CN114668766A

CN114668766A - Pharmaceutical composition of rimazolam

Info

Publication number: CN114668766A
Application number: CN202111597951.8A
Authority: CN
Inventors: 李振斌; 刘艳秀; 刘凯
Original assignee: Fujian Shengdi Pharmaceutical Co ltd; Jiangsu Hengrui Medicine Co Ltd
Current assignee: Fujian Shengdi Pharmaceutical Co ltd; Jiangsu Hengrui Medicine Co Ltd
Priority date: 2020-12-25
Filing date: 2021-12-24
Publication date: 2022-06-28

Abstract

The present disclosure provides a pharmaceutical composition of remazolam. In particular, the present disclosure provides pharmaceutical compositions comprising remazolam or a pharmaceutically acceptable salt thereof and leucine. In the pharmaceutical composition provided by the disclosure, the redissolution effect of the freeze-dried preparation is greatly improved by adding leucine, the redissolution time is shortened to about 30s, and the redissolution solution obtained is clear and free of insoluble substances; the pharmaceutical compositions of the present disclosure also have good stability.

Description

Pharmaceutical composition of rimazolam

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a composition containing remazolam and pharmaceutically acceptable salts thereof.

Background

Remazolam (Remimazolam) chemical name: the (4S) -8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazole [1,2-a ] [1,4] benzodiazepine-4-propionic acid methyl ester has a structural formula shown in a formula (I), is designed by GSK company and developed by PAION company, and has a code number of CNS7056, is an ultra-quick-acting sedative and anesthetic and acts on a GABAA receptor.

Remazolin is a sedative superior to the like products currently used, has quick response and failure, stable sedative effect, short recovery time, short half-life, inactive metabolite, predictable pharmacokinetics, wide treatment window, low potential of interaction among medicaments, reversible sedation of flumazenil and no sedation again. The aim of its development is to obtain a new drug which combines the positive activities of midazolam and propofol, without the associated drawbacks. According to research results, remazol is superior to the two commercially available products, is a breakthrough new chemical entity and is very likely to become a new gold standard in the field of sedation/anesthesia.

CN101501019A discloses the besylate salt of remazolam and its polymorphs and discloses a series of possible compositions it could make, but does not disclose how to obtain a stable composition; CN103221414A, CN109956947A disclose the p-toluenesulfonic acid salt of remazolen and its polymorphic forms, but do not disclose the composition thereof.

CN103202815A discloses a freeze-dried preparation of remazolen containing mannitol or glycine, but in the solution before freeze-drying or after reconstitution, the concentration of remazolen is low, the relative proportion of the auxiliary materials is high, and a large amount of solution is needed for clinical use, which is very inconvenient. CN104968348A discloses a composition of benzodiazepine compound and at least one hygroscopic excipient, especially lactose and/or dextran, but the excipient lactose is an animal-derived excipient, and there is a certain safety risk in large-scale injection due to the possible residual impurity protein in the excipient lactose.

CN107198691A discloses a lyophilized preparation of remazolen containing β -cyclodextrin, which is known to those skilled in the art that β -cyclodextrin as an adjuvant of oral preparations has no safety problem, but β -cyclodextrin has toxicity when administered parenterally, such as forming ulcer after intramuscular injection, and intravenous injection can cause hemolysis and nephrotoxicity.

The remazolin can be hydrolyzed in an aqueous solution and stored for a long time to generate inactive impurities shown as a formula I (impurity A), and a medical composition containing a large amount of remazolin is needed in clinical situations, so that a high-concentration remazolin solution can be prepared in a short time by using a small amount of solvent, the preparation time of clinical medication is shortened, the using amount of auxiliary materials in the remazolin solution is reduced, the using safety risk of the medicine is reduced, the clinical use efficiency is improved, and a better anesthetic effect is achieved.

Disclosure of Invention

The present disclosure provides a pharmaceutical composition comprising remazolam, which greatly improves the reconstitution effect of the lyophilized preparation by adding leucine, the reconstitution time is shortened to about 30s, the solution obtained by reconstitution is clear, and no insoluble substances are present; compared with the prior art, when a patient uses the active ingredient with the same dosage, the dosage of the auxiliary material is lower, and the medicine safety is higher; the pharmaceutical composition disclosed by the invention also has good stability, and after the pharmaceutical composition is placed at 60 ℃ for 0-10 days, the appearance of the product is unchanged, the product is white loose blocks or powder, and the redissolution can be completed within about 30s, wherein the content of the impurity A is not higher than 1.5%, the content of other single impurities is not higher than 1.0%, and the content of total impurities is not higher than 2.0%.

The present disclosure provides a composition comprising remazolam or a pharmaceutically acceptable salt thereof and leucine.

Wherein, the remazolam pharmaceutically acceptable salt includes but is not limited to tosylate, besylate, isethionate, esylate, mesylate, hydrochloride, hydrobromide, acetate, propionate, sulfate, phosphate, lactate, succinate, maleate, fumarate, tartrate, citrate, malate, citrate, p-toluenesulfonate, 1, 5-naphthalenedisulfonate, 2-naphthalenesulfonate, oxalate, amino acid salt and other common inorganic acid salts; remazolam p-toluenesulfonate is preferred.

In the pharmaceutical composition, the mass ratio of remazolam or pharmaceutically acceptable salt thereof to leucine in terms of free base is 20: 1-1: 20, 5: 1-1: 20, 10: 1-1: 10, 2: 1-1: 10, 1: 1-1: 10, 5: 1-1: 5, 2: 1-1: 5, 1: 1-1: 4, 1:2-1:4 and 1:2-1: 3.

The pharmaceutical composition of the present disclosure may be a solution before lyophilization, or may be a solid preparation after lyophilization, or may be a solution obtained after reconstitution of a solid preparation after lyophilization.

In certain embodiments, the pharmaceutical composition is a solid form formulation after lyophilization; the lyophilized solid form preparation is often described as a lyophilized powder or lyophilized preparation.

In certain embodiments, the pharmaceutical composition is a pre-lyophilization solution.

In certain embodiments, the pharmaceutical composition is a solution obtained after reconstitution of a lyophilized solid form formulation.

In the pharmaceutical composition of the present disclosure, the content of leucine is 1.0 to 50mg, 1.0 to 30mg, 1.0 to 20mg, 1.0 to 15mg, 1.0 to 10mg, 2.0 to 20mg, 2.0 to 15mg, 3.0 to 20mg, 3.0 to 15mg, or 3.0 to 10mg per ml of the composition in the solution before lyophilization.

In certain embodiments, a metal ion chelating agent selected from disodium edetate, calcium sodium edetate, disodium calcium edetate; wherein the mass ratio of the remazolam or the pharmaceutically acceptable salt thereof to the metal ion chelating agent calculated by free base is 30:1-1:1, or 30:1-3:1, or 20:1-5:1, or 20:1-10:1, or 15:1-5:1, or 15:1-10: 1.

In certain embodiments, the concentration of remazolam or a pharmaceutically acceptable salt thereof in the solution before lyophilization is selected from 0.1 to 50mg/ml, further selected from 0.5 to 30mg/ml, further selected from 0.5 to 20mg/ml, further selected from 1 to 15mg/ml, further selected from 1 to 5mg/ml, based on remazolam base. In particular, in certain embodiments, the concentration of remazolam or a pharmaceutically acceptable salt thereof in the solution prior to lyophilization, based on remazolam base, can be 2.0mg/ml, 2.1mg/ml, 2.2mg/ml, 2.3mg/ml, 2.4mg/ml, 2.5mg/ml, 2.6mg/ml, 2.7mg/ml, 2.8mg/ml, 2.9mg/ml, 3.0mg/ml, 3.1mg/ml, 3.2mg/ml, 3.3mg/ml, 3.4mg/ml, 3.5mg/ml, 3.6mg/ml, 3.7mg/ml, 3.8mg/ml, 3.9mg/ml, 4.0mg/ml, 4.1mg/ml, 4.2mg/ml, 4.3mg/ml, 4.4mg/ml, 4.5mg/ml, 4.6mg/ml, 4.7mg/ml, 4.1mg/ml, 4.2mg/ml, 4.3mg/ml, 4.4.5 mg/ml, 4.6mg/ml, 4.9mg/ml, 4.0mg/ml, 4.5mg/ml, 4.9mg/ml, 4mg/ml, 4.5mg/ml, 4.9mg/ml, 4.5mg/ml, 4mg/ml, 4.5mg/ml, 4.9mg/ml, or a, 5.1mg/ml, 5.2mg/ml, 5.3mg/ml, 5.4mg/ml, 5.5mg/ml, 5.6mg/ml, 5.7mg/ml, 5.8mg/ml, 5.9mg/ml, 6.0 mg/ml.

In the pharmaceutical composition of the present disclosure, the pH of the pharmaceutical preparation is selected from 2.0 to 5.0, preferably 2.5 to 4.5, and more preferably 3.0 to 4.0. In some embodiments, the pH may be 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0.

In certain embodiments, a collapse temperature modifier is further included, wherein the collapse temperature modifier is selected from the group consisting of hydroxyethyl starch, glucose, fructose, galactose, mannitol, galactosamine, glucosamine, polyvinylpyrrolidone, inorganic salts; the collapse temperature regulator can also be selected from polyvidone K12, polyvidone K17, mannitol, trehalose, sodium carboxymethylcellulose, sodium chloride, hydroxyethyl starch; the collapse temperature regulator can also be selected from hydroxyethyl starch, mannitol; the collapse temperature modifier may also be selected from mannose.

The pharmaceutical composition disclosed by the disclosure, wherein the mass ratio of the collapse temperature regulator to remazolen or pharmaceutically acceptable salt thereof in terms of free base is 10: 1-0.1: 1; or 10:1 to 1: 1; or 7: 1-1: 1; or 5: 1-1: 1; or 3: 1-1: 1; or 3: 1-2: 1.

The pharmaceutical composition disclosed by the disclosure, wherein the mass ratio of the collapse temperature regulator to leucine is 1: 10-1: 0.1; or 1: 5-5: 1; or 1: 1-3: 1; or 1:1 to 2: 1.

In a particular embodiment, the collapse temperature modifier is present in an amount of from 0.1 to 50mg, preferably from 0.1 to 30mg, more preferably from 0.1 to 20mg, more preferably from 0.1 to 15mg, more preferably from 0.1 to 10mg per ml of the composition in the solution prior to lyophilization; specifically, the amount of the compound may be 0.5mg, 1.0mg, 1.5mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 5.5mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg, 9.0mg, 9.5mg, 10.0mg, 10.5mg, 11.0mg, 11.5mg, 12.0mg, 12.5mg, 13.0mg, 13.5mg, 14.0mg, 14.5mg, 15.0 mg.

When the pharmaceutical composition is a solution obtained after the reconstitution of a lyophilized solid form preparation, the pharmaceutical composition comprises 1mg/ml to 5mg/ml of remazolen or pharmaceutically acceptable salt thereof in terms of free base; preferably 1mg/ml to 4 mg/ml; more preferably 1mg/ml to 3 mg/ml; more preferably 1mg/ml to 2 mg/ml; most preferably 2 mg/ml.

The pharmaceutical composition of the present disclosure, when the pharmaceutical composition is a solution obtained after reconstitution of a lyophilized solid form preparation, comprises leucine at a concentration of 1mg/ml to 20mg/ml, preferably 1mg/ml to 15mg/ml, more preferably 2mg/ml to 15mg/ml, and more preferably 3mg/ml to 10 mg/ml.

The pharmaceutical composition of the present disclosure, when the pharmaceutical composition is a solution obtained after reconstitution of a lyophilized solid form preparation, comprises mannitol in a concentration of 1mg/ml to 10mg/ml, preferably 1mg/ml to 8mg/ml, and more preferably 1mg/ml to 5 mg/ml.

The pharmaceutical composition of the present disclosure, when the pharmaceutical composition is a solution obtained after reconstitution of a lyophilized solid form preparation, comprises calcium disodium edetate at a concentration of 0.1-1.0mg/ml, preferably 0.1-0.5 mg/ml.

The lyophilized solid form preparations described in the present disclosure may be reconstituted with various aqueous diluents widely known in the art, such as water for injection, physiological saline, 5% aqueous glucose solution, and the like, suitable for intravenous injection solvents, to obtain a solution for injection. The normal saline is selected from 9% sodium chloride injection.

The pharmaceutical composition disclosed by the disclosure, wherein the mass of remazolam or pharmaceutically acceptable salt thereof calculated by free base is 5% -60%, or 5% -50%, or 5% -45%, or 10% -40%, or 10% -38%, or 10% -36%, or 10% -35%, or 10% -33%, or 10% -32%, or 10% -31%, or 10% -30%, or 10% -28%, or 10% -25%, or 10% -23%, or 15% -40%, or 15% -38%, or 15% -36%, or 15% -35%, or 15% -33%, or 15% -32%, or 15% -31%, or 15% -30%, or 15% -28% of the total mass of solid matters in the pharmaceutical composition, Or 15% -25%, or 15% -23%.

The pharmaceutical composition disclosed by the disclosure, wherein the mass of the leucine is 10% -90%, or 20% -90%, or 25% -90%, or 30% -90%, or 15% -80%, or 20% -70%, or 20% -65%, or 20% -60%, or 25% -60%, or 30% -60% of the total mass of the solid matters in the pharmaceutical composition.

The pharmaceutical composition of the present disclosure, wherein the mass of calcium disodium edetate is 0.1% -10%, or 0.5% -8%, or 0.5% -7%, or 0.5% -6%, or 0.5% -5%, or 1.0% -10%, or 1.0% -8%, or 1.0% -7%, or 1.0% -6%, or 1.0% -5% of the total mass of the solid in the pharmaceutical composition.

The pharmaceutical composition of the disclosure, wherein the mass of the collapse temperature regulator is 0% -60%, or 0% -55%, or 0% -50%, or 0% -45%, or 5% -50%, or 10% -50% of the total mass of the solids in the pharmaceutical composition. Wherein the collapse temperature regulator can be hydroxyethyl starch or mannitol or other ones conventionally selected by those skilled in the art, or can be a combination of hydroxyethyl starch and mannitol or other ones conventionally selected by those skilled in the art.

The pharmaceutical composition of the present disclosure, wherein the solid in the pharmaceutical composition is the substance of the composition without the aqueous diluent, and the total mass of the solid is the mass of the pharmaceutical composition without the aqueous diluent, and may be approximately the total weight when the pharmaceutical composition is a lyophilized solid preparation.

The pharmaceutical composition of the present disclosure comprises, based on the total mass of solids in the pharmaceutical composition:

1) 5% -50% of remazolam or a pharmaceutically acceptable salt thereof based on the free base; preferably 5% to 40% remazolam or a pharmaceutically acceptable salt thereof, calculated as the free base;

2) 20% -90% of leucine;

3) 0-60% mannitol and/or hydroxyethyl starch;

4) 0.5% -5% of calcium disodium edetate.

1) 10% -30% of remazolam or a pharmaceutically acceptable salt thereof based on free base;

2) 20% -90% of leucine; preferably 20% to 60% leucine;

3) 10% -60% of mannitol and/or hydroxyethyl starch;

4) 0.5% -5% of calcium disodium edetate.

The concentration of remazolam or pharmaceutically acceptable salt thereof in a solution obtained after reconstitution with an aqueous diluent is 0.01-30 mg/ml, preferably 0.5-10 mg/ml, more preferably 1-5 mg/ml, more preferably 1-3mg/ml, more preferably 1-2mg/ml, more preferably 2mg/ml in terms of free base.

The present disclosure provides a pharmaceutical composition, wherein reconstitution of a lyophilized solid form formulation using an aqueous diluent can be completed within about 1min, i.e., a clear and transparent solution is formed, wherein no insoluble solids are present in the solution, preferably within about 45s, more preferably within about 30 s. In the present disclosure, "about" means a regimen that includes an error of ± 5%.

The present disclosure provides a pharmaceutical composition, wherein the content of impurity a is not higher than 2.0% when the lyophilized solid form preparation thereof is left for 0-10 days at 60 ℃; preferably, the content of the impurity A is not higher than 1.5%; the content of the impurity A is preferably not more than 1.0%.

The present disclosure provides a pharmaceutical composition having a content of other single impurities of not higher than 1.0%, preferably not higher than 0.8%, more preferably not higher than 0.5%, more preferably not higher than 0.3%, more preferably not higher than 0.2%, more preferably not higher than 0.1% when the lyophilized solid form preparation is left for 0 to 10 days at 60 ℃.

The present disclosure provides a pharmaceutical composition having a total impurity content of not higher than 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1% when the lyophilized solid form preparation is left for 0-10 days at 60 ℃.

Wherein the other single impurity is a substance that has a retention time of about 19.6min when the detection method described in the present disclosure is used.

The pharmaceutical composition of the present disclosure does not contain glycine, and the absence of glycine is no glycine addition.

On the other hand, the disclosure also provides a method for preparing the composition containing the remazolen and the pharmaceutically acceptable salt thereof, and the method is simple to operate, good in reproducibility and easy to industrialize. The method comprises the following steps:

1) Dissolving leucine and calcium disodium edetate in water solvent, adjusting pH value with acid,

2) adding remazolin or pharmaceutically acceptable salt thereof,

3) the aqueous solvent was added to the final volume.

In certain embodiments, further comprising the step of lyophilizing the solution obtained in step 3).

In certain embodiments, the solution resulting from step 3) is a pre-lyophilization solution.

The aqueous solvent described in the present disclosure includes, but is not limited to, an aqueous diluent or a mixed system of an organic solvent and water, wherein the organic solvent may be selected from alcohols, such as methanol, ethanol, propylene glycol, isopropanol, and other common monohydric or dihydric alcohols.

The contents (including percentages) and ratios of the various substances described in this disclosure are all allowed to be within a tolerance of + -5%.

The terms "mixing" and "mixing" in the present disclosure mean not to limit the order of addition of the components, and for example, mixing a into B may mean adding a into B, or may mean adding B into a, or mixing a and B may mean adding a into B, or may mean adding B into a.

Detailed Description

The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way. In the embodiment of the invention, the detection of related substances is carried out by using a high performance liquid chromatograph, and the type of the high performance liquid chromatograph is as follows: agilent 1260 or Thermo U3000, the detection conditions are as follows:

A chromatographic column: the specific model of the filler of octadecylsilane chemically bonded silica is Kromasil C184.6mm multiplied by 250mm and 5 mu m;

detection wavelength: 230nm, flow rate: 1.0ml/min, column temperature: 45 ℃, sample introduction: 10 mu l of the mixture;

mobile phase A: 0.01mol/L ammonium dihydrogen phosphate buffer solution (1.15 g ammonium dihydrogen phosphate, water 800ml for dissolution, 0.5ml triethylamine, pH 3.8 adjusted with phosphoric acid, water 1000ml for dilution)

Mobile phase B: acetonitrile

Gradient:

comparative example 1

The adjuvants of the prescription amount in Table 1 were sequentially added into water for injection, stirred to dissolve, then the pH was measured, and the pH was adjusted with 3M HCl. Then the prescribed amount of remazolam tosylate was added and stirred until dissolved. And finally adding water for injection to a constant volume, and uniformly stirring. Filtering with 0.22umPES filter membrane, loading into penicillin bottles according to the filling amount, marking the outer walls of the bottles, half plugging, and freeze-drying.

TABLE 1

Specifically, as shown in table 2, when the mass of remazolam or a pharmaceutically acceptable salt thereof in the solution before lyophilization is 50mg calculated as a free base, lyophilization is performed by using the lyophilization procedure shown in retention time-1, and when the mass of remazolam or a pharmaceutically acceptable salt thereof in the solution before lyophilization is 100mg calculated as a free base, lyophilization is performed by using the lyophilization procedure shown in retention time-2.

TABLE 2

TABLE 3

And (3) redissolving the obtained freeze-dried preparation by using a 0.9% sodium chloride solution, wherein the concentration of the redissolved preparation is calculated by remazolam or pharmaceutically acceptable salt thereof as free base. As can be seen from the data in Table 3, when glycine was used as an excipient in the comparative example, the reconstitution time of the lyophilized preparation was still long when the amount was increased from 7.5mg/ml to 40mg/ml, insoluble substances were present, and the reconstitution effect was not satisfactory; when the freeze-dried preparation is prepared before infusion, if the reconstitution time is too long, not only the efficiency of clinical operation is affected and the use of a patient is delayed, but also the possibility of pollution is increased due to the too long preparation time, and microorganisms and the like are introduced, so that the safety problem of the medicine is caused.

Example 1

Example 1 the preparation method is substantially the same as that of comparative example 1, a lyophilized powder injection preparation (filling amount is 10ml) with the specification of 10mg/ml (calculated by remazolen free base) is prepared by using remazolen tosylate, and the preparation formula is re-dissolved to obtain a solution with the concentration of 2mg/ml (calculated by remazolen free base).

TABLE 4

As can be seen from the data in Table 4, the reconstitution time is not ideal when the lyophilized preparation is prepared by using glycine/trehalose, glycine/mannitol, and glycine/sodium chloride, and the reconstitution time is greatly shortened after leucine is added into the preparation.

Example 2

Example 2 the preparation method is substantially the same as that of comparative example 1, and the freeze-dried powder injection preparation is prepared by using the remazolam tosylate, and the specifications of the preparation are calculated by remazolam free base.

TABLE 5

Redissolving the prescription of the preparation to obtain a solution with the concentration of 2mg/ml (calculated by remazolin free alkali), and dissolving the solution clearly within 30 s; the lyophilized preparation was placed at 60 ℃ for the purpose of investigating the stability of the preparation.

TABLE 6

According to the data in table 6, the formulations in table 5 all have good stability, and the freeze-dried formulations of 0-10 days are white loose blocks or powder in appearance and can be re-dissolved within 30s, wherein the impurity a is the impurity shown in formula II, and the retention time of other single impurities is 19.6min when the detection method disclosed by the application is used.

Example 3

Example 3 was prepared in substantially the same manner as in comparative example 1 using remazolam tosylate to produce a lyophilized formulation, all as remazolam free base.

TABLE 7

Re-dissolving the preparation prescription to obtain a solution with the concentration of 2mg/ml (calculated by remazolam free base), and dissolving the solution clearly within 30 s; the lyophilized preparation was placed at 60 ℃ for the purpose of investigating the stability of the preparation.

TABLE 8

According to the data in table 8, the formulations of the formulations 14 to 21 in table 7 all have good stability, and the freeze-dried formulations of 0 to 10 days are white loose blocks or powder all the time, and can be re-dissolved within 30s, wherein the impurity A is the impurity shown in the formula II, and the retention time of other single impurities is 19.6min when the detection method disclosed by the application is used.

Claims

1. A pharmaceutical composition comprising remazolam or a pharmaceutically acceptable salt thereof and leucine.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of remazolam is selected from the group consisting of benzenesulfonate, p-toluenesulfonate, isethionate, hydrobromide, methanesulfonate, ethanesulfonate, 1, 5-naphthalenedisulfonate, hydrochloride, sulfate, 2-naphthalenesulfonate, ethanedioate, amino acid salt; remazolam p-toluenesulfonate is preferred.

3. The pharmaceutical composition according to claim 2, wherein the mass ratio of remazolam or its pharmaceutically acceptable salt to leucine in terms of free base is selected from 5: 1-1: 20, preferably 2: 1-1: 10, more preferably 1: 1-1: 5, more preferably 1: 1-1: 4, and most preferably 1: 2-1: 3.

4. The pharmaceutical composition of claim 1, further comprising a metal ion chelating agent selected from the group consisting of disodium edetate, calcium sodium edetate; calcium sodium edetate is preferred.

5. The pharmaceutical composition according to claim 4, wherein the mass ratio of remazolam or a pharmaceutically acceptable salt thereof to the metal ion chelating agent, calculated as the free base, is selected from 30:1 to 1:1, preferably 30:1 to 3:1, more preferably 20:1 to 5:1, more preferably 15:1 to 10: 1.

6. The pharmaceutical composition according to any one of claims 4 to 5, wherein the mass of remazolam or a pharmaceutically acceptable salt thereof, calculated as the free base, is between 10% and 45%, preferably between 15% and 40%, more preferably between 15% and 40%, most preferably between 15% and 38% of the total mass of the solids in the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pH of the pharmaceutical composition is selected from the group consisting of 2.0 to 5.0, preferably 2.5 to 4.5, more preferably 3.0 to 4.0.

8. The pharmaceutical composition of any one of claims 1-7, further comprising a collapse temperature modifier.

9. The pharmaceutical composition of claim 8, wherein the collapse temperature modifier is selected from the group consisting of hydroxyethyl starch, glucose, fructose, galactose, mannitol, leucine, galactosamine, glucosamine, polyvinylpyrrolidone, inorganic salts; preferably povidone K12, povidone K17, mannitol, trehalose, sodium carboxymethylcellulose, sodium chloride, hydroxyethyl starch; more preferably the collapse temperature modifier is selected from hydroxyethyl starch, mannose; mannitol is most preferred.

10. The pharmaceutical composition according to claim 9, wherein the mass ratio of the collapse temperature regulator to the remazolam or the pharmaceutically acceptable salt thereof is 10: 1-0.1: 1 on a free base basis; preferably 5: 1-1: 1; more preferably 3:1 to 1: 1; most preferably 3:1 to 2: 1.

11. The pharmaceutical composition according to claim 9, wherein the mass ratio of the collapse temperature regulator to leucine is 1: 10-1: 0.1; preferably 1: 5-5: 1; more preferably 1:1 to 3: 1; most preferably 1:1 to 2: 1.

12. The pharmaceutical composition of any one of claims 1-11, comprising, based on the total mass of solids in the pharmaceutical composition:

1) 5% -50% of remazolam or a pharmaceutically acceptable salt thereof based on free base; preferably 5% to 40% remazolam or a pharmaceutically acceptable salt thereof, calculated as the free base;

2) 20% -90% of leucine;

3) 0-60% mannitol and/or hydroxyethyl starch;

4) 0.5% -5% of calcium disodium edetate.

13. The pharmaceutical composition according to any one of claims 1 to 12, comprising, based on the total mass of solids in the pharmaceutical composition:

1) 10% -30% of remazolam or a pharmaceutically acceptable salt thereof as a free base;

2) 20% -90% leucine; preferably 20% to 60% leucine;

3) 10% -60% of mannitol and/or hydroxyethyl starch;

4) 0.5% -5% of calcium disodium edetate.

14. The pharmaceutical composition of any one of claims 1-13, which is a lyophilized solid form formulation.

15. The pharmaceutical composition according to claim 2, wherein remazolam or a pharmaceutically acceptable salt thereof is included at a concentration of 1mg/ml to 5mg/ml in terms of free base; preferably 1mg/ml to 4 mg/ml; more preferably 1mg/ml to 3 mg/ml; more preferably

1mg/ml-2 mg/ml; most preferably 2 mg/ml.

16. The pharmaceutical composition according to claim 2, wherein leucine is comprised in a concentration of 1mg/ml to 20mg/ml, preferably 1mg/ml to 15mg/ml, more preferably 2mg/ml to 15mg/ml, more preferably 3mg/ml to 10 mg/ml.

17. The pharmaceutical composition according to claim 9, wherein mannitol is included in a concentration of 1mg/ml to 10mg/ml, preferably 1mg/ml to 8mg/ml, more preferably 1mg/ml to 5 mg/ml.

18. The pharmaceutical composition according to claim 4, wherein calcium disodium edetate is contained in a concentration of 0.1-1.0mg/ml, preferably 0.1-0.5 mg/ml.

19. The pharmaceutical composition according to claim 14, which upon reconstitution with an aqueous diluent results in a pharmaceutical composition according to any one of claims 15-18.

20. The pharmaceutical composition of any one of claims 1-19, wherein glycine is absent.

21. A method of preparing a composition according to any one of claims 1 to 20, comprising the steps of:

2) adding remazolin or pharmaceutically acceptable salt thereof,

3) the aqueous solvent is added to the final volume.

22. The method of claim 21, further comprising the step of lyophilizing the solution obtained in step 3).