CN104825431A - Pharmaceutical composition of compound diisopropylamine dichloroacetate freeze-dried powder for injection - Google Patents

Abstract

The present invention relates to a compound diisopropylamine dichloroacetate freeze-dried powder injection pharmaceutical composition for injection. Specifically, on the one hand, the present invention relates to a freeze-dried powder injection pharmaceutical composition, which contains diisopropylamine dichloroacetate and sodium gluconate, and an optional acid-base regulator. The weight ratio of the diisopropylamine dichloroacetate to the sodium gluconate is 40:30-50. On the other hand, the present invention also relates to a method for preparing the compound diisopropylamine dichloroacetate freeze-dried powder injection pharmaceutical composition for injection, which comprises a liquid preparation process and a freeze-drying process. The compound diisopropylamine dichloroacetate freeze-dried powder injection for injection of the present invention can be used for fatty liver, intrahepatic cholestasis, as well as acute and chronic hepatitis, hepatomegaly, and early liver cirrhosis. The freeze-dried powder injection pharmaceutical composition of the present invention has desired good properties.

Description

Pharmaceutical composition of compound diisopropylamine dichloroacetate freeze-dried powder for injection

technical field

The invention belongs to the technical field of medicine and relates to a freeze-dried powder injection pharmaceutical composition for protecting the liver, which can be used for fatty liver and intrahepatic cholestasis. This product is used for acute and chronic hepatitis, hepatomegaly, and early liver cirrhosis. In particular, the present invention relates to a pharmaceutical composition of compound diisopropylamine dichloroacetate freeze-dried powder for injection. The active ingredients of the composition include: diisopropylamine dichloroacetate and sodium gluconate. The freeze-dried powder injection pharmaceutical composition of the present invention has expected good properties.

Background technique

Diisopropylamine Dichloroacetate is diisopropylamine dichloroacetate (1:1), its molecular formula is C8H17O2NCl2, its molecular weight is 230.14, and its CAS registration number is 660-27-5. The chemical structural formula of diisopropylamine dichloroacetate is:

The synonyms of diisopropylamine dichloroacetate include dichloroacetic acid diisopropylammonium salt, diisopropylammonium dichloroacetate, diisopropylamine dichloroethanoate, DADA, DIPA-DCA, DIEDI, etc. Common foreign commercially available products have trade names such as Disotat (Isis), Kalodil (Fidia), Oxypangam (Sanorania) and so on. The synthesis of diisopropylamine dichloroacetate is referring to GB 862248 (1961, Italseber). For the pharmacology of diisopropylamine dichloroacetate see: V.A.E. Kraushaar et al., Arzneim.-Forsch. 13, 109 (1963). For the Ames mutagenicity test of diisopropylamine dichloroacetate see: M.D.Gelernt, V.Herbert, Nutr.Cancer 3, 129 (1982). For the pharmacokinetics of diisopropylamine dichloroacetate see: J.-M.Yang et al., Gen. Pharmacol.19, 683 (1988). For a pharmacological review of diisopropylamine dichloroacetate, see P.W.Stacpoole, J.Clin.Pharmacol.J.New Drugs 9, 282-291 (1969). Diisopropylamine dichloroacetate is a white crystalline powder with a slightly bitter taste. Diisopropylamine dichloroacetate is easily soluble in water, ethanol or chloroform, slightly soluble in ether, and almost insoluble in petroleum ether. The melting point of diisopropylamine dichloroacetate (Appendix VIC) is 119-122°C. Oral LD50 of mice with diisopropylamine dichloroacetate: 1700mg/kg (Kraushaar).

Sodium gluconate is also known as sodium pentahydroxyhexanoate, D-Gluconate sodium salt, etc., molecular formula: C6H11NaO7, molecular weight: 218.14, CAS registration number: 527-07-1. Sodium gluconate is white or light yellow crystalline powder, melting point (°C): 206, acute toxicity of sodium gluconate: rabbit intravenous LD50: 7630mg/kg. Solubility of sodium gluconate in water (25°): 59g/100ml, slightly soluble in ethanol, insoluble in ether.

Compound drugs consisting of diisopropylamine dichloroacetate and sodium gluconate have been on the market for many years. Typical preparations include freeze-dried powder injections and small water injections, while tablets use a combination of diisopropylamine dichloroacetate and calcium gluconate.

A typical freeze-dried powder injection compound drug consisting of diisopropylamine dichloroacetate and sodium gluconate is produced by Shandong Beida Gaoke Huatai Pharmaceutical Co., Ltd., the product name is Erqi, the approval number is Guoyao Zhunzi H20052437, and the official generic name is: Compound diisopropylamine dichloroacetate for injection, English name: Compound Diisopropylamine Dichloroacetate for Injection. The usual formulation specification of this product is that each bottle contains 40mg of diisopropylamine dichloroacetate and 38mg of sodium gluconate. There is also compound diisopropylamine dichloroacetate for injection containing 80 mg diisopropylamine dichloroacetate and 76 mg sodium gluconate per bottle on the market.

Commercially available compound diisopropylamine dichloroacetate freeze-dried powder for injection is white or off-white loose block or powder. Its indications are liver-protecting drugs; it is used for fatty liver and intrahepatic cholestasis. This product is used for acute and chronic hepatitis, hepatomegaly, and early liver cirrhosis.

The dosage of commercially available compound diisopropylamine dichloroacetate freeze-dried powder for injection is as follows: intramuscular injection: dissolve with an appropriate amount of water for injection, 40 mg once (calculated as diisopropylamine dichloroacetate), 1-2 times/day; .Intravenous injection: dissolved in appropriate amount of water for injection, 40mg once (calculated as diisopropylamine dichloroacetate), 1-2 times/day; 3. Intravenous infusion: 40-80mg once (calculated as diisopropylamine dichloroacetate) , 1-2 times/day, dissolve with an appropriate amount of water for injection, and then dilute to an appropriate amount (50-100ml) with 5% or 10% glucose solution, or 0.9% sodium chloride solution. Please follow the doctor's advice for the course of treatment. During the infusion, the infusion rate should be slowed down and the patient should be bedridden. Use with caution in patients with hypotension. In individual cases during injection, temporary discomfort, such as dizziness, nausea and vomiting, can be taken to slow down the injection speed and make the patient rest in bed.

Pharmacology and toxicology of compound diisopropylamine dichloroacetate freeze-dried powder for injection: 1. Effects on fatty liver: (1) consumption of liver fat: this product is decomposed into diisopropylamine and dichloroacetic acid in vivo, and the former is activated by ATP Under the action of methionine, the latter is metabolized into glycine, and under the action of glycine lyase, N5N10-CH2-FH4 (methyltetrahydrofolate) is generated, and energy is supplied at the same time. Both can provide methyl groups to promote the synthesis of choline , Choline interacts with liver fat to generate lecithin, which promotes the decomposition of liver fat; (2) Run liver fat: Lecithin, liver fat, cholesterol and apolipoprotein combine to form lipoprotein. Lipoproteins are easily soluble in plasma, thereby transferring fat from the liver to the outside of the liver, reducing the accumulation of fat in the liver; (3) This product can reduce the concentration of glycerol and free fatty acids in arterial blood, reduce the absorption of glycerol by the liver, and at the same time Stimulate triglycerides to enter the blood as very low-density lipoprotein (VLDL), thereby effectively inhibiting the synthesis of triglycerides in the liver. 2. Effects on lipid metabolism: (1) This product inhibits fat mobilization by inhibiting the activity of hormone-sensitive lipase; (2) Inhibits the synthesis of cholesterol by inhibiting the activity of the rate-limiting enzyme (HMGCoA reductase) for synthesizing cholesterol. (3) Inhibit the synthesis of fatty acids by inhibiting the activities of citrate synthase and acetyl-CoA carboxylase in the citric acid-pyruvate cycle. 3. Liver protection: (1) Improve the energy metabolism of liver cells. Enhances the fluidity of hepatocyte membranes by promoting the sequential methylation of membrane phospholipids. (2) Improve the activity of Na+-K+-ATPase, which is the main driving force of bile secretion and flow; promote the functional repair of damaged liver cells and improve the respiratory function and oxygen utilization rate of tissue cells. (3) Improve the metabolic activity of fatty acids, accelerate the oxidation of fatty acids, and create conditions for the recovery of liver function.

Freeze-dried preparations are generally prepared by freeze-drying technology, that is, the drug solution to be dried is pre-frozen into a solid, and then under low temperature and low pressure conditions, water is directly sublimated from the solid state without passing through the liquid state. However, in order to ensure the quality of the preparation and the feasibility of the process, auxiliary materials (also known as carriers or support agents) are usually added to the prescription of the drug, such as adding an appropriate amount of mannitol, lactose, dextran, glucose, sodium chloride, phosphate wait. Adding excipients to the lyophilized preparation is beneficial to the molding of the preparation and the feasibility of the process, but the addition of excipients is obviously insufficient: (1) increases the production cost of the preparation; (2) increases the complexity of the formulation and improves the quality control of the drug (3) A large amount of exogenous substances are introduced into the body when the patient injects the drug intravenously, which increases the possibility of causing harm to the patient's body.

Therefore, those skilled in the art still look forward to providing a freeze-dried powder injection compound pharmaceutical preparation composed of diisopropylamine dichloroacetate and sodium gluconate with good pharmaceutical properties for clinical use.

Contents of the invention

The object of the present invention is to provide a freeze-dried powder injection containing both diisopropylamine dichloroacetate and sodium gluconate with some/certain good properties, and it is expected to have one or more good pharmaceutical properties. The present inventors surprisingly found that the freeze-dried powder injection containing both diisopropylamine dichloroacetate and sodium gluconate with a specific formula has desirable good characteristics. The present invention has thus been accomplished.

In addition, the object of the present invention is to provide a freeze-dried preparation of compound diisopropylamine dichloroacetate for injection without any auxiliary materials and a preparation process: the addition of auxiliary materials can be completely avoided through the present invention, so that the quality of the preparation is easier to control, The production cost is reduced, and the drug safety of patients is more assured.

Due to the properties of diisopropylamine dichloroacetate and sodium gluconate, it cannot be prepared into a freeze-dried preparation without auxiliary materials by using common freeze-drying techniques. The technical key of the present invention is to use a special freeze-drying technique of multiple pre-freezing and sublimation methods to achieve the purpose of the invention. The technical key can significantly improve the crystallization behavior and air permeability of freeze-dried samples, so that water vapor can escape smoothly and sublimation The process went smoothly.

Therefore, the first aspect of the present invention provides a freeze-dried powder injection comprising diisopropylamine dichloroacetate and sodium gluconate.

The freeze-dried powder injection according to any embodiment of the first aspect of the present invention, wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:30-50.

The freeze-dried powder injection according to any embodiment of the first aspect of the present invention, wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:35-45.

The freeze-dried powder injection according to any embodiment of the first aspect of the present invention, wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:38.

The freeze-dried powder injection according to any embodiment of the first aspect of the present invention does not contain freeze-dried excipients. For example, it does not contain sucrose, glucose, mannitol, lactose, sorbitol, glycine, etc.

The freeze-dried powder injection according to any embodiment of the first aspect of the present invention further comprises an acid-base regulator.

According to the freeze-dried powder injection according to any embodiment of the first aspect of the present invention, wherein the acid-base regulator is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate , dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof. In one embodiment, the acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

According to the freeze-dried powder injection described in any embodiment of the first aspect of the present invention, wherein the amount of the acid-base regulator is such that the freeze-dried powder injection is dissolved in water for injection to contain diisopropylamine dichloroacetate at a concentration of 20 mg /ml of the solution, the pH of the solution is in the range of 5.0 to 6.5, for example, the pH of the solution is in the range of 5.5 to 6.0.

As we all know, the freeze-dried powder injection obtained by low-temperature freeze-vacuum drying (usually referred to as freeze-dried powder injection or freeze-dried powder injection) is firstly dissolved in a solvent (usually dissolved in water), and prepared into a solution, and then subjecting the solution to low-temperature freezing, and then vacuumizing, subliming, and drying to obtain a substantially anhydrous (generally speaking, the water content is less than 5%, especially generally less than 3%) powder or Lumps. Therefore, the pH of the lyophilized solid is usually controlled by adjusting the pH of the solution during the preparation process; or it can be adjusted through the prescription so that the lyophilized solid obtained controls the pH of the dissolved/diluted solution at a prescribed degree of dissolution/dilution value to control (this is called controlling the pH of the solid lyophilized product); the latter method is usually more commonly used, for example, many freeze-dried powder injections listed in the Pharmacopoeia control the pH of the product in this way, and this method controls the pH of the product. The pH of the product usually does not specify the prescription amount of the acid-base regulator, but only the pH of the final product. Also applicable to the present invention is the freeze-dried powder injection according to any embodiment of the first aspect of the present invention, wherein the amount of the optional acid-base regulator is such that the prepared freeze-dried powder injection When the water for injection is dissolved into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml, the pH of the solution is in the range of 5.0 to 6.5, for example, the pH of the solution is in the range of 5.5 to 6.0.

The freeze-dried powder injection according to any embodiment of the first aspect of the present invention is basically prepared by the following steps:

(a) take by weighing the sodium gluconate of recipe quantity, add appropriate amount of water for injection (such as 30-40% of the prescription volume of dosing), make dissolving, then add gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (for example, 15-20% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the liquid reaches 20-30%, then add activated carbon, stir, filter and decarbonize ; Mix the two liquid medicines;

(b) Add water for injection to the prescribed amount, stir evenly, measure the pH value of the solution and optionally measure the content of active ingredients, adjust to pH 5.0-6.5 with an acid-base regulator according to the deviation of the pH value of the medicinal solution, preferably pH5.5～6.0;

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

According to the freeze-dried powder injection described in any embodiment of the first aspect of the present invention, its freeze-drying process is:

(i). Cool down to -30~-50°C, drop 1~2°C per minute, keep warm for 2~4 hours, then raise the temperature of the sample to -15~-30°C, increase the temperature by 2~5°C per hour (for example, 2°C ), keep at this temperature for about 1 hour, then lower the temperature to -30～-50℃, drop 1～2℃ per minute, keep warm for 2～5 hours, and repeat the pre-freezing for 0～3 times;

(ii). Vacuum again to make the vacuum degree 0.01-200Pa (eg 10Pa), raise the temperature of the sample to -15--30°C, increase the temperature by 2-5°C (eg 2°C) per hour, and carry out once at this temperature Drying for 2 to 50 hours (for example, 15 to 30 hours);

(iii). Then the sample is heated up to 10-30° C., and kept at this temperature until the degree of vacuum changes little, and then kept for 1 hour to end the whole freeze-drying process.

According to the freeze-dried powder injection described in any embodiment of the first aspect of the present invention, wherein the amount of activated carbon in the preparation of the two medicinal liquids in step (a) is 0.02% to 0.5% (w/v) of the solution weight, preferably 0.02% % to 0.2%. The consumption of this activated carbon is conventional consumption.

According to the freeze-dried powder injection according to any embodiment of the first aspect of the present invention, wherein the water for injection in the "recipe amount" in "adding water for injection to its prescription amount" in step (b) is dichloroacetic acid dichloroacetate 10-50 times, such as 15-30 times, such as about 18-25 times the weight of isopropylamine. The amount of this water for injection can be easily controlled by the solid content in step (c).

According to the freeze-dried powder injection according to any embodiment of the first aspect of the present invention, wherein the acid-base regulator in step (b) is an aqueous solution of an acid-base regulator selected from the following: sodium hydroxide, potassium hydroxide, Monosodium hydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof. The concentration of these aqueous solutions is well known to those skilled in the art, such as 1-10%, such as 2%-5%. In one embodiment, the acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

According to the freeze-dried powder injection according to any embodiment of the first aspect of the present invention, wherein the filtered filtrate obtained in step (c) has a solid content of 2-20% (w/v), preferably 2-15% (w/v), still more preferably 2 to 10%.

According to the freeze-dried powder injection according to any embodiment of the first aspect of the present invention, wherein the moisture content in the freeze-dried material obtained after removing moisture in step (d) is lower than 10%, preferably lower than 8%, preferably lower than 5% , more preferably less than 3%.

Further, the second aspect of the present invention provides a method for preparing the freeze-dried powder injection according to any embodiment of the first aspect of the present invention, which basically includes the following steps:

(a) take by weighing the sodium gluconate of recipe quantity, add appropriate amount of water for injection (such as 30-40% of the prescription volume of dosing), make dissolving, then add gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (for example, 15-20% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the liquid reaches 20-30%, then add activated carbon, stir, filter and decarbonize ; Mix the two liquid medicines;

(b) Add water for injection to the prescribed amount, stir evenly, measure the pH value of the solution and optionally measure the content of active ingredients, adjust to pH 5.0-6.5 with an acid-base regulator according to the deviation of the pH value of the medicinal solution, preferably pH5.5～6.0;

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

According to the method described in any embodiment of the second aspect of the present invention, its freeze-drying process is:

(i). Cool down to -30~-50°C, drop 1~2°C per minute, keep warm for 2~4 hours, then raise the temperature of the sample to -15~-30°C, increase the temperature by 2~5°C per hour (for example, 2°C ), keep at this temperature for about 1 hour, then lower the temperature to -30～-50℃, drop 1～2℃ per minute, keep warm for 2～5 hours, and repeat the pre-freezing for 0～3 times;

(ii). Vacuum again to make the vacuum degree 0.01-200Pa (eg 10Pa), raise the temperature of the sample to -15--30°C, increase the temperature by 2-5°C (eg 2°C) per hour, and carry out once at this temperature Drying for 2 to 50 hours (for example, 15 to 30 hours);

(iii). Then the sample is heated up to 10-30° C., and kept at this temperature until the degree of vacuum changes little, and then kept for 1 hour to end the whole freeze-drying process.

According to the method described in any embodiment of the second aspect of the present invention, wherein the amount of activated carbon described in the preparation of the two medicinal liquids in step (a) is 0.02% to 0.5% (w/v) of the solution weight, preferably 0.02% to 0.2% %. The consumption of this activated carbon is conventional consumption.

According to the method described in any embodiment of the second aspect of the present invention, wherein the water for injection of the "recipe amount" in "adding water for injection to its prescription amount" in step (b) is diisopropylamine dichloroacetate by weight 10-50 times, such as 15-30 times, such as about 18-25 times. The amount of this water for injection can be easily controlled by the solid content in step (c).

According to the method described in any embodiment of the second aspect of the present invention, wherein the acid-base regulator described in step (b) is an aqueous solution of an acid-base regulator selected from the following: sodium hydroxide, potassium hydroxide, dihydrogen phosphate Sodium, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof. The concentration of these aqueous solutions is well known to those skilled in the art, such as 1-10%, such as 2%-5%. In one embodiment, the acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

According to the method described in any embodiment of the second aspect of the present invention, wherein the filtered filtrate obtained in step (c) has a solid content of 2 to 20% (w/v), preferably 2 to 15% (w/ v), still more preferably 2 to 10%.

According to the method described in any embodiment of the second aspect of the present invention, wherein the moisture content in the freeze-dried material obtained after removing moisture in step (d) is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.

According to the method described in any embodiment of the second aspect of the present invention, wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:30-50.

According to the method described in any embodiment of the second aspect of the present invention, wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:35-45.

According to the method described in any embodiment of the second aspect of the present invention, wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:38.

The method according to any embodiment of the second aspect of the present invention, wherein no lyophilization excipient is included. For example, it does not contain sucrose, glucose, mannitol, lactose, sorbitol, glycine, etc.

According to the method described in any embodiment of the second aspect of the present invention, wherein the amount of the acid-base regulator is such that the lyophilized powder injection is dissolved in water for injection to contain diisopropylamine dichloroacetate at a concentration of 20 mg/ml. In the case of a solution, the pH of the solution is in the range of 5.0 to 6.5, for example, the pH of the solution is in the range of 5.5 to 6.0.

In the steps of the above-mentioned preparation method of the present invention, although the specific steps described in it are different from the steps described in the preparation examples of the specific embodiment section below in some details or language descriptions, those skilled in the art according to The detailed disclosure of the present invention in its entirety can fully summarize the method steps described above.

Any embodiment of any aspect of the present invention may be combined with other embodiments as long as they do not contradict each other. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as there is no contradiction between them.

The present invention will be further described below.

All the documents cited in the present invention are incorporated herein by reference in their entirety, and if the meaning expressed in these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have common meanings known to those skilled in the art. Even so, the present invention still hopes to make a more detailed description and explanation of these terms and phrases here. The terms and phrases mentioned are as follows: If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail.

According to the present invention, the term "excipient" may also be referred to as excipient, filler or the like.

As used herein, "pharmaceutically acceptable excipient" refers to an excipient that can be used in the formulation of a drug, which has substantially no adverse effects on the organism and is generally tolerated by the organism.

In the present invention, after the preferred lyophilized powder injection of the present invention is made into a solution containing 20 mg of active ingredient in terms of diisopropylamine dichloroacetate in every 1 ml of water, it is prepared according to the Chinese Pharmacopoeia 2010 edition two appendix VI H items. The method is the determination of pH value.

The water content in the freeze-dried powder injection is generally below 8%, preferably below 5%, more preferably below 3%. Moisture control can be controlled by adjusting the freeze-drying program appropriately. The moisture content in the freeze-dried powder injection can be determined according to many known methods, such as the loss on drying method.

In the present invention, in order to adjust the pH value of the medicinal solution when necessary, an appropriate pH regulator (also referred to as an acid-base regulator in the present invention) can be added to the composition. Although the present inventors only adjust with strong acid or strong alkali solutions without buffering capacity such as aqueous sodium hydroxide solution and aqueous hydrochloric acid solution, those skilled in the art understand that if the pH regulator treatment without buffering capacity of this kind can meet the requirements of the system pH requirements, then the pH regulator with buffering capacity will be more able to achieve the purpose of the present invention, so these buffering agents can not only adjust the pH value, but also stabilize the pH value. Therefore, any pH regulator listed in the present invention or its combination is included in the spirit and scope of the present invention.

When preparing the freeze-dried powder injection of the present invention, in the prepared medicinal solution, the solid content is 5-25% (w/v), preferably 5-20% (w/v), more preferably 5-15% . Since lyophilized powder injections are usually obtained by freeze-drying in tubular vials, those skilled in the art understand that this product usually presents a round cake before obtaining the finished product or even being used by a doctor, although the volume of the round cake is theoretically Said above will be less than the volume of the original aqueous solution (slightly reduced), but usually this reduction is usually not reduced to 50% of the original aqueous solution volume, usually between 80-120% of the original aqueous solution volume, more usually in the original aqueous solution volume Between 90-100% of the final product, and traces of the liquid level of the original aqueous solution can be observed in the final product vial (the trace of the liquid level remaining on the bottle wall after the main body cake shrinks due to freeze-drying, even if the freeze-dried in the vial If the product is powdered due to various reasons such as collision, the original liquid surface traces can still be retained usually), based on this trace, the volume of the aqueous solution of the freeze-dried composition before freeze-drying can also be estimated. Therefore, although the present invention provides a substantially anhydrous freeze-dried powder injection, it is still possible to roughly estimate the volume of the liquid medicine at least before the start of freeze-drying at the time of preparation according to the powder injection, and according to the estimated The volume and the weight of the dried final product in the vial can also be calculated into the content of solids in the prepared medicinal liquid when preparing the freeze-dried powder injection of the present invention. Therefore, according to the freeze-dried powder injection of the first aspect of the present invention, the solid content of the liquid medicine when it is prepared is 5-25% (w/v), preferably 5-20% (w/v), more Preferably 5 to 15%.

The term "solid content" means that a solid substance (such as the active compound of the present invention and all excipients used, weight/gram) is added in a solvent (such as water for injection) to obtain a solution after dissolving, and the weight of the solid substance Divide by the percentage of the final solution volume (weight/volume percentage, eg g/100ml). For example, in the present invention, if a total of 5 g of raw drug and all solid excipients is added to an appropriate amount of aqueous solution for injection to prepare a solution with a final volume of 100 ml, then the solid content of the drug solution is 5%.

In the present invention, the symbol % may have a meaning easily understood by those skilled in the art according to the context in which it is used. For example, when referring to the solid content, the symbol represents the percentage of weight/volume (w/v, such as g/100ml); Below %, the symbol % at this time represents the percentage of weight/weight (w/w, g/100g). Generally speaking, when a solid is dispersed in a liquid, % means weight/volume percentage; when a solid is dispersed in a solid or a liquid is dispersed in a solid (such as the water content of a powder), % means a weight/weight percentage. In other cases, the symbols % represent weight/weight percentages, unless stated otherwise.

When preparing the medicinal solution of the present invention, it is well known to those skilled in the art that for example, a microporous filter membrane of about 0.45um can be used for coarse filtration; The microporous filter membrane is used for fine filtration to eliminate bacteria, and can be filtered multiple times if necessary.

The freeze-dried powder injection according to the present invention is a freeze-dried powder injection. In one embodiment, the freeze-dried powder injection is a single-dose preparation (for example, a vial-packed powder injection), and the amount of the active compound in each unit dose (if not otherwise specified in the present invention, it is expressed as dichloroacetic acid dichloroacetate) Isopropylamine) can be, for example but not limited to, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg.

According to the freeze-dried powder injection of the present invention, it is reconstituted with water for injection, generally speaking, the reconstitution time is within 60 seconds, preferably within 50 seconds, more preferably within 40 seconds.

According to the freeze-dried powder injection of the present invention, after it is made into a solution containing 20 mg of active ingredient diisopropylamine dichloroacetate per 1 ml with water, the pH value of the solution is 5.0-6.5. In one embodiment, the pH is between 5.5 and 6.0.

The freeze-dried powder injection provided by the invention can be stored in a dry place below 25°C for at least 24 months, which can meet the general storage requirements of the freeze-dried powder injection.

The freeze-dried powder injection obtained in the present invention, especially the freeze-dried powder injection, is usually a white or off-white freeze-dried block or fragment or powder thereof, odorless, bitter in taste, and easily soluble in water.

Diisopropylamine dichloroacetate (DIPA), also known as Ganle, Liganeng, DADA, the main pharmacological effect of DIPA is to regulate lipid metabolism disorders and provide methyl for choline and membrane phospholipids; the effect of DIPA on fat is mainly by inhibiting Citrate lyase activity, inhibits the synthesis of fatty acid and cholesterol synthesis raw material - acetyl coenzyme A (acetyl CoA) in the cytosol, reduces the synthesis of fatty acid and cholesterol; DIPA can also inhibit the key enzyme of cholesterol synthesis - hydroxymethylglutaryl CoA Reductase activity, thereby inhibiting the synthesis of cholesterol; DIPA also inhibits the activity of hormone-sensitive triglyceride lipase in adipose tissue, reduces fat mobilization, and reduces the level of free fatty acids and glycerol in blood; DIPA activates pyruvate dehydrogenase (PDH) The activity of the complex increases the oxidation of glucose and promotes the tricarboxylic acid cycle to supply energy for liver cells; the effect of DIPA on liver cells is to promote the sequential methylation of membrane phospholipids, enhance the fluidity of liver cell membranes, and improve the secretion and flow of bile. The main driving force is -Na+--K+--ATPase activity, which promotes the recovery of the physiological function of damaged liver cells, promotes the production of lecithin, repairs the liver cell membrane, and promotes liver regeneration. Therefore, DIPA has a better effect on improving the symptoms and physical symptoms of patients with steatohepatitis; it can also effectively improve the disturbance of glucose and lipid metabolism, and has the effect of rapidly and significantly reducing serum triglyceride and cholesterol.

In addition, DIPA can be used as the donor of the methyl group required by the body to synthesize choline, which has the functions of detoxification, improving liver function, reducing liver fat deposition, etc.; it can also relax blood vessels and increase blood supply to the brain. It is mainly used for adjuvant treatment of acute and chronic hepatitis, early liver cirrhosis, fatty liver and insufficient blood supply to the brain. Domestic: DIPA is used for the treatment of fatty liver, intrahepatic cholestasis, and general liver dysfunction; for acute and chronic hepatitis, hepatomegaly, and early cirrhosis. Abroad: DIPA is also used for various disorders caused by stroke sequelae, cerebral hemorrhage, encephalomalacia, arteriosclerosis, hypertension, angina, myocardial infarction, myocarditis and cardiac insufficiency.

The present invention has the advantages of providing a freeze-dried preparation of compound diisopropylamine dichloroacetate that does not contain any auxiliary materials for injection and a preparation process; the present invention can completely avoid the addition of auxiliary materials, making the quality of the preparation easier to control, The production cost is reduced, and the drug safety of patients is more assured.

Detailed ways

The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made in the present invention without departing from the spirit and scope of the present invention. The present invention provides general and/or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible. The following examples further illustrate the invention without limiting it. In the following examples, the pH regulator (i.e. acid-base regulator in the present invention) used, if not otherwise specified, is 1M sodium hydroxide solution or 1M hydrochloric acid solution, and its consumption is to make when preparing powder injection, make The pH value of the prepared solution before freeze-drying is adjusted to a certain specified value or range, and the specified value or range is to make the prepared freeze-dried powder injection dissolved in water for injection to contain diisopropylamine dichloroacetate at a concentration of 20 mg/ The value or range of pH measured in ml of a solution. The following preparation steps are for the purpose of illustration, and based on the comparability of each example, some specific descriptions are made. Those skilled in the art can fully obtain the method for preparing the freeze-dried powder injection of the present invention based on the existing knowledge.

In each of the following examples, the same batch of commercially available raw materials was used to prepare the preparations. The batch of raw materials and prepared preparations were tested for related substances according to #909 method, and the content of RRT1.19 impurity (relative to diisopropylamine dichloroacetate) was 0.136%. Above-mentioned #909 method refers to the method of CN102297909B embodiment 1, specifically as follows:

The main component self-dilution control method of high performance liquid chromatography was adopted;

Chromatographic conditions: BDS-C18 chromatographic column: use octadecylsilane bonded silica gel as filler, particle size is 5 μm, specification is 250mm×4.6mm (Hypersil); column temperature is 25°C, perchloric acid solution-acetonitrile ( The volume ratio of perchloric acid solution to acetonitrile is 100:1) as the mobile phase, and the flow rate is 1mL/min; the detection wavelength is 225nm;

The preparation method of the perchloric acid solution is as follows: add 0.8ml of perchloric acid to 1000ml with water, then add 2ml of triethylamine, adjust the pH value to 4.2 with phosphoric acid, and obtain the perchloric acid solution;

Preparation of the test solution: take the test product compound diisopropylamine dichloroacetate for injection (comprising diisopropylamine dichloroacetate and sodium gluconate; it has been found that the presence or absence of excipients will not affect the measurement results) appropriate amount , add mobile phase to dissolve and dilute to make a solution containing 5 mg of diisopropylamine dichloroacetate in every 1 ml, as the test solution;

Control solution preparation: Accurately measure 1mL of the test solution, put it in a 100ml measuring bottle, add mobile phase to dissolve and dilute to the mark, shake well, and use it as a control solution;

Blank solution preparation: take sodium gluconate and appropriate amount of corresponding optional auxiliary materials according to the prescription ratio of the test product, add mobile phase to dissolve and dilute to make sodium gluconate equivalent to 5 mg of diisopropylamine dichloroacetate and corresponding The solution of the optional adjuvant, as a blank solution;

Assay method: accurately measure 20 μ l of the control solution and inject it into the high-performance liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak (the chromatographic peak of diisopropylamine dichloroacetate) is 20% of the full scale, and then accurately measure Each 20 μ l of need testing solution, contrast solution and adjuvant blank solution are injected into the high performance liquid chromatograph respectively, and the chromatogram is recorded to 2.5 times of the retention time of the main component peak (the chromatographic peak of diisopropylamine dichloroacetate); Except the chromatographic peak of corresponding retention time that appears in the figure, the percentage of other each impurity peak area and contrast solution main peak (chromatographic peak of diisopropylamine dichloroacetate) area ratio is the content of this impurity (related substance), each impurity The percentage of the ratio of the sum of the peak areas to the area of the main peak of the contrast solution (the chromatographic peak of diisopropylamine dichloroacetate) is the amount of the total related substances. As described in #909 method, the relative retention time of the impurity at retention time about 7.750min in table 1 is about 1.19 with respect to the main peak (the chromatographic peak of diisopropylamine dichloroacetate), so this impurity can be called for short in the present invention It is RRT1.19 impurity.

It has been unexpectedly found that when the method of the present invention is used for liquid formulation and freeze-drying, not only can the RRT1.19 impurity content in the resulting preparation be effectively reduced, but also the RRT1.19 impurity content of the resulting preparation can be reduced during long-term storage. content increase is very limited. In addition, it has been found that in the preparation process of the above-mentioned liquid preparation and freeze-dried powder injection of the present invention, if conventional excipients in the field are added, the obtained powder injection cannot effectively control the RRT1. 19 Impurity content increases.

One, powder injection preparation embodiment part

Example 1

Prescription: (1000 vials, containing diisopropylamine dichloroacetate 20mg and sodium gluconate 19mg)

Diisopropylamine dichloroacetate 20g

Sodium Gluconate 19g

Water for injection, add appropriate amount to 1000ml

Preparation Process:

1. Under clean conditions, take freshly prepared water for injection (about 80% of the prescription), lower the temperature to below 40°C, add the prescribed amount of diisopropylamine dichloroacetate and sodium gluconate, and stir to dissolve;

2. Add 0.1% activated carbon for needles according to the prepared amount, stir and absorb for 15 minutes, then filter and decarbonize;

3. Add water for injection below 40°C to the prescribed amount, stir well, and filter to sterilize with a 0.22μm microporous membrane;

4. Fill in vials at 1ml/bottle, place in a freeze dryer, and freeze-dry according to the following freeze-drying process:

a. Cool down to -40°C at 1°C per minute, keep it warm for 2 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -20°C, keep it at this temperature for about 1 hour, and then cool down to 1°C per minute -40°C, keep warm for 2 hours; repeat this pre-freezing once;

b. Vacuum again to make the vacuum degree 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -20°C, and perform a drying at this temperature for 20 hours;

c. Then the sample is heated up to 10° C. and kept at this temperature until the degree of vacuum changes little, and then kept for 1 hour to end the whole freeze-drying process.

Example 2

Prescription: (1000 vials, containing diisopropylamine dichloroacetate 40mg and sodium gluconate 38mg)

Diisopropylamine dichloroacetate 40g

Sodium gluconate 38g

Water for injection, add appropriate amount to 2000ml

Preparation Process:

1. Under clean conditions, take freshly prepared water for injection (about 80% of the prescription), lower the temperature to below 40°C, add the prescribed amount of diisopropylamine dichloroacetate and sodium gluconate, and stir to dissolve;

2. Add 0.1% activated carbon for needles according to the prepared amount, stir and absorb for 15 minutes, and decarbonize by filtration:

3. Add water for injection below 40°C to the prescribed amount, stir well, and filter to sterilize with a 0.22μm microporous membrane;

4. Fill in vials at 2ml/bottle, place in a freeze dryer, and freeze-dry according to the following freeze-drying process:

a. Cool down to -50°C at 2°C per minute, keep it warm for 3 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -20°C, keep it at this temperature for about 1 hour, and then cool down at 2°C per minute to -50°C, keep warm for 3 hours; repeat this process for 2 times;

b. Vacuum again to make the vacuum force 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -20°C, and perform a drying at this temperature for 30 hours;

c. Then the sample is heated up to 20° C., and kept at this temperature until the degree of vacuum changes little, and kept for 1 hour to end the whole freeze-drying process.

Example 3

Prescription: (1000 vials, containing diisopropylamine dichloroacetate 10mg and sodium gluconate 9.5mg)

Diisopropyl dichloroacetate 10g

Sodium Gluconate 9.5g

Water for injection, add appropriate amount to 1000ml

Preparation Process:

1. Under clean conditions, take freshly prepared water for injection (about 80% of the prescription), lower the temperature to below 40°C, add the prescribed amount of diisopropylamine dichloroacetate and sodium gluconate, and stir to dissolve;

2. Add 0.05% activated carbon for needles according to the prepared amount, stir and absorb for 30 minutes, and filter for decarbonization;

3. Add water for injection below 40°C to the prescribed amount, stir well, and filter to sterilize with a 0.22μm microporous membrane;

4. Fill in vials at 1ml/bottle, place in a freeze dryer, and freeze-dry according to the following freeze-drying process:

a. Cool down to -30°C at 1°C per minute, keep it warm for 3 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -15°C, keep at this temperature for about 1 hour, and then cool down at 1°C per minute to -30℃, keep warm for 3 hours;

b. Vacuum again to make the vacuum degree 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -15°C, and perform a drying at this temperature for 15 hours:

c. Then the sample is heated up to 30° C., and kept at this temperature until the degree of vacuum changes little, and kept for 1 hour to end the whole freeze-drying process.

Example 4

Prescription: (1000 vials, containing 80mg diisopropylamine dichloroacetate and 76mg sodium gluconate)

Diisopropylamine dichloroacetate 80g

Sodium gluconate 76g

Water for injection, add appropriate amount to 1000ml

Preparation Process:

1. Under clean conditions, take newly prepared water for injection (about 80% of the prescription), lower the temperature to below 40°C, and stir to dissolve the prescribed amount of diisopropylamine dichloroacetate and sodium gluconate;

2. Add 0.2% activated carbon for needles according to the prepared amount, stir and absorb for 45 minutes, and decarbonize by filtration;

3. Add water for injection below 40°C to the prescribed amount, stir well, and filter to sterilize with a 0.22μm microporous membrane:

4. Fill in vials at 1ml/bottle, place in a freeze dryer, and freeze-dry according to the following freeze-drying process:

a. Cool down to -50°C at 1°C per minute, keep it warm for 4 hours, then raise the temperature of the sample to -30°C at 2°C per hour, keep at this temperature for about 1 hour, and then cool down to 1°C per minute -50°C, keep warm for 4 hours; repeat the pre-freezing process 3 times;

b. Vacuum again to make the vacuum degree 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -30°C, and perform a drying at this temperature for 30 hours;

c. Then the sample is heated up to 25° C., and kept at this temperature until the degree of vacuum changes little, and kept for 1 hour to end the whole freeze-drying process.

When the powder injection obtained in the above Examples 1-4 is dissolved with water for injection into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml, the pH value of the solution is all in the range of 5.5 to 6.0.

Example 11

Prescription: (1000 vials, containing diisopropylamine dichloroacetate 20mg and sodium gluconate 19mg)

Diisopropylamine dichloroacetate 20g

Sodium glucurate 19g

Water for injection, add appropriate amount to 1000ml

Preparation Process:

(a) take by weighing the sodium gluconate of prescription quantity, add appropriate amount of water for injection (about 35% of the prescription volume of dosing), make dissolving, then add 0.05% gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (about 20% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the medicinal solution reaches 25%, then add 0.05% activated carbon, stir, filter and decarbonize; Mix the two liquids;

(b) add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the active ingredient content, adjust to pH5.5～6.0 with an acid-base regulator according to the deviation of the pH value of the medicinal solution (thereby When the obtained powder injection is dissolved into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml with water for injection, the pH value of the solution is all in the range of 5.5 to 6.0);

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

Its freeze-drying process is:

i. Cool down to -40°C at 1°C per minute, keep it warm for 2 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -20°C, keep it at this temperature for about 1 hour, and then cool down at 1°C per minute to -40°C, keep warm for 2 hours; repeat this pre-freezing once;

ii. Vacuum again to make the vacuum degree 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -20°C, and perform a drying at this temperature for 20 hours;

iii. Then the sample is heated up to 10° C., and kept at this temperature until the degree of vacuum changes little, and kept for 1 hour to end the whole freeze-drying process.

Example 12

Prescription: (1000 vials, containing diisopropylamine dichloroacetate 40mg and sodium gluconate 38mg)

Diisopropylamine dichloroacetate 40g

Sodium gluconate 38g

Water for injection, add appropriate amount to 2000ml

Preparation Process:

(a) take by weighing the sodium gluconate of recipe quantity, add appropriate amount of water for injection (about 30% of the prescription volume of dosing), make dissolving, then add 0.1% gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (about 15% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the medicinal solution reaches 20%, then add 0.1% activated carbon, stir, filter and decarbonize; Mix the two liquids;

(b) add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the active ingredient content, adjust to pH5.5～6.0 with an acid-base regulator according to the deviation of the pH value of the medicinal solution (thereby When the obtained powder injection is dissolved into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml with water for injection, the pH value of the solution is all in the range of 5.5 to 6.0);

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

Its freeze-drying process is:

i. Cool down to -50°C at 2°C per minute, keep it warm for 3 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -20°C, keep it at this temperature for about 1 hour, and then cool down at 2°C per minute to -50°C, keep warm for 3 hours; repeat this process for 2 times;

ii. Vacuum again to make the vacuum force 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -20°C, and perform a drying at this temperature for 30 hours;

iii. Then the sample is heated up to 20° C., and kept at this temperature until the degree of vacuum changes little, and kept for 1 hour to end the whole freeze-drying process.

Example 13

Prescription: (1000 vials, containing diisopropylamine dichloroacetate 10mg and sodium gluconate 9.5mg)

Diisopropyl dichloroacetate 10g

Sodium Gluconate 9.5g

Water for injection, add appropriate amount to 1000ml

Preparation Process:

(a) take by weighing the sodium gluconate of prescription quantity, add appropriate amount of water for injection (about 40% of the prescription volume of dosing), make dissolving, then add 0.02% gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (about 15% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the medicinal solution reaches 30%, then add 0.02% activated carbon, stir, filter and decarbonize; Mix the two liquids;

(b) add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the active ingredient content, adjust to pH5.5～6.0 with an acid-base regulator according to the deviation of the pH value of the medicinal solution (thereby When the obtained powder injection is dissolved into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml with water for injection, the pH value of the solution is all in the range of 5.5 to 6.0);

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

Its freeze-drying process is:

i. Cool down to -30°C at 1°C per minute, keep it warm for 3 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -15°C, keep it at this temperature for about 1 hour, and then cool down at 1°C per minute to -30℃, keep warm for 3 hours;

ii. Vacuum again to make the vacuum degree 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -15°C, and perform a drying at this temperature for 15 hours:

iii. Then the sample is heated up to 30° C., and kept at this temperature until the degree of vacuum changes little, and then kept for 1 hour to end the whole freeze-drying process.

Example 14

Prescription: (1000 vials, containing 80mg diisopropylamine dichloroacetate and 76mg sodium gluconate)

Diisopropylamine dichloroacetate 80g

Sodium gluconate 76g

Water for injection, add appropriate amount to 1000ml

Preparation Process:

(a) take by weighing the sodium gluconate of prescription quantity, add appropriate amount of water for injection (about 35% of the prescription volume of dosing), make dissolving, then add 0.2% gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (about 20% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the medicinal solution reaches 25%, then add 0.2% activated carbon, stir, filter and decarbonize; Mix the two liquids;

(b) add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the active ingredient content, adjust to pH5.5～6.0 with an acid-base regulator according to the deviation of the pH value of the medicinal solution (thereby When the obtained powder injection is dissolved into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml with water for injection, the pH value of the solution is all in the range of 5.5 to 6.0);

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

Its freeze-drying process is:

i. Cool down to -50°C at 1°C per minute, keep it warm for 4 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -30°C, keep it at this temperature for about 1 hour, and then cool down at 1°C per minute to -50°C, keep warm for 4 hours; repeat the pre-freezing process 3 times;

ii. Vacuum again to make the vacuum degree 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -30°C, and perform a drying at this temperature for 30 hours;

iii. Then the sample is heated up to 25° C., and kept at this temperature until the degree of vacuum changes little, and kept for 1 hour to end the whole freeze-drying process.

Example 15

Prescription: (1000 vials, containing diisopropylamine dichloroacetate 20mg and sodium gluconate 19mg)

Diisopropylamine dichloroacetate 20g

Sodium glucurate 19g

Water for injection, add appropriate amount to 2000ml

Preparation Process:

(a) take by weighing the sodium gluconate of prescription quantity, add appropriate amount of water for injection (about 35% of the prescription volume of dosing), make dissolving, then add 0.05% gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (about 20% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the medicinal solution reaches 25%, then add 0.05% activated carbon, stir, filter and decarbonize; Mix the two liquids;

(b) add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the active ingredient content, adjust to pH5.5～6.0 with an acid-base regulator according to the deviation of the pH value of the medicinal solution (thereby When the obtained powder injection is dissolved into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml with water for injection, the pH value of the solution is all in the range of 5.5 to 6.0);

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

Its freeze-drying process is:

i. Cool down to -40°C at 1°C per minute, keep it warm for 2 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -20°C, keep it at this temperature for about 1 hour, and then cool down at 1°C per minute to -40°C, keep warm for 2 hours; repeat this pre-freezing once;

ii. Vacuum again to make the vacuum degree 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -20°C, and perform a drying at this temperature for 20 hours;

iii. Then the sample is heated up to 10° C., and kept at this temperature until the degree of vacuum changes little, and kept for 1 hour to end the whole freeze-drying process.

Example 16

Prescription: (1000 vials, containing diisopropylamine dichloroacetate 40mg and sodium gluconate 38mg)

Diisopropylamine dichloroacetate 40g

Sodium gluconate 38g

Water for injection, add appropriate amount to 1000ml

Preparation Process:

(a) take by weighing the sodium gluconate of recipe quantity, add appropriate amount of water for injection (about 30% of the prescription volume of dosing), make dissolving, then add 0.1% gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (about 15% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the medicinal solution reaches 20%, then add 0.1% activated carbon, stir, filter and decarbonize; Mix the two liquids;

(b) add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the active ingredient content, adjust to pH5.5～6.0 with an acid-base regulator according to the deviation of the pH value of the medicinal solution (thereby When the obtained powder injection is dissolved into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml with water for injection, the pH value of the solution is all in the range of 5.5 to 6.0);

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

Its freeze-drying process is:

i. Cool down to -50°C at 2°C per minute, keep it warm for 3 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -20°C, keep it at this temperature for about 1 hour, and then cool down at 2°C per minute to -50°C, keep warm for 3 hours; repeat this process for 2 times;

ii. Vacuum again to make the vacuum force 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -20°C, and perform a drying at this temperature for 30 hours;

iii. Then the sample is heated up to 20° C., and kept at this temperature until the degree of vacuum changes little, and kept for 1 hour to end the whole freeze-drying process.

Example 17

Prescription: (1000 vials, containing diisopropylamine dichloroacetate 10mg and sodium gluconate 9.5mg)

Diisopropyl dichloroacetate 10g

Sodium Gluconate 9.5g

Water for injection, add appropriate amount to 1500ml

Preparation Process:

(a) take by weighing the sodium gluconate of prescription quantity, add appropriate amount of water for injection (about 40% of the prescription volume of dosing), make dissolving, then add 0.02% gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (about 15% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the medicinal solution reaches 30%, then add 0.02% activated carbon, stir, filter and decarbonize; Mix the two liquids;

(b) add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the active ingredient content, adjust to pH5.5～6.0 with an acid-base regulator according to the deviation of the pH value of the medicinal solution (thereby When the obtained powder injection is dissolved into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml with water for injection, the pH value of the solution is all in the range of 5.5 to 6.0);

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

Its freeze-drying process is:

i. Cool down to -30°C at 1°C per minute, keep it warm for 3 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -15°C, keep it at this temperature for about 1 hour, and then cool down at 1°C per minute to -30℃, keep warm for 3 hours;

ii. Vacuum again to make the vacuum degree 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -15°C, and perform a drying at this temperature for 15 hours:

iii. Then the sample is heated up to 30° C., and kept at this temperature until the degree of vacuum changes little, and then kept for 1 hour to end the whole freeze-drying process.

Example 18

Prescription: (1000 vials, containing 80mg diisopropylamine dichloroacetate and 76mg sodium gluconate)

Diisopropylamine dichloroacetate 80g

Sodium gluconate 76g

Water for injection, add appropriate amount to 1500ml

Preparation Process:

(a) take by weighing the sodium gluconate of prescription quantity, add appropriate amount of water for injection (about 35% of the prescription volume of dosing), make dissolving, then add 0.2% gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (about 20% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the medicinal solution reaches 25%, then add 0.2% activated carbon, stir, filter and decarbonize; Mix the two liquids;

(b) add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the active ingredient content, adjust to pH5.5～6.0 with an acid-base regulator according to the deviation of the pH value of the medicinal solution (thereby When the obtained powder injection is dissolved into a solution containing diisopropylamine dichloroacetate at a concentration of 20 mg/ml with water for injection, the pH value of the solution is all in the range of 5.5 to 6.0);

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

Its freeze-drying process is:

i. Cool down to -50°C at 1°C per minute, keep it warm for 4 hours, then raise the temperature at 2°C per hour to raise the temperature of the sample to -30°C, keep it at this temperature for about 1 hour, and then cool down at 1°C per minute to -50°C, keep warm for 4 hours; repeat the pre-freezing process 3 times;

ii. Vacuum again to make the vacuum degree 10Pa, raise the temperature by 2°C per hour to raise the temperature of the sample to -30°C, and perform a drying at this temperature for 30 hours;

iii. Then the sample is heated up to 25° C., and kept at this temperature until the degree of vacuum changes little, and kept for 1 hour to end the whole freeze-drying process.

Embodiment 21: formula and preparation method refer to embodiment 1-4, embodiment 11-18 respectively, difference is to add mannitol together with diisopropylamine dichloroacetate, the amount of mannitol is identical with diisopropylamine dichloroacetate, 12 powder injection samples were obtained.

Embodiment 22: formula and preparation method refer to embodiment 1-4, embodiment 11-14 respectively, and difference is that mannitol is added together with diisopropylamine dichloroacetate, and the amount of mannitol is 4 times that of diisopropylamine dichloroacetate times, and 8 powder injection samples were obtained.

Embodiment 23: The formula and preparation method refer to Example 2 respectively, the difference is that the following lyophilized excipients are added together with diisopropylamine dichloroacetate: lactose, sorbitol, sucrose, dextran, sodium chloride, or Glucose, the addition amount of this lyophilized excipient is the same as the amount of diisopropylamine dichloroacetate in the formula, and 6 powder injection samples are obtained.

Embodiment 24: The formula and preparation method refer to Example 12 respectively, the difference is that the following lyophilized excipients are added together with diisopropylamine dichloroacetate: lactose, sorbitol, sucrose, dextran, sodium chloride, or Glucose, the addition amount of this lyophilized excipient is the same as the amount of diisopropylamine dichloroacetate in the formula, and 6 powder injection samples are obtained.

Embodiment 25: formula and preparation method refer to embodiment 11-18 respectively, and difference is that ethanol is not added when preparing the medicinal liquid containing diisopropylamine dichloroacetate and directly adds water for injection (about 40% of the prescription volume of dosing) ) was dissolved to obtain 8 powder injection samples.

Example 26: Refer to Examples 1-4 for the formulation and preparation method, except that sodium gluconate is not added to obtain 4 powder injection samples; refer to Examples 11-14 for the formulation and preparation method, except that sodium gluconate is not added Sodium gluconate, get 4 powder injection samples.

Example 27: According to the formula and preparation method of Example 1 of CN1628650A (200310111617.2, Liu Li), the powder injection was prepared.

Example 28: According to the method of CN 103304424 B (201310274191.6, Merrill Lynch) Example 1, diisopropylamine dichloroacetate bulk drug was prepared, and then the bulk drug was prepared according to the formula and preparation method of CN 103304424 B Example 3 to obtain powder injection.

2. Investigation of the test case part

1. Detection of powder injection

In the process of preparing powder injections in the above-mentioned Examples 1-4, Examples 11-18, and Examples 21-28, the #909 method was used to detect that the content of the active ingredient diisopropylamine dichloroacetate in the final product powder injections was consistent with the theoretical The feeding amount is completely consistent, showing that the active ingredient diisopropylamine dichloroacetate will not be lost in the method of the present invention.

In the process of preparing powder injections in the above-mentioned Examples 1-4, Examples 11-18, and Examples 21-28, the #909 method was used to detect RRT1.19 impurities in the bulk drug and the final obtained powder injection (relative to two Diisopropylamine chloroacetate) content. For each batch of powder injection, compare the changes of the RRT1.19 impurity in the powder injection and the diisopropylamine dichloroacetate bulk drug used in #909 method detection. The results showed that the changes of the RRT1.19 impurity were significantly different in the powder injections prepared by different formulations/processes. In particular, in the powder injections prepared in Examples 11-18 of the present invention, the content of the RRT1.19 impurity is far lower than the content of the RRT1.19 impurity (relative to diisopropylamine dichloroacetate) in the bulk drug, and the steps (a) The content of RRT1.19 impurity (relative to diisopropylamine dichloroacetate) in the obtained liquid medicine and the final powder injection is basically the same, which shows that after step (a) treatment, it can effectively reduce the Miscellaneous RRT1.19 impurities. The reduced amount of this RRT1.19 impurity can be characterized by the RRT1.19 impurity residual in the present invention, and the RRT1.19 impurity residual (%) can be calculated by the following formula:

RRT1.19 impurity residue = [powder injection RRT1.19 impurity content ÷ API RRT1.19 impurity content] × 100%

The closer the above-mentioned RRT1.19 impurity residual (%) is to 100%, it means that the RRT1.19 impurity in the raw material drug is removed less after step (a) treatment, when it is lower than 100% and farther away from 100%, it indicates that RRT1 .19 The more impurities are removed.

Result: the powder injection obtained in Example 1-4, the powder injection obtained in Example 21 according to the powder injection obtained in Example 1-4, the powder injection obtained in Example 22 according to Example 1-4, the powder injection obtained in Example 23, and the powder injection obtained in Example 25 Powder injection, embodiment 26 are respectively according to embodiment 1-4 gained powder injection, embodiment 27 gained powder injection, embodiment 28 gained powder injection, these do not use ethanol to process diisopropylamine dichloroacetate in the liquid preparation process, gained powder The RRT1.19 impurity residues in the injections were all greater than 93%, and were all in the range of 93.4 to 102.1%, indicating that the powder injections obtained after treating diisopropylamine dichloroacetate without ethanol could not reduce the content of RRT1.19 impurities; implement Example 11-18 obtained powder injection, embodiment 21 respectively according to embodiment 11-18 obtained powder injection, embodiment 22 respectively according to embodiment 11-14 obtained powder injection, embodiment 24 obtained powder injection, embodiment 26 according to embodiment respectively The powder injections obtained in 11-14, which used ethanol to treat diisopropylamine dichloroacetate in the liquid preparation process, the RRT1.19 impurity residues of the obtained powder injections were all less than 17%, all in the range of 6.3% to 16.5%, indicating that these The content of RRT1.19 impurity in the powder injection obtained after treating diisopropylamine dichloroacetate with ethanol can be significantly reduced.

2. Detection of powder injection

For the powder injections prepared in the above-mentioned Examples 1-4, Examples 11-18, and Examples 21-28, place them at room temperature of 40±2°C for 6 months, measure and calculate the time of these powder injections at 0 months And the growth rate of RRT1.19 impurity content (relative to diisopropylamine dichloroacetate) in June. For a powder injection, its RRT1.19 impurity content growth rate (%) is calculated as follows:

RRT1.19 impurity content growth rate (%) =

[(June RRT1.19 impurity content-0 month RRT1.19 impurity content)÷0 month RRT1.19 impurity content]×100%

The closer the above RRT1.19 impurity content growth rate (%) is to 0%, the smaller the RRT1.19 impurity increase in the powder injection during the simulated long-term sample retention process.

Result: the powder injection obtained in Example 21, the powder injection obtained in Example 22, the powder injection obtained in Example 23, the powder injection obtained in Example 24, the powder injection obtained in Example 27, the powder injection obtained in Example 28, these were added in the formula Conventional excipients, the RRT1.19 impurity content growth rate (%) of the obtained powder injections are all greater than 138%, both in the range of 138.7% to 196.2%, indicating that even the powder injections with conventional excipients, During the long-term sample retention process, the RRT1.19 impurity increased quite significantly; the powder injections obtained in Examples 1-4, the powder injections obtained in Examples 11-18, the powder injections obtained in Example 25, and the powder injections obtained in Example 26, these are in the formula No conventional excipients were added in the powder, and the RRT1.19 impurity content growth rates (%) of the obtained powder injections were all less than 25%, all in the range of 8.7% to 24.1%, indicating that these non-added excipients even conventional excipients In the powder injection, the RRT1.19 impurity increase is quite small during the long-term sample retention process.

3. Example of powder injection quality inspection:

For the 8 batches of powder injections obtained in Examples 11-18 above and the commercially available compound diisopropylamine dichloroacetate for injection (H20052438, produced by Peking University Hi-Tech Huatai, each bottle contains 40 mg of diisopropylamine dichloroacetate and 38 mg of sodium gluconate) According to the following methods, the quality/property indicators such as clarity and color, acidity, related substances, loss on drying, sterility, visible foreign matter, insoluble particles, and content of their solutions are detected:

Clarity and color of the solution: take the test sample, add water to make a solution containing 20mg of diisopropylamine dichloroacetate per 1ml, the field usually requires that the solution should be clear and colorless; if it is cloudy, compare it with No. 1 turbidity standard solution (Chinese Pharmacopoeia 2010 edition two appendix IXB), this field usually requires no thicker; such as color development, compared with the yellow No. 1 standard colorimetric solution (Chinese pharmacopoeia 2010 edition two appendix IXA), this field usually requires no darker .

Acidity: Take the test sample, add water to make a solution containing 20 mg of diisopropylamine dichloroacetate per 1 ml, and measure according to the law (Chinese Pharmacopoeia 2010 Edition, Part Two, Appendix VIH). This field usually requires a pH value of 5.0 to 6.5.

Related substances: get the test product, add mobile phase to dissolve and dilute to make a solution containing about 5mg of diisopropylamine dichloroacetate in every 1ml, as the test product solution; accurately measure an appropriate amount of the test product solution, add mobile phase to dilute A solution containing about 50 μg of diisopropylamine dichloroacetate per 1 ml was used as a control solution. According to the chromatographic condition test under the content determination item, take 20 μ l of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component peak is about 10% to 20% of the full scale; then take 20 μl of the above two solutions respectively Inject the liquid chromatograph, record the chromatogram to 3 times of the retention time of the main component peak, if there is an impurity peak in the chromatogram of the test solution, the area generally requires that the sum of the impurity peak areas must not be greater than the sum of the main peak areas of the contrast solution (1.0% ).

Loss on drying: Take the test sample and dry it at 80°C to constant weight. It is generally required in this field that the weight loss should not exceed 2.5% (Appendix VIII L of Part Two of the Chinese Pharmacopoeia 2010 Edition).

Sterility: Take the test product and check according to the law (Appendix ⅪH of Part Two of the Chinese Pharmacopoeia 2010 Edition), which is usually required to meet the regulations in this field.

Visible foreign matter: Take the test product and check according to the law (Appendix IX H of Part Two of the Chinese Pharmacopoeia 2010 Edition), and the general requirements in this field should meet the regulations.

Insoluble particles: Take the test sample and inspect according to the law (Appendix IXC of Part II of the Chinese Pharmacopoeia 2010 Edition), and the general requirements in this field should meet the regulations.

Determination of content: measure according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix ⅤD);

Chromatographic conditions and system suitability test: use octadecylsilane bonded silica gel as filler; use perchloric acid aqueous solution (0.82ml → 1000ml, add triethylamine 2ml, adjust pH value to 3.0 with H3PO4)-acetonitrile (98 : 2) be mobile phase, regulate flow rate and make sodium gluconate peak retention time be 4～5 minutes, detection wavelength is 215nm. The number of theoretical plates should not be less than 2000 based on the peak of diisopropylamine dichloroacetate;

Determination method Accurately weigh an appropriate amount of the test product (equivalent to 10 mg of diisopropylamine dichloroacetate), put it in a 10ml measuring bottle, add mobile phase to dilute to the mark, shake well, and use it as the test solution; take another diisopropylamine dichloroacetate Add appropriate amount of propylamine reference substance and sodium gluconate reference substance, add mobile phase to make a solution containing 1 mg of diisopropylamine dichloroacetate and 1 mg of sodium gluconate per 1 ml, as the reference solution; draw 20 μl of each of the above two solutions, respectively Inject into the liquid chromatograph, calculate with the peak area according to the external standard method, get final product; This field usually requires to calculate according to the average loading capacity, containing diisopropylamine dichloroacetate (C8H17O2NCl2) and sodium gluconate (C6H11NaO7) should be the marked amount (Theoretical feeding amount) 93.0%～107.0%.

Each batch of powder injections to be tested was tested according to the above-mentioned method, and all the indicators were within the ranges usually specified by the above-mentioned indicators.

4. Long-term stability test example:

For the 8 batches of powder injections obtained from Preparation Example 11 to Preparation Example 18 above and the commercially available compound diisopropylamine dichloroacetate for injection (H20052438, produced by Peking University Hi-Tech Huatai, each bottle contains 40 mg of diisopropylamine dichloroacetate and sodium gluconate 38 mg), these samples were placed at room temperature of 40±2°C for 6 months, referring to the method of "3. Quality inspection example of powder injection" above, to investigate the indicators of these powder injections at 0 months and 6 months . The results showed that all the tested powder injections were placed at 40°C for 6 months, and all the detection indexes were still within the ranges usually stipulated by the above-mentioned indexes. Show that the powder injection of the present invention has excellent stability.

5. Safety test example:

This test example carries out safety test investigation to the composition powder injection of the present invention

The powder injection of the obtained sample of the present invention Example 11, Example 12 powder injection, Example 13 powder injection, Example 14 powder injection, and commercially available compound diisopropylamine dichloroacetate for injection (H20052438, produced by Peking University High-Tech Huatai, Each bottle contains 40 mg of diisopropylamine dichloroacetate and 38 mg of sodium gluconate), according to the current drug registration regulations (research group of "Technical Guidelines for Chemical Drug Irritation, Allergy and Hemolysis Research"; chemical drug irritation, Allergy and Hemolysis Research Technical Guidelines, Drug Research Technical Guidelines, Beijing: China Medical Science and Technology Press, 2006: 124), conducted vascular stimulation experiments, hemolysis experiments, and allergic experiments, and the results showed that these samples were all consistent with vascular Regulations for irritation test, hemolysis test and allergy test. It shows that the composition of the present invention has good safety. For example, in terms of irritation, the skin and veins at the injection sites of all tested powder injection samples showed similar changes, and no abnormal phenomena such as congestion, edema, induration, and necrosis were seen.

Claims (10)

1. A freeze-dried powder injection, which comprises diisopropylamine dichloroacetate and sodium gluconate. 2. according to the freeze-dried powder injection of claim 1, it is characterized in that: Wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:30～50; Wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:35-45; and/or Wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:38. 3. according to the freeze-dried powder injection of claim 1, it is characterized in that: which does not contain lyophilization excipients; and/or It does not contain sucrose, glucose, mannitol, lactose, sorbitol, glycine, etc. 4. according to the freeze-dried powder injection of claim 1, it is characterized in that: It also contains acid-base regulators; The acid-base regulator is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or a combination thereof; The acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution; and/or The dosage of the acid-base regulator is that when the freeze-dried powder for injection is dissolved into a solution containing diisopropylamine dichloroacetate with a concentration of 20 mg/ml, the pH value of the solution is within the range of 5.0 to 6.5. , such as the amount in which the pH of the solution is within the range of 5.5 to 6.0. 5. according to the lyophilized powder injection of claim 1, it is prepared by the steps comprising following substantially: (a) take by weighing the sodium gluconate of recipe quantity, add appropriate amount of water for injection (such as 30-40% of the prescription volume of dosing), make dissolving, then add gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (for example, 15-20% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the liquid reaches 20-30%, then add activated carbon, stir, filter and decarbonize ; Mix the two liquid medicines; (b) Add water for injection to the prescribed amount, stir evenly, measure the pH value of the solution and optionally measure the content of active ingredients, adjust to pH 5.0-6.5 with an acid-base regulator according to the deviation of the pH value of the medicinal solution, preferably pH5.5～6.0; (c) sterilize and filter the medicinal liquid, and fill it in a vial; (d) Freeze-drying to remove moisture, and stoppering, to obtain. 6. according to the freeze-dried powder injection of claim 5, its freeze-drying process is: (i). Cool down to -30~-50°C, drop 1~2°C per minute, keep warm for 2~4 hours, then raise the temperature of the sample to -15~-30°C, increase the temperature by 2~5°C per hour (for example, 2°C ), keep at this temperature for about 1 hour, then lower the temperature to -30～-50℃, drop 1～2℃ per minute, keep warm for 2～5 hours, and repeat the pre-freezing for 0～3 times; (ii). Vacuum again to make the vacuum degree 0.01-200Pa (eg 10Pa), raise the temperature of the sample to -15--30°C, increase the temperature by 2-5°C (eg 2°C) per hour, and carry out once at this temperature Drying for 2 to 50 hours (for example, 15 to 30 hours); (iii). Then the sample is heated up to 10-30° C., and kept at this temperature until the degree of vacuum changes little, and then kept for 1 hour to end the whole freeze-drying process. 7. according to the freeze-dried powder injection of claim 5, it is characterized in that: The amount of activated carbon used in the preparation of the two medicinal solutions in step (a) is 0.02% to 0.5% (w/v) of the solution weight, preferably 0.02% to 0.2%. The consumption of this gac is conventional consumption; The water for injection of the "prescription amount" in "adding water for injection to its prescription amount" in step (b) is 10-50 times of the weight of diisopropylamine dichloroacetate, such as 15-30 times, such as about 18- 25 times. The amount of this water for injection can be easily controlled by the solids content described in the step (c); The acid-base regulator described in step (b) is the aqueous solution of the acid-base regulator selected from following: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate , hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof; The filtered filtrate obtained in step (c), wherein the solid content is 2-20% (w/v), preferably 2-15% (w/v), more preferably 2-10%; The moisture content in the freeze-dried material obtained after removing moisture in step (d) is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably lower than 3%. 8. the method for preparing the freeze-dried powder injection of any one of claim 1-7, it comprises the steps substantially: (a) take by weighing the sodium gluconate of recipe quantity, add appropriate amount of water for injection (such as 30-40% of the prescription volume of dosing), make dissolving, then add gac, stir, filter decarbonate; Diisopropylamine chloroacetate, add an appropriate amount of water for injection (for example, 15-20% of the volume of the prescription) to dissolve, add absolute ethanol until the ethanol concentration of the liquid reaches 20-30%, then add activated carbon, stir, filter and decarbonize ; Mix the two liquid medicines; (b) Add water for injection to the prescribed amount, stir evenly, measure the pH value of the solution and optionally measure the content of active ingredients, adjust to pH 5.0-6.5 with an acid-base regulator according to the deviation of the pH value of the medicinal solution, preferably pH5.5～6.0; (c) sterilize and filter the medicinal liquid, and fill it in a vial; (d) Freeze-drying to remove moisture, and stoppering, to obtain. 9. according to the method for claim 8, its freeze-drying process is: (i). Cool down to -30~-50°C, drop 1~2°C per minute, keep warm for 2~4 hours, then raise the temperature of the sample to -15~-30°C, increase the temperature by 2~5°C per hour (for example, 2°C ), keep at this temperature for about 1 hour, then lower the temperature to -30～-50℃, drop 1～2℃ per minute, keep warm for 2～5 hours, and repeat the pre-freezing for 0～3 times; (ii). Vacuum again to make the vacuum degree 0.01-200Pa (eg 10Pa), raise the temperature of the sample to -15--30°C, increase the temperature by 2-5°C (eg 2°C) per hour, and carry out once at this temperature Drying for 2 to 50 hours (for example, 15 to 30 hours); (iii). Then the sample is heated up to 10-30° C., and kept at this temperature until the degree of vacuum changes little, and then kept for 1 hour to end the whole freeze-drying process. 10. according to the freeze-dried powder injection of claim 8, it is characterized in that: The amount of activated carbon used in the preparation of the two medicinal solutions in step (a) is 0.02% to 0.5% (w/v) of the solution weight, preferably 0.02% to 0.2%. The consumption of this gac is conventional consumption; The water for injection of the "prescription amount" in "adding water for injection to its prescription amount" in step (b) is 10-50 times of the weight of diisopropylamine dichloroacetate, such as 15-30 times, such as about 18- 25 times. The amount of this water for injection can be easily controlled by the solids content described in the step (c); The acid-base regulator described in step (b) is the aqueous solution of the acid-base regulator selected from following: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate , hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof; The filtered filtrate obtained in step (c), wherein the solid content is 2-20% (w/v), preferably 2-15% (w/v), more preferably 2-10%; The moisture content in the freeze-dried material obtained after removing moisture in step (d) is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably lower than 3%; Wherein the weight ratio of diisopropylamine dichloroacetate to sodium gluconate is 40:30～50; Wherein the weight ratio of diisopropylamine dichloroacetate and sodium gluconate is 40:35～45; Wherein the weight ratio of diisopropylamine dichloroacetate and sodium gluconate is 40:38; It does not contain lyophilized excipients; It does not contain sucrose, glucose, mannitol, lactose, sorbitol, glycine, etc.; The dosage of the acid-base regulator is that when the freeze-dried powder for injection is dissolved into a solution containing diisopropylamine dichloroacetate with a concentration of 20 mg/ml, the pH value of the solution is within the range of 5.0 to 6.5. , such as the amount in which the pH of the solution is within the range of 5.5 to 6.0.