SUBCUTANEOUS FORMULATIONS OF PALONOSETRON
Background of the invention
Palonosetron is chemically described as (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline. Palonosetron belongs to the class 5-HT3 receptor antagonists. Palonosetron differs from other agents in its class by its higher receptor-binding affinity and longer half-life. These pharmacological properties have resulted in improved antiemetic activity in clinical trials, particularly in the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) following moderate emetogenic chemotherapy. Palonosetron has the following chemical structure:
Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol. Palonosetron hydrochloride exists as a single isomer.
Palonosetron hydrochloride is marketed in the US under the brand name Aloxi® by Helsinn Healthcare. Each vial of Aloxi® contains Palonosetron hydrochloride, mannitol, disodium edetate and citrate buffer in water for intravenous administration. The pH of the solution in 5 mL and 1.5 mL vials is 4.5 to 5.5. Aloxi® is available in 0.25 mg/5 mL and 0.075 mg/1.5mL strengths.
U.S Patent No 5,202,333 to Jacob et al., discloses 5-HT3 receptor antagonists such as Palonosetron, pharmaceutical compositions containing them and methods of preparing these compounds.

U.S Patent No.s 7,947,724; 7,947,725 to Giorgio et al. disclose stable liquid formulations comprising of Palonosetron at a pH of 4.0 to 6.0, and an aqueous pharmaceutically acceptable carrier including a chelating agent.
U.S Patent application No 2011/0178118 to Alberto et al. discloses a method of treating chemotherapy or radiotherapy-induced acute and delayed emesis comprising administering to an animal a treatment-effective amount of Palonosetron.
U.S Patent No 8,598,218 to Giorgio et al. discloses a method of manufacturing and terminally sterilizing a finished single unit dose vial of Palonosetron or a pharmaceutically acceptable salt thereof.
Commercially Palonosetron is available as Aloxi® capsules and Aloxi® intravenous (IV) Injection. Intravenous administration of a pharmaceutical drug requires a trained healthcare professional for placement of the catheter and administration of the drug solution in contrast to subcutaneous (SC) administration. Moreover SC Palonosetron seems to be a valid alternative to IV administration for control of emesis when conventional routes are difficult or impossible to use, for example, when heavy vomiting precludes oral intake or when IV administration is not possible in an outpatient setting. Further SC route might be an interesting alternative for patients receiving oral chemotherapy that do not require IV medication. Hence there exists a need to develop alternate formulations of Palonosetron. The present invention addresses this need.
The inventors of the present invention have developed stable liquid parenteral formulations of Palonosetron intended for subcutaneous administration.

Summary of the invention
The present invention relates to stable liquid parenteral formulations of Palonosetron for subcutaneous administration and methods of preparing such formulations.
One aspect of the present invention provides stable liquid parenteral formulations of Palonosetron for subcutaneous administration, wherein the formulation is free of chelating agent.
Another aspect of the present invention provides stable liquid parenteral formulations of Palonosetron for subcutaneous administration, wherein the formulation has a pH range of about 5 to 9.
Yet another aspect of the invention provides stable liquid parenteral formulations of Palonosetron for subcutaneous administration comprising of Palonosetron and pharmaceutically acceptable excipients, having a pH range of about 5 to 9, wherein the formulation is free of chelating agent and citric acid.
Yet another aspect of the invention relates to subcutaneous liquid formulations of Palonosetron free of chelating agent, having a pH range of about 5 to 9, wherein the injection volume ranges from about 100µl to 1000µl. Preferably the injection volume ranges from about 100µl to 500µl. More preferably the injection volume ranges from about 100µl to 300µl.
Detailed description of the invention
As used herein the term, “chelating agent” includes the following agents such as
DOTA (1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid), DTPA
(diethylenetriamine pentaacetic acid), EGTA (ethylene glycol-bis(β-aminoethyl
ether)-N,N,N',N'-tetraacetic acid), HEDTA (N (hydroxy ethyl)

ethylenediaminetriacetic acid), EDTA (Ethylenediamine tetraacetic acid), DOTRP (tetraethyleneglycol-1,5,9-triazacyclododecane-N,N',N",tris(methylenephosphonic acid) its salts, analogues and the like.
The term “free of” is intended to mean formulations that have less than 5%, or more specifically less than 2% of the said component.
In the context of this invention “Palonosetron” refers to the pharmaceutically acceptable salts, solvates, hydrates and anhydrous forms thereof, preferably Palonosetron Hydrochloride.
The term “about” is meant to encompass a pH range of ± 0.5 from the specified value or range.
The inventors of the present invention developed stable subcutaneous formulations of Palonosetron which provides an alternative to IV administration and thus overcomes the disadvantages of IV formulations.
The major advantages associated with the Palonosetron SC formulation of the invention are as follows:
(i) It provides a convenient alternative to the patient compared to the i.v
formulation (ii) The volume of the SC injection is significantly less compared to the i.v
formulation. The volume of the SC injection of the invention ranges from
100µl to 1000µl as compared to the volume of i.v formulation which is
5ml and 1.5ml. (iii) The SC formulation can be administered in the outpatient setting and does
not require hospital admission. (iv) The pain at the injection site for the SC formulation is significantly less as
compared to the i.v formulation.

One embodiment of the invention provides stable liquid parenteral formulations of
Palonosetron comprising:
(i) Palonosetron and
(ii) pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise of a buffering agent, pH adjusting agent, tonicity modifier, solvents, preservative or any other suitable adjuvant, wherein the formulation is intended for subcutaneous administration.
Another embodiment of the invention provides stable liquid parenteral
formulations of Palonosetron comprising: (i) Palonosetron
(ii) and atleast two or more excipients selected from the group comprising of buffering agents, pH adjusting agents, tonicity modifiers, solvents and preservatives, wherein the formulation is free of chelating agent and has a pH range of about 5 to 9 and is intended for subcutaneous administration.
Yet another embodiment of the invention provides subcutaneous liquid formulations of Palonosetron free of chelating agent, having a pH range of about 5 to 9, wherein the injection volume ranges from about 100µl to 1000µl. Preferably the injection volume ranges from about 100µl to 500µl. More preferably the injection volume ranges from about 100µl to 300µl.
Yet another embodiment of the invention provides stable subcutaneous liquid
formulations of Palonosetron comprising: (i) Palonosetron
(ii) Buffering agent selected from the group consisting of acids and bases such as phosphate buffer, bicarbonate buffer, tartrate buffer, TRIS buffer, acetate buffer or any other suitable buffer, other than citrate buffer. (iii) One or more excipients selected from pH adjusting agent, preservative, tonicity-modifiers, anti-oxidant and stabilizers. (iv) One or more solvents

wherein the formulation is free of chelating agent and has a pH range of about 5 to 9.
The pharmaceutical formulations of the present invention comprise buffers such as phosphate buffer, bicarbonate buffer, tartrate buffer, TRIS buffer, acetate buffer or any other suitable buffer(s) other than citrate buffer.
pH adjusting agents include, but not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, ammonium carbonate, hydrochloric acid, lactic acid, phosphoric acid, sodium phosphate, sulfuric acid and the like.
Tonicity modifiers are the compounds which make the formulation isotonic with blood, may be added. Suitable tonicity modifiers include the following, but are not limited to sorbitol, glycerol, mannitol, dextrose, lactose, sucrose, sodium chloride, amino acids, trehalose and mixtures.
Suitable solvents include ethanol, n-propanol, dimethylacetamide, dimethyl sulfoxide, tertiary butanol, glycerine, polyethylene glycols, propylene glycol, water and the like. Water is the preferred solvent.
The pharmaceutical formulations of the present invention may optionally include one or more anti-oxidants and preservatives such as butylated hydroxyanisole, butylated hydroxy toluene, tocopherol, monothioglycerol, ascorbic acid, propyl gallate, phenylmercuric nitrate, thiomersal, benzyl alcohol, benzalkonium chloride, benzethonium chloride, phenol, cresol, chlorobutanol, aminoacids and mixtures.
The invention also provides process of preparing subcutaneous liquid formulations of Palonosetron comprising of following steps:

(ii) Addition of required excipients such as tonicity modifier, preservative, pH
adjusting agent to the above solution. (iii) Addition of Palonosetron to the solution of step (ii). (iv) Aseptically filtering and filling the solution.
The present invention also relates to multiple dose devices (or multiple dose medication dispensing device) comprising a formulation according to any one of the embodiments described herein above. Suitable examples of multi dose devices include multi dose vials, multi dose cartridges, multi dose injection pens and the like. Primary pack container can be made of glass, polypropylene, polycarbonate, crystal zenith, cyclic olefins such as cyclic olefin copolymers and cyclic olefin polymers. The stopper assembly may be optionally laminated or coated with an inert material, selected from the group consisting of tetrafluoroethylene resin, an ethylene tetrafluoroethylene resin, a ultra-high molecular weight polyethylene resin, or various carbon coatings therof.
Palonosetron formulations prepared according to the invention were tested for stability at 25°C/60% RH, 40°C/75%RH and at 60°C for a period of 2 months. The formulations remained stable with no significnant change in pH and no increase in impurities. The stability data of the invention formulation is summarized in table 1.

The formulation of the invention is also evaluated for the release profile using dissolution dialysis. The experiment is carried out using a 1000kD Float-a-lyzer.
Dissolution profile of Palonosetron subcutaneous Injection (prepared as per Example 1) is evaluated using 1000 kD Float-a-lyzer (2.5 mg/mL) by HPLC.
Dissolution Parameters:
Medium : Purified water
Volume : 500 mL
Apparatus : USP Apparatus II (paddle)
Float-a-lyzer : 1000 kD
RPM : 50
Temperature : 37 ± 0.5°C
Time (Mins) : 5min, 10min, 15min, 30min, 60 min.
Sampling Volume : 1 mL
Preparation of test solution:
The Float-a-lyzer was removed from the packaging. 0.1 mL of the sample was pipetted and transferred into the Float-a lyzer and 0.9 mL of pH 7.5 phosphate saline buffer was added. The Float-a-lyzer is threaded through the hole in the floatation ring. It is then floated vertically in the dissolution apparatus and dissolution is carried out using the above mentioned parameters. 1 mL of sample solution was withdrawn from each dissolution vessel at respective time points and quantity of Palonosetron released was determined using HPLC.
Chromatographic Conditions
Column : Cosmosil PYE NAP, 250 x 4.6mm, 5µm
(COS- 08086-31)
Column Temperature : 25°C
Flow rate : 1.0 mL per minute.
Detector : UV

The data shows that 95% of the drug is released within 15minutes. This is clinically advantageous wherein onset of desired action is anticipated within 30 minutes of SC injection of Palonosetron.
The following examples further describe certain specific aspects and embodiments of the present invention and demonstrates the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Manufacturing Process
Tromethamine was added to the compounding vessel containing water for Injection. Sodium chloride was added followed by the addition of benzyl alcohol. pH of the solution was adjusted to 7.0±0.2 with hydrochloric acid/sodium hydroxide. Palonosetron hydrochloride was added to the above solution and stirred till a uniform solution was obtained.
Manufacturing Process
Tromethamine was added to the compounding vessel containing water for Injection. Sodium chloride was added followed by the addition of benzyl alcohol. pH of the solution was adjusted to 7.0±0.2 with hydrochloric acid/sodium hydroxide. Palonosetron hydrochloride was added to the above solution and stirred till a uniform solution was obtained.

We claim
Claim 1: A stable liquid parenteral formulation comprising of Palonosetron and pharmaceutically acceptable excipients, wherein the formulation is intended for subcutaneous administration.
Claim 2: The stable, liquid parenteral formulation of claim 1, wherein the pH ranges from about 5 to 9.
Claim 3: The stable, liquid parenteral formulation of claim 1, wherein the volume of the injection is in the range of 100µl to 1000µl.
Claim 4: A stable liquid parenteral formulation of Palonosetron for subcutaneous administration, comprising:
(i) Palonosetron
(ii) Buffering agent selected from the group consisting of acids and bases
such as phosphate buffer, bicarbonate buffer, tartrate buffer, TRIS buffer,
acetate buffer or any other suitable buffer.
(iii) One or more excipients selected from pH adjusting agents,
preservatives, tonicity-modifiers, anti-oxidants and stabilizers.
(iv) One or more solvents wherein the formulation is free of chelating agent and has a pH range of about 5 to 9