Injectable formulations of dexamethasone

Abstract

Title: Injectable Formulations of Dexamethasone The present invention relates to the injectable formulations of dexamethasone. In particular the invention relates to the stable, injectable formulation of dexamethasone that are ready to use diluted form. The invention further relates to process to prepare injectable formulations of dexamethasone and method of use thereof.

Description

[0001] “INJECTABLE FORMULATIONS OF DEXAMETHASONE”

[0002] Field of Invention

[0003] The present invention relates to injectable formulations of dexamethasone, their processes, method of use and kits comprising such formulations. In particular the invention relates to ready-to-inject formulations.

[0004] Background of Invention

[0005] Dexamethasone is an adrenocortical steroid that has been in use for several autoimmune disorders and inflammatory diseases. It is also prescribed for emergency treatment of allergic conditions intractable to adequate trials of conventional treatment such as seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, serum sickness, drug hypersensitivity reactions or severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa. It is also indicated among others for collagen diseases, dermatological, respiratory and hematologic diseases, palliative management of leukaemia and gastrointestinal diseases. Dexamethasone is on the World Health Organization's (WHO) list of essential medicines. Its varied use makes it a highly prescribed medicine around the globe.

[0006] Many dosage forms of dexamethasone are available in the market, however injectable remains preferred dosage forms especially in cases of emergency situations or when the patient is unconscious and cannot take the medicine orally. Also, parenteral dosing is useful when there is a need of large amount of slow and repetitive dosing after specific intervals. For e.g. for the treatment of unresponsive shock the dosage regimen ranges from 1 to 6 mg / kg of body weight as a single intravenous injection to 40 mg initially followed by repeat intravenous injection every 2 to 6 hours while shock persists.

[0007] There are few injectable compositions of dexamethasone that are disclosed in the prior references. For instance, EP2735305 discloses liquid composition of dexamethasone with solubilizing aqueous system comprising propylene glycol in combination with cyclodextrins, further comprising EDTA.

[0008] EP3003318 discloses liquid formulations for ocular use comprising dexamethasone and tri ethyl O -acetyl citrate (ATEC).

[0009] US10350222 discloses composition comprising microparticles of dexamethasone and a block copolymer comprising a poly-lactide-co-glycolide (PLGA) block and a polyethylene glycol (PEG) block.

[0010] W02020102474A1 discloses formulation comprising dexamethasone and reduced levels of preservatives or antioxidant acting preservatives. The stability of the formulation is attributed to the ratio of headspace volume (ml) to dexamethasone content (mg), which is said to be less than 0.007. Such formulation is said to be stable in containers such as vial, ampoule, solvent reservoir, storage bottle, medical bottle, syringe, or bottle. The exemplified compositions comprise 26.23 mg / mL, 10 mg / mL, 30 mg / mL and 45 mg / mL of dexamethasone sodium phosphate.

[0011] All the reported references relate to the dexamethasone formulations that have high concentrations of dexamethasone. For slow infusion of the drug, these formulations are diluted by the medical practitioner. Such dilution practices, even if performed by an expert, are dangerous in many ways such as loss of product during dilution, contamination, and wastage of time in a very critical situation.

[0012] Therefore, it is a need of this hour to develop dexamethasone product that is easy to handle, ready to use without dilution with no risk of contamination. It is also necessary to develop a diluted product of dexamethasone that is stable, can be produced efficiently and is industrially scalable without undue burden with respect to process or cost. Object of Invention:

[0013] The object of present invention is to develop a diluted formulation of dexamethasone.

[0014] It is also an object of the present invention to develop a cost effective, efficient and reproducible process to prepare such formulation.

[0015] Further, it is also an object to develop a method of treatment of a subject in need of treatment using dexamethasone, wherein the method is less prone to accidents, loss of products or contamination.

[0016] It is an object of present invention to develop a product comprising high volume, injectable formulation of dexamethasone, wherein the dexamethasone formulation is stable.

[0017] Summary of Invention

[0018] According to an aspect, the present invention provides a pharmaceutical composition of dexamethasone or pharmaceutically acceptable salts thereof.

[0019] In an aspect, the composition is an injectable composition.

[0020] In another aspect, the composition comprises less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof.

[0021] According to an aspect, the present invention provides stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof.

[0022] According to an aspect, the present invention provides stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient. According to another aspect, the present invention provides stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof and at least one pH adjuster.

[0023] According to yet another aspect, the present invention provides a stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof and at least one buffer.

[0024] According to an aspect, the present invention provides a stable injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one pH adjuster and optionally an antioxidant and / or a stabilizer.

[0025] According to another aspect, the present invention provides a stable injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one buffer and optionally an antioxidant and / or a stabilizer.

[0026] According to yet another aspect, the present invention provides a stable injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one pH adjuster, at least one buffer and optionally an antioxidant and / or a stabilizer.

[0027] According to an aspect, the present invention provides a stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one pH adjuster and optionally a chelating agent and / or a stabilizer.

[0028] According to another aspect, the present invention provides a stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one buffer and optionally a chelating agent and / or a stabilizer. According to yet another aspect, the present invention provides a stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one pH adjuster, at least one buffer and optionally a chelating agent and / or a stabilizer.

[0029] According to an aspect, the present invention provides a stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one pH adjuster, optionally an antioxidant and / or a stabilizer and optionally a chelating agent and / or a stabilizer.

[0030] According to another aspect, the present invention provides a stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one buffer, optionally an antioxidant and / or a stabilizer and optionally a chelating agent and / or a stabilizer. According to another aspect, the present invention provides a stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one pH adjuster, at least one buffer, optionally an antioxidant and / or a stabilizer and optionally a chelating agent and / or a stabilizer.

[0031] According to another aspect, the present invention provides a stable, injectable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof, at least one pH adjuster, at least one buffer, a chelating agent, and optionally an antioxidant.

[0032] According to an aspect, the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; c) from about 0.1 mg / mL to about 20 mg / mL isotonicity agent; and d) optionally a chelating agent and / or a stabilizer; and e) optionally an antioxidant and / or a stabilizer; and wherein the pH of the composition is from 5 to 10.

[0033] According to an aspect, the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; and c) optionally an excipient selected from the group of chelating agent, and antioxidant; and wherein the pH of the composition is from 5 to 10.

[0034] According to an aspect, the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; c) a metal chelating agent; and d) optionally an antioxidant; and wherein the pH of the composition is from 5 to 10.

[0035] According to an aspect, the present invention provides a stable pharmaceutical composition comprising less than 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt, wherein the composition optionally comprises sodium metabisulfite.

[0036] According to an aspect, the present invention provides a flexible intravenous (IV) bag comprising a stable, injectable pharmaceutical composition comprising less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt.

[0037] According to an aspect, the present invention provides a sealed polymeric flexible intravenous bag comprising a stable, injectable pharmaceutical composition comprising less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt.

[0038] According to an aspect of the present invention, the said sealed polymeric flexible intravenous bag comprising a stable, injectable pharmaceutical composition comprising less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt, wherein the bag optionally protected by oxygen scavenger.

[0039] The composition according to any one of the previous aspects is stable when stored at 25°C.

[0040] The composition according to any one of the previous aspects is stable when store at between 2°C and 8°C.

[0041] According to any one of the previous aspects, the composition of present invention is a ready to use composition and has volume of not less than about 40 ml.

[0042] According to an aspect, the present invention provides a process to prepare composition according to any one of previous aspects.

[0043] According to an aspect, the present invention provides a method of treatment of a condition treatable by dexamethasone, wherein the method comprises injecting a composition of dexamethasone or pharmaceutically acceptable salt thereof, according to any one of the previous aspects, to a subject in need of such treatment.

[0044] According to another aspect, the present invention provides a method of treatment of a condition treatable by dexamethasone, wherein the method comprises injecting a composition of dexamethasone or pharmaceutically acceptable salt thereof to a subject in need of such treatment, and wherein the composition comprises less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salt thereof. According to another aspect, the present invention provides a method of prevention of chemotherapy-induced nausea and vomiting (CINV) and for the prevention of postoperative nausea and vomiting indications (PONV), wherein the method comprises injecting a composition of dexamethasone or pharmaceutically acceptable salt thereof to a subject in need of such treatment, and wherein the composition comprises less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salt thereof.

[0045] Brief Description of Drawings:

[0046] Fig. 1 illustrates a dual chamber bag

[0047] Detail Description of Drawings

[0048] The given drawing is for representation and clarity purpose only and it does not restrict the scope of the invention in any manner.

[0049] Figure 1 shows a representative drawing of an infusion bag. The said bag or a pouch (1) comprises a drug product, a nozzle (2) and a port (3) to connect with the IV set up.

[0050] Detail Description of Invention

[0051] The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. As used herein, the following terms and phrases shall have the meaning set forth below.

[0052] Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows. Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.

[0053] Further, words like “a”, “an”, “at least” and “the” should be construed to not only cover singular quantities but also plural quantities of the elements immediately following them.

[0054] Dexamethasone was introduced for medical use in 1958. It’s an emergency medication and has been listed as essential medicine by WHO. It has been long time, unmet need to develop a product that is ready to use with protected from contamination. It has been a challenge to develop dexamethasone product that is diluted, stable at room temperature, readily available for use, easy to handle and convenient for storage and transport.

[0055] The invention herein provides a solution to all these long-term challenges.

[0056] In an aspect, the present invention relates to the composition comprising dexamethasone.

[0057] For the purpose of present invention, the terms composition and formulation are used interchangeably, meaning of both the terms is well withing the knowledge and understanding of the person skilled in the art. According to a preferred embodiment, the composition is an injectable composition. The injectable composition may be a solid formulation for injection or a liquid formulation. It will be appreciated by the person skilled in the art that the composition of the present invention may comprise dexamethasone as such or its pharmaceutically acceptable salt. The meaning of the term pharmaceutically acceptable is as understood by the person skilled in the art. According to an embodiment, the pharmaceutically acceptable salts of dexamethasone can be selected from dexamethasone acetate or dexamethasone sodium phosphate. According to a preferred embodiment, the composition of the present invention comprises dexamethasone sodium phosphate.

[0058] In an embodiment, the present invention relates to stable composition comprising dexamethasone or its pharmaceutically acceptable salt.

[0059] The term ‘stable’ composition means a composition that does not change physically or chemically when stored under specific conditions for specific period. It will be appreciated by the skilled person that the composition may change physically or chemically, but the changes are within the acceptable limits as per pharmacopeial guidelines. The composition is said to exhibit physical stability if the composition after stability period appears same as that at the initiation of stability period, upon observation. The composition is said to be chemically stable if the related known or unknown impurities in the composition are within the acceptable limits when analysed using chemical assays or other known analytical techniques at the beginning and end of stability period. The term stability period is the period over which the composition is monitored under specified stability conditions. Such periods and conditions are well within the knowledge of the person skilled in the art. For the purpose to present invention the stability period may vary from 1 day to 24 months. The stability conditions may include temperature from about 2°C to 25°C, 25% to 75% relative humidity, presence or absence of oxygen and an opaque or transparent container. In an embodiment, the temperatures for stability conditions are from 2°C to 8°C or from 20°C to 25°C. According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable at temperature between 2°C and 25°C.

[0060] According to an embodiment, the composition is stable at temperature between 2°C and 8°C.

[0061] According to another embodiment, the composition is stable at temperature between 20°C and 25°C.

[0062] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable for the period of at least 1 day when stored at temperature between 2°C and 25°C.

[0063] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable for the period of at least 7 days when stored at temperature between 2°C and 25°C.

[0064] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable for the period of at least 30 days when stored at temperature between 2°C and 25°C.

[0065] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable for the period of at least 3 months when stored at temperature between 2°C and 25°C.

[0066] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable for the period of at least 6 months when stored at temperature between 2°C and 25°C.

[0067] According to another embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable for the period of at least 9 months when stored at temperature between 2°C and 25°C.

[0068] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable for the period of at least 12 months when stored at temperature between 2°C and 25°C.

[0069] According to another embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable for the period of at least 18 months when stored at temperature between 2°C and 25°C.

[0070] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is stable for the period of at least 24 months when stored at temperature between 2°C and 25°C.

[0071] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is said to be chemically stable, if the total impurities detected after said stability period under specified stability conditions are less than 6% or less than 5% or less than 4% or less than 3% or less than 2.5%.

[0072] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is said to be chemically stable, if the total impurities detected after said stability period under specified stability conditions are less than 5%.

[0073] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is said to be chemically stable, if the total impurities detected after said stability period under specified stability conditions are less than 3%.

[0074] According to an embodiment, the present invention provides a composition comprising dexamethasone or its pharmaceutically acceptable salt, wherein the composition is said to be chemically stable, if the total impurities detected after said stability period under specified stability conditions are less than 2.5%.

[0075] The impurities in injectable formulations of dexamethasone are well within the understanding and knowledge of person skilled in the art. The impurities may be process related that are formed during preparation of active substance may be dexamethasone or its salt. The impurities may be formed degradation of active substance during formulating and later during the stability period of the formulation. All such impurities are also known as related impurities. In particular, when a salt of dexamethasone is used as active ingredient, the person skilled in the art understands that dexamethasone itself will be considered as related impurity. Other non-limiting examples of known impurities that are process related or formed due to degradation may include betamethasone sodium phosphate, dexamethasone ethyl ester, 17-oxo dexamethasone, fluoroandrostadiene carboxylic acid, 16(17)a- homodexamethasone sodium phosphate, 16(17)a-homobetamethasone sodium phosphate, 16(17)a-17R-homodexamethasone sodium phosphate, 13(17)a- homodexamethasone sodium phosphate, dexamethasone sodium phosphate diester.

[0076] High Performance Liquid Chromatography (HPLC) methods are used in identification of dexamethasone sodium phosphate and other impurities in the formulation before and after stability periods to determine stability of the final formulation. Such methods are known to the person skilled in the art.

[0077] In an aspect, the present invention provides a stable composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salt thereof.

[0078] According to an embodiment, the composition comprises less than about 3 mg / mL or about 2 mg / mL or about 1 mg / mL of dexamethasone or its pharmaceutically acceptable salt.

[0079] According to an embodiment, the composition comprises between about 1 mg / mL and about 0.01 mg / mL of dexamethasone or its pharmaceutically acceptable salt. In one preferred embodiment, the composition comprises about 0.5 mg / mL or about 0.3 mg / mL or about 0.2 mg / mL or about 0.18 mg / mL or about 0.16 mg / mL or about 0.14 mg / mL of dexamethasone or its pharmaceutically acceptable salt.

[0080] In one of the preferred embodiments, the composition comprises about 0.16 mg / mL of dexamethasone or pharmaceutically acceptable salt thereof.

[0081] In an embodiment, the present invention provides a diluted composition of dexamethasone.

[0082] According to an embodiment, the composition may be diluted to total volume of not less than 40 mL.

[0083] According to another embodiment, the composition may be diluted to total volume of between about 50 mL and about 1000 mL. It would be appreciated by the skilled person that the dilution may be carried out using a diluent or solvent such as water for injection, sodium chloride, dextrose, mannitol, lactose monohydrate, glycerine, polyethylene glycol or combination thereof. In some aspects, the composition of present invention may be devoid of diluent. In some aspects, the composition of the present invention may comprise water for injection as diluent. It would be further appreciated by the skilled person that the diluent is also an isotonicity agent that adjust the isotonicity of the composition to that of plasma. Therefore, the concentration of isotonicity agent would depend on the diluent that is used and the amount that is required. For the purpose of present invention, the concentration of diluent may by between about 0.3 mg / mL to about 10 mg / mL.

[0084] The composition of present invention may further comprise one or more excipients. Excipients are the inactive ingredients present in the composition that may not be effective in the treatment of disease or reduction of symptoms of the disease. However, they may be formulated along with active ingredient for reasons such as to improve solubility or stability of the active ingredient, to reduce viscosity or increase flowability, make the formulation easy to handle or increase its absorption. Suitable excipients may be selected from those known in the prior art or those listed in the standard reference books such as The Handbook of Pharmaceutical Excipients or those which are listed in Inactive Ingredient Database of US FDA website.

[0085] In yet another embodiment, the composition of present invention may further comprise an excipient such as pH adjuster or buffer or combination thereof.

[0086] As understood by the skilled person pH adjuster is an ingredient that regulates the pH of the composition in the expected range. The expected pH range is the range between highest and lowest pH at which the composition is stable. The composition of the present invention is stable at the pH of above 5.

[0087] According to an embodiment the pH of the composition of the present invention is between about 5 and about 10.

[0088] According to another embodiment, the pH of the composition of the present invention is between about 6 and about 10. According to yet another embodiment, the pH of the composition of the present invention is between about 7 and about 9. In an aspect the pH adjuster used for the present invention may be an acid or a base or combination thereof. The pH may also be adjusted and maintained using buffer solutions. The acids used as pH adjuster may include mineral acid such as hydrochloric acid, citric acid, tartaric acid or nitric acid; organic acid such as dicarboxylic acid or tricarboxylic acid and the bases used as pH adjuster may include but not limited to sodium carbonate, sodium bicarbonate or sodium hydroxide. The amount of acid or base or combination thereof may vary based on the components (excipients) present in the composition and pH of the composition prior to the addition of pH adjuster, therefore the amount and concentration of acid and base can be arrived at the skilled person based on the knowledge and understanding to the formulation chemistry. For the purpose of present invention, the acid or base or its combination may be added to the composition to adjust the pH to between about 5 and about 10.

[0089] The buffer solutions used as pH adjuster may include but not limited to sodium citrate dihydrate (SCD), potassium dihydrogen phosphate, tris(hydroxymethyl) aminomethane (Tris), sodium hydrogen orthophosphate, citric acid or citrate, tartrate, acetate, disodium hydrogen phosphate, sodium dihydrogen phosphate or combinations thereof. The concentration of one buffer solution may vary from about 0.01 mg / mL to about 3 mg / mL. The concentration of other buffer solution may vary from 0.0001 mg / mL to 50 mg / mL.

[0090] For the purpose of present invention the concentration of disodium hydrogen phosphate anhydrous may vary from 0.005 mg / mL to 8 mg / mL. In particular the concentration of disodium hydrogen phosphate anhydrous may be between 0.003 mg / mL and 5 mg / mL. Similarly the concentration of sodium dihydrogen phosphate may be between 0.001 mg / mL and 1 mg / mL. In particular, the concentration of sodium dihydrogen phosphate may be between 0.0015 mg / mL and 0.9 mg / mL.

[0091] In an embodiment, the concentration of Tris may be between 0.1 mg / mL to 45 mg / mL. In another embodiment, the concentration of Tris may be between 0.1 mg / mL to 25 mg / mL. In yet another embodiment, the concentration of Tris may be between 0.1 mg / mL to 15 mg / mL. In an embodiment, the concentration of Tris may be between 0.1 mg / mL to 5 mg / mL. In another embodiment, the concentration of Tris may be between 0.2 mg / mL to 3 mg / mL.

[0092] In an embodiment, the concentration of citric acid anhydrous may be between 0.01 mg / mL to 15 mg / mL. In another embodiment, the concentration of citric acid anhydrous may be between 0.01 mg / mL to 10 mg / mL. In yet another embodiment, the concentration of citric acid anhydrous may be between 0.01 mg / mL to 5 mg / mL. In an embodiment, the concentration of citric acid anhydrous may be between 0.05 mg / mL to 3 mg / mL. In yet another embodiment, the concentration of citric acid anhydrous may be between 0.1 mg / mL to 1 mg / mL.

[0093] According to an aspect the composition of the present invention may optionally comprise an antioxidant or meta ion chelator or a stabilizer or combination thereof. It would be appreciated by the skilled person that an antioxidant, metal ion chelator and stabilizer are added to the formulation to avoid formation of impurities due to oxidation or due to the unwanted reaction between metal ion and components of the formulation. For better stability of the composition, it may deem necessary to add antioxidant, metal ion chelator and / or stabilizer to the composition. Surprisingly the composition of the present invention was found to be stable in the absence of antioxidant or stabilizer.

[0094] In another embodiment, the composition of the present invention is devoid of antioxidant or stabilizer. Surprisingly the composition of the present invention was found to be stable in the absence of antioxidant. In some aspect, the composition of the present invention is devoid of metal ion chelator and / or stabilizer. Surprisingly, the composition of the present invention was found to be stable in the absence of metal ion chelator and / or stabilizer.

[0095] In yet another embodiment, the composition of present invention optionally comprises at least one antioxidant or at least one metal ion chelator or at least one stabilizer or combination thereof. An antioxidant, metal ion chelator or stabilizer may be selected as per the knowledge and understanding of the person skilled in the art. Some of the non-limiting examples of antioxidants are sodium metabisulfite, sodium sulfite or citric acid. Some of the non-limiting examples of metal ion chelator are ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(P- aminoethyl ether)-A,A,A', A-tetraacetic acid (EGTA), diethylenetriaminepentaacetic acid, edetic acid, citric acid or salts thereof.

[0096] For the purpose of present invention, the terms stabilizer is used as synonymous with antioxidants and metal ion chelators. It will be understood by the person skilled in the art that the term stabilizer may also include amino acids, surfactants, polymers, sugars and polymers. According to an embodiment the stabilizer of present invention is selected from the group of antioxidants, metal ion chelators and combination thereof. According to another embodiment the stabilizer of the present invention is selected from the group comprising amino acids, surfactants, polymers, sugars and polymers.

[0097] According to an embodiment, the antioxidant or stabilizer may be present in the composition at a concentration of about 0.01 mg / mL to about 1 mg / mL.

[0098] According to an embodiment, the ratio of dexamethasone or its salt to antioxidant or stabilizer may be in the range of from about 1 :0.01 to about 1 :0.5.

[0099] According to the above embodiments, the metal ion chelator or stabilizer may be present in the composition at a concentration of about 0.001 mg / mL to about 0.5 mg / mL.

[0100] According to an embodiment, the ratio of dexamethasone or its salt to metal ion chelator or stabilizer may be in the range of from about 1 :0.01 to about 1 :0.2.

[0101] According to an embodiment the composition of the present invention may comprise solvent. According to an aspect the solvent may be water for injection. According to an embodiment, the composition of the present invention may comprise preservative. According to an aspect, the composition of the present invention is devoid of preservation.

[0102] According to an embodiment the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; wherein the pH of the composition is from 5 to 10.

[0103] According to another embodiment the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; c) from about 0.1 mg / mL to about 20 mg / mL isotonicity agent; wherein the pH of the composition is from 5 to 10.

[0104] According to yet another embodiment, the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; c) from about 0.1 mg / mL to about 20 mg / mL isotonicity agent; d) a chelating agent; wherein the pH of the composition is from 5 to 10.

[0105] According to another embodiment, the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; c) from about 0.1 mg / mL to about 20 mg / mL isotonicity agent; d) an antioxidant; wherein the pH of the composition is from 5 to 10.

[0106] According to an aspect, the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; c) a metal chelating agent; and d) optionally an antioxidant; and wherein the pH of the composition is from 5 to 10.

[0107] According to another embodiment, the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) less than about 5 mg / mL of pH adjuster or buffer or combination thereof; c) from about 0.1 mg / mL to about 20 mg / mL isotonicity agent; d) a chelating agent; e) an antioxidant; wherein the pH of the composition is from 5 to 10.

[0108] According to an embodiment, the composition of the present invention is stable in the absence of dissolved oxygen in the composition. According to another embodiment, the composition of the present invention is stable when the dissolved oxygen content in the composition is less than 10 ppm. According to yet another embodiment the composition of the present invention is stable when the dissolved oxygen content in the composition is less than 5 ppm.

[0109] In an embodiment, the present invention provides a stable pharmaceutical composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; wherein the pH of the composition is from 5 to 10 and wherein the dissolved oxygen in the composition is less than 10 ppm.

[0110] The methods of determining and reducing dissolved oxygen are as per known in the art.

[0111] In yet another embodiment, the present invention provides a process for the preparation of compositions of the present invention. In another aspect, the present invention provides a process for the preparation of stable, injectable, diluted composition of dexamethasone or salts thereof. The composition of the present invention may be prepared by adding and dissolving each of the excipient one after other to a solvent, wherein solvent may be purged with an inert gas to reduce dissolved oxygen to less than 10 ppm. pH of the excipient solution may be adjusted to 5 to 10 using pH adjusters and / or buffer. Dexamethasone or its salt may be added to the pH adjusted solution and stirred. The composition may be sterilized if required.

[0112] The method of preparation of the composition can vary as per understanding and the knowledge of the skilled person. For example, necessity of filtrations and the required filters, temperatures during the processes or the sequence of addition of excipients are within the ambit of knowledge of the skilled person. The composition of the present invention is an injectable composition, where in the composition is in the solid form for dilution. Such solid composition may be packed in container such as vial. The composition of the present invention may be in the liquid form and may be packed in a container such as vial, ampoule, pen, syringe or infusion bag or bottles. According to an aspect, the present invention relates to a product comprising a container comprising stable injectable composition of dexamethasone or its salt.

[0113] According to an embodiment, the diluted composition of the present invention may be packed in high volume infusion bag or bottle. Infusion bag or bottle may be a multilayer polymeric bag or bottle made up of polymeric materials such as polyolefin polymers, polyethylene, polypropylene; cyclo olefin polymers, cyclo olefin copolymers, polypropylene based polyolefin polymers; polycarbonates; modified polyolefin-polyethylene polymers or styrene-polyolefin based polymers or block co-polymers. Such polymeric container may be either preformed or blow fill sealed.

[0114] The volume of the infusion bag or bottle is according to the diluted composition. For the purpose of present invention, the volume may be between 40 mL and 1000 mL. The volume in particular is between 50 mL and 500 mL.

[0115] The polymeric bag or bottle of the present invention is further sealed using a tamper-evident cap such as break-off cap or twist-off cap.

[0116] The polymeric bag or bottle may be optionally covered using light air, or oxygen barrier material such as metal film including but not limited to aluminum wrap or aluminum pouch and / or an oxygen absorber. In an embodiment the product of the present invention is not covered by light, air or oxygen barrier. In an embodiment, the product of the present invention is covered by light, air or oxygen barrier. Surprisingly the composition of the present invention was stable with or without light, air or oxygen barrier. In an aspect the present invention provides an IV container comprising a stable, injectable, diluted, ready to use composition of dexamethasone or its salt.

[0117] In an aspect the present invention provides an IV bag comprising a stable, injectable, diluted, ready to use composition of dexamethasone or its salt.

[0118] It will be appreciated by the person skilled in the art that the high-volume product of the present invention are ready to use or ready to infuse. Such composition do not need further dilution or preparation before administering. Therefore the present invention negates the need of preparation of administrable product by the pharmacist or hospital staff which makes the composition of the present invention easy to handle, cost effective, economic with no possibility of loss due to handling. In an embodiment, the present invention provides an IV container comprising stable, injectable, diluted, ready to use composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; wherein the pH of the composition is from 5 to 10.

[0119] In another embodiment, the present invention provides an IV container comprising stable, injectable, diluted, ready to use composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; wherein the pH of the composition is from 5 to 10 and wherein the dissolved oxygen in the composition is less than 10 ppm.

[0120] In yet another embodiment, the present invention provides an IV container comprising stable, injectable, diluted, ready to use composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; wherein the pH of the composition is from 5 to 10, and wherein the container is optionally wrapped with oxygen scavenger.

[0121] In an embodiment, the present invention provides an IV container comprising stable, injectable, diluted, ready to use composition comprising: a) less than about 5 mg / mL of dexamethasone or its pharmaceutically acceptable salt; b) pH adjuster or buffer or combination thereof; wherein the pH of the composition is from 5 to 10 and wherein the dissolved oxygen in the composition is less than 10 ppm, and wherein the container is optionally wrapped with oxygen scavenger.

[0122] In an aspect, the present invention provides a process to prepare a product comprising an IV container, wherein the container comprises stable, injectable, diluted, ready to use composition of dexamethasone or its pharmaceutically acceptable salt of the present invention.

[0123] According to an aspect, the present invention provides a method of treatment of a condition treatable by dexamethasone, wherein the method comprises administering a composition of present invention to a subject in need of such treatment, wherein the composition is ready to administer.

[0124] According to an aspect, the present invention provides a method of treatment of a condition treatable by dexamethasone, wherein the method comprises administering a composition of present invention to a subject in need of such treatment, wherein the composition is administered without dilution.

[0125] Dexamethasone composition has been approved for several indications including but not limited to endocrine disorders such as primary or secondary adrenocortical insufficiency, Acute adrenocortical insufficiency, adrenal insufficiency, congenital adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia associated with cancer; rheumatic disorders such as osteoarthritis, rheumatoid arthritis, acute and subacute bursitis, epicondylitis, acute nonspecific tenosynovitis, acute gouty arthritis, psoriatic arthritis, ankylosing spondylitis; collagen diseases such as systemic lupus erythematosus, acute rheumatic carditis; dermatologic diseases such as pemphigus, exfoliative dermatitis, severe psoriasis, mycosis fungoides; allergic states such as asthma, dermatitis, drug hypersensitivity reactions, allergic rhinitis, urticarial transfusion reactions, acute non-infectious laryngeal edema, serum sickness; ophthalmic diseases arising due to acute and chronic allergic and inflammatory processes involving the eye; gastrointestinal diseases such as ulcerative colitis; regional enteritis; respiratory diseases symptomatic sarcoidosis, berylliosis, aspiration pneumonitis; hematologic disorders such as acquired (autoimmune) haemolytic anaemia, thrombocytopenia, erythroblastopenia, congenital (erythroid) hypoplastic anaemia, neoplastic diseases such as leukemia and tuberculous meningitis.

[0126] According to an embodiment, the composition of present invention may be used in the prevention or treatment of all such indications.

[0127] According to another embodiment, the composition of present invention may be used in the prevention or treatment of chemotherapy-induced nausea and vomiting (CINV) and for the prevention of postoperative nausea and vomiting indications (PONV).

[0128] In an aspect the present invention provides a method of prevention of CINV and PONV. In another aspect, the present invention provides a method of prevention of CINV and PONV, wherein the method comprises injecting a composition of dexamethasone or pharmaceutically acceptable salt thereof to a subject in need of such treatment, and wherein the composition comprises less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salt thereof. The subject for the purpose of present invention is a mammal, preferably a human.

[0129] It will be appreciated by the skilled person that the composition of the present is injected to the subject intravenously. The obvious variations to the present invention related to composition, its process and method of use are included and are well within the scope of this invention.

[0130] Examples

[0131] Below given examples demonstrate the best mode of performing the invention. They are representative of the present invention and explain the invention such that the skilled person can arrive at the present invention without undue experimentation. Below examples are only for understanding, clarity and demonstration purpose and they do not restrict the scope of the invention in any manner. Any variations in the experimentation that are understood by the skilled person are included in the present invention.

[0132] Example 1:

[0133] The above composition was prepared by the process given below:

[0134] 1. 110% of water for inj ection (WFI) was purged with nitrogen gas to achieve not more than (NMT) 2 ppm of oxygen content; 2. to the 80% of the WFI from step 1, disodium EDTA, tris buffer, citric acid anhydrous, sodium metabisulfite and NaCl was added and stirred to dissolved one after other to prepare excipient solution;

[0135] 3. to the excipient solution of step 2, dexamethasone sodium phosphate was added and stirred to dissolve;

[0136] 4. pH of the solution obtained in step 3 was adjusted between 7.70 and 8.30 using sodium hydroxide and citric acid;

[0137] 5. the volume of the composition was finally adjusted to 100% using WFI of step 1;

[0138] 6. filtered the composition obtained in step 5 using 0.2p PES filter;

[0139] 7. packed the composition under sterile conditions in the IV bag of 50 mL and stored at 2°C to 8°C and 25°C.

[0140] Example 2:

[0141] The composition was prepared by the process as given below:

[0142] 1. 110% of water for injection (WFI) was purged with nitrogen gas to achieve not more than (NMT) 2 ppm of oxygen content;

[0143] 2. to the 80% of the WFI from step 1 , disodium hydrogen phosphate anhydrous and sodium dihydrogen phosphate anhydrous was added and stirred to dissolve; 3. disodium EDTA, Sodium metabisulfite and NaCl was added one after other to the solution of step 2 and stirred well to obtain clear excipient solution;

[0144] 4. pH of the excipient solution obtained in step 3 was adjusted between 7.70 and 8.30 using sodium hydroxide and hydrochloric acid;

[0145] 5. to the pH adjusted solution of step 4, dexamethasone sodium phosphate was added and stirred to dissolve while maintaining the pH at 8.0;

[0146] 6. the volume of the composition was finally adjusted to 100% using WFI of step 1;

[0147] 7. filtered the composition obtained in step 6 using 0.2p PES filter;

[0148] 8. packed the composition under sterile conditions in the IV bag of 50 mL and stored at 2°C to 8°C and 25°C.

[0149] Example 3

[0150] The composition was prepared by the process as given below:

[0151] 1. 110% of water for injection (WFI) was purged with nitrogen gas to achieve not more than (NMT) 2 ppm of oxygen content;

[0152] 2. to the 80% of the WFI from step 1, disodium EDTA was added, stirred and dissolved to obtain clear solution;

[0153] 3. to the clear solution of step 2, dexamethasone sodium phosphate was added and stirred to dissolve;

[0154] 4. adjusted the pH of the above solution using sodium hydroxide and / or citric acid between 7.70 and 8.30;

[0155] 5. the volume of the composition was finally adjusted to 100% using WFI of step 1;

[0156] 6. filtered the composition obtained in step 5 using 0.2p PES filter; 7. packed the composition under sterile conditions in the IV bag of 50 mL and stored at 2°C to 8°C and 25°C.

[0157] Example 4

[0158] The composition was prepared by the process similar to that of Example 3.

[0159] Example 5:

[0160] The composition was prepared by the process similar to that of Example 2.

[0161] Example 6:

[0162] The composition was prepared by the process similar to that of Example 2.

[0163] Example 7:

[0164] The stability data for composition of Example 3 and Example 4 is as given in Table 1 and Table 2:

[0165] Table 1: stability data composition of Example 3

[0166] Table 2: stability data composition of Example 4 up to 3 months at 25°C ± 2°C / 60% ± 5% RH.

[0167] Example 8: Table 3 and 4 below give stability data for Example 1 and 2 respectively.

[0168] Table 3: stability data for composition of Example 1

[0169] ND: Not Detected

[0170] Table 4: stability data for composition of Example 2 Example 9:

[0171] Table 5 and 6 below give stability data for Example 5 and 6 respectively.

[0172] Table 5: stability data for composition of Example 5

[0173] Table 6: Stability data for composition of Example 6

Claims

We claim,1. A pharmaceutical composition comprising less than 5 mg / mL of dexamethasone or pharmaceutically acceptable salts thereof.

2. The composition as claimed in claim 1, wherein the composition comprises dexamethasone, dexamethasone acetate or dexamethasone Sodium Phosphate.

3. The composition as claimed in claim 1, wherein the concentration of dexamethasone or its pharmaceutically acceptable salts in the composition is between 1 mg / mL and 0.14 mg / mL.

4. The composition as claimed in claim 2, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

5. The composition as claimed in claim 4, wherein the excipient is selected from the group of pH adjuster, buffer, isotonicity agent or solvent.

6. The composition as claimed in claim 5, wherein the pH adjuster is selected from the group comprising hydrochloric acid, citric acid, tartaric acid, nitric acid sodium hydroxide, sodium carbonate, sodium bicarbonate and mixture thereof.

7. The composition as claimed in claim 6, wherein the pH of the composition is from 6 to 10.

8. The composition as claimed in claim 5, wherein the buffer is selected from the group of sodium citrate dihydrate (SCD), potassium dihydrogen phosphate, tris(hydroxymethyl) aminomethane (Tris), citric acid, sodium hydrogen orthophosphate, citrate, tartrate, acetate, di sodium hydrogen phosphate, sodium dihydrogen phosphate and combinations thereof.

9. The composition as claimed in claim 8, wherein the concentration of buffer in the composition is between 0.0001 mg / mL to 50 mg / mL.

10. The composition as claimed in claim 5, wherein the isotonicity agent is selected from sodium chloride, dextrose, mannitol, lactose monohydrate, glycerine or polyethylene glycol or combination thereof.

11. The composition as claimed in claim 10, wherein the concentration of isotonicity agent in the composition is between 5 mg / mL to 10 mg / mL12. The composition as claimed in claim 5, wherein the solvent is water for injection or an isotonicity agent or combination thereof.

13. The composition as claimed in claim 5, wherein the composition optionally further comprises an excipient selected from the group of antioxidant, chelating agent and / or stabilizer.

14. The composition as claimed in claim 13, wherein the chelating agent is selected from EDTA, EGTA, diethylenetriaminepentaacetic acid, edetic acid citric acid, or pharmaceutically acceptable salt thereof.

15. The composition as claimed in claim 14, wherein the antioxidant is selected from sodium metabisulfite, sodium sulfite or citric acid.

16. A stable injectable composition comprising less than 5 mg / mL of dexamethasone or pharmaceutically acceptable salt thereof and a pH adjuster.

17. The composition as claimed in claim 16, wherein the pH of the composition is adjusted between 5 and 10.

18. A stable injectable composition comprising less than 5 mg / mL of dexamethasone or pharmaceutically acceptable salt thereof and a buffer.

19. A stable pharmaceutical composition comprising: a. less than 5 mg / mL of dexamethasone or pharmaceutically acceptable salt thereof; b. between 0.0001 mg / mL to 50 mg / mL of buffer; c. between 5 mg / mL and 10 mg / mL of isotonicity agent; d. optionally a chelating agent; and e. optionally an antioxidant; wherein the pH of the composition is from 5 to 10.

20. A process for the preparation of an injectable composition claimed in any of the preceding claims.

21. A product comprising a container, wherein the container has a volume between 50 mL and 500 mL and wherein the container comprises stableinjectable, ready to administer, highly diluted composition of dexamethasone or pharmaceutical salt thereof.

22. A sealed polymeric flexible intravenous bag comprising a stable, injectable pharmaceutical composition comprising less than about 5 mg / mL of dexamethasone or pharmaceutically acceptable salt thereof.

23. A method of treatment wherein the method comprises administering a composition comprising less than 5 mg / mL of dexamethasone or pharmaceutical salt thereof to a subject in need of such treatment, and wherein the composition is administered without dilution.

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