DESC:FIELD OF THE INVENTION
The present invention relates to photostable and room-temperature storable liquid compositions of sugammadex. The invention further provides a process for preparation of the said compositions.

BACKGROUND OF THE INVENTION
Sugammadex or 6-per-deoxy-6-per-(2-carboxyethyl)thio-gamma-cyclodextrin is a modified gamma cyclodextrin molecule which acts as a neuromuscular blockade (NMB) reversal agent, and is indicated to reverse drug-induced neuromuscular blockade caused due to aminosteroid non-depolarizing muscle relaxants such as rocuronium and vecuronium. Sugammadex is commercially available as an injection (BRIDION®) which is an aqueous solution that contains 100 mg of sugammadex or 108.8 mg sugammadex sodium per ml of the solution. The solution for injection has a pH of 7 to 8, and is presented as a 2 ml vial containing 200 mg of sugammadex or a 5 ml vial containing 500 mg of sugammadex. BRIDION vials are stored at 25°C (with excursions permitted to 15°C to 30°C), protected from light. When not protected from light, the solution in the vial should be used within 5 days.

U.S. Patent 7,265,099 relates to the use of chemical chelators for the preparation of a medicament for the reversal of drug induced neuromuscular block and its reversal, and a kit providing the same.

U.S. Patent Application 20210000739 relates to a method for preparing sterile aqueous liquid pharmaceutical compositions of sugammadex suitable for injection, having lower content of impurities.

Chinese Application 112933040 relates to preparation method of sugammadex sodium injection comprising steps: under the protection of inert gas preparing a sugammadex injection, adding a protective agent in the preparation process, and removing the residual protective agent through a reverse osmosis membrane after rough filtration of a liquid medicine; wherein the protective agent is inositol phosphate and derivatives thereof.

Chinese Application 111714459 relates to sugammadex Sodium Gluconate powder for injection.

Sugammadex is prone to degradation in aqueous solutions, particularly when subjected to high temperature and humidity conditions, especially due to which numerous organic impurities, and inorganic impurities may be present in the solutions. The presence of such impurities tends effect the long-term stability of the composition. Sugammadex is susceptible to photolytic degradation wherein degradation can occur due to reactions catalysed by the absorption of photons from light (infrared radiation/visible light/ultraviolet light). A common reaction catalysed by photons is oxidation. Due to photolytic degradation, commercially available sugammadex solution for injection (BRIDION®) needs to be used within 5 days when not protected from light.

In the present invention, it has been found that when liquid compositions of sugammadex have a dissolved oxygen content of less than about 3 parts per million (ppm), preferably less than about 2 ppm, more preferably less than about 1.5 ppm, and most preferably less than about 1 ppm, they result in compositions with a significantly enhanced photostability and the desired room-temperature stability.

Further, when the said liquid compositions are filled in containers and the headspace oxygen content of the containers is less than about 3%, preferably less than about 2.5%, more preferably less than about 2%, by volume, the compositions they result in compositions with enhanced photostability and desired room-temperature stability.

In an aspect, the said liquid compositions of sugammadex are prepared using a vehicle having a dissolved oxygen content of less than about 3 ppm, preferably less than about 2 ppm, more preferably less than about 1.5 ppm, and most preferably less than about 1 ppm.

The said sugammadex liquid compositions are photostable i.e. no degradation occurs even when the compositions are continuously exposed to light for upto 14 days, preferably upto 21 days. The said photostable liquid compositions of sugammadex can be used upto 21 days even when not protected from light, in a significant improvement over the commercially available sugammadex solutions, which must be used within 5 days when not protected from light.

OBJECTS OF THE INVENTION
The principal object of the present invention is to provide photostable liquid compositions of sugammadex.

Another objective of the present invention is to provide photostable liquid compositions of sugammadex, such that the liquid compositions can be used for upto 21 days when not protected from light.

Yet another objective of the present invention is to provide liquid compositions of sugammadex, the said liquid compositions being stable and storable, at room temperature conditions.

Yet another objective of the present invention is to provide photostable, room-temperature storable liquid compositions of sugammadex in the form of a solution for parenteral administration.

Yet another objective is to provide a process for the preparation of the said liquid compositions.

SUMMARY OF THE INVENTION
The present invention relates to photostable, room-temperature storable, liquid compositions comprising sugammadex. The compositions, preferably in the form of solutions, can be administered parenterally. The present invention also provides a process for the preparation of such liquid compositions.

DETAILED DESCRIPTION OF THE INVENTION
Sugammadex liquid compositions of the present invention exhibit the desired storage chemical stability and photostability, at room temperature conditions.

“Room temperature conditions” as used herein refers to temperatures ranging from about 150C to about 320C, and/or humidity ranging from about 55% RH to about 80% RH. ‘Room temperature’ represents the temperature and/or humidity conditions prevailing in a work area, which can range from 150C to 250C (± 20C), and 60% ± 5% relative humidity for Mediterranean and Subtropical climatic regions (Zone II of the ICH Stability Climatic Zone), to 300C ± 20C and 75% ± 5% relative humidity for hot and highly humid regions (Zone IVB of the ICH Stability Climatic Zone). The temperature and/or humidity ranges encompass the usual and customary working environment and temperatures that are generally experienced in pharmacies, hospitals, and warehouses, and during shipping, in these regions. ICH guidelines recommend conducting long-term storage stability studies at “room temperature conditions” of the various zones to establish its stability and shelf-life.

“Accelerated temperature conditions” as used herein refers to 400C ± 20C and/or 75% ± 5% relative humidity.

“Stability” as used herein means that the content of sugammadex is not less than about 85%, preferably not less than about 90%, more preferably not less than about 95%, and most preferably not less than about 98%, by weight, of the label claim, and the content of total impurities is not more than about 3%, preferably not more than about 2.5%, more preferably not more than about 2%, and most preferably not more than about 1%, by weight.

“Photostability” refers to the stability of the drug or composition when exposed to light such as visible light, ultraviolet light or infra-red light. Photostability studies are conducted by exposing liquid compositions of sugammadex, filled in clear and colorless containers, to continuous and fixed intensity of light (such as visible light, ultraviolet light), for specified periods of time. The content of sugammadex, known impurities, and total impurities, in the liquid compositions, is determined at the specific time-periods.

“Photostable” as used herein means when subjected to photostability studies, the content of sugammadex is not less than 90%, preferably not less than 93%, and more preferably not less than 95%, by weight, of the label claim, and content of total impurities is not more than 3%, preferably not more than 2.5%, and more preferably not more than 2%, by weight.

“Dissolved Oxygen” as used herein refers to the content of oxygen dissolved in a vehicle or liquid composition.

“Headspace Oxygen” as used herein refers to the content of oxygen in headspace of a closed container filled with a composition i.e. oxygen content in the gas mixture present in the volume of the closed container unoccupied by the composition.

‘Sugammadex’ as used herein includes sugammadex, and its pharmaceutically acceptable salts, hydrates, derivatives or solvates thereof. Sugammadex can be in crystalline and/or amorphous form. Sugammadex sodium is the preferred salt.

Liquid compositions of sugammadex, of the present invention, have a dissolved oxygen content of less than about 3 ppm, preferably less than about 2.5 ppm, more preferably less than about 2 ppm, and most preferably less than about 1.5 ppm and exhibit the desired photostability and room-temperature stability.

In an aspect, the photostable sugammadex liquid compositions have a dissolved oxygen content of about 0.1 ppm to about 3 ppm, preferably about 0.1 ppm to about 2.5 ppm, more preferably about 0.1 ppm to about 2 ppm, and most preferably about 0.1 ppm to about 1.5 ppm.

In another aspect, the photostable sugammadex liquid compositions have a dissolved oxygen content of less than about 1 ppm, preferably less than about 0.8 ppm, more preferably less than about 0.6 ppm and most preferably less than about 0.5 ppm.
In yet another aspect, the photostable sugammadex liquid compositions have a dissolved oxygen content of about 0.1 ppm to about 1 ppm, preferably about 0.1 ppm to about 0.8 ppm, more preferably about 0.1 ppm to about 0.6 ppm, and most preferably about 0.1 ppm to about 0.5 ppm.

Photostability studies of liquid compositions of sugammadex of the present invention were carried out to evaluate their quality during their manufacture, storage and use, where they may be exposed to light.
• In Method 1, photostability was evaluated by exposing the containers containing the said liquid compositions to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter as per the guidelines of ICH Q1B (Photostability testing of New Drug Substances and Products).
• In Method 2, photostability of the said liquid compositions was evaluated by continuously exposing the containers containing the liquid compositions to visible light, at an intensity of not less than 350 lux, for 5 days, 15 days or 21 days.

Sugammadex liquid compositions, when subjected to photostability studies, were found to be photostable, wherein the content of sugammadex was not less than 90% by weight of the label claim, and the content of total impurities was not more than 3% by weight, at the end of the photostability studies.

In an embodiment, the sugammadex liquid compositions when subjected to photostability studies were found to be photostable, with a sugammadex content of not less than 95% by weight of the label claim, and the total impurities content of not more than 2% by weight.

In an embodiment, the sugammadex liquid compositions, when exposed to light at an intensity of not less than 350 lux, for at least 21 days, contain sugammadex not less than 95% by weight of the label claim, and contain total impurities not more than 2% by weight.
Photostable liquid compositions of sugammadex, of the present invention, exhibit the desired stability, when stored at room temperature conditions over extended periods of time

In an aspect, the photostable sugammadex liquid compositions of the present invention are stable at room temperature conditions for at least 6 months, preferably for at least 12 months, more preferably for at least 18 months, and most preferably for at least 24 months.

Photostable liquid compositions of sugammadex can be in the form of solutions, suspensions, colloids, or emulsions. Preferably, the liquid compositions of sugammadex are in the form of a solution.

In an aspect of the invention, the photostable liquid compositions may be dried using processes such as spray-drying, fluid bed drying, or freeze drying (lyophilisation) to provide powders. The said powder can be reconstituted with liquid vehicles to provide liquid compositions such as solutions, suspensions, colloids, or emulsions.

Photostable liquid compositions of sugammadex, of the present invention, can be administered parenterally. The parenteral route can be intravenous, subcutaneous, intra-dermal, intra-muscular, or intra-arterial. The intravenous route is the preferred one.

In an aspect, the photostable liquid compositions of sugammadex comprise sugammadex and at least one vehicle.

In another aspect, the photostable liquid compositions of sugammadex consist essentially of sugammadex and a vehicle.

The concentration of sugammadex or its salts, hydrates, derivatives or solvates, in the liquid compositions of the present invention, is equivalent to 10 mg/ml to about 400 mg/ml of sugammadex, preferably equivalent to 10 mg/ml to about 300 mg/ml of sugammadex, more preferably equivalent to about 10 mg/ml to about 250 mg/ml of sugammadex, and most preferably equivalent to about 10 mg/ml to about 200 mg/ml of sugammadex. In an embodiment the liquid composition contains sugammadex sodium equivalent to about 100 mg/ml of sugammadex.

One or more vehicles in the liquid compositions of sugammadex are selected from aqueous vehicles such as water for injection, alcohols (such as ethyl alcohol), glycols (such as propylene glycol, butylene glycol, glycerol, polyethylene glycol), dioxalanes, dimethylacetamide, hydroxyethyl lactamide, dimethylsulfoxide, and non-aqueous vehicles like polyoxyethylated castor oils, oils (such as corn oil, cottonseed oil, sesame oil, peanut oil), fixed oils, ethyl oleate, isopropyl myristate, and benzyl benzoate. Preferably, the vehicle in the sugammadex liquid compositions of the present invention is water for injection.

In another aspect, the photostable liquid compositions comprise sugammadex and water as the vehicle.

In yet another aspect, the photostable liquid compositions consist essentially of sugammadex and water as the vehicle.

Vehicle used in the preparation of sugammadex liquid compositions is sparged with a non-oxygen containing gas such that the dissolved oxygen content of the vehicle is less than about 3 ppm, preferably less than about 2 ppm, more preferably less than about 1.5 ppm, and most preferably less than about 1 ppm.

In an embodiment, the vehicle used in the preparation of sugammadex liquid compositions is sparged with a non-oxygen containing gas such that the dissolved oxygen content of the vehicle is about 0.1 ppm to about 3 ppm, preferably about 0.1 ppm to about 2 ppm, more preferably about 0.1 ppm to about 1.5 ppm, and most preferably about 0.1 ppm to about 1 ppm.

Determination of Dissolved Oxygen in the vehicle or liquid compositions can be made using routinely used Dissolved Oxygen Meters/Probes which are designed to measure oxygen in compositions using optical sensors or electrochemical sensors (polarography, pulsed polarography, galvanic).
Non-oxygen containing gas, used in sparging, is selected from nitrogen, argon, helium, and neon. Nitrogen is the preferred non-oxygen containing gas.

Photostable liquid compositions comprising sugammadex may further optionally comprise excipients selected from pH-adjusting agents, buffering agents, tonicity agents, and stabilizers such as anti-oxidants and chelating agents.

pH-adjusting agents can be acid or base. The base can be oxides, hydroxides, carbonates, bicarbonates and the like. The oxides can be metal oxides such as calcium oxide, and magnesium oxide; hydroxides can be of alkali metals and alkaline earth metals such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; and carbonates can be sodium carbonate, sodium bicarbonates, potassium carbonates, and potassium bicarbonates. The acid can be mineral acids or organic acids such as hydrochloric, nitric, phosphoric, acetic, citric, sulfuric, fumaric, maleic, malic, tartaric, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, lactic, ascorbic acid, and glycine hydrochloride.

Buffering agents are selected from those known in the art and can be citrates, acetates, phosphates, carbonates, other organic buffers and the like.

Tonicity agents are selected from those known in the art and can be selected from ionic tonicity agents such as sodium chloride, potassium chloride, magnesium chloride or calcium chloride, or non-ionic tonicity agents such as glycerine, dextrose, and mannitol.

Anti-oxidants are selected from those known in the art such as butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium metabisulfite, sodium sulfite, sodium bisulfite, citric acid, ascorbic acid or mixtures thereof.

Chelating agents are selected from those known in the art such as ethylenediaminetetraacetic acid (EDTA), ethylenediamine-N, N'-diacetic-N, N'-dipropionic acid, diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis(beta-aminoethyl ether)- tetraacetic acid (EGTA), N-(hydroxy ethyl) ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA), or salts, hydrates, solvates and derivatives thereof.

In an embodiment, the photostable liquid compositions of the present invention, comprising sugammadex and water as a vehicle, are free of stabilizers.

Photostable liquid compositions of sugammadex are filled in containers, which are capped and sealed. The headspace of the container is overlayed with non-oxygen containing gas.

Non-oxygen containing gas, used in overlaying, is selected from nitrogen, argon, helium, and neon. Nitrogen is the preferred non-oxygen containing gas.

Containers that are used to hold and store the photostable liquid compositions include vials, bottles, ampoules, cartridges, flexible bags and pre-filled syringes. The said containers maybe made of glass or plastic, or any other suitable material. The containers may be clear, colorless or amber coloured (for light protection). The volume of the containers may range from 0.5 ml to 50 ml. In a preferred aspect the volume of the container is selected form 1 ml, 2 ml, 5 ml and 10 ml.

Photostable liquid compositions of sugammadex are filled in containers and the headspace of the filled container is overlayed with non-oxygen containing gas.

Non-oxygen containing gas, used in overlaying, is selected from nitrogen, argon, helium, and neon. Nitrogen is the preferred non-oxygen containing gas.

Commercially available sugammadex solution for injection (BRIDION®), which is available as 2 ml and 5 ml vials, has a headspace oxygen content of greater than 20% (by volume).

In distinct contrast, the photostable liquid composition of the present invention, comprising sugammadex and a vehicle, is filled in a container, and the headspace oxygen content of the filled container is less than about 3%, preferably less than about 2.5%, and more preferably less than about 2% by volume.

In an aspect, the photostable liquid composition is filled in a container, and the headspace oxygen content of the filled container is from about 0.1% to about 3%, preferably from about 0.1% to about 2.5%, and more preferably from about 0.1% to about 2%, by volume.

In yet another aspect, the photostable liquid composition is filled in a container, and the headspace oxygen content of the filled container is from about 0.5% to about 3%, preferably from about 0.5% to about 2.5%, and more preferably from about 0.5% to about 2%, by volume.

In yet another aspect, the photostable liquid composition, comprising sugammadex and a vehicle, is filled in a container such that the headspace of the filled container comprises at least one non-oxygen containing gas at not less than 97% by volume.

Determination of Oxygen Content in headspace of containers can be made using routinely used headspace oxygen meters/analysers which are designed to measure oxygen in pharmaceutical packages using techniques such as like fibre optics, laser absorption, electrochemical, and fluorescence.

In an aspect, the photostable liquid compositions of the present invention, comprising sugammadex sodium and a vehicle, have a dissolved oxygen content from about 0.1 ppm to about 1 ppm, and when filled in a container, the filled container has a headspace oxygen content from about 0.1% to about 3% by volume.

In another aspect, the photostable liquid composition of the present invention, comprising sugammadex sodium and a vehicle, has a dissolved oxygen content from about 0.1 ppm to about 0.6 ppm, and when filled in a container, the filled container has a headspace oxygen content from about 0.1% to about 2% by volume.

Photostable liquid compositions of sugammadex of the present invention are prepared by using processes such as dissolving or dispersing sugammadex and/or other excipients in a vehicle, mixing, stirring, homogenization, adjusting the pH using pH-adjusting agents, sparging the resulting liquid composition with non-oxygen containing gas, adding vehicle to obtain the final volume, filtering the liquid composition, filling the liquid composition in a container, overlaying the headspace of the container with non-oxygen containing gas, sealing the container, capping the container, and sterilizing the liquid composition.

Processes for the preparation of photostable liquid compositions of sugammadex for parenteral administration is preferably carried out under an overlay of a non-oxygen containing gas.

In an aspect, the process for preparing photostable liquid compositions comprising sugammadex, comprises the following steps:
(i) providing a solution comprising sugammadex under non-oxygen containing gas overlay;
(ii) optionally adjusting the pH of the solution obtained in step (i) from about 7 to about 8;
(iii) filtering the solution obtained in step (i) or (ii);
(iv) sterilizing the solution obtained in step (iii)
wherein the dissolved oxygen content of the liquid composition is from about 0.1 ppm to about 1 ppm.

In another aspect, the process for preparing photostable liquid compositions comprising sugammadex, comprises the following steps:
(i) providing a solution comprising sugammadex under non-oxygen containing gas overlay;
(ii) optionally adjusting the pH of the solution obtained in step (i) from about 7 to about 8;
(iii) filtering the solution obtained in step (i) or (ii), through a membrane filter with pores of diameter 0.45 micron or less;
(iv) filling the solution obtained steps (i), (ii), or (iii) in a suitable container and capping and sealing the container;
(v) terminally sterilizing the solution obtained step (iv) at a temperature from 110ºC to 130ºC for about 20 minutes;
wherein the dissolved oxygen content of the liquid composition is from about 0.1 ppm to about 1 ppm.

In an embodiment, the photostable sugammadex liquid composition is prepared by a process comprising steps of:
(i) sparging vehicle with a non-oxygen containing gas till the dissolved oxygen content is less than 3 ppm;
(ii) dissolving or dispersing sugammadex in vehicle sparged with non-oxygen containing gas from step (i);
(iii) optionally dissolving or dispersing excipients selected from anti-oxidants, chelating agents, buffering agents and/or tonicity agents, in water sparged with non-oxygen containing gas from step (i) or liquid from step (ii);
(iv) adjusting the pH of the liquid obtained in step (ii) or (iii) from about 7 to about 8, by adding pH adjusting agent(s);
(v) adding vehicle to the liquid and mixing it, to obtain the final batch volume of sugammadex liquid composition.
wherein the process steps (ii) to (v) are carried out under an overlay of a non-oxygen containing gas; and
wherein the dissolved oxygen content of the sugammadex liquid composition is from about 0.1 ppm to about 1 ppm.

In another embodiment, the photostable sugammadex liquid composition is prepared by a process comprising steps of:
(i) sparging water with a non-oxygen containing gas till the dissolved oxygen content is less than about 3 ppm, preferably less than about 2 ppm, more preferably less than about 1.5 ppm, most preferably less than about 1 ppm;
(ii) dissolving or dispersing sugammadex in water for injection sparged with non-oxygen containing gas from step (i) under stirring;
(iii) optionally dissolving or dispersing excipients selected from anti-oxidants, chelating agents, buffering agents and/or tonicity agents, in water sparged with non-oxygen containing gas from step (i) or liquid from step (ii), under stirring;
(iv) adjusting the pH of the liquid obtained in step (ii) or (iii) from about 7 to about 8, by pH adjusting agent(s);
(v) adding water to the solution and mixing it, to obtain the final batch volume of the sugammadex liquid composition.
wherein the process steps (i) to (v) are carried out under an overlay of a non-oxygen containing gas; and
wherein the dissolved oxygen content of the liquid composition is from about 0.1 ppm to about 1 ppm.

In yet another embodiment, the photostable sugammadex liquid composition is processed using one or more of the following steps:
(i) providing liquid composition of sugammadex under non-oxygen containing gas overlay;
(ii) sterilizing liquid composition of sugammadex (filtration)
(iii) filling sugammadex liquid composition in containers
(iv) overlaying the headspace in the container with non-oxygen containing gas till the headspace oxygen content is less than 3% by volume;
(v) capping the container
(vi) sealing the container

In yet another embodiment, the photostable sugammadex liquid composition is processed using one or more of the following steps:
(i) filtering sugammadex liquid composition through one or more filters
(ii) filling sugammadex liquid composition in containers
(iii) overlaying the headspace in the container with non-oxygen containing gas till the headspace oxygen content is less 3% by volume;
(iv) capping the container
(v) sealing the container
(vi) sterilizing the liquid composition in the container.

In an embodiment, the said process provides photostable sugammadex liquid composition having a dissolved oxygen content of about 0.1 ppm to about 1 ppm, preferably about 0.1 ppm to about 0.8 ppm, more preferably about 0.1 ppm to about 0.6 ppm, and most preferably about 0.1 ppm to about 0.5 ppm.

In another aspect, the said process provides photostable sugammadex liquid composition filled in containers, having a headspace oxygen content of about 0.1% to about 3%, preferably of about 0.5% to about 3%, preferably of about 0.5% to about 2.5%, and most preferably of about 0.5% to about 2%, by volume.

Photostable liquid compositions of sugammadex, for parenteral administration, can be sterilized by dry heat sterilization, moist heat sterilization, chemical sterilization, radiation sterilization, and filtration sterilization.

Filter materials used in the filtration sterilization of liquid compositions include but are not limited to nylon, polycarbonate, cellulose acetate, polyvinylidene fluoride (PVDF), and polyethersulfone (PES). Pore sizes of the filters may range from 0.1 microns to 5 microns.

Photostable liquid compositions of sugammadex of the present invention are evaluated by one or more of evaluation parameters such as appearance, pH, sugammadex content, impurity content, osmolality, dilution stability, and storage stability.
In one aspect, liquid compositions of sugammadex, in the form of solutions, appear clear, colorless and free from visible particles.

Particulate matter in liquid compositions of sugammadex of the present invention was evaluated by the light obscuration method. The liquid compositions should have not more than 6000 particles (per container) greater than or equal to 10 microns, and not more than 600 particles greater than or equal to 25 microns.

pH of liquid compositions of sugammadex can range from about pH 6 to about pH 9, more preferably from about pH 7 to about pH 8.

Tonicity of the liquid compositions of sugammadex, for parenteral administration, was evaluated by determining the osmolality of the liquid compositions. Osmolality of liquid compositions of sugammadex of the present invention, as determined using a Freezing Point Osmometer (Osmomat 3000) using 0.9% sodium chloride solution as the standard, is not more than 600 mOsmol/kg. It is generally recommended that the osmolality of parenteral composition should not be more than 600 mOsmol/kg for drug products intended for intramuscular or subcutaneous injection, not more than 1000 mOsmol/kg for small-volume injections (=100 ml), and not more than 500 mOsmol/kg for large-volume injections (>100ml).

Photostable sugammadex liquid compositions have an osmolality ranging from about 200 mOsmol/kg to about 600 mOsmol/kg, more preferably from 250 mOsmol/kg to about 550 mOsmol/kg, and most preferably from 300 mOsmol/kg to about 500 mOsmol/kg.

Photostable sugammadex liquid compositions, of the present invention, were evaluated in terms of sugammadex content, percent known impurity, and percent total impurities. Known impurities include impurities such as sugammadex monosulfoxide diasterioisomer-1 (SG-Isomer-1), sugammadex monosulfoxide diasterioisomer-2 (SG-Isomer-2), sugammadex monothio (SG-monothio), and sugammadex monothio dimer (SG-Dimer).

Content of sugammadex, in the liquid compositions, as determined by an HPLC assay method, is not less than about 85%, preferably not less than about 90%, and more preferably not less than about 95%, and most preferably not less than about 98%, by weight, of the label claim.

Content of known impurity (SG-Isomer-1, SG-Isomer-2, SG-monothio, or SG-Dimer), in sugammadex liquid compositions, is not more than 2%, preferably not more than 1.5%, more preferably not more than 1.0%, and most preferably not more than 0.6%, by weight.

Content of total impurities, in sugammadex liquid compositions, is not more than 3%, preferably not more than 2.5%, more preferably not more than 2%, and most preferably not more than 1%, by weight.

Storage stability of the liquid compositions of the present invention was evaluated by subjecting the liquid compositions to storage conditions ranging comprising temperatures ranging from about 150C to about 320C, and/or humidity ranging from about 55% RH to about 80% RH.

In an aspect storage stability was determined at the following conditions:
• Room temperature conditions: 250C ± 20C and 60% ± 5% RH, or 300C ± 20C and 75% ± 5% RH,
• Accelerated temperature conditions: 400C ± 20C and 75% ± 5% RH

Liquid compositions of sugammadex subjected to storage stability were analysed for sugammadex content, percent known impurity, and percent total impurities, after specific time periods of storage.

Photostable liquid compositions of sugammadex, when filled in containers, are stable after storage in the upright orientation or inverted orientation, at room temperature conditions, or accelerated temperature conditions, for various time periods.

In an aspect of the invention, the content of sugammadex in sugammadex liquid compositions, when filled in containers and stored in an upright or inverted orientation, is not less than about 85%, preferably not less than about 90%, and more preferably not less than about 95%, and most preferably not less than about 98%, by weight, of the label claim,

In another aspect of the invention, content of known impurity (SG-Isomer-1, SG-Isomer-2, SG-monothio, SG-Dimer) in sugammadex liquid compositions, when filled in containers and stored in an upright or inverted orientation, is not more than about 2%, preferably not more than about 1.5%, more preferably not more than about 1%, and most preferably not more than about 0.6%, by weight, after storage for at least 6 months at accelerated conditions, or for 18 to 24 months at room temperature conditions.

In yet another aspect of the invention, content of total impurities in sugammadex liquid compositions, when filled in containers and stored in an upright or inverted orientation, is not more than about 3%, preferably not more than about 2.5%, more preferably not more than about 2%, and most preferably not more than about 1.5%, by weight, after storage for at least 6 months at accelerated conditions, or for 18 to 24 months at room temperature conditions.

In another embodiment, the photostable liquid compositions comprising sugammadex and water as a vehicle, when stored at room temperature conditions, in vials in an upright orientation or inverted orientation, contain sugammadex not less than 95% by weight of the label claim, and contain total impurities not more than about 2% by weight, at the end of 18 to 24 months.

Photostable liquid compositions of sugammadex, in the form of solutions, for parenteral administration, may have to be aseptically diluted with suitable infusion fluids before administration to a patient.

Photostable liquid compositions of sugammadex for parenteral administration are stable to dilution. The liquid compositions of sugammadex are stable when 1 part of the sugammadex liquid composition is diluted to about 10 parts using infusion fluids (intravenous line solution diluents). In an aspect, the liquid compositions of sugammadex are stable when diluted with suitable infusion fluids to a concentration of about 10 mg/ml. The said solutions, after dilution with infusion fluids, are clear and colorless, and do not show precipitation or turbidity for at least 24 hours, preferably for at least 48 hours.

Suitable infusion fluids are selected from those known in the art such as 5% dextrose solution in water (5% dextrose injection), 2.5% dextrose solution in water (2.5% dextrose injection), 0.45% sodium chloride solution in water (0.45% sodium chloride injection), 0.9% sodium chloride solution in water (0.9% sodium chloride injection), multiple electrolytes and dextrose injection, lactate ringer injection, ringer’s injection, 5% dextrose and 20 meq potassium chloride solution in water, and mixtures thereof.

The invention is now illustrated with non – limiting examples.

Example 1
Water for injection (1400 ml) was purged with nitrogen gas for about 20 minutes. After nitrogen purge, the dissolved oxygen content of the water for injection was 0.3 ppm.

Sugammadex sodium (217.6 g) was added to the water for injection and continuously stirred till a clear solution was obtained. The solution was further stirred at low speed for not less than 15 minutes. The process was carried out under nitrogen overlay and the dissolved oxygen content of the solution was 0.36 ppm.

The pH of the solution was adjusted to about 7.4 ± 0.1 using 3.7%w/v hydrochloric acid and/or 0.1N sodium hydroxide. Water (sparged with nitrogen) was added to obtain the final volume (2000 ml) under continuous stirring for about 20 minutes to obtain sugammadex liquid composition in the form of a solution. The process was carried out under nitrogen overlay and the dissolved oxygen content of the sugammadex liquid composition was found to be 0.31 ppm.

The solution was filtered through 0.45 micron PVDF filter, and further through a 0.22 micron PVDF filter. The solution was filled in clear, colorless glass vials (2R clear vial Fiolax-13 mm (USP Type I)), such that each vial had a fill volume of 2 ml. The vial headspace was overlayed with nitrogen till the headspace gas had less than 3% oxygen. The vials were stoppered using 13mm chlorobutyl rubber closure, and sealed using 13mm aluminium flip-top seals. The headspace oxygen content of the vials was found to be in the range of 1.228% and 1.922%.

The vials were sterilized by autoclaving at about 121ºC to 124ºC for 20 minutes at about 15-20 pounds per square inch gauge. The headspace oxygen content of the vials, after sterilization, was found to be in the range of 1.261% and 1.601%.

The sugammadex liquid composition was clear, colorless and free from visible particles. The solution had a pH of 7.73, and osmolality of 357 mOsmol/kg. The particulate matter of the compositions met the acceptance criteria: about 72 particles/vial greater than or equal to 10 micron and around 3 particles/vial greater than or equal to 25 microns.

Example 2
Water for injection (3500 ml) was purged with nitrogen gas for about 20 minutes. After nitrogen purge, the dissolved oxygen content of the water for injection was found to be 0.39 ppm.

Sugammadex sodium (544.0 g) was added to the water for injection and continuously stirred till a clear solution was obtained. The solution was further stirred at low speed for not less than 15 minutes. The process was carried out under nitrogen overlay and the dissolved oxygen content of the solution was found to be 0.34 ppm.

The pH of the solution was adjusted to about 7.4 ± 0.1 using 3.7%w/v hydrochloric acid and/or 0.1N sodium hydroxide. Water (sparged with nitrogen) was added to obtain the final volume (5000 ml) under continuous stirring for about 20 minutes to obtain sugammadex liquid composition in the form of a solution. The process was carried out under nitrogen overlay and the dissolved oxygen content of the sugammadex liquid composition was found to be 0.32 ppm.

The solution was filtered through 0.45 micron PVDF filter, and further through a 0.22 micron PVDF filter. The solution was filled in clear, colorless glass vials (2R clear vial Fiolax-13 mm (USP Type I)), such that each vial had a fill volume of 5 ml. The vial headspace was overlayed with nitrogen till the headspace gas had less than 3% oxygen. The vials were stoppered using 13mm chlorobutyl rubber closure, and sealed using 13mm aluminium flip-top seals. The headspace oxygen content of the vials was found to be in the range of 0.930% and 1.589%.

The vials were sterilized by autoclaving at about 1210C to 1240C for 20 minutes at about 15-20 pounds per square inch gauge. The headspace oxygen content of the vials, after sterilization, was found to be in the range of 1.713% and 2.012%.

Sugammadex liquid composition was clear, colorless and free from visible particles. The solution had a pH of 7.68, and osmolality of 348 mOsmol/kg. The particulate matter of the compositions met the acceptance criteria: about 117 particles/vial greater than or equal to 10 micron and around 4 particles/vial greater than or equal to 25 microns.

Storage Stability: The storage stability of sugammadex liquid compositions of examples 1 and 2, on storage (upright and inverted positions), at room temperature and accelerated conditions, was evaluated by determining sugammadex content and percent impurities. The results are given in Tables 1-2.

Table 1: Storage stability of Example 1 at 6, 18 and 24 months
Room Temperature Condition - 250C ± 20C / 60% ± 5%RH
Evaluation Parameter Time-period of storage
Initial 6M ? 6M ? 18M ? 18M ? 24M ? 24M ?
% Sugammadex 99.5 101.1 101.3 97.7 98.8 97.9 99.0
% SG-Isomer-1 0.06 0.20 0.19 0.35 0.33 0.35 0.37
% SG-Isomer-2 0.07 0.22 0.21 0.40 0.38 0.40 0.41
% SG-Monothio 0.53 0.15 0.16 0.01 0.01 0.01 0.01
% SG-Dimer 0.05 0.12 0.12 0.20 0.21 0.19 0.18
% Total Impurities 0.85 1.03 0.99 1.44 1.41 1.51 1.52
Room Temperature Condition - 300C ± 20C / 75% ± 5%RH
Evaluation Parameter Time-period of storage
Initial 6M ? 6M ? 18M ? 18M ? 24M ? 24M ?
% Sugammadex 99.5 101.5 100.9 99.4 99.8 100.5 100.9
% SG-Isomer-1 0.06 0.22 0.25 0.39 0.40 0.41 0.42
% SG-Isomer-2 0.07 0.23 0.26 0.44 0.45 0.46 0.48
% SG-Monothio 0.53 0.16 0.14 0.01 0.01 0.01 0.01
% SG-Dimer 0.05 0.14 0.15 0.21 0.20 0.19 0.18
% Total Impurities 0.85 1.11 1.10 1.55 1.55 1.66 1.69
Accelerated Condition - 400C ± 20C / 75% ± 5%RH
Evaluation Parameter Time-period of storage
Initial 6M ? 6M ?
% Sugammadex 99.50 100.7 100.9
% SG-Isomer-1 0.06 0.36 0.40
% SG-Isomer-2 0.07 0.39 0.44
% SG-Monothio 0.53 0.03 0.03
% SG-Dimer 0.05 0.19 0.17
% Total Impurities 0.85 0.98 1.40
M = Month(s); ‘?’ = Upright orientation of vial; ‘?’ = Inverted orientation of vial

Table 2: Storage stability of liquid compositions of sugammadex prepared in accordance to example 2 at 6, 18 and 24 months
Room Temperature Condition - 250C ± 20C / 60% ± 5%RH
Evaluation Parameter Time-period of storage
Initial 6M ? 6M ? 18M ? 18M ? 24M ? 24M ?
% Sugammadex 98.7 100.9 100.7 99.3 99.5 99.8 100.1
% SG-Isomer-1 0.08 0.17 0.17 0.28 0.29 0.32 0.34
% SG-Isomer-2 0.08 0.19 0.19 0.32 0.33 0.37 0.38
% SG-Monothio 0.46 0.26 0.28 0.01 0.01 0.01 BDL
% SG-Dimer 0.06 0.11 0.11 0.16 0.16 0.17 0.17
% Total Impurities 0.86 1.10 1.10 1.20 1.34 1.39 1.48
Room Temperature Condition - 300C ± 20C / 75% ± 5%RH
Evaluation Parameter Time-period of storage
Initial 6M ? 6M ? 18M ? 18M ? 24M ? 24M ?
% Sugammadex 98.7 100.9 100.4 97.2 97.0 99.5 99.6
% SG-Isomer-1 0.08 0.20 0.22 0.34 0.35 0.37 0.36
% SG-Isomer-2 0.08 0.22 0.25 0.39 0.40 0.42 0.40
% SG-Monothio 0.46 0.20 0.18 0.01 0.01 0.01 0.01
% SG-Dimer 0.06 0.12 0.13 0.17 0.17 0.16 0.17
% Total Impurities 0.86 1.10 1.20 1.35 1.37 1.47 1.46
Accelerated Condition - 400C ± 20C / 75% ± 5%RH
Evaluation Parameter Time-period of storage
Initial 6M ? 6M ?
% Sugammadex 98.7 100.0 100.40
% SG-Isomer-1 0.08 0.37 0.42
% SG-Isomer-2 0.08 0.40 0.45
% SG-Monothio 0.46 0.16 0.16
% SG-Dimer 0.06 0.06 0.04
% Total Impurities 0.86 1.40 1.50
M = Month(s); ‘?’ = Upright orientation of vial; ‘?’ = Inverted orientation of vial; BDL = Below detection Limit

Dilution Study
Liquid composition of example 1 (100 mg/ml) was diluted to a concentration of 10 mg/ml using diluents selected from 5% dextrose injection, 2.5% dextrose injection, 0.9% sodium chloride injection, multiple electrolytes and dextrose injection, lactate ringer injection, and ringer’s injection. Storage stability of the diluted liquid compositions (diluted with each of the diluents) was evaluated at 250C ± 20C and 50C ± 30C, for 24 hours and 48 hours. The diluted liquid compositions were evaluated in terms of appearance, pH, osmolality, content of sugammadex, content of known impurities, and content of total impurities.

Diluted liquid compositions of example 1, in all the diluents and at both the temperature conditions, were found to provide the desired storage stability for upto 48 hours. The results of the evaluation of the diluted solutions are given below:
• Appearance: clear, colorless, free from visible particles
• pH of the diluted solutions: about 7 to about 8
• Osmolality: 200 to 600 mOsmol/kg
• Content of sugammadex: Not less than 95%, by weight
• Content of each of the known impurities: Not more than 0.5% by weight
• Content of Total impurities: Not more than 1.5% by weight

Photostability Study (Light Exposure Study)
Liquid compositions of sugammadex, prepared in accordance with examples 1 and 2, were filled in clear, colorless vials and evaluated for photostability using Method 1 and Method 2. The compositions were evaluated for the content of sugammadex, content of known impurities and content of total impurities, after light exposure.

In a study using Method 1, the dissolved oxygen content of the liquid solutions was found to be 0.3 ppm and 0.52 ppm respectively. The results of the photostability study are presented in Table 3.

Table 3: Photostability of examples 1 and 2 in accordance with Method 1
Evaluation Parameter Example 1 Example 2
Initial End of Study Initial End of Study
% Sugammadex 99.8 102.9 99.2 100.5
% SG-Isomer-1 0.07 0.12 0.07 0.14
% SG-Isomer-2 0.08 0.12 0.08 0.16
% SG-Monothio 0.48 0.04 0.54 0.39
% SG-Dimer 0.03 0.41 0.03 0.05
% Total Impurities 0.80 1.3 0.89 1.2

In a 5-day study using Method 2, the vials were kept on the benchtop and continuously exposed to visible light for 5 days. The dissolved oxygen content of the liquid solutions was found to be 0.948 ppm. The headspace oxygen content of the liquid solutions prepared in accordance with Example 1 was in the range of 0.951% and 2.440%, and with Example 2 was in the range of 0.479% and 1.543%. The results of the photostability study are presented in Table 4.
Table 4: 5-day Photostability study of examples 1 and 2
Evaluation Parameter Example 1 Example 2
Initial 5 days Initial 5 days
% Sugammadex 98.8 98.3 100.0 99.7
% SG-Isomer-1 0.62 0.62 0.20 0.20
% SG-Isomer-2 0.70 0.70 0.24 0.24
% SG-Monothio 0.02 0.02 0.02 0.02
% SG-Dimer 0.42 0.41 0.21 0.21
% Total Impurities 3.2 3.2 1.9 2.0

In another extended time-period study using Method 2, the vials were kept on the benchtop and continuously exposed to visible light at an intensity of not less than 350 lux for upto 21 days. The results are given in Table 5

Table 5: 21-day photostability study of Examples 1 and 2
Evaluation Parameter Initial 5 days 15 days 21 days
Example 1
% Sugammadex 99.8 97.7 96.4 96.6
% SG-Isomer-1 0.10 0.10 0.14 0.13
% SG-Isomer-2 0.12 0.13 0.16 0.14
% SG-Monothio 0.29 0.26 0.24 0.22
% SG-Dimer 0.01 0.01 0.03 0.02
% Total Impurities 1.57 1.60 1.79 1.65
Example 2
% Sugammadex 97.8 98.0 97.0 96.2
% SG-Isomer-1 0.11 0.10 0.13 0.11
% SG-Isomer-2 98.7 98.7 0.15 0.14
% SG-Monothio 0.29 0.27 0.28 0.22
% SG-Dimer 0.01 0.01 0.02 0.02
% Total Impurities 1.67 1.61 1.80 1.60

Thus, liquid pharmaceutical compositions of the present invention, comprising sugammadex and a vehicle, having a dissolved oxygen content from about 0.1 ppm to about 1 ppm, and when filled in a container having a headspace oxygen content of about 0.1% to about 3% by volume of the headspace of the filled container, are photostable and room-temperature stable.

The photostable sugammadex liquid compositions, of the present invention, can be used for upto 21 days even when not protected from light. This is a significant improvement over the commercially available sugammadex solutions, which must be used within 5 days when not protected from light.

Further, the photostable sugammadex liquid compositions, of the present invention, exhibit storage stability at room-temperature conditions for at least 24 months. The said liquid compositions exhibit the desired pH, tonicity, dilution stability, particulate matter, content of sugammadex, and content of total impurities. ,CLAIMS:1. A photostable, room-temperature storable, liquid composition comprising sugammadex sodium and a vehicle;
wherein the dissolved oxygen content of the composition is from about 0.1 ppm to about 1 ppm;
wherein the composition is filled in a container and the headspace oxygen content of the filled container is from about 0.1% to about 3% by volume.

2. The liquid composition as claimed in claim 1, wherein the concentration of sugammadex sodium in the liquid composition is equivalent to about 10 mg/ml to about 250 mg/ml of sugammadex.

3. The liquid composition filled in the container as claimed in claim 1, wherein the composition is overlayed with a non-oxygen containing gas selected from nitrogen, argon, helium, and neon.

4. The liquid composition filled in the container as claimed in claim 1, wherein the container is selected from a vial, bottle, ampoule, cartridge, flexible bag or pre-filled syringe, and has a volume of about 0.5 ml to about 50 ml.

5. The liquid composition as claimed in claim 1, wherein the pH of the composition ranges from about pH 6 to about pH 9, and the osmolality of the composition ranges from about 200 mOsmol/kg to about 600 mOsmol/kg.

6. The liquid composition as claimed in claim 1, wherein the composition is stable to dilutions when 1 part of the liquid composition is diluted to about 10 parts, using infusion fluids.

7. The liquid composition as claimed in claim 1, wherein the composition when exposed to light at an intensity of not less than 350 lux for at least 21 days, or when stored in vials in an upright orientation or inverted orientation at room temperature conditions for 24 months, contains sugammadex not less than 95% by weight of the label claim and contains total impurities not more than 2% by weight.

8. A process for the preparation of photostable, room-temperature storable, sugammadex sodium liquid compositions, the process comprising steps of:
(i) sparging vehicle with a non-oxygen containing gas till the dissolved oxygen content is not more than 2 ppm;
(ii) dissolving sugammadex sodium in the vehicle from step (i);
(iii) optionally dissolving excipients selected from buffering agents, tonicity agents, anti-oxidants, and chelating agents, in the liquid from step (ii);
(iv) adjusting the pH of the liquid obtained in step (ii) or (iii) from about 6 to about 9, by adding pH adjusting agents;
(v) adding vehicle to the liquid of step (iv) and mixing it, to obtain the final batch volume of the sugammadex sodium liquid composition;
(vi) filtering the sugammadex sodium liquid composition of step
(v);
(vii) filling the sugammadex sodium liquid composition of step (vi) in a container;
(viii) overlaying the headspace in the container with non-oxygen containing gas, and capping and sealing the container;
wherein the process steps (ii) to (vi) are carried out under an overlay of a non-oxygen containing gas such that the dissolved oxygen content of the sugammadex sodium liquid composition is from about 0.1 ppm to about 1 ppm, and
wherein headspace oxygen content of the container in step (viii) is about 0.1% to about 3% by volume.

9. The process as claimed in claim 8, wherein the liquid composition is filtered through a membrane filter with pores of diameter 0.45 micron or less.

10. The process as claimed in claim 8, wherein the liquid composition is sterilized by dry heat sterilization, moist heat sterilization, chemical sterilization, radiation sterilization, or filtration sterilization.