Ready to use compositions of remimazolam

Abstract

The present application provides stable ready to use (RTU) aqueous compositions of Remimazolam 2.5mg / ml. Compositions of the invention are directly prepared as clear aqueous solutions and hence do not require reconstitution. The composition comprises at least one amino acid and at least one alcohol in specific proportions. The invention also provides a process a process for the preparation of such compositions.

Description

[0001]READY TO USE COMPOSITIONS OF REMIMAZOLAM Technical Field of the Invention Present invention relates to clear stable ready to use (RTU) aqueous compositions more specifically injectable compositions comprising Remimazolam or pharmaceutically acceptable different solid-state forms, polymorphs, salts, solvates or hydrates thereof up to equivalent to Remimazolam base 2.5mg / ml. The invention also relates to the process to prepare compositions. Background of Invention: Remimazolam approved in the U. S. in July 2020 is ultra-short-acting intravenous benzodiazepine medication for the induction and maintenance of procedural sedation for invasive diagnostic or surgical procedures lasting 30 minutes or less. It exhibits faster recovery, predictable, consistent pharmacokinetics, more rapid onset and a shorter duration than midazolam. Remimazolam Present invention is described using besylate salt of Remimazolam. Remimazolam besylate is methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4] benzodiazepin-4- yl] propanoate benzenesulfonic acid and has molecular formula C27H25BrN4O5S, molecular weight of 597.48 g / mol. Remimazolam is off-white to pale-yellow solid powder, slightly hygroscopic, practically insoluble or very slightly soluble in aqueous media with pH ≥5.0. Sparingly soluble at acidic pH. It exhibits stereoisomerism and polymorphism. Its solid-state forms, salt forms and few polymorphic forms are known. Remimazolam besylate marketed in several territories under different brand names such as Byfavo in South Korea, Anerem® in Japan, Aptimyda™ in EU and Ruima® in China is sensitive to hydrolysis, to oxidation and light. Label states that each vial of “Byfavo” 20 mg powder for solution for injection contains remimazolam besylate equivalent to 20 mg remimazolam. After reconstitution each mL contains 2.5 mg remimazolam. Each vial contains 79.13 mg of dextran 40 for injection, Lactose monohydrate Hydrochloric acid (for pH adjustment) Sodium hydroxide (for pH adjustment). Some of these excipients may support growth of microbes. Chemical and physical in use stability of the reconstituted solution has been demonstrated for 24 hours under controlled room temperature at 20°C to 25°C. Solutions if not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. Composition before reconstitution is to be protected from light. US9914738 and US20150148338, WO / 2013 / 174883 and 9013 / CHENP / 2014 describe compositions which require reconstitution before administration. CN107198691A describes use of betacyclodextrin. When dissolved it is free of solid state characteristics. No clear stable ready to use aqueous injectable compositions comprising Remimazolam are available for human or veterinary use. Clear stable RTU aqueous compositions more specifically injectable compositions comprising solubilized and stabilized Remimazolam or its acid addition salts or base addition salts such as Remimazolam besylate in aqueous media to provide clear stable ready to use aqueous compositions more specifically injectable compositions is an unmet and unfulfilled challenge although Remimazolam injectable composition is known since 2020. Marketed product is a lyophilized powder to be diluted with solvent before use. There are many restrictions on preparation, storage and use of solutions such as use within 24 hours, storage at 2-80C. Lyophilized compositions necessitate carrying additional inventory of solvent or diluent and is troublesome. Their storage, transport is cost intensive, inconvenient. It results into wastage and safety problems. Reconstituted aqueous solutions have to be stored under specific conditions, have to be consumed immediately as these are unstable. Manufacturing of lyophilized or freeze-dried powders require costly equipment and complicated technology making the product costly. Dissolving an active ingredient in an organic or nonaqueous or water immiscible solvent and its use may not be advisable due to safety reasons. Polar solvents water though an ideal solvent may impact stability of active. Not all polar solvents are pharmacologically acceptable. Clear stable ready to use aqueous compositions offer distinct advantages over compositions which are to be reconstituted into solutions before administration. There is an urgent need to provide clear stable ready to use aqueous compositions more specifically injectable compositions comprising Remimazolam or its salts such as Remimazolam Besylate equivalent to 2.5 mg / ml of Remimazolam base, free from crystallization defect at lower temperatures and the process to produce said compositions. Objects of the Invention The main object of the invention is to provide clear stable RTU aqueous injectable compositions comprising Remimazolam or its pharmaceutically acceptable hydrate, solvate, polymorphs, solid state forms or acid or base addition salts such as Remimazolam Besylate [hereinafter referred as Remimazolam] equivalent to 2.5 mg / ml of Remimazolam base. Yet another object of the invention is to provide a process to prepare a clear stable clear RTU aqueous injectable compositions comprising Remimazolam equivalent to 2.5 mg / ml of Remimazolam base. Summary of the Invention The present invention provides a clear stable RTU aqueous compositions comprising Remimazolam equivalent to Remimazolam base 2.5mg / ml and method for preparation thereof. It was unexpectedly found that Remimazolam 2.5mg / ml can be solubilized and stabilized in aqueous environment in the presence of at least one amino acid with or without another amino acid and an alcohol when taken in certain specific proportion to each other and to Remimazolam The composition optionally comprises at least one excipient selected from solvents, cosolvent, pH modifier or buffer, surfactant, preservative, antioxidants, chelating agent, antimicrobial agent and tonicity modifier. The present invention provides a ready to use composition of Remimazolam comprising at least one amino acid, at least one alcohol and water. The composition comprises Remimazolam in an amount of 2.5 mg / ml. The composition comprises at least one amino acid in an amount of 1.2 to 6.1 mg / ml. In one embodiment, the amino acid is present in an amount from 1.6 mg / mL to 6.1 mg / ml. In another embodiment, the amino acid is present in an amount from 1.6 to 4.6 mg / ml. In particular embodiment, the composition comprises amino acid in an amount selected from 1.2 mg / ml, 1.4mg / ml, 1.6 mg / ml, 1.8mg / ml, 4.6 mg / ml and 6.1 mg / ml. In one preferred embodiment, the amount of amino acid is 1.6 mg / ml. The amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, pyroglutamatic, glycine, histidine, hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or a combination thereof. In another embodiment, the amino acid is selected from L- Histidine and L-Threonine, or a combination thereof. In one preferred embodiment the composition comprises L-Histidine. In another preferred embodiment the composition comprises combination of L-Histidine and L-Threonine. The composition comprises amino acid and Remimazolam in a ratio of 0.48:1 to 2.44:1. In one embodiment, the ratio of amino acid and Remimazolam is from 0.48:1 to 0.72:1. In one particular embodiment, the ratio of amino acid and Remimazolam is 0.64:1. The composition comprises alcohol in an amount from 30 to 70% (v / v). In an embodiment, the amount of alcohol is from 30 to 50% (v / v). In particular embodiments, the composition comprises alcohol in an amount selected from 30% (v / v), 35 % (v / v), 50% (v / v), 60% (v / v), 65% (v / v) and 70% (v / v). In one preferred embodiment, the amount of alcohol is 30% (v / v). The alcohol is selected from a monohydric, a polyhydric alcohol or mixture thereof. In one embodiment the alcohol is selected from ethyl alcohol, benzyl alcohol, and propylene glycol. In one particular embodiment, the alcohol is ethyl alcohol. The composition comprises alcohol and Remimazolam in a ratio from 12:1 to 28:1 wherein alcohol is expressed in terms of % (v / v) in composition and Remimazolam is in mg. The ratio of alcohol to amino acid in the composition is from 58.33:1 to 8.2:1 when alcohol is expressed in % (v / v) of composition and amino acid / s in mg. The composition comprises water in an amount from 70 to 30% (v / v). The ratio of the water to Remimazolam in the composition is from 0.12:1 to 0.28:1 where water is in ml and Remimazolam is in mgs. The ratio of water to Remimazolam is 12:1 to 28:1 when water is expressed as %(v / v) and Remimazolam in mg. The ratio of alcohol percent: water percent % in total composition is from 0.429:1 to 2.33:1. The same is 0.45:1 to 2.51:1 when alcohol and water both are expressed in ml. The composition optionally comprises one or more pharmaceutically acceptable excipients. The pharmaceutical excipients are selected from solvents, cosolvents, surfactant, pH modifier or buffer, antibacterial preservatives and tonicity imparting agents or tonicity contributors The pH of the composition of the present invention is from 2.5 to 4.5. In one embodiment the pH of the composition is from 2.5 to 4. In one preferred embodiment, the pH of the composition is from 3.1 to 3.4. The viscosity of the composition is below 5 cPs, preferably below 3 cPs.at 250C+20C. In one particular embodiment, the composition comprises Remimazolam in an amount of 2.5 mg / ml, an amino acid in an amount of 1.6 mg / ml, the alcohol in amount of 30% v / v and water in an amount of 70% (v / v). In one preferred embodiment, the amino acid is L-histidine and alcohol is ethyl alcohol. In another particular embodiment, the composition comprises Remimazolam in an amount of 2.5 mg / ml, two amino acids in an amount of 4.6-6.1 mg / ml, the alcohol in amount of 50-70% v / v and water in an amount of 50-30% (v / v). In one preferred embodiment, the composition comprises amino acids L-histidine and L-Threonine. When alcohol is in the range of 30% to 70%, water is present 70% to 30% or 0.7 to 0.3ml or 700mg to 300mg. The aqueous injectable composition of Remimazolam provided in the present invention is fit for administration via multiple routes such as IV and infusion. Detailed Description of the Invention Remimazolam exists in different forms such as solvates, salts, hydrates, polymorphs, solvates or hydrates, solid state forms, acid or base addition salts including sulfates and sulfonates, toluenesulfonic, ethanesulfonic or benzenesulfonic or sulfonic acid salts. These are referred as Remimazolam in the specification and are to be understood interchangeably or meaning same and construed accordingly unless specified or defined differently. Solid state forms stabilize in different three dimensional structures of some definite energy content and at times they undergo spontaneous conversion from one form to another more stable form and revert when they absorb energy or if there is energy loss. Differences in three dimensional structures create difference in attributes such as solubility, hardness, solvent content, stability etc. All known salts, polymorphs, solid state forms, acid addition salts, base addition salts, solvates or hydrates of Remimazolam fall within the ambit of present invention as present invention relates to clear, stable aqueous solution of Remimazolam. When dissolved, it is devoid of any solid-state characteristics. Compositions according to the present invention might comprise the free form or Remimazolam base or a salt with counter ion such as fluoride, chloride or bromide, sulfate, organic sulfates, sulfonate, organic sulfonates, nitrate, phosphate, salicylate, tartrate, citrate, maleate, formiate, malonate, succinate, isethionate, lactobionate and sulfamate. Remimazolam of pharmaceutically acceptable grade is sourced from Wavelength Pharmaceuticals. It was unstable in aqueous media and immediately developed colour. The besylate salt of Remimazolam is used to explain various embodiments of the invention. The terms “mg / mL” and “mg / ml” are used interchangeably in the description below and have the same meaning. In the present application weight of ingredients such as Remimazolam or amino acids is expressed in milligrammes or milligrams or in mgs in terms of per ml basis i.e. mg / ml. The term "pharmaceutically acceptable excipient" as used herein may include one or more of solvents, cosolvents, surfactant, pH modifier or buffer, antibacterial preservatives and tonicity imparting agents or tonicity contributors. Related Substances are structurally related to a drug substance. These substances may be identified or unidentified degradation products or impurities arising from a manufacturing process or during storage of a material. These are also known as impurities. “NMT” means not more than. “RRT” refers to relative retention time. “RSD” refers to Relative standard deviation. “RRF” refers to Relative Response Factor. These terms are known to persons skilled in analytical work. RMMZ Acid is (S)-3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f] imidazo [1,2- a][1,4]diazepin-4-yl) propanoic acid with RRT of 0.51. BHDP refers to Methyl 3-((3S)-7- bromo-2 -((2-hydroxypropyl) amino)-5-(pyridin-2-yl)-3H-benzo[e] [1,4] diazepin-3-yl) propanoate. BBDP is Methyl (S)-3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H- benzo[e][1,4]diazepin-3-yl) propanoate. BHDP elutes at different RRTs. BHDP 1elutes at RRT 0.56. BHDP 2 elutes at RRT 0.58. BBDP elutes at RRT is 0.84. Ready to use (RTU) compositions of the present invention are referred to compositions that do not require reconstitution before these are either diluted or administered. Compositions of the present invention are already in liquid form and may be further diluted or administered as such. In one aspect, the present invention provides a ready to use stable aqueous composition of Remimazolam. The composition comprises Remimazolam or its pharmaceutically acceptable different solid-state forms, polymorphs, salts, solvates or hydrates thereof upto equivalent to Remimazolam base 2.5mg / ml. The composition is an injectable composition. In second aspect, the present in invention provides a process for preparing a ready to use stable aqueous composition of Remimazolam. The composition is prepared by step wise addition of ingredients as shown below: 1. Prepare a diluent solution of 30-70% (v / v) of an alcohol by dissolving alcohol in water. 2. Add amino acid in an amount varying from 1.2-6.1 mg / ml under mild stirring 3. Add Remimazolam Besylate in an amount equivalent to 2.5 mg / ml of Remimazolam base under continuous stirring 4. Adjust the pH of the solution in the range preferably from 3.1 to 3.4 5. The solution after adjusting the pH is optionally filtered through 0.45 micron prefilter and 0.22 micron filter. The filtered solution is filled in suitable container such as ampoule / vial, preferably amber coloured glass containers such as vial under nitrogen flushing. The present invention provides ready to use stable aqueous compositions of Remimazolam. As explained above, Remimazolam is unstable in aqueous form and is generally available in powder form. It was surprisingly found by the Applicants that that Remimazolam can be solubilized and stabilized in the presence of an amino acid and an alcohol. It was found that a clear and stable aqueous composition of Remimazolam can be obtained in the presence of at least one amino acid, and an alcohol when used in specific proportions with Remimazolam and to each other. The present invention provides a clear stable ready to use aqueous liquid compositions more specifically injectable compositions comprising Remimazolam equivalent to 2.5 mg / ml of Remimazolam, at least one alcohol and at least one amino acid. The composition optionally comprises one pharmaceutically acceptable excipient selected from, pH modifier or buffer, surfactant, cosolvent, preservative, antimicrobial agent, antioxidants, chelating agent and tonicity modifier. The composition comprises at least one amino acid in an amount of 1.2 to 6.1 mg / ml. In one embodiment, the amino acid is present in an amount from 1.6 mg / mL to 6.1 mg / ml. In another embodiment, the amino acid is present in an amount from 1.6 to 4.6 mg / ml. In particular embodiment, the composition comprises amino acid in an amount selected from 1.2 mg / ml, 1.4mg / ml, 1.6 mg / ml, 1.8 mg / ml, 4.6 mg / ml and 6.1 mg / ml. In one preferred embodiment, the amount of amino acid is 1.6 mg / ml. The amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, pyroglutamatic, glycine, histidine, hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or a combination thereof. In another embodiment, the amino acid is selected from L- Histidine and L-Threonine. In one preferred embodiment the composition comprises L- Histidine. In another embodiment, the composition comprises more than one amino acid. In one embodiment the composition comprises two amino acids. In one preferred embodiment, the composition comprises L-Histidine and L-Threonine. In one embodiment, the composition comprises L-Histidine in an amount from 1.2 mg / mL to 1.8mg / ml, preferably at 1.4 mg / ml to 1.8mg / ml or more preferably 1.6-1.8mg / ml optionally with L-Threonine from 3- 4.5mg / ml. Remimazolam in water is unstable. The aqueous solution of Remimazolam was found unstable in 20% alcohol and 80% water. When, the amount of alcohol was increased to 30% v / v, the resultant solution was stable at room temperature. The solution was stable till the amount of alcohol 70%. The composition comprises alcohol in proportion from 30%v / v to 70%v / v. In an embodiment, the amount of alcohol is from 30 to 50% (v / v). In one particular embodiment, the composition comprises alcohol in an amount selected from 30% (v / v), 35 % (v / v), 50% (v / v), 60% (v / v), 65% (v / v) and 70% (v / v). In one preferred embodiment, the amount of alcohol is 30% (v / v). In one embodiment, the composition comprises ethyl alcohol. The alcohol may be selected from ethyl alcohol, polyethylene glycol. Ethyl alcohol available commercially, from state distillery corporation, or alcohol of the strength 96%v / v or above is useful for the present invention. Other alcohols such as glycerin or glycerol, monothioglycerol, benzyl alcohol, or propylene glycol or sorbitol may be used as cosolvents. Combination of alcohols also results into stable compositions. One may use monohydric alcohol or polyhydric alcohol. An alcohol with one single OH group in molecule is monohydric alcohol. Alcohol with more than one OH group in molecule is polyhydric alcohol. As compositions of the present invention are aqueous, presence of little moisture or water vapor in alcohol does not make much difference. It was observed that the relative quantitative proportions of the essential ingredients of the composition were critical for the stability and solubility of the composition of Remimazolam provided in the present invention. Use of indiscriminate quantities of alcohol and amino acid / s result into unstable solutions that exhibit discoloration either immediately or after lapse of some days when stored at room temperature and Remimazolam content falls by more than 5% with or without crystallization. Development of colour indicates formation of some impurity. Presence of precise quantities of alcohol, water, amino acid / s and Remimazolam in relation to each other produces a synergistic clear stable RTU compositions of the invention. The composition comprises amino acid and Remimazolam in a ratio of 0.48:1 to 2.44:1 where both are in milligrammes or milligrams or in mgs. In one embodiment, the ratio of amino acid and Remimazolam is from 0.48:1 to 0.72:1. In one particular embodiment, the ratio of amino acid and Remimazolam is 0.64:1. Alcohol and Remimazolam are present in the composition in a ratio of 12:1 to 28:1, when the amount of alcohol is expressed in % (v / v) and for Remimazolam in mg / ml. This ratio is 0.13:1 to 0.3:1 wherein alcohol is expressed in ml and Remimazolam is expressed in mg; and the same ratio is 98.79:1 to 237.65:1 wherein both alcohol and Remimazolam are expressed in milligrammes or milligrams or in mg. (Calculations: Alcohol from ml is converted to mg by multiplying ml with 0.789 and then by 1000 whereas water in ml is converted to mg multiplying it with 1 and then by 1000. Accordingly, calculations are to be considered). The composition comprises alcohol and amino acid in a ratio of 58.33:1 to 8.2:1, where alcohol is expressed in %(v / v) and amino acid / s in mg. This ratio is 495.1:1 to 67.39:1 when both alcohol and amino acid are expressed in mg. whereas if alcohol is in ml and amino acid in mg., the same ratio is 0.63:1 to 0.09:1 The ratio of water to Remimazolam in the composition is 120:1 to 280:1 when both are expressed in mgs. This ratio is 12:1 to 28:1 when water is expressed as %(v / v) and Remimazolam in mg. This ratio is 0.12:1 to 0.28:1 where water is expressed in ml and Remimazolam is in mg. The composition comprises alcohol (% v / v) and water (% v / v) in a ratio of 0.429:1 to 2.33:1. This ratio is 0.45:1 to 2.51:1 when alcohol and water both are expressed in ml. The ratio is 0.35:1 to 1.98:1 when alcohol and water are expressed in mg. Poor aqueous solubility of Remimazolam causes Remimazolam to crystallize from aqueous and organic solutions. The invention provides therapeutically effective amount of Remimazolam base in clear stable ready to use aqueous injectable compositions suitable for administration by multiple routes. Extent to which Remimazolam could be dissolved into biologically acceptable fluids to provide clear stable aqueous injectable compositions was unknown. Ethyl alcohol 10%v / v or 20% v / v with 1.6mg / ml of L-Histidine did not stabilize Remimazolam. Surprisingly it was noticed that alcohol in proportion from 30%v / v to 70%v / v with at least one amino acid such as 1.6 mg of L-Histidine optionally with another amino acid such as L- Threonine resulted into clear colourless compositions comprising Remimazolam are stable for over 6 months at 25°C / 60%RH or 400c / 75%RH. In another embodiment incorporation of Disodium EDTA resulted into stable composition. Ethyl alcohol content as depicted into following table resulted into clear stable aqueous compositions in presence of amino acid such as L-Histidine optionally with L-Threonine. L-Histidine 1.2 mg / mL to 1.8mg / ml, preferably 1.4 mg / ml to 1.8mg / ml or more preferably 1.6 to 1.8mg / ml optionally with L-Threonine 3mg / ml to 4.5mg / ml result into clear stable compositions in presence of alcohol. It was observed that ratio of alcohol: amino acid such as L-Histidine optionally with L-Threonine is of critical importance to prepare clear stable aqueous RTU Remimazolam compositions. Ratios of Remimazolam, alcohol and amino acid / s and water are critical. More stable compositions are formed when L-Histidine is 1.6mg / ml optionally with L-Threonine from 3mg / ml to 4.5mg / ml. It was observed that ratio of alcohol: amino acid such as L-Histidine optionally with L-Threonine is of critical importance to prepare clear stable aqueous RTU Remimazolam compositions. Ratios of Remimazolam, alcohol and amino acid / s and water are critical. Against prior art limitations, present invention successfully solubilized and stabilized Remimazolam equivalent to 2.5 mg / ml of Remimazolam base to provide clear stable aqueous RTU compositions more specifically injectable compositions. The compositions exhibit viscosity. below 5 cPs at 250C±20C when measured by Ostwald viscometer. In some embodiments viscosity is below 3 cPs. A centipoise (cP) is a unit of measurement for viscosity equivalent to one-hundredth of a poise. Compositions of the present invention were filled in plain and amber USP type I and type II glass vials and ampoules and subjected to stability testing at 40°C / 75%RH, 25°C / 60%RH and 2°C-8°C and were found to be stable. Amber glass containers are preferred. One may fill and pack these solutions in plastic containers. Compositions of the present invention were prepared by method of dissolving ingredients in to aqueous solvents. Process to prepare compositions and working of the invention is described now. Strength of Remimazolam is 2.50 mg / mL. Manufacturing Procedure 1. Take water for injection (WFI) and cool to room temperature to prepare aqueous phase. 2. Add calculated quantity of Alcohol into the aqueous phase obtained in step 1 to prepare the diluent solution. 3. In suitable container take 30% to 50% portion of diluent solution prepared in step 2. Add calculated quantity of at least one amino acid such as L-Histidine (and L-Threonine if it is present in the ingredient list) under mild stirring to dissolve completely to prepare Amino acid solution. 4. Add calculated quantity of Remimazolam Besylate into the Amino acid solution obtained in step 3 and stir well to dissolve to prepare Remimazolam solution. 5. Make up the volume of Remimazolam solution obtained in step 4 with diluent prepared in step 2 to prepare unfiltered solution.6. Check the pH (Limit- 3.1 to 3.4) of the unfiltered solution obtained in step 5 to obtain pH checked solution. 7. Analyze the pH checked solution obtained in step 6 for complete characterization. 8. Optionally filter the pH checked solution obtained in step 6 through 0.22 micron filter, preferably after prefiltration through suitable filter such as 0.45 micron. Fill it into suitable container such as plain or amber coloured glass ampoule / vial of USP Type I or II after flushing nitrogen into container and blanketing it with Nitrogen after filling. Quantitative proportion of water, alcohol, amino acid in relation to active i.e. Remimazolam and in relation to each other is critical to solubilize and stabilize Remimazolam in aqueous solutions wherein the alcohol may be a monohydric or polyhydric alcohol or mixture thereof. The present invention teaches manner to stabilize Remimazolam salt equivalent to 2.5mg of base / ml in aqueous solution. In preferred embodiment clear stable ready to use aqueous compositions fit for parenteral administration, comprising Remimazolam up to 2.5 mg / ml are prepared in presence of ethyl alcohol with or without glycerin. Ethyl alcohol to Propylene glycol in the ratio of 1:10 to 10:1 may be employed. Given procedure, examples enable persons skilled in the art to prepare compositions. Incorporation of more than one alcohol is done by similar procedure as described herein before. Simplest way is to mix more than one alcohol and then add to aqueous phase as described in procedure above. The compositions of the present invention prepared and subjected to sterilization by filtration were subjected to stability study at conditions as mentioned here before and were found to be stable. Stabilization means solubilizing Remimazolam equivalent Remimazolam base 2.5 mg / ml and preventing its crystallization when stored under prescribed storage conditions or if any crystals are formed they go into solution or quickly dissolve when container is stirred or shaken. Stabilization or stable compositions also means that content of Remimazolam and impurities remain within prescribed limits for a specified period from one month to more than 6 months and product conforms to predetermined in-house or pharmacopoeial specifications when stored at 40°C / 75% RH or at 25°C / 60% RH or at 2°C - 8°C storage conditions. Stable compositions also mean % of single impurity and total impurities should be NMT 0.2% and NMT 2.0% respectively. Compositions are very stable and impurities limits were narrowed. 9 month Stability data of composition REM-2301 which is identical to composition C17 of Example 1 has narrower limits for impurities wherein % of single unknown impurity and total impurities should be Not more than (NMT) 0.2% and NMT 1% (without RMMZ acid) respectively. BHDP-1 is reduced to 0.3% and BHDP-2 is reduced to 0.2%. Compositions of the present invention are easily syringeable and can be administered with ease by the health workers. Solvent used in the invention is water with cosolvent. When more than one solvent is used at least one of them is to be interpreted as cosolvent. Preferred cosolvent is an alcohol, either monohydric or polyhydric or mixture of both. Examples of monohydric alcohol are ethyl alcohol or benzyl alcohol. Polyhydric alcohols are Propylene glycol, Monothioglycerol or mixture of both. The most preferred monohydric alcohol is Ethyl alcohol. Polyethylene glycol may be used. Ratio of alcohol%: water% in total composition is 0.429:1 to 2.33:1 and the same is from 0.45:1 to 2.51:1 when alcohol and water both are expressed in ml and is from 0.35:1 to 1.98:1 when both are in milligrammes ie mgs is critical and necessary. Permissible quantities of allowable excipients for use are derived from USFDA inactive ingredient database or such other data base. Antimicrobial preservatives may be selected from but not limited to benzethonium Chloride, m-Cresol, parabens like methyl paraben, propyl paraben, phenol, Benzyl Alcohol, Benzalkonium Chloride, Chlorobutanol, 2- PhenoxyEthanol, Phenyl Mercuric Nitrate, Thimerosal and mixtures thererof. In another embodiment, optionally formulation may comprise chelating agent selected from but not limited to Sodium EDTA, Disodium EDTA, Edetate Calcium Disodium, EDTA Acetic acid salt, Versetamide, Calteridol Calcium and alike. Optionally Surfactants and cosurfactants selected from but not limited to Polysorbates like Polysorbate 20, Polysorbate 80, Lecithin, Polyoxyethylene-Polyoxypropylene copolymers and mixtures thereof may be employed. Optionally one or more Antioxidants selected from but not limited to Sodium Sulfite, Sodium Bisulfite, Cysteine Hydrochloride, Potassium Metabisulfite, Methionine and Monothioglycerol, Dithionite Sodium, Genticic Acid, Genticic Acid Ethanolamine, Propyl Gallate, Alpha Tocopherol, Butylated Hydroxy Toluene, Ascorbyl Palmitate, Ascorbate, Sodium Thioglycolate, Glutathione Formaldehyde Sulfoxylate Sodium, Sodium metabisulfite may be employed. The composition may include tonicity modifier such as sugars (dextrose, mannitol, sucrose, trehalose) and salts (sodium chloride, potassium chloride) or glycerin. The tonicity modifier is selected to adjust the osmolality in the range from 250 mOsm / kg to 700 mOsm / kg. Suitable concentrations of tonicity modifiers are 5.0% mannitol or 0.9% of sodium chloride or upto 20% for trehalose or sucrose can be employed. The pH is critical for maintaining stability of the compositions of the present invention and can be maintained in desired range by employing suitable buffering agents. The pH of the compositions is maintained from 2.5 to 4.5, preferably from 2.5 to 4 and more preferably from 2.9-3.7. The preferable range of pH in which the compositions were found stable is 3.1 to 3.4. Optionally the buffering agents selected from, but not limited to mono or di Potassium Phosphate, Sodium Acetate, Sodium Citrate, monosodium phosphate or disodium phosphate, Meglumine, Methanesulfonic Acid, Disodium Citrate, Trisodium Citrate, Ammonium Sulfate, Ammonium Hydroxide, sodium, potassium or ammonium salt of a weak acid, tris- (hydroxymethyl)-aminomethane, Tris base-65, Tris acetate, Tris HCl -65, boric acid, Maleic acid, Sodium Carbonate, Sodium Bicarbonate, Citric Acid, Benzene Sulfonic Acid, Monoethanolamine, Sodium Succcinate, Disodium Succcinate, Sodium Tartrate, phosphate buffers, citric acid, acetic acid, phosphoric acid, succinic acid with suitable salts, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine, triethanolamine, or any combination thereof may be employed. In another aspect of the invention, formulation may be available with or without Polysorbate 80, with or without Monothioglycerol. In another embodiment, the injectable composition may be filled in USP type I glass (borosilicate glass) or type II glass, plain glass or amber coloured glass vials / ampoules preferably amber coloured USP Type I glass vials / ampoules and vials or PFS or special syringes after aseptic filtration and flushed under nitrogen blanket or terminally sterilized. The composition may be available as single use or multiple use vials or glass ampoules preferably amber glass containers. In another embodiment, closures used may include sealing or rubber stoppers, closures or disc seals, screw-caps or cap-stopper combination seals closures may be used as a component of packaging. Ampoules are heat sealed or hermetically sealed using suitable means. The composition may be sterilized by aseptic filtration. Sterilization can be attained by electron beam irradiation, γ-irradiation, natural light, microwave heat viz. moist heat sterilization or terminal sterilization. Some examples of compositions of the present invention and the process to prepare compositions are given in the examples section. Compositions envisaged, claimed and covered by this invention include all compositions comprising concentrations of Remimazolam salt equivalent to Remimazolam base 2.5 mg / ml of expressed in different volumes. Thus 1.25 mg / 0.5ml or 5mg / 2ml or alike concentrations fall within the ambit of present invention in whichever container or pack size they are presented. Compositions in which additional active is incorporated while ratios of amino acid, alcohol, Remimazolam and water are identical to ranges claimed herein fall within the ambit of claims of this invention. Composition of the formula as depicted in Example 1 was prepared as per the procedure as depicted in Example 2 and was found to be stable for 6 Months at 40°C / 75% RH, 25°C / 60% RH and 2°C - 8°C. Related Substances (RS) or impurities were within the prescribed limits at the end of stability testing intervals. Impurities were found within the prescribed limits at the end of stability testing intervals. While the present invention has been described in terms of a few specific examples, modifications and equivalents thereof, in light of teaching and disclosure of the present invention, which are apparent to the skilled artisan, are to be construed as included within the scope of the invention. The examples are only illustrative in nature . Examples Example 1: Compositions employing different proportions of alcohol are provided. Batch sizes: 5 liters. Compositions C14 - C17 depicted above exhibit viscosity less than 3 cPs at 25°C. Example 2: Manufacturing Procedure: Quantity of water and alcohol to be taken is in same ratio as that in compositions depicted in Example 1. To prepare batch of 5 liters, for C14, C15, C16 and C17 one has to take water 30%, 40%, 50% and 70% of 6 liters respectively and add alcohol 70%,50%, 40% and 30% of 6 liters respectively, to prepare diluent solution, depending upon the composition to be prepared, as per the procedure described below. 1. Taken water for injection (WFI) and cooled to room temperature to obtain aqueous phase. [4.2 liters which is 70% of 6 liters, for C17] 2. Added ethanol into the aqueous phase obtained in step 1 to prepare the diluent solution. [1.8 liters which is 30% of 6 liters, for C17] 3. Taken 30% to 50% of diluent solution prepared in step 2 and added Amino acid L- Histidine (and another amino acid when and if present in the composition) under mild stirring to dissolve completely to prepare Amino acid solution. 4. Added Remimazolam Besylate into the Amino acid solution obtained in step 3 and stirred well to dissolve to prepare Remimazolam solution. 5. Made up the volume of Remimazolam solution obtained in step 4 up to 5 Liters with balance quantity of diluent obtained in step 2 to prepare unfiltered solution. 6. Checked the pH of the unfiltered solution obtained in step 5 to obtain pH checked solution. It was within the Limit- 3.1 to 3.4 7. Analyzed the unfiltered solution obtained in step 5 for complete characterization. 8. Filtered the pH checked solution obtained in step 6 through 0.45 micron prefilter and 0.22 micron filter and filled it into as Amber glass USP Type I vial after flushing nitrogen into the container and blanketing it with Nitrogen after filling into container and subjected it to stability testing. Example 3 Composition T1and T2.Batch size 1 liter and ingredients to be taken accordingly. The compositions are prepared in accordance with the procedure explained in Example 2. Example 4: Stability of the compositions In-House testing procedure for Remimazolam Assay: (By HPLC) Procedure: Buffer: 7.0 mL of triethylamine and 3.0 mL of orthophosphoric acid in 1000 ml water. Mobile phase: Prepare a mixture of Buffer and Acetonitrile (600:400). Diluent: Water. Standard solution: Weigh about 35.0 mg of Remimazolam besylate WS in 250 ml of diluent. Sample solution: take 2.0 mL of sample under analysis in 50 mL volumetric flask and make up the volume with diluent. Mode: LC, Detector: UV 215 nm, Column: 4-mm × 125-cm; 5-μm ODS Hypersil, Column: Ambient, Flow rate: 1.0 mL / min, Injection volume: 20 μL, Suitability requirements: Relative standard deviation: NMT 2.0%, Standard solution. Analysis: Samples: Standard solution and Sample solution Calculate the percentage of Remimazolam besylate equivalent to Remimazolam in the portion of Remimazolam besylate taken: Result = (r U / r S) × (C S / C U) ×0.7352 ×Potency r U = peak response from the Sample solution, r S = peak response from the Standard solution C S = concentration of Remimazolam besylate WS in the Standard solution (mg / mL) C U = concentration of Remimazolam besylate in the Sample solution (mg / mL) Related substances: (By HPLC) Buffer Preparation: 3.48 g of di potassium hydrogen phosphate anhydrous in 1000 ml water, adjust pH to 3.5 ± 0.05 with dilute orthophosphoric acid. Solvent mixture: Acetonitrile: Methanol (700:300), Diluent: Acetonitrile: Water (800:200) Mobile phase A: Buffer: solvent mixture (800:200), Mobile phase B: Solvent mixture. Solution A: Weigh 5 mg of each RMMZ acid, BBDP and BHDP in to a 20 mL volumetric flask sonicate to dissolve and complete to volume with diluent. Solution B: Transfer 3.0 mL of solution A in to 100 mL volumetric flask and complete to volume with diluent. Preparation of system suitability solution: Weigh 25.0 mg Remimazolam besylate WS in to 50 mL volumetric flask add 5.0 mL of solution B and complete to volume with diluent. Standard solution: Weigh 10.0 mg of Remimazolam besylate WS in 20 mL volumetric flask make up to volume with diluent and mix. Transfer 1.0 mL of above solution in to 100 mL volumetric flask and complete to volume with diluent. Take 5.0 mL of this solution in 50 mL volumetric flask and complete to volume with diluent. Sensitivity solution: Transfer 3.0 mL of standard solution in to 10 mL volumetric flask and complete to volume with diluent. Preparation of Test solution: Take 2.0 mL of sample in 10 mL volumetric flask make up to volume with diluent. CHROMATOGRAPHIC CONDITIONS Use a stainless steel column (150 mm x 4.6 mm, 2.7 µm) ( Agilent poroshell 120 EC- C185 is suitable). Ghost buster column: Welch, 4.6 x 50 mm (b) Use gradient elution and the mobile phase described below. (c) Use a flow rate of 1 mL per minute. (d) Use a column temperature of 35°C. (e) Use an autosampler temperature of 10°C. (f) Use a detection wavelength of 230 nm. (g) Inject 5 µL of each solution. (h) Retention time about 11 minutes. Procedure: Analysis: Inject equal volume of Blank, system suitability solution, Placebo solution, standard solution and sample solution. SYSTEM SUITABILITY The RSD of five replicate injection of standard solution should not be more than 10.0%. The tailing factor for Remimazolam besylate peak in standard solution should be NMT 2.0. The resolution factor between RMMZ Acid and BHDP-1 peak should NLT 2.0 in system suitability solution. Calculation: Calculate the % known and unknown impurities by given formula: At Ws 1 5 10 P = ------ × ------× ------ ×------ x----- × --------x 0.7352 (Factor) As 20 100 50 2 LC At = peak response of each impurity from the Sample solution As = peak response of Remimazolam besylate from the Standard solution LC = label claim, 0.7352 = Factor. Example 5: Batch size 1 Liter. Remimazolam Besylate equivalent to Remimazolam 2.5 mg / ml. The compositions are prepared according to the process explained in Example 2. Example 6: 6 Month Stability data of the composition C17 in Example 1. RS means related substances. Limits of RS are stated in specification column. Example 7: 1 Month Stability of Compositions T1and T2from Example 3. Example 8: 1-liter Composition with 65% Ethanol. Remimazolam and L-Histidine in mg / ml. Alcohol and Water expressed as % of total composition, in ml and mgs. Prepared by process similar to Example 2 with pro rata quantities. Example 9: 9 Month Stability data of composition REM-2301 which is identical to composition C17 of Example 1. Comparative examples: Batch sizes 1 liter. Quantities of ingredients are expressed per ml of composition. Comparative Example 1: In Trial 1 and Trial 2 Essential element Alcohol and Amino acid absent respectively. Trial 3 had alcohol content only 20%. Comparative Example 2: Compositions depicted in Example 1 prepared as per procedures given in the specification and subjected to stability testing. Compositions failed in the test of “Description” or “Appearance”, and were unstable, hence were not analyzed further. Comparative Example 3: Compositions with at least one essential element present beyond claimed quantities. Batch size 1 liter. Prepared as per procedure given in the specification. In Trial 4 Alcohol was present in higher quantity and water in lower quantity. L-Histidine was difficultly soluble. Some part remained insoluble. In Trial 5, alcohol was present in lower quantity and water in higher quantity and both were beyond claimed ratios. In Trial 6 and 7 amino acid was present in lower and higher quantities respectively hence amino acid containing ratios were beyond claimed ratios. In Trials 7, part of amino acid remained insoluble. Comparative Example 4: Results of stability testing at 1 month at 400C / 75 % RH and 20C- 80C of compositions in Example 3 When at least one essential element is absent or any one of them is present in quantities higher or lower than claimed, at least one of the ratios of essential elements goes beyond claimed ratios and all such compositions were found unstable at the end of one month. In some Trial compositions, amino acid was difficulty soluble and part remained insoluble. They developed colour, turned hazy or turbid. Thus, in order to prepare clear stable RTU compositions of the invention, all essential elements have to be present and they have to be present in quantities and ratios as claimed.

Claims

aim:

1. A ready to use composition comprising Remimazolam, at least one amino acid, at least one alcohol and water; wherein Remimazolam is present in an amount of 2.5 mg / ml.

2. The composition as claimed in claim 1, wherein the composition comprises amino acid in an amount of 1.2 to 6.1 mg / ml; alcohol in an amount of 30 to70% (v / v); and water in an amount of 70 to 30% (v / v).

3. The composition as claimed in claim 1, wherein the amino acid is present in an amount from 1.6 mg / mL to 6.1 mg / ml; preferably in an amount from 1.6 to 4.6 mg / ml and more preferable in an amount selected from 1.2 mg / ml, 1.4mg / ml, 1.6 mg / ml, 1.8mg / ml, 4.6 mg / ml and 6.1 mg / ml.

4. The composition as claimed in claim 1, wherein alcohol is present in an amount selected from 30% (v / v), 35 % (v / v), 50% (v / v), 60% (v / v), 65% (v / v) and 70% (v / v).

5. The composition as claimed in claim 1, wherein the ratio of alcohol to Remimazolam is from 12:1 to 28:

1.

6. The composition as claimed in claim 1, wherein the ratio of amino acid to Remimazolam is from 0.48:1 to 2.44:1; preferably from 0.48:1 to 0.72:1; and more preferably from 0.64:

1.

7. The composition as claimed in claim1, wherein the ratio of water to Remimazolam is from 12:1 to 28:1 8. The composition as claimed in claim 1, wherein the ratio of alcohol to amino acid is from 58.33:1 to 8.2:

1.

9. The composition as claimed in claim 1, wherein the ratio of alcohol to water is from 0.429:1 to 2.33:1 and preferably from 0.45:1 to 2.51:

1.

10. The composition as claimed in claim 1, wherein the amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, pyroglutamatic, glycine, histidine, hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or a combination thereof.

11. The composition as claimed in claim 10, wherein the composition comprises amino acids Histidine and Threonine, preferably, L-Histidine and L-Threonine.

12. The composition as claimed in claim 10, wherein the composition comprises L- Histidine.

13. The composition as claimed in claim 1, wherein the alcohol is selected from a monohydric, a polyhydric alcohol or mixture thereof.

14. The composition as claimed in claim 13, wherein the alcohol is selected from ethyl alcohol, benzyl alcohol, and propylene glycol.

15. The composition as claimed in claim 13, wherein the alcohol used is ethyl alcohol.

16. The composition as claimed in claim 1 wherein the pH of the compositions is from 2.5 to 4.5, preferably from 2.5 to 4 and more preferably from 3.1 to 3.

4.

17. The composition as claimed in claim 1 wherein the viscosity of compositions is below 5 cPs , preferably below 3 cPs. at 250C+20C.

18. The composition as claimed in claim 1, wherein the composition comprises Remimazolam in an amount of 2.5 mg / ml, the amino acid in an amount of 1.6 mg / ml, the alcohol in amount of 30% v / v and water in an amount of 70% (v / v).

19. The composition as claimed in claim 18, wherein the amino acid is L-histidine and alcohol is ethyl alcohol.

20. The composition as claimed in any preceding claim, wherein the composition comprises one or more pharmaceutically acceptable excipients.

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