from 0.001% to 10%, preferably from about 0.001% to about 5%, preferably from about 0.001% to about 2%, preferably about 0.001% to about 1%, preferably about 0.001% to 0.5%, preferably about 0.001% to about 0.25% based on the total weight of the composition.

[0069] In some other embodiments of the present invention, the concentration of buffering agent ranges from 0.01% to 10%, preferably from about 0.01% to about 5%, preferably from about 0.01% to about 2%, preferably about 0.01% to about 1%, preferably about 0.01% to 0.5%, preferably about 0.01% to about 0.25% based on the total weight of the composition.

[0070] In some other embodiments of the present invention, the concentration of buffering agent ranges from 0.1% to 10%, preferably from about 0.1% to about 5%, preferably from about 0.1% to about 2%, preferably about 0.1% to about 1%, preferably about 0.1% to 0.5%, preferably from about 0.1% to about 0.25% based on the total weight of the composition.

[0071] It is understood that a higher quantity of alkalizer or acidifier can be used in ranges different from those mentioned here, considering that they neutralize the effect of one another.

[0072] As used herein, the term “chelating agent” refers to compounds that help stabilize the formulation of the present invention by means of chelating undesired compounds or elements or ions. Suitable chelating agents that may be used in the present invention include, but are not limited to, edetate disodium (EDTA); edetate trisodium, edetate tetrasodium; and diethylene amine pentaacetate or derivatives thereof. In certain preferable embodiments, the formulations comprise di sodium edetate.

[0073] In some embodiments of the present invention, the concentration of chelating agents ranges from 0.001% to 5%, preferably from about 0.001% to about 2%, preferably from about0.001% to about 1%, preferably from about 0.001% to about 0.5%, preferably from about 0.001% to about 0.1% based on the total weight of the composition.

[0074] In some other embodiments of the present invention, the concentration of chelating agents ranges from 0.01% to 5%, preferably from about 0.01% to about 2%, preferably from about 0.01% to about 1%, preferably from about 0.01% to about 0.5%, preferably from about 0.01% to about 0.1% based on the total weight of the composition.

[0075] As used herein, the term “antioxidant” refers to agents that protect the composition (primarily active ingredient) of the present invention from oxidative degradation. Examples include, without limitation, methionine, sodium / potassium bisulfite, sodium metabisulfite, potassium metabisulfite, sodium ascorbate, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, cysteine, glutathione, monothioglycerol, propyl gallate, sodium / potassium sulfite, tocopherol (such as alpha-tocopherol) or its salt and esters (such as D-alpha-tocopheryl polyethylene glycol 1000 succinate), and combinations thereof.

[0076] In some embodiments of the present invention, the concentration of antioxidants ranges from about 0.001% to about 5%, preferably from about 0.01% to about 2%, preferably from about 0.01% to about 1%, preferably from about 0.01% to about 0.5%, preferably from about 0.01% to about 0.2% based on total weight of the composition.

[0077] In some embodiments of the present invention, the concentration of antioxidants ranges from about 0.05% to about 2%, preferably from about 0.1% to about 2%, preferably from about 0.1% to about 2%, preferably from about 0.1% to about 1%, preferably from about 0.1% to about 0.5% based on total weight of the composition.

[0078] As used herein, the term “viscosity adjusting agent” refers to any compound or combination of compounds added to a formulation of the present invention to modify or maintain its viscosity, ensuring optimal flow, pourability, suspension stability, and ease of administration of the final liquid product. Suitable viscosity adjusting agents include, but are not limited to, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose; natural gums like xanthan gum, guar gum, acacia gum, carrageenan, locust bean gum; polyvinylpyrrolidone (PVP), polyvinyl alcohol, alginates such as sodium alginate, and carbomers. In some embodiments of the present invention, the concentration of viscosity adjusting agent ranges from about 0.001% to about 10%, preferably from about 0.01% to about 5%, preferably from about 0.1% to about 2%, and even more preferably from about 0.1% to about 1% by total weight of the composition, depending on the desired consistency and properties of the material grade.

[0079] As used herein, the term “surfactant” refers to any ingredient that reduces the surface tension between particle and liquid medium, allowing for better wetting and preventing agglomeration in the liquid formulation of the present invention.

[0080] In an embodiment, the liquid formulation of frovatriptan may contain suitable surfactants such as ionic or non-ionic surface-active agents. Suitable ionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include potassium, sodium, ammonium salts of long chain alkyl sulfonates, and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2- ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate; quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene. In an embodiment, the concentration of ionic surfactant ranges from about 0.01% to 3%, preferably from about 0.05% to about 2%, preferably from about 0.05% to about 1%, preferably from about 0.05% to about 0.5%, preferably from about 0.05% to about 0.25% based on the total weight of the composition.

[0081] Suitable nonionic surfactants optionally used include, but are not limited to, glycol stearates such as ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, polyethylene glycol dilaurate, polyethylene glycol monolaurate, polysorbates, polyoxyethylene octylphenylether, polyethylene glycol cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, stearoyl monoisopropanolamide, polyoxyethylene hydrogenated tallow amide, polyoxyl-ethylated castor oils (CREMOPHOR®), polyoxyethylene esters of 12-hydroxystearic acid (SOLUTOL®) and PEGylated glycerides (LABRASOL®). In another embodiment, the concentration of non-ionic surfactant ranges from about 0.02% to 2%, based on the total weight of the composition. In another embodiment, polysorbate is the non-ionic surfactant at a concentration of less than about 7% (w / w) of the total composition, less than about 6% (w / w) of the total composition, less than about 5% (w / w) of the total composition, less than about 4% (w / w) of the total composition, less than 3% (w / w) of the total composition, less than 2% (w / w) of the total composition, less than 1% (w / w) of the total composition.

[0082] As used herein, the term “sweetening agent” refers to both bulk (caloric) and intense (noncaloric) sweeteners, which impart a sweet taste to the frovatriptan liquid formulation of the present invention. Non-limiting examples of sweeteners include glucose, sucralose, trehalose, fructose, xylose, dextrose, galactose, tagatose, maltose, sucrose, glycerol, dulcitol, mannitol, lactitol, sorbitol, xylitol, saccharine or the corresponding sodium, potassium or calcium salt, cyclamate or the corresponding sodium or calcium salt, aspartame, or acesulfame or the potassium salt thereof,dulcin or ammonium glycyrrhizinate, alitame, inulin, isomalt, neohesperidin dihydrochalcone, thaumatin and the like or any combinations thereof. In some embodiments of the present invention, the concentration of sweeteners ranges from about 0.001% to about 40%, preferably from about 0.01% to about 20%, preferably from about 0.01% to about 10%, preferably from about 0.01% to about 5%, preferably from about 0.01% to about 2%, preferably from about 0.1% to about 2% based on the total weight of the composition. It is understood that bulk sweeteners such as sorbitol may require higher amounts while intense sweeteners such as sucralose may require lesser amounts.

[0083] As used herein, the term “flavoring agent” refers to an agent or a mixture of agents that adds flavor to the frovatriptan liquid formulation of the present invention. A flavoring agent is selected from the group comprising of a natural flavor, an artificial flavor, and mixtures thereof. Non-limiting examples of flavoring agents are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, peppermint, tutti frutti flavor and so forth and the like or any combinations thereof. Solid forms, such as spray dried forms of flavoring agents, may also be useful in the liquid dosage forms disclosed herein. In some embodiments of the present invention, the concentration of flavoring agent ranges from about 0.001% to about 5%, preferably from about 0.001% to about 2%, preferably from about 0.001% to about 1%, preferably from about 0.001% to about 0.1%, preferably from about 0.01% to about 0.1% based on total weight of the composition.

[0084] As used herein, the term “solubilizing agent” or “solubilizer” refers to any ingredient that enhances the solubility of frovatriptan or its pharmaceutically acceptable salt in liquid formulation of the present invention. Examples of solubilizer include, without limitation, surfactant, acid, base, hydrophilic polymer, ethanol, polyhydric alcohol, polyethylene glycol, carbohydrate, glycerin, propylene glycol, polyethylene glycol (such as 200, 300, 400, 600, or 1000), polysorbate (such as 20, 40, 60 or 80), polyvinylpyrrolidone (PVP, such as PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, or PVP KI 20), sodium lauryl sulfate, copovidone, pol oxamer, fructose, sucrose, sorbitol, etc.

[0085] As used herein, the term “anti-foaming agent” or “defoamers” refers to ingredients suitable to be used in the formulation of the present invention that disrupt the stability of the foam or prevent the foaming by destabilizing the thin liquid films or lamellae that form the bubble walls, causing them to rupture and collapse. Non-limiting examples of anti-foaming agents are simethicone, polydimethylsiloxane, organomodified silicones, mineral oil, vegetable oil, polypropylene glycol, fatty alcohols, aliphatic esters, triglycerides or combination thereof. In an embodiment of the present invention, the concentration of anti-foaming agent is from about 0.001% to about 5%.

[0086] As used herein, the term “dispersing agent” refers to any substance that facilitates the uniform distribution of solid particles within a liquid medium, thereby preventing aggregation or clumping and ensuring homogeneity of the formulation of the present invention. Dispersing agents improve the stability and consistency of suspensions by enhancing the separation of individual particles and maintaining their even distribution throughout storage and dosing. Non-limiting examples of dispersing agents include polysorbates, lecithin, polyvinylpyrrolidone (PVP, such as PVP KI 2, PVP K30, PVP K90), pol oxamers, sodium lauryl sulfate, sodium citrate, sodium carboxymethyl cellulose, and phospholipids, as well as certain surfactants and amphiphilic polymers. In some embodiments of the present invention, the concentration of dispersing agent ranges from about 0.01% to about 5%, preferably from about 0.05% to about 2%.

[0087] As used herein, the term “wetting agent” refers to any substance that facilitates the dispersion and penetration of solid particles by reducing the interfacial tension between the solid and the liquid medium in a formulation. Wetting agents play a crucial role in enhancing the ability of the liquid to spread across the surface of solids, thereby improving uniformity and consistency in pharmaceutical suspensions and other liquid formulations. Non-limiting examples of wetting agents suitable for use in the present invention include, but are not limited to, polysorbates (such as polysorbate 20, Polysorbate 40, Polysorbate 60, or Polysorbate 80), sodium lauryl sulfate, poloxamers, lecithin, polyoxyethylene sorbitan monolaurate, polyvinylpyrrolidone (PVP), sorbitan esters, cetyl alcohol, stearyl alcohol, glycerol monostearate, polyethylene glycol (such as PEG 200, 300, 400, 600, or 1000), and sodium dioctyl sulfosuccinate. In some embodiments of the present invention, the concentration of wetting agent ranges from about 0.01% to about 5% based on the total weight of the composition, preferably from about 0.05% to about 2%, and more preferably from about 0.1% to about 1%.

[0088] As used herein, the term “crystallization inhibitors” refers to ingredients that prevent or reduce the formation and growth of crystals of frovatriptan or its pharmaceutically acceptable salt within a liquid formulation, thereby stabilizing the active ingredient in a supersaturated or amorphous state and improving the clarity and homogeneity of the final product. Suitable crystallization inhibitors include, without limitation, hydrophilic polymers such as polyvinylpyrrolidone (PVP, including PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, or PVP KI 20), polyethylene glycol (PEG 200, PEG 300, PEG 400, PEG 600, or PEG 1000), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, poloxamers, povidone, copovidone, cyclodextrins, and polysorbates (such as Polysorbate 20, Polysorbate 40, Polysorbate 60, or Polysorbate 80). In some embodiments of the present invention, the concentration of crystallization inhibitor ranges from about 0.01% to about 10% based on the total weight of the composition.

[0089] The term "Suspension" as used herein means a liquid with solid particles dispersed substantially throughout the formulation. The properties of a liquid suspension, according to the invention, are greatly influenced by the particle size of the drug substance, i.e. frovatriptan. As used herein, a "particle" may be a crystal, a granule, agglomerate, or any un-dissolved solid material. To achieve the rapid onset of activity, which is desirable, a small particle size is essential, ensuring the fastest possible dissolution of drug substance. The particle size distribution in suspension is also a very important factor characterizing the physical stability (for example, sedimentation ratio, etc.) of the formulation. Generally, as the particle size becomes smaller, the sedimentation ratio increases, and the physical stability is improved.

[0090] In an embodiment of present invention, the particle size distribution (PSD) of Frovatriptan is such that it is suitable for suspension for intranasal administration and includes at least 90% of the particles that are smaller than 10 pm, preferably from about 5 pm to about 15pm.

[0091] As used herein, the term “suspending agent” refers to a substance that helps keep the solid particle dispersed and prevent or slow down the settling to the bottom of the liquid. Suspending agents suitable for use in the liquid oral suspensions of the present invention include, cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone (PVP, such as PVPK12, PVPK15, PVPK17, PVPK25, PVPK30, PVP K60, PVP K90, or PVP KI 20), alginate, guar gum, xanthan gum, carrageenan, acacia gum, tragacanth, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene and polyoxypropylene ether.

[0092] As used herein, the term “polyhydric alcohol” refers to a compound with more than one hydroxyl group. Non-limiting examples of polyhydric alcohols that can be used are glycerin, propylene glycol, polyethylene glycol, xylitol, maltitol, sorbitol, sucrose, sucralose, glucose, and mannitol.

[0093] In some embodiments of the present invention, the concentration of polyhydric alcohol ranges from about 0.1% to 75%, preferably from about 0.1% to about 40%, preferably from about 0.1% to about 5%, preferably from about 0.1% to about 1%, preferably from about 0.1% to 0.5% based on the total weight of the composition.

[0094] In an embodiment of the present invention, the concentration of suspending agent ranges from about 0.01% to 5%, preferably from about 0.05% to about 5%, preferably from about 0.1% to about 4%, preferably from about 0.1% to about 3%, preferably from about 0.1% to about 2% based on the total weight of the composition.

[0095] In some embodiments, the frovatriptan liquid formulation is preservative-free.

[0096] In some other embodiments, the frovatriptan liquid formulation is sterile.

[0097] In an embodiment, the frovatriptan liquid formulation is filled into a suitable pharmaceutically acceptable container selected from the group consisting of bottles, bags, sprayers, ampules (plastic or glass), blisters, sachets, syringes, cartridges, and vials.

[0098] In an embodiment, the frovatriptan liquid formulation is filled into a suitable pharmaceutically acceptable container that reasonably protects the composition from air and light that otherwise may degrade frovatriptan or any vehicle or excipient within the container.

[0099] In an embodiment, the frovatriptan liquid formulation is administered via sublingual or nasal route to the patient as a fluid stream, drop(s), droplet(s), spray, or combination thereof.

[0100] In an embodiment, the pharmaceutically acceptable container for the liquid frovatriptan containers may be a bottle, wherein the bottle is selected from a group consisting of glass bottles or plastic bottles, wherein glass bottle is selected from a group consisting of Type I, II, and III borosilicate glass bottles, wherein the glass bottle may be amber color glass bottle or clear glass bottle.

[0101] In another embodiment, the pharmaceutically acceptable container for the liquid frovatriptan formulations may be a bottle, wherein the bottle is selected from a group consisting of high-density polyethylene (HDPE) bottle, polyethylene terephthalate (PET) and polypropylene (PP), wherein the plastic bottle may be amber colored, white opaque or translucent plastic bottle.

[0102] In an embodiment, the ready-to-use liquid formulation of frovatriptan is packaged in a flexible polymeric bag contained in a secondary outer packaging.

[0103] In an embodiment, the glass and HDPE bottles for the liquid frovatriptan formulations may be available in range from about 2, 3, 5, 10, 30, 60, 90, 100, 120, 125, 150, 180, 200, 250, 300, 350 or up to 500 mL fill volumes. Any volume within this range is within the scope of the present invention. In another embodiment, the fill volume of the frovatriptan liquid formulation of the present invention in suitable primary packaging is from about 0.05 mL to 0.2 mL for unit dose nasal spray or unit dose sublingual spray, from about 0.1 mL to about 30 mL for multiple dose nasal spray or multiple dose sublingual spray, from about 2 mL to 500 mL for oral liquid dosage form, or from about 0.1 mL to 20 mL, preferably from 0.1 mL to 5mL, more preferably from 0.1 mL to 1 mL for sterile injectable dosage form. In another embodiment, the pharmaceutical composition of the present application may be packed in a kit comprising a bottle with a childresistant cap, adapter, and dosing syringe.

[0104] In an embodiment, the liquid formulation of frovatriptan of the present invention suitable for intranasal, parenteral, and / or sublingual administration, preferably intranasal and / or intramuscular administration is a solution comprising frovatriptan or its salt such as frovatriptan succinate (from about 0.05%w / v to about 10%w / v, preferably from about 0.1%w / v to about 5%w / v, more preferably at about 2.5%w / v), vehicle (quantity sufficient to 100%w / v) and anoptional ingredient selected from group comprising of tonicity adjusting agent (from about 0.1%w / v to about 10%w / v, preferably from about l%w / v to 5%w / v), permeability enhancer (from about 0.001%w / v to about 5%w / v, preferably from about 0.01%w / v to l%w / v), preservative (from about 0.001%w / v to about l%w / v, preferably from about 0.01%w / v to about 0.5%w / v), pH adjusting agent (quantity sufficient to pH from about 3 to about 7, preferably from about 3 to about 6, more preferably from about 3 to about 5), viscosity adjusting agent (from about 0.01%w / v to about 5%w / v, preferably from about 0.01%w / v to about 2%w / v, preferably from about 0.01%w / v to 0.5%w / v), surfactant (from about 0.01%w / v to about 2%w / v), sweetener (from about 0.01%w / v to about 10%w / v), flavoring agent (from about 0.001%w / v to about l%w / v), buffering agent (from about 0.001%w / v to about 5%w / v, preferably from about 0.01%w / v to about l%w / v), antioxidant (from about 0.001%w / v to about 0.5%w / v, preferably from about 0.01%w / v to about 0.5%w / v), stabilizer (from about 0.01%w / v to about 5%w / v, preferably from about 0.01w / v% to about l%w / v), and combinations thereof.

[0105] In some embodiments of the present invention, the liquid formulation is administered to the patient at a dosing frequency of once a day, optionally twice a day, optionally twice a day at least about 2 hours apart, optionally thrice a day, optionally thrice a day at least about 2 hours apart, optionally once a week, optionally twice a week, optionally every other day, optionally once a month, optionally twice a month, optionally once a day every week, optionally once a day every other week, optionally once a day every month, optionally up to treating four migraine attacks in a 30-day period, optionally as needed, optionally after the onset of symptoms of the disease treatable by frovatriptan, optionally prior to onset of the symptoms of the disease treatable by frovatriptan (as prophylaxis), or any other dosing frequency suitable for the patient need.

[0106] In some embodiments of the present invention, the Tmax (time to reach maximum plasma concentration in human) of frovatriptan liquid formulation, when administered via intranasal, parenteral or sublingual route to humans, is less than about 10 minutes, less than about 15 minutes, less than about 30 minutes, less than about 45 minutes, less than about 1 hour, less than about 1.5 hours, less than about 2 hours, or about 2 hours.

[0107] In some embodiments of the present invention, the absolute bioavailability of frovatriptan liquid formulation, when administered intranasally to humans, is more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80% or more than about 90%.

[0108] In some embodiments of the present invention, the AUCo-® (area as measured under a plasma drug concentration curve and extrapolated to infinity) of frovatriptan liquid formulation, when administered vial intranasal, parenteral or sublingual route to humans, is from about 1 ng.h / Lto about 5000 ng.h / L, from about 5 ng.h / L to about 1000 ng.h / L, from about 10 ng.h / L to about 500 ng.h / L, from about 50 ng.h / L to about 250 ng.h / L.

[0109] In some embodiments of the present invention, the Cmax (maximum plasma concentration) of frovatriptan liquid formulation, when administered to human via intranasal, intramuscular or sublingual route, is from about 0.1 ng / mL to about 500 ng / mL, from about 1 ng / mL to about 500 ng / mL, from about 1 ng / mL to about 250 ng / mL, from about 1 ng / mL to about 100 ng / mL, from about 5 ng / mL to about 100 ng / mL, from about 5 ng / mL to about 75 ng / mL, from about 5 ng / mL to about 50 ng / mL, from about 5 ng / mL to about 25 ng / mL.

[0110] In an embodiment, the present invention provides a process for preparing frovatriptan solution suitable for intranasal administration comprising the steps of: (1) adding vehicle to manufacturing vessel; (2) adding optional ingredients one-by-one with mixing until dissolved; (3) adding frovatriptan drug substance with mixing until dissolved; (4) optionally filtering the solution using suitable filter such as 0.2pm filter; (5) filling the frovatriptan solution in vials, closed with polymeric stopper and assemble with unit or bi-dose nasal spray device; and (6) optionally packaging such device further into tray or carton.[OHl] In an embodiment, the present invention provides a process for preparing frovatriptan solution suitable for injectable route of administration comprising the steps of: (1) adding vehicle to manufacturing vessel; (2) adding optional ingredients one-by-one with mixing until dissolved; (3) adding frovatriptan drug substance with mixing until dissolved; (4) sterilizing the solution using sterile grade 0.2pm filter; (5) aseptically filling the frovatriptan solution in suitable primary package such as cartridge, vial or pre-fillable syringe; (6) closing the primary container with appropriate closure; and (7) optionally terminally sterilizing the containers using suitable methods such as moist heat sterilization at about 121°C for about 5 to about 20 minutes.

[0112] In an embodiment, the present invention provides a process for preparing frovatriptan solution suitable for oral or sublingual administration comprising the steps of : (1) adding vehicle to manufacturing vessel; (2) adding optional ingredients one-by-one with mixing until dissolved; (3) adding frovatriptan drug substance with mixing until dissolved; (4) optionally filtering the solution using suitable filter such as form about 0.2pm to about 20pm filter; (5) filling the frovatriptan solution in suitable primary packaging containers; and (6) closing the containers.

[0113] In some embodiments of the present invention, the liquid formulation of frovatriptan is prepared by making in-situ salt using an acidic compound, such as succinic acid, tartaric acid, citric acid, oxalic acid, etc. For this, frovatriptan free base is dissolved and / or suspended in suitable vehicle such as water at or below room temperature, a dilute acid solution is slowly added in mole ratio from about 0.5: 1, preferably about 1 : 1 (acid: frovatriptan) with mixing to obtain a solution offrovatriptan salt, followed by adding one or more optional excipients and making up the volume to batch size, filtering the solution and filling into containers, and closing the containers.

[0114] In some embodiments, the pharmaceutical composition of the present invention includes frovatriptan or its pharmaceutically acceptable salt, a vehicle, and optionally one or more pharmaceutically acceptable excipients, wherein the composition may additionally include caffeine. The caffeine, when present, is present in an amount ranging from about 1 mg / mL to about 100 mg / mL, preferably from about 5 mg / mL to about 25 mg / mL.

[0115] It is understood that the order of addition of ingredients in preparing the liquid formulation of frovatriptan could be changed depending on functionality of the ingredient, manufacturing capabilities, convenience and batch size.DOSE VOLUME AND CONCENTATION

[0116] In some embodiments of the present invention, the relationship between concentration of frovatriptan (free base bases) and intranasal or sublingual dose is shown in Table 1, while with for injectable dose is shown in Table 2.Table 1. Frovatriptan dose volume vs. concentration for given intranasal dose.Table 2. Frovatriptan dose volume vs. concentration for given injectable dose.SOLUBILITY OF FROVATRIPTAN SUCCINATE

[0117] The inventor evaluated the solubility of frovatriptan succinate monohydrate (FSM) in water and sodium chloride solutions. An excess amount of FSM was added to water and aqueous sodium chloride solutions ranging from 0.3% to 1%, followed by mixing for approximately 24 hours. Supernatants were collected and filtered using a 0.22 pm PVDF filter, and assays were conducted via HPLC analysis and presented in Table 3. Solubility in propylene glycol and PEG 400 was evaluated by visual observation based on required quantity of material in given solvent. Table 3. Solubility of frovatriptan succinate monohydrate

[0118] Notably, the results demonstrated a significant decrease in the solubility of frovatriptan in the presence of sodium chloride. This finding is particularly important because higher concentrations of frovatriptan are necessary for intranasal spray and autoinjector applications, where accommodating large doses within small volumes is required. This also further suggests that organic co-solvent such as propylene glycol or polyethylene glycol 400 can be incorporated in the composition to improve solubility and it will also help in improving absorption. In some aspects of the invention, sodium chloride reduces the solubility of frovatriptan succinate and by that way, it may improve the absorption forming unionized frovatriptan. In one aspect of the invention, the liquid formulation of frovatriptan contains sodium chloride

[0119] The present invention is further illustrated by, but is by no means limited to, the following examples.EXAMPLESExamples 1-4

[0120] Example 1-4 describe the liquid formulations of frovatriptan prepared using ingredients detailed in Table 4, by dissolving (where applicable) dibasic sodium phosphate, monobasic sodium phosphate, citric acid, and tri-sodium citrate in about 80% of the required quantity of purifiedwater. Required quantity of frovatriptan succinate monohydrate (FSM) was added to the prepared liquid composition and mixed until dissolved. Volume of the batch was made to the batch size using purified water and filtered using suitable filter. The filtered solution was filled into USP type I glass vial, closed with closure.Table 4. Compositions for liquid formulation of frovatriptanExamples 5-10

[0121] Example 5 to 10 are the liquid formulation of frovatriptan that were prepared using ingredients detailed in Table 5, by dissolving (where applicable) dextrose, benzalkonium chloride, edetate disodium, citric acid, and trisodium citrate, one-by-one, in about 80% of the batch required quantity of purified water. Where applicable, pH was adjusted using sodium hydroxide. Frovatriptan succinate monohydrate (FSM) was added and mixed until clear solution was obtained. Volume of the batch was made to the batch size using purified water and filtered using suitable filter. The filtered solution was filled into USP type I glass vial, closed with closure.Table 5. Liquid formulation of FrovatriptanExamples 11-14

[0122] Example 11 to 14 are the liquid formulations of frovatriptan prepared using ingredients detailed in Table 6, by dissolving (where applicable) dextrose, benzalkonium chloride, edetate disodium, caffeine, and sucralose, one-by-one, in about 80% of the batch required quantity of purified water. Where applicable, glycerin and propylene glycol were added and mixed to homogenize. Frovatriptan succinate monohydrate (FSM) was added and mixed until clear solution was obtained. Volume of the batch was made to the batch size using purified water and filtered using suitable filter. The filtered solution was filled into USP type I glass vial, closed with closure.Table 6. Liquid formulation of FrovatriptanExamples 15-18

[0123] Example 15 to 18 are the liquid formulation of frovatriptan prepared using ingredients detailed in Table 7, by dissolving (where applicable) mannitol, benzalkonium chloride, and edetate disodium dihydrate, one-by-one, in about 80% of the batch required quantity of purified water. Frovatriptan succinate monohydrate (FSM) was added and mixed until a clear solution was obtained. Where applicable, pH was adjusted using hydrochloric acid or sodium hydroxide.Volume of the batch was made to the batch size using purified water and filtered using 0.2pm filter. The filtered solution was filled into USP type I glass vial, closed with closure.Table 7. Liquid formulation of FrovatriptanExamples 19-25

[0124] Example 19 to 25 are the liquid formulation of frovatriptan prepared using ingredients detailed in Table 8, by dissolving (where applicable) citric acid monohydrate, tri-sodium citrate dihydrate, benzalkonium chloride, edetate disodium dihydrate, and sucralose, one-by-one, in about 60% of the batch required quantity of purified water. Where applicable, propylene glycol and polyethylene glycol 400 were added and mixed to homogenize. Frovatriptan free base was added and mixed until a clear solution was obtained. Volume of the batch was made to the batch size using purified water and filtered using suitable filter. The filtered solution was filled into USP type I glass vial, closed with suitable closure.Table 8. Liquid formulation of FrovatriptanExamples 26-33

[0125] Example 26 to 33 are the liquid formulation of frovatriptan prepared using ingredients detailed in Table 9, by dissolving (where applicable) mannitol, edetate disodium dihydrate, and citric acid monohydrate, one-by-one, in about 80% of the batch required quantity of purified water. Frovatriptan succinate monohydrate was added and mixed until a clear solution was obtained. Volume of the batch was made to the batch size using purified water and filtered using 0.2pm filter. The filtered solution was filled into USP type I glass vial, closed with closure. The products were then sterilized by moist heat sterilization at about 121 °C for about 15 minutes in autoclave.Table 9. Liquid formulation of FrovatriptanExamples 34-43

[0126] Example 34 to 43 are the liquid formulation of frovatriptan prepared using ingredients detailed in Table 10, by dissolving (where applicable) mannitol, and dextrose in about 75% of the required quantity of purified water. Frovatriptan succinate monohydrate (FSM) was added and mixed until a clear solution was obtained. pH was adjusted using citric acid solution or 1 N sodium hydroxide. Volume of the batches were made to the batch size using purified water and filtered using 0.2pm filter. The filtered solution was filled into USP type I glass vial, closed with closure.The products were then sterilized by moist heat sterilization at about 121°C for about 15 minutes in autoclave.Table 10. Liquid formulation of Frovatriptan

[0127] Stability testing results for above examples at initial are provided in the table below. Purity, highest single impurity and total impurities are tested using HPLC analysis.Table 11. Analytical test results at initial (0 month).

[0128] Stability testing results for examples are provided in the table below after storage at controlled room temperature (15 - 20°C) for up to 9 months. Purity, highest single impurity and total impurities are tested using HPLC analysis.Table 12. Analytical test results after up to 9 months storage at room temperature (15 - 20°C).

[0129] Stability testing results, for examples, are provided in the table below after storage at 40°C for up to 6 months. Purity, highest single impurity and total impurities are tested using HPLC analysis.Table 13. Analytical test results after up to 6 months storage at 40°C.Examples 44-55

[0130] Following are the additional non-limiting examples of frovatriptan liquid formulations according to the present invention suitable for nasal or injectable route of administration.Table 14. Liquid formulation of FrovatriptanTable 15. Liquid formulation of FrovatriptanExamples 56-62

[0131] Following are the additional non-limiting examples of frovatriptan liquid formulations according to the present invention suitable for intranasal, injectable, or sublingual route of administration.Table 16. Liquid formulation of Frovatriptan*Sodium chloride quantity is from 0 to less than 1%. The concentration is less than precipitating concentration in given solvent system.Table 17. Liquid formulation of Frovatriptan for intranasal administration.*Quantity of water or alcohol is added to adjust the viscosity in the range from about 1 cP to about 50 cP.DOSE DELIVERY ANALYSIS

[0132] It is important that the target dose is delivered when the unit dose nasal spray device is used by the user. Dose delivery testing was performed by filling liquid formulation of Frovatriptan in accordance with example 6 (39.1 mg / mL frovatriptan succinate monohydrate or 25 mg / mL frovatriptan free base) into USP type I vial (microvials, shown in FIG. 3 - 301) with -0.12 mL fill volume. The filled vials were closed with plunger (FIG. 3 - 303) and assembled in unit dose device (FIG. 3) with target dose delivery of 0. ImL equivalent to 2.5 mg frovatriptan free base. The device was actuated in two directions, upright and horizontal, into a collection tube, followed by rinsing and diluted with diluent. Total 6 devices were tested (3 devices at upright and 3 devices at horizontal orientation). The samples were tested for assay using HPLC analysis.Table 18. Delivered dose from unit dose devices.

Claims

CLAIMS1. A liquid pharmaceutical formulation comprising: frovatriptan or its pharmaceutically acceptable salt at a concentration from about 1 mg / mL to about 80 mg / mL; a vehicle; and optionally, one or more pharmaceutical excipients.

2. A liquid formulation of claim 1, wherein the frovatriptan is in the form of frovatriptan succinate.

3. A liquid formulation of claim 1, wherein at least one vehicle is selected from the group comprising of water, propylene glycol, polyethylene glycol, or glycerin.

4. A liquid formulation of claim 1, wherein the frovatriptan concentration is from about 5 mg / mL to about 50 mg / mL.

5. A liquid formulation of claim 1, wherein the frovatriptan concentration is from about 25 to 50 mg / mL.

6. A liquid formulation of claim 1, wherein the pH of the formulation is from about 3 to about 9.

7. A liquid composition of claim 1, wherein the pH of the formulation is from about 4 to about 5.5.

8. A liquid formulation of claim 1, wherein the formulation is administered to the patient in need thereof via an intranasal route of administration.

9. The liquid formulation of claim 1, wherein the formulation is contained within a vial and assembled in a nasal spray device, which, upon actuation, delivers from about 1 mg to about 8 mg of frovatriptan.

10. A liquid formulation of claim 1, wherein the formulation is preservative free prepared by sterile filtration using 0.2pm filter or by terminal sterilization using moist heat.I L A liquid formulation of claim 1, wherein the formulation is administered to the patient in need thereof via subcutaneous, intramuscular, or intravenous route of administration.

12. A liquid formulation of claim 1, wherein the formulation is a solution.

13. A liquid formulation of claim 1, wherein one or more excipient(s) is selected from the group comprising tonicity adjusting agent, preservative, solubilizer, pH adjusting agent, buffering agent, stabilizer, antioxidant, chelating agent, viscosity adjusting agent, permeability enhancer and combinations thereof.

14. A liquid formulation of claim 1, wherein any single individual degradation impurity is not more than about 1% after at least 3 months of storage at controlled room temperature of about 15°C to about 25°C.

15. A liquid formulation of claim 1, wherein the total degradation impurities are not more than about 5% after at least 3 months of storage at controlled room temperature of about 15°C to about 25°C.

16. A method of treatment of migraine or cluster headache, with or without aura, comprising administering a therapeutically effective amount of the liquid formulation according to claim 1 to a patient in need thereof.

17. A liquid formulation of claim 1, wherein the formulation further contains caffeine.

18. A liquid formulation of claim 1, wherein the formulation contains sodium chloride at a concentration below the level that causes frovatriptan succinate to precipitate in aqueous solution.

19. A liquid formulation of claim 1, wherein the formulation contains at least one tonicity adjusting agent other than sodium chloride.

20. A method of manufacturing liquid formulation of frovatriptan or its pharmaceutically acceptable salt comprising the steps of:(i) solubilizing frovatriptan or its pharmaceutically acceptable salt in vehicle;(ii) optionally solubilizing one or more pharmaceutical excipient;(iii) optionally sterile filtering the frovatriptan liquid formulation using 0.2pm filter;(iv) filling the frovatriptan liquid formulation into primary packaging container;(v) closing the container; and(vi) optionally sterilizing the container using moist heat sterilization.

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