CN112279937A - Novel compounds for muscle relaxation antagonism - Google Patents

Abstract

Novel compounds antagonistic to muscle relaxation. The theta type, beta, gamma, lambda, kappa, nu, tau, omega, nu, theta, gamma,

the new compounds have less hygroscopicity and better storage stability, are more beneficial to the quality control of medicaments and preparations and the like, and are suitable for preparing the medicaments for treating or preventing the specific binding neuromuscular blockade antagonist medicaments, antagonistic neuromuscular blockade induced by rocuronium or vecuronium bromide and the like.

Description

Novel compounds for muscle relaxation antagonism

Technical Field

The invention relates to the technical field of medicines, and particularly provides a novel compound with a novel molecular formula, wherein the novel compound is better in stability of muscle relaxation antagonist sugammadex sodium.

Background

Sugammadex Sodium (CAS: 343306-79-6, formula C)₇₂H₁₀₄Na₈O₄₈S₈M ═ 2178.01) is the sodium salt of the synthetic gamma-cyclodextrin ring structure surrounded by 8 glucose molecules, and the first selective muscle relaxation antagonist (SRBA) developed successfully in recent 20 years. Sugammadex has a lipophilic lumenAnd a hydrophilic outer edge having an inner cavity sized to accommodate an amino-steroid muscle relaxant ROC. The inner lipophilicity and the outer edge hydrophilicity of the device are increased by 8 side chain carboxyl groups with negative charges protruding from the edge, the device is tightly combined with quaternary ammonium ions with positive charges of ROC molecules through static electricity in a ratio of 1:1, the quaternary ammonium ions are packaged in a ring to form a stable chelate structure, the blood concentration of free muscle relaxants is further effectively reduced, a concentration gradient is formed between an effect chamber (a neuromuscular junction) and a central chamber (blood plasma), the muscle relaxant molecules in the effect chamber are rapidly transported to the central chamber along the concentration gradient difference, the concentration in the effect chamber is rapidly reduced, the combination of the muscle relaxants and a nicotine-like receptor is reduced, the muscle relaxant effect is reversed, and the device is not influenced by pH and temperature. Can rapidly improve ROC severe anaphylaxis, improve the condition of unable intubation ventilation, and effectively reverse the research progress of moderate and deep NMB (Liujia, Berlin, novel muscle relaxation antagonist sugammadex [ ]]China pharmacy 2017,28(05): 702-706).

Some published documents report the synthesis, analysis, preparation, pharmacology, clinical and the like of sugammadex sodium (for example, patent documents: US 6670340, US 7265099, US 6949527, the reversal reagent of 6-mercaptocyclodextrin derivatives for drug-induced neuromuscular anesthesia, patent application specification CN 00816360; a preparation method of sugammadex sodium and intermediates thereof, CN 105273095; a preparation method of sugammadex sodium, CN 104844732; a preparation method of high-purity sugammadex sodium, CN 106749771; a refining method of sugammadex sodium, CN 107325202; a preparation method of sugammadex sodium, CN 107325204; sugammadex sodium crystal form a and preparation method and use thereof, CN 107400182; a preparation method of sugammadex and intermediates thereof, CN 107849157; a preparation and purification method of high-purity sugammadex sodium and intermediates thereof, CN 108047354; a purification method of sugammadex sodium, CN 105348412; a process for the preparation of sugammadex sodium, CN 109021148; a preparation method of amorphous sugammadex sodium, CN 109053933; a method for purifying sugammadex sodium, CN 106565858; a preparation process of sugammadex sodium, CN 109438591; a preparation method of high-purity sugammadex sodium, CN 109517093; a method for purifying sugammadex sodium, CN 109553702; for example, non-patent documents: the synthesis process research of Yangjialiang, Roger, Xiyongmei, Shugeng sodium gluconate [ J ] chemical engineering and equipment 2016(06): 4-6%; a synthetic process [ J ] of Wei word, Wanghong and Shugeng sodium gluconate, which is modern application pharmacy in China 2016,33(04):431 and 433); pueraria, Egomorpha, Shugeng sodium gluconate [ J ]. J.Chem.Chem.China, 2016,26(05):433+ 435.; ).

The stability of the raw material medicine is the basis for ensuring the stability and good preparation performance of the pharmaceutical preparation, the basis for ensuring the curative effect and preventing unexpected adverse reactions caused by the instability of the medicine, and the search for the most stable form of the raw material medicine is pursued in pharmacology continuously. Accurate dosage is the basis for ensuring the curative effect and preventing unexpected adverse reaction brought by the medicine. The pharmacology is an experimental science, the molecular form with good stability is unpredictable in advance, and a plurality of cases for searching for drug molecules with better stability exist in the world drug development history, so that the continuous development and progress of the pharmacology are objectively promoted. As unknown to many professionals, some bulk drugs produced industrially for years have great differences in stability among different batches of raw materials fed into the same batch of raw materials even in the same workshop and the same equipment under the same process flow, some bulk drugs can only keep stability for about 3 months even under specified conditions, some quality control indexes have obvious changes in different degrees, which causes confusion or trouble problems, various potential threat problems continue, and even though the products or bulk drugs are recorded by pharmacopoeias of various countries for a long time, the products or bulk drugs have great unexpected risks to patients in clinical application. From the actual situation at present, sugammadex sodium is easy to wrap impurities such as inorganic salts and small molecular organic matters in the production process, although sugammadex sodium has been on the market for some time, problems still exist in the stability of sugammadex sodium, such as large hygroscopicity, reduced storage period content or excessive increase of related substances, and the problems can not be solved for many years, and general or even most professionals cannot see or cannot imagine the problems to exist! This has led us to seek solutions to the problem of stability of compounds. Although valuable results are expected to be obtained by obtaining changes of crystal forms and the like through some experiments on the basis of unchanged molecular formulas of the compounds, obvious improvements are not obtained, and different problems still exist.

The size of the hygroscopicity of the powder medicine is closely related to the selection of proper packaging and storage conditions, and even the selection of proper preparation process and dosage form. It is a common phenomenon that changes in intrinsic quality occur due to changes in the appearance of a drug, such as agglomeration, deliquescence, discoloration, caused by improper packaging or storage conditions, and therefore, the hygroscopicity of a powdered drug has been examined as a property of the drug by some national pharmacopoeias. When a drug is exposed to air with certain humidity or an auxiliary material containing free water is contained in the same preparation, the drug can cause moisture absorption to change certain properties such as powder flowability, dispersibility, compactibility, tablet hardness and the like, and can also cause caking, deliquescence, stability reduction and even content change of the drug, so that the moisture absorption of the drug is an important characteristic influencing the stability, effectiveness and safety of the drug (bear Jing, rock, Wujian Min, Huchangchang, Tandle, Zealand, and the relationship between the moisture absorption and water solubility of the chemical is analyzed based on non-parametric tests [ J ]. China pharmaceutical journal, 2016,51(20):1786 and 1789 ]. The improvement of the hygroscopicity of the medicine and the physicochemical properties of the medicine, such as stability, melting point, solubility, hygroscopicity, metabolic stability, dispersion rate, dissolution rate, slow release of the medicine, mechanical properties, bioavailability and the like, are the leading edge and the focus of research of international crystal engineering at the present stage (chenjiao, synthesis and characterization of novel medicine co-crystals [ D ]. jilin university, 2011.).

At present, the moisture absorption test of the medicine is added no matter in European pharmacopoeia medicine standard or Chinese pharmacopoeia to examine the quality of the medicine and/or guide the research of innovative medicine or improved medicine.

Although medicinal chemistry and pharmacy are continuously developed practice science, new guiding pharmaceutical progress is continuously developed, pharmaceutical safety is continuously improved to guide development of medicines and preparations and guide clinical medication, even though pharmacy influences development of pharmacy, preparations and clinical medication by changing physical states of bulk drugs, however, due to difficulty and uncertainty of synthesis, documents which are not disclosed at home and abroad report deep innovative research and accurate synthesis of new stable chemical states of sugammadex sodium, and new compounds with determined chemical molecular formulas, molecular weights or structural formulas, such as omega-type crystal compounds, v-type compounds and the like, which are easier to prepare or have better stability, and preparation methods and applications thereof.

Thermal analysis methods have important value and status in material science, chemistry or pharmaceutical analysis, etc., and can be used alone to detect or characterize changes in a compound or its polymorphic or crystalline form (lee, thermal analysis, university of qinghua press, first edition 8 months 1987). Differential Thermal Analysis (DTA) is a relatively common analytical method used for both qualitative and quantitative identification of substances, and is used by Barta et al to identify unknown compounds as early as the second international conference on thermal analysis in 1968. The pharmacopoeia of many countries has already collected the differential thermal analysis method, and over a decade ago, the differential thermal analysis method has been widely applied to chemical and pharmaceutical systems.

Disclosure of Invention

It is well recognized in the chemical arts that the presence or absence of a specific solvent compound for a compound is unpredictable, cannot be defined in advance by the Markush formula, and that some solvent compounds are highly toxic, some are highly hygroscopic, some are easily weathered, and some are poorly stable. The invention relates to a novel crystalline hydrate of sugammadex sodium as muscle relaxation antagonist, a preparation method and an application thereof₇₂H₁₀₄Na₈O₄₈S₈·nH₂O, n ═ 3.5, 5, 5.5, 6, 6.5, 7, 7.5, 9, 12, 14.5; i.e. sodium sugammadex theta, beta, gamma, lambda, kappa, gamma, omega, tau, upsilon,

The new compound, i.e. the new molecular formula and molecular weight of sugammadex sodium, the new molecular structure compound and the preparation method and the application thereof.

In carrying out the present invention, it has been unexpectedly found that although the current literature reports that sugammadex sodium is the only pharmacological testIn the first option, the research finds that the sugammadex sodium anhydrate is not the optimal choice in pharmacology, the stability of the anhydrous sulgamide sodium anhydrate is not good, and the pharmaceutical raw materials can be unqualified in the storage process or the content of the anhydrous sulgamide sodium anhydrate in the preparation process can be inaccurate, so that the safety, the effectiveness and the like of clinical medication can be influenced. Moreover, due to the proximity of the preparation solvents, more importantly, even during the preparation of crystalline hydrates of sugammadex sodium, it was found that it is easier to prepare sugammadex sodium theta, beta, gamma, lambda, kappa, nu, omega, tau, nu, beta, gamma, lambda, kappa, gamma,

And the like, which has been ignored for a long time.

The prepared sugammadex sodium theta type, beta, gamma, lambda, kappa, gamma, omega, tau, upsilon,

Among the novel compounds of the type I, the unexpected discovery is that sodium sugammadex

The novel compound has low hygroscopicity but larger viscosity, and can be used as raw material of preparation, such as sugammadex theta type, beta, gamma, lambda, kappa, nu, omega, tau, nu,

The novel compounds of the type I are more advantageous.

Moreover, the invention also finds that the theta-type, beta, gamma, lambda, kappa, nu, omega, tau, nu-type compounds of the sugammadex sodium with definite molecular formula are easy to prepare, and the stability meets the requirement of pharmacy, which reflects that the theta-type, beta, gamma, lambda, kappa, nu, omega, tau, nu-type compounds of the sugammadex sodium with definite molecular formula are more convenient to produce or apply.

The sugammadex sodium compound with the new molecular formula and the new molecular structure, which is obtained by the invention, has the advantages that the hygroscopicity of the sugammadex sodium containing crystal water is lower than that of the sugammadex sodium without crystal water, and the sugammadex sodium compound is more beneficial to storageThe novel compounds of the invention, in particular the compounds of the theta, beta, gamma, lambda, kappa, nu, omega, tau, nu type, are present in addition to

The novel compounds have good sliding property, so that the operability of the preparation is improved, and the substance can exist more stably than sugammadex sodium without crystal water, is easier to prepare than sugammadex sodium anhydride, is convenient to store and transport, is beneficial to reducing the manufacturing cost and cost, and is also beneficial to the preparation of the preparation and the controllability of the quality of the preparation. The sugammadex sodium crystalline hydrate of the present invention has different advantages in stability and manufacturability. Furthermore, the invention finds that the theta type, beta, gamma, lambda, kappa, nu, omega, tau, nu type and other compounds of the sodium sulgamate have better industrial value or medicinal value than the anhydrous sulgamate sodium, and are more beneficial to the safety and the effectiveness of clinical medication.

Surprisingly, the hydrates of the present invention characteristically have a corresponding endothermic peak at the weight loss plateau (under the weight loss curve before about 132 ℃ or before about 145 ℃) of the thermogram (TG-DSC or TG-DTA) showing sugammadex sodium compound, sugammadex sodium compound of novel formula or novel compound structure. Even if different crystalline forms of the same substance formula are prepared or obtained, they may have real or potential or future significance or value in pharmacology, not to mention that the obtaining of different substances of the same substance formula may have real or potential or future significance or value in pharmacology.

Preparation of sugamogluconic acid can be found in literature methods [ CN 109021147 a; CN 105348412B and the like

The preparation of the novel sugammadex sodium compound comprises the following steps:

in a reaction vessel, adding sugamonic acid, adding water and/or an organic solvent C₁-C₆Is selected from low molecular alcohol (such as methanol, ethanol, isopropanol, n-butanol, etc.), C₂-C₈Low molecular ether (selected from but not limited to diethyl ether,Tetrahydrofuran, isopropyl ether, methyltetrahydrofuran, etc.), C₂-C₆Stirring at 10-80 deg.C, adding one or more of sodium hydroxide solution or sodium carbonate solution, water and C₁-C₆Low molecular alcohol of (2), C₂-C₈Low molecular ether of (2), C₃-C₈Stirring one or more solutions of organic solvents such as low molecular ketone, reacting for 0.2-2 hr, adding organic solvent C₁-C₆Is selected from low molecular alcohol (such as methanol, ethanol, isopropanol, n-butanol, etc.), C₂-C₈Low molecular ether (selected from but not limited to diethyl ether, tetrahydrofuran, isopropyl ether, methyl tetrahydrofuran, etc.), C₂-C₆Low molecular nitrile (selected from but not limited to acetonitrile, propionitrile, etc.), C₂-C₈Low molecular ester of (2), C₁-C₆Standing at below 25 deg.C to precipitate solid, filtering, and adding organic solvent C₁-C₆Low molecular alcohol of (2), C₂-C₈Low molecular ether of (2), C₃-C₈Low molecular ketone of (2), C₂-C₆Low molecular nitrile of (2), C₂-C₈Low molecular ester of (2), C₁-C₆Washing one or more of the low molecular weight halogenated hydrocarbons for 1-3 times, filtering, and mixing the obtained solid with water and C₁-C₆Low molecular alcohol of (2), C₂-C₈Low molecular ether of (2), C₃-C₈Low molecular ketone of (2), C₁-C₆A low molecular weight halogenated hydrocarbon (selected from but not limited to methylene chloride, chloroform, etc.), C₂-C₈Low molecular ester of (2), C₂-C₆Recrystallizing one or more of low molecular nitrile and DMF with crystallization solvent for one or more times, filtering, standing below 25 deg.C to precipitate crystals, filtering, and extracting with organic solvent C1-C6 low molecular alcohol, C2-C8 lower ether, C3-C8 low molecular ketone, or C3-C8₂-C₈Washing one or more of low molecular ester and C1-C6 lower halogenated hydrocarbon, filtering, and drying to obtain new sugammadex sodium compound;

or recrystallizing the anhydrous sulgammadex or amorphous sulgammadex according to the above operation, washing with organic solvent, filtering, and drying to obtain new compound of sulgammadex;

among them, sugamogluconic acid used in the reaction: the sodium hydroxide or sodium carbonate has an equivalence ratio of about 1:1 to 1.1; sulbrotrogluconic acid (weight g) used in the reaction and water, or C1-C6 low molecular alcohol, or C2-C8 lower ether (selected from but not limited to diethyl ether, tetrahydrofuran, isopropyl ether, methyl tetrahydrofuran, etc.), or C2-C6 lower nitrile (selected from but not limited to acetonitrile, propionitrile, etc.), C2-C6 lower nitrile₁-C₆A low molecular weight halogenated hydrocarbon (selected from but not limited to dichloromethane, chloroform, dichloroethane, etc.), C₂-C₈One or more of the organic solvents such as low molecular ester, DMF and the like in the weight-volume ratio are as follows: 1 (g): 2 to 100(ml), preferably in the ratio: 1 (g): 6-60 (ml); the volume ratio of water to the organic solvent used in the crystallization or recrystallization is generally 1: 1-200, preferably the ratio is: 1:1 to 60.

The crystallization or recrystallization solvent of the new compound of the sugammadex sodium is selected from one or more of water, acetonitrile, methanol, ethanol, isopropanol, n-butanol, acetone, ethyl acetate, butyl acetate, ethyl formate, diethyl ether, tetrahydrofuran, isopropyl ether, dichloromethane, chloroform and the like; the sugammadex sodium crystallization or recrystallization solvent is preferably one or more of water, acetonitrile, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, ethyl acetate, diethyl ether, isopropyl ether, dichloromethane and chloroform.

The carbon number of the organic solvent lower alcohol or low molecular alcohol in the present invention is defined as C1-C6 (i.e., alcohol of 1-6 carbon atoms), and is selected from, but not limited to, methanol, ethanol, isopropanol, n-butanol, etc.; the number of carbon atoms of the lower ether or low molecular ether is defined as C2-C8, and is selected from but not limited to diethyl ether, dibutyl ether, tetrahydrofuran, etc.; the lower halogenated hydrocarbon has carbon number defined as C1-C6, and is selected from but not limited to dichloromethane, dichloroethane, chloroform, etc.; the number of carbon atoms of the lower ester is defined as C2-C8, and includes methyl acetate, butyl acetate, ethyl formate, etc., unless otherwise specified as a lower ester of formic acid; the C3-C8 low molecular ketone is defined as ketone with 3-8 carbon atoms, and is selected from but not limited to acetone, butanone, isohexanone and the like; the labeling method for the number of carbon atoms of any of the compounds described as "lower or low molecular" appears once in the text, and the number of carbon atoms of any of the other unlabeled compounds of the same class described as "lower or low molecular" is consistent with the number already indicated herein.

The product of the present invention may be dried at various temperatures (e.g., between 20-80 c), for drying times (e.g., 0.5 hours to several days), or in ambient conditions with other drying agents (including silica gel, phosphorus pentoxide, anhydrous calcium chloride, anhydrous sodium sulfate, etc.), or using atmospheric or reduced pressure. The drying temperature is preferably from 25 to 80 ℃.

Sugammadex sodium anhydrate as referred to in the present invention: taking a commercially available sugammadex anhydrous sample for experiment, or taking a sugammadex sample or preparing the sugammadex sample according to a literature method, drying the sugammadex sample in a vacuum drying oven at the temperature of between 90 and 100 ℃ for about 4 hours under high vacuum, then placing a triangular flask containing enough phosphorus pentoxide in the vacuum drying oven, vacuumizing the flask again (the reading of a vacuum gauge is about 0.08 MPa), continuously keeping vacuum drying for two days at room temperature to obtain the sugammadex anhydrous substance, and measuring the moisture content of the sugammadex anhydrous substance by a Karl Fischer method to be about 0.7 percent or less.

Methods of reference for the detection of sugammadex sodium and novel compounds of sugammadex sodium in the present invention or in the examples. The moisture determination of the new sugammadex compound or the sugammadex sodium in the invention refers to a first method of a VIII M moisture determination method in the second appendix of the 2010 version of Chinese pharmacopoeia, and methanol and DMSO (volume ratio is 1:1) are used as solvents, and a Karl Fischer method is adopted for determination.

The content of sugammadex sodium or its preparation including injection and related substances were measured by the method of the reference (literature, a method for purifying sugammadex sodium 2016108966086, Wangli). Wherein, the chromatographic conditions of the high performance liquid chromatography detection method for the content of the sugammadex sodium and related substances are as follows: detection wavelength: 200nm, the column temperature is 30 ℃, and the chromatographic column: KROMASIL 4.6mm × 250mm,5 μm, C18 column, mobile phase: mobile phase B: acetonitrile and mobile phase B: 0.1mol/L potassium dihydrogen phosphate solution (pH value is adjusted to 7.5 by 2mol/L sodium hydroxide solution; flow rate: 1mL/min, sample amount: 20. mu.L.

Powder X-ray diffraction can generally be used to characterize and/or identify polymorphic forms, for which the modifier "about" is used before the peak is reported when characterizing and/or identifying. This is common practice in the field of solid state chemistry in view of the inherent variation of the peak. Typical accuracy of the 2 theta X-axis values of the peaks of the powder pattern spectrum is on the order of + -0.2 deg. 2 theta, therefore, a powder X-ray diffraction peak occurring at "about 8.0 deg. 2 theta" means that the peak may be between 7.8 deg. 2 theta and 8.2 deg. 2 theta when measured on most X-ray diffractometers. The change in peak intensity is a result of how the individual crystals are oriented in the sample container relative to the external X-ray source, the orientation effect not providing structural information about the crystals.

In one aspect, the present invention provides compounds of different novel molecular formulas and novel molecular structures of sugammadex sodium.

In another aspect, the invention provides different novel molecular formulas and novel molecular structures and methods for their preparation.

In another aspect, the present invention provides a pharmaceutical composition comprising any one or more of the sugammadex sodium novel compounds prepared by the process of the present invention, and one or more pharmaceutically acceptable excipients.

The present invention further provides a process for the preparation of a pharmaceutical formulation comprising the combination of any one or more of the formulations of the sugammadex sodium novel compound prepared by the process of the present invention or with at least one or pharmaceutically acceptable excipients.

The invention further provides the use of the novel compound of sugammadex sodium in the same way as sugammadex sodium in the preparation of medicaments or pharmaceutical compositions for treatment and the like.

The new compound of sugammadex sodium provided by the invention is more stable, and is beneficial to the manufacture, quality control and clinical medication safety of medicines.

The new crystalline drug substance at the same time it expands the library of materials available to formulation scientists for designing pharmaceutical dosage forms of, for example, drugs with a targeted release profile or other desired characteristics, the construction of libraries of compounds of drugs is of great importance, not only for comparative research purposes, etc., there is a need in the art for new crystalline sulgamac sodium or new crystalline hydrates of sulgamac sodium.

The new sugammadex sodium compound provided by the invention is a crystal substance, is convenient to filter and dry, and has higher stability than an anhydrous sugammadex sodium.

The new compound sugammadex sodium may be a specific antagonist of an aminosteroid muscle relaxant.

The new sugammadex sodium compound is used for combined administration with other muscle relaxation antagonists or preparation of compound pharmaceutical compositions.

The common route of administration of the sugammadex compound is selected from, but not limited to, oral or intravenous drip: the usage amount can be similar to that of the sugammadex sodium.

The hygroscopicity of the medicine is an important content for investigating the stability of the medicine and a necessary work in the process of medicine research, the selection of a more reasonable form of a compound as a raw material medicine of the medicine is one of the contents of medicine research, and the pharmacology always tends to select a compound with better stability as a raw material medicine, which is closely related to the safe, effective and accurate manufacture of the medicine in clinic and the controllable quality. The advantages of the novel sugammadex sodium compound of the invention are also shown below: the novel sugammadex sodium compound of the invention can be stably stored. The sugammadex sodium crystalline hydrate and the anhydrous sample of the invention are compared in hygroscopicity test to find out the advantages.

1. Wicking test

The sugammadex sodium crystal hydrate is more beneficial to stable storage. Samples of the new compound sugammadex and anhydrate were subjected to the hygroscopicity test: respectively taking 5g of the sugammadex sodium anhydrate and each new compound of the invention, placing the anhydrous sugammadex sodium anhydrate and each new compound of the invention in a dry constant-weight surface dish, precisely weighing the anhydrous sugammadex sodium anhydrate and each new compound of the invention, placing the weighed anhydrous sugammadex sodium anhydrate and each new compound of the invention in an experimental box with the temperature of about 25 +/-2 ℃ and the relative humidity of about 50 +/-5%, respectively sampling in test 0h and test 8h, and calculating the percentage of moisture-attracting weight increase.

TABLE 1 moisture wicking test results

The moisture absorption test result shows that the difference of the anhydrous moisture absorption of the compound is very significant compared with that of the new sugammadex sodium compound, the new compound is observed to have no efflorescence phenomenon in the experimental process, and the new sugammadex sodium compound can better and stably respond to the change of drying temperature or humidity and the like and is more beneficial to stable storage.

The administration dose of sugammadex sodium per se is very low, the effective dose is highly closely related to the dose with severe toxicity reaction, and the accuracy of the preparation dose is very important. The new compound of the sugammadex sodium is different from deliquescence of anhydrous substances, so that air is isolated during treatment to prevent adhesion and the like, and the new compound has good sliding property, so that the operability in the preparation process is improved, the dosage is more accurate in the preparation process, the yield of raw material medicines or preparation production is improved, the unqualified products are prevented, the scrapping loss is forced to occur in the production process, or the unqualified products are introduced into the market.

The moisture-wicking experiment shows that the storage stability of the sugammadex sodium anhydrate is not as good as that of the novel sugammadex sodium compound, but the pharmaceutical science always tends to select the compound with better stability as the raw material medicine, and obviously, the experiment shows that the novel sugammadex sodium compound is a more reasonable better choice for the medicine form of the raw material medicine.

2. Raw material quality and preparation quality controllability comparative experiment

Because the content of each preparation cannot have absolute equality due to the existence of errors such as tablet weight in the preparation process or loading amount in the filling process, the marked amount range of 93-107% of the main drug of the sugammadex preparation for injection in the drug standard is used as the qualified index for controlling the content of the preparation. Nevertheless, the condition of the preparation based on sugammadex sodium inevitably causes the problem of whether the content of the preparation is accurate, and particularly when the content of the pediatric preparation is low, the content specification of the preparation is relatively small, and the feeding error of the raw material medicine can bring about adverse amplification influence, so that the failure rate of the preparation is increased, and the clinical medication safety of children is influenced.

However, particularly when the raw material drug is dosed by 98% of the labeled amount of the main drug, if the raw material drug absorbs moisture to cause inaccurate sample weighing, the content of the finished product of the preparation must be controlled within the range of 93-107% of the legal labeled amount of the main drug, and because the operation error in the manufacturing process cannot be avoided, the error is amplified, which leads to the great increase of the rejection rate of the finished product.

During preparation, raw material medicines (raw materials prepared by methods such as an example 1 method, an example 2 method, an example 3 method and the like, and sulgammadex anhydride) with determined content of sulgammadex sodium as different main medicines are exposed in the air for 4 hours at RH57 +/-5% and 25 +/-2 ℃, then samples are respectively weighed to prepare samples (the labeled amount is 93-107% of the samples, the content specification is 50 mg/count of sulgammadex sodium) according to the method of the example 12 method in the specification, 100% of the labeled amount of the main medicines is calibrated in advance before experiments, that is, 5g of sulgammadex sodium with the same weight is precisely weighed according to the absolute anhydride for preparing 200 single-position preparations, and other auxiliary materials and the mixture ratio are the same. The final preparation product is respectively sampled at random for 50 injections to determine the content of the main ingredient of the sugammadex sodium, and the content of the main ingredient of the sugammadex sodium exceeding 93-107% of the marked amount (50 mg/injection) is unqualified or overproof, and the experimental results are shown in the following table 2.

Table 2. Experimental results comparing quality of raw materials with controllability of preparation

Raw material medicines (raw materials prepared by the method of example 1, raw materials prepared by the method of example 2 and anhydrous sugammadex) with determined sugammadex content of the main medicine of different sources are exposed in the air for 3 hours at the temperature of RH52 +/-5% and 25 +/-2 ℃, then samples are respectively weighed according to the method of example 12 in the specification to prepare samples (the content specification is 200 mg/branch of sugammadex) with the marked amount of 93-107%, the raw material medicines are weighed according to 100% of the marked amount of the main medicine determined in advance before the experiment, namely 20g of the main medicine of sugammadex with the same weight is precisely weighed according to the calculation of absolute anhydrous substance and used for preparing 200 single-position preparations, and other auxiliary materials and the mixture ratio are the same. The final preparation product is respectively sampled at random for 50 injections to determine the content of the main drug, and the main drug sugammadex sodium content exceeding 93-107% of the marked amount (200 mg/injection) is unqualified or exceeds standard, and the experimental result is shown in the following table 3.

TABLE 3 comparative experimental results of quality of raw materials and controllability of preparation

Preparation samples	Content standard exceeding rate of main medicine in product
		EXAMPLE 15 method sample (example 1 method starting material)	0％
EXAMPLE 15 method sample (example 2 method starting material)	0％
		EXAMPLE 15 method sample (example 3 method starting material)	4％
EXAMPLE 15 method sample (example 4 method starting material)	4％
		EXAMPLE 15 method sample (example 5 method starting material)	4％
EXAMPLE 15 method sample (example 6 method starting material)	4％
		EXAMPLE 15 method sample (example 7 method starting material)	2％
EXAMPLE 15 method sample (example 8 method starting material)	0％
		EXAMPLE 15 method sample (example 10 method starting material)	0％
EXAMPLE 15 method sample (Shugammadex sodium anhydrate starting material)	12％

The experimental results show that for the same preparation process, the product reject ratio of the sugammadex anhydrous serving as the raw material is far higher than that of the new sugammadex compound, and the experimental results are lower than the content of the new sugammadex compound. Because sugammadex sodium is a selective muscle relaxation antagonist, the reversion of postoperative anesthetic is closely related to the operation safety, and when the dosage is insufficient, the safety of clinical medication is greatly influenced.

The application of the novel sugammadex sodium compound of the invention comprises the following steps: the compound is used for preparing solid preparations, suppositories, injections, ointments, gels, emulsions and pharmaceutically acceptable preparations containing the compound, wherein the injections are selected from but not limited to freeze-dried powder injections for injection, small-volume injections, sterile subpackaged powder injections, large infusion preparations, injectable liposome preparations or injection microsphere preparations and the like, and the large infusion preparations are selected from but not limited to sodium chloride injections, bottled or bagged large infusions, double-chamber instant large infusions, non-PVC solid-liquid double-chamber instant large infusions, instant large infusions prepared from non-PVC multilayer co-extruded films and other pharmaceutically acceptable large infusion preparations; the solid preparation is selected from, but not limited to, tablets, capsules, liposome-containing preparations, and the like.

The sugammadex sodium new compound or the pharmaceutical composition thereof is used for preparing pharmaceutically acceptable solid preparations, and the used auxiliary materials can comprise fillers, lubricants, binders, disintegrants, antioxidants, emulsifiers, preservatives or stabilizers and the like.

Can be used for preparing pharmaceutically acceptable tablet (including enteric coated tablet, rapidly disintegrating tablet, etc.), capsule (including enteric coated capsule, sustained release capsule), etc., wherein the preparation can contain pharmaceutically acceptable adjuvants or carriers, such as filler such as starch, modified starch, lactose, microcrystalline cellulose, cyclodextrin, sorbitol, mannitol, calcium phosphate, amino acids, etc.; pharmaceutically acceptable disintegrants such as starch, modified starch, microcrystalline cellulose, croscarmellose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, surfactants (sodium lauryl sulfate, etc.); pharmaceutically acceptable wetting agents and binders such as gelatinized starch, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, alginic acid and salts thereof, and the like; pharmaceutically acceptable lubricants and glidants, such as stearic acid, magnesium stearate, polyethylene glycol 4000-; pharmaceutically acceptable sweetening agents and flavoring agents, such as aspartame, sodium cyclamate, saccharin sodium, sucralose, edible flavoring agents, etc.

An injection of a new compound sugammadex sodium, prepared by:

preparing sterile subpackaged powder injection: the packaging is carried out using sterile raw materials as is customary.

The large infusion preparation comprises large infusion in bottle or bag, large infusion in dual-chamber instant type, large infusion in non-PVC solid-liquid dual-chamber instant type, and large infusion in instant type prepared by non-PVC multilayer co-extrusion film, and can be prepared by conventional method.

The preparation method of the freeze-dried powder injection preparation comprises the following steps: taking the sugammadex sodium crystal hydrate, adding a pharmaceutically acceptable freeze-drying supporting agent or an auxiliary agent, a stabilizing agent and injection water, stirring to dissolve, adjusting the pH to 7.2-8.8 by using pharmaceutically acceptable acid and alkali if required, adding 0.005-0.5% (W/V) of activated carbon, stirring for 15-45 min, filtering, replenishing water, performing sterile filtration, subpackaging (the content of the main drug) according to 20-300 mg/bottle, freeze-drying and plugging to obtain a finished product.

The freeze-drying support agent or auxiliary agent is selected from one or more of xylitol, sorbitol, mannitol, invert sugar, maltose, dextran, sodium chloride, sodium lactate, etc.

The heat source removing and sterilizing mode can be that activated carbon with the liquid preparation amount of 0.005-3% is added to remove the heat source, a microporous filter membrane is used for sterilization and hot-pressing sterilization, and the modes of sterilization and heat source removal such as ultrafiltration can also be adopted. In the ultrafiltration method, the ultrafiltration filter can be flat plate type, roll type, tubular type, hollow fiber type or round box type, and the like, preferably roll type and hollow fiber type ultrafiltration filters, most of heat-generating substances and bacteria are removed by adopting a filter membrane with the intercepted relative molecular mass of 5-30 ten thousand, and then residual heat sources are removed by adopting an ultrafiltration membrane with the intercepted relative molecular mass of 5000-60000, and preferably the ultrafiltration membrane with the intercepted relative molecular mass of 6000-20000.

The pharmaceutically acceptable pH regulator can be pharmaceutically acceptable inorganic acid or organic acid, inorganic base or organic base, or generalized Lewis acid or base, and can contain one or more of hydrochloric acid, phosphoric acid, propionic acid, acetic acid and acetate, such as sodium acetate, etc., lactic acid and lactic acid medicinal salt, citric acid medicinal salt, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, phosphate, tartaric acid and medicinal salt thereof, borax, boric acid, succinic acid, hexanoic acid, adipic acid, fumaric acid, maleic acid, polyhydroxy carboxylic acid and medicinal salt, such as glucuronic acid, gluconic acid, lactobionic acid, malic acid, threonic acid, glucoheptonic acid, etc.

The pharmaceutically acceptable antioxidant and stabilizer thereof is selected from but not limited to sulfurous acid, sulfite, bisulfite, pyrosulfite, dithionite, thiosulfate, organic sulfur compound thiourea, glutathione, dimercaprol, thioglycolic acid and salts, thiolactic acid and salts, thiodipropionic acid and salts, phenol compounds such as gallic acid and salts, caffeic acid and salts, ferulic acid and salts, di-tert-butyl-p-phenol, 2, 5-dihydroxybenzoic acid and salts, salicylic acid or salts; ascorbic acid and its salt, isoascorbic acid and its salt, nicotinamide, tartaric acid, nitrate, phosphate, acetic acid medicinal salt, citrate, EDTA and EDTA salt, such as one or more of EDTA disodium, EDTA calcium sodium salt, EDTA tetrasodium, N-di (2-hydroxyethyl) glycine, etc.

The novel crystalline sodium sugammadex compound of the present invention, or a pharmaceutical composition thereof, is suitable for use in: the following conditions for the preparation of a human or animal: can be used as a specific antagonist of an amino-steroid muscle relaxant, and is applied to drugs for reversing neuromuscular blockade (NMB) induced by rocuronium bromide (ROC), vecuronium bromide and the like in adult surgery.

Generally, when the sugammadex sodium new compound or the pharmaceutical composition thereof is intravenously administered, the sugammadex sodium new compound or the pharmaceutical composition thereof can be dissolved in a sodium chloride injection with a volume of more than 50ml or a 5% glucose injection and the like for instillation.

Drawings

FIG. 1 is a thermogram of sugammadex sodium 7.5 hydrate (example 1)

FIG. 2 is a powder X-ray diffraction pattern of sugammadex sodium 7.5 hydrate (example 1)

FIG. 3 is a thermogram of sugammadex sodium 7 hydrate (example 2)

FIG. 4 is a powder X-ray diffraction pattern of sugammadex sodium 7 hydrate (example 2)

FIG. 5 is a thermogram of sugammadex sodium 3.5 hydrate (example 3)

FIG. 6 is a thermogram of sugammadex sodium 6 hydrate (example 6)

FIG. 7 is a powder X-ray diffraction pattern of sugammadex sodium 6 hydrate (example 6)

FIG. 8 is a thermogram of sugammadex sodium 6.5 hydrate (example 7)

FIG. 9 is a thermogram of sugammadex sodium 12 hydrate (example 8)

FIG. 10 is a thermogram spectrum of sugammadex sodium 14.5 hydrate (example 9)

Detailed Description

Other than in the examples, and where otherwise indicated, all numbers expressing quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about", and thus, unless otherwise indicated, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure, and at the very least, and are not intended to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations. The numerical values set forth in the specific examples are reported as precisely as possible, and any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing.

It is noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents and, therefore, for example, unless the context clearly dictates otherwise. If reference is made to a composition containing "a compound" including mixtures of two or more compounds, it is further noted that the term "or" generally includes "and/or" unless the context clearly dictates otherwise.

As used herein, the term "obtained" or "obtaining" refers to isolating a compound of value at a level of content or purity, including but not limited to, greater than 90%, 95%, 96%, 97%, 98%, and 99%. The content or purity level may be determined by, but is not limited to, high performance liquid chromatography methods or other literature methods specified in pharmacopoeial standards for sugammadex sodium. The infrared spectrum data of the sample is measured by a Fourier transform infrared spectrometer, and the used instruments comprise a Nexus intelligent Fourier transform infrared spectrometer (Thermo Nicolet) and the like.

The present "solvate" is meant herein to also include crystalline forms of molecules, atoms and/or ions of solvent molecules that penetrate into the crystal structure, which may be in a regular and/or disordered arrangement, and which are solvates of the present invention.

Polymorphism herein refers to crystals having the same chemical composition but differing in the spatial arrangement of the molecules, atoms and/or ions that form the crystal.

The pharmaceutical composition comprises: as used herein, "pharmaceutical composition" refers to a composition of matter that may contain at least one pharmaceutically acceptable adjuvant or carrier.

As used herein, "pharmaceutically acceptable adjuvant or carrier" refers to a pharmaceutically acceptable carrier or vehicle suitable for administration of the compounds provided herein, including any such carriers known to those skilled in the art to be suitable for a particular mode of administration.

In the present invention, the "which" in the pharmaceutically acceptable salt or solvate thereof or the clathrate thereof represents one of them or either of them unless otherwise specified.

In the present invention, unless otherwise specified, "suitable amount" means a preferred or optimum amount or the minimum required amount or mass or weight or volume or the like required for carrying out the present invention.

In the present invention, unless otherwise specified, "such a combination or a combination thereof" means a multi-component mixture of the respective elements described, for example, two, three, four and up to the maximum possible multi-component mixture.

In the present invention, all "parts" and percentages (%) may refer to parts by weight or percent by weight volume, unless otherwise indicated.

When preparing the sterile raw materials, solvents such as sterile water for injection or sterile solvents, or raw and auxiliary materials or packaging materials or facilities are used, and the equipment, facilities and the environment are subjected to cleaning treatment or sterilization.

For a further understanding of the invention, reference will now be made to the preferred embodiments of the present invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the present invention, and not to limit the scope of the claims.

Infrared spectrum: potassium bromide pellets were pressed and the IR spectral data of the samples were measured using instruments including the US Thermo electric company NICOLET 5700FTIR Spectrometer, Nexus intelligent Fourier transform Infrared Spectrometer (Thermo Nicolet) and the like. Name of infrared spectrometer instrument company: the usage function of the NiCOLET 5700FTIR Spectrometer of the United states thermoelectric company is that the mid-infrared ray 4000-.

Thermal analysis method

And (3) testing conditions are as follows: setsys 16, Setaram corporation, sample size about 3-10mg, rate of temperature rise: 10K/min, N2 flow rate: 50ml/min, temperature: generally, the temperature is about room temperature to 400 ℃.

Surprisingly, characteristically, the hydrates of the present invention have corresponding endothermic peaks at the weight loss plateau of the thermogram (TG-DTA or TG-DSC) showing crystalline hydrates of sugammadex sodium, such as its 7 hydrate, etc.

Powder X-ray diffraction method

Using a D/MX-III A X radiation diffractometer, voltage: about 30-60kv, current: about 30-100mA, scanning speed: 10 deg/min, copper target, wavelength wavelengh (A) 1.54, diffraction angle 2 theta, scanning range 3-60 degA powder X-ray diffraction pattern of the crystalline hydrate of sugammadex sodium was determined with all peak positions within ± 0.2 ° 2 Θ; or by using D8Advance X-ray diffractometer of Bruker, Germany, wavelength

1.54, diffraction angle 2 theta, scan range 3-60 deg., and other indices (voltage, current, etc.) approximately as before, the samples were measured.

Fig. 4 of example 2 in this specification is compatible with the following data.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Example 1 preparation of sugammadex sodium 7.5 hydrate (omega type compound)

Adding 5g of sugamonic acid, 1ml of methanol and 8ml of water into a 250ml three-neck flask, stirring, introducing nitrogen for protection, heating to 30-40 ℃, stirring, adding 6M sodium hydroxide solution to adjust the pH value of the solution to be about 9.5, stirring for dissolving, continuing to stir for about 20 minutes, evaporating part of the solvent under reduced pressure, then adding 20ml of acetonitrile and 80ml of absolute ethyl alcohol, standing at 0 ℃, fully precipitating after precipitation, performing suction filtration, washing with a small amount of ethyl alcohol for 3 times, performing suction filtration, spreading the obtained solid, performing forced air drying at about 35 ℃ in an oven for about 2 hours, and performing forced air drying at about 58 ℃ for about 3 hours to obtain about 4.2g of white-like solid; and (3) identification: HPLC: the retention time of the main peak of HPLC in the content measurement is consistent with that of the sugammadex sodium control; the Karl method determines that the water content is 5.86%, and the thermal analysis shows that the platform weight loss is about 5.87% (see figure 1), and the corresponding endothermic peak (DTA) is arranged under the weight loss platform before about 152 ℃, which is in an error range with the result that the sample contains 7.5 crystal water (the theoretical value is 5.84%); infrared spectrum (v)^KBr _max cm^-1)：3422.7，2924.7，1640.8，1565.6，1401.8，1309.6，1217.1，1157.7，1101.4，1072.5，1041.1，937.5，593.9；MS ESI(m/z)：2023.40[M+8H-7Na]⁺(ii) a X powder diffraction (see figure 2): measured at diffraction angle 2 θ, in the range of 3-60 °, there are a number of distinct characteristic peaks (powder X-ray diffraction) around: 5.56, 7.13, 7.77, 8.76, 10.12, 11.75, 12.63, 15.73, 16.28, 16.82, 17.13, 17.59, 18.81, 19.94, 20.51, 21.57, 22.18, 23.06, 24.09, 24.65, 26.51, 27.87; sugammadex sodium content (HPLC method): measured value: 93.75%, theoretical value: 94.14 percent.

Example 2 preparation of sugammadex sodium 7 hydrate (v type compound)

Adding 8g of sugamonic acid and a proper amount of water into a 250ml three-neck flask, stirring, introducing nitrogen for protection, heating to 30-40 ℃, stirring, adding a 4M sodium hydroxide solution to adjust the pH value of the solution to be about 9.8, stirring to dissolve, then adding 50ml of methanol and 100ml of ethanol, standing at about 0 ℃, fully precipitating a precipitate, carrying out suction filtration, washing with a small amount of ethanol, carrying out suction filtration, spreading the obtained solid, drying in an oven at about 61 ℃ by blowing for about 2 hours to obtain about 7.3g of a white-like solid; and (3) identification: HPLC: the retention time of the main peak of HPLC in the content measurement is consistent with that of the sugammadex sodium control; the Karl method determines that the water content is 5.51%, and the thermal analysis shows that the platform weight loss is about 5.49% (see figure 3), and the corresponding endothermic peak (DTA) is arranged under the weight loss platform before about 140 ℃, which is in an error range with the result that the sample contains 2 crystal water (the theoretical value is 5.47%); infrared spectrum (v)^KBr _max cm^-1)：3422.3，2926.6，1640.2，1565.1，1401.5，1309.4，1217.3，1156.8，1072.0，1040.7，937.9，593.4；MS ESI(m/z)：2023.40[M+8H-7Na]⁺(ii) a X powder diffraction (see figure 4): measured at diffraction angle 2 θ, in the range of 3-60 °, there are a number of distinct characteristic peaks (powder ray diffraction) around: 6.32, 8.27, 11.46, 13.76, 14.69, 16.27, 17.24, 17.81, 18.93, 20.42, 21.38, 22.40, 22.97, 24.32, 26.48; sugammadex sodium content (HPLC method): measured value: 94.21%, theoretical value: 94.53 percent.

Example 3 preparation of sugammadex sodium 3.5 hydrate (compound type θ)

Sushu better is added into a 250ml three-neck flaskAdding a proper amount of water into 8g of sodium gluconate anhydrous substance, introducing nitrogen for protection, stirring, heating to about 40 ℃, stirring to be completely dissolved, adding 60ml of acetonitrile and 100ml of methanol, cooling to below 5 ℃, standing until precipitates are fully separated out, performing suction filtration, washing with a small amount of ethanol for 3 times, performing suction filtration, spreading the obtained solid, performing forced air drying at 35 ℃ in an oven for about 3 hours, and performing forced air drying at about 81 ℃ for about 3 hours to obtain 7.3g of white-like solid; and (3) identification: HPLC: the HPLC main peak retention time in the content determination is consistent with that of the anhydrous sodium sugammadex; the Karl method determines that the water content is 2.83%, and the thermal analysis shows that the platform weight loss is about 2.76% (see figure 5), and the corresponding endothermic peak (DTA) is arranged under the weight loss platform before about 155 ℃, which is in an error range with the result that the sample contains 3.5 crystal water (the theoretical value is 2.81%); infrared spectrum (v)^KBr _max cm^-1)：3440.0，2930.6，1639.2，1564.3，1402.1，1309.4，11548，1071.3，1040.0，938.9，593.2；MS ESI(m/z)：2452.33[M+8H-Na]⁺(ii) a Sugammadex sodium content (HPLC method): measured value: 96.82%, theoretical value: 97.19 percent.

Example 4 preparation of sugammadex sodium 5 hydrate (beta-type compound)

Adding 8g of sodium sugamide anhydrous into a 250ml three-neck flask, adding a proper amount of water, introducing nitrogen for protection, stirring, heating to about 40 ℃, stirring until the solution is dissolved, adding 50ml of ethanol, 60ml of acetone and 60ml of acetonitrile, cooling to below 5 ℃, standing until the precipitate is fully separated out, performing suction filtration, washing with a small amount of cold ethanol for 3 times, performing suction filtration, spreading the obtained solid to be thin, and performing vacuum drying in an oven at about 50 ℃ for about 4 hours to obtain 6.6g of white-like solid; and (3) identification: HPLC: the HPLC main peak retention time in the content determination is consistent with that of the anhydrous sodium sugammadex; the specific rotation is +121.2 degrees; the Karl method determines that the water content is 3.93%, the thermal analysis is that the platform weight loss is about 4.05%, and the corresponding endothermic peak (DTA) is arranged under the weight loss platform before about 155 ℃, which is in the error range with the result that the sample contains 5 crystal waters (the theoretical value is 3.97%); infrared spectrum (v)^KBr _max cm^-1)：3422.0，2929.2，1639.3，1564.7，1401.6，1309.1，1155.3，1071.8，1040.5，938.7，593.2；MS ESI(m/z)：2023.40[M+8H-7Na]⁺(ii) a Sugammadex sodium content (HPLC method): measured value: 95.64%, theoretical value: 96.03 percent.

Example 5 preparation of sugammadex sodium 5.5 hydrate (gamma type compound)

Adding 8g of sugamonic acid and a proper amount of water into a 250ml three-neck flask, stirring, introducing nitrogen for protection, heating to about 35 ℃, stirring, adding 6M sodium hydroxide solution to adjust the pH value of the solution to about 9.5, stirring to dissolve, then adding 50ml of acetonitrile, 50ml of methanol and 50ml of isopropanol, standing at about 0 ℃, fully precipitating the precipitate, carrying out suction filtration, washing with a small amount of cold ethanol for 3 times, carrying out suction filtration, spreading the obtained solid, and carrying out forced air drying at about 75 ℃ in an oven for about 3 hours to obtain 7.0g of white-like solid; and (3) identification: HPLC: the HPLC main peak retention time in the content determination is consistent with that of the anhydrous sodium sugammadex; the specific rotation is +121.5 degrees; the Karl method determines that the water content is 4.33%, the thermal analysis is that the platform weight loss is about 4.39%, and the corresponding endothermic peak (DTA) is provided under the weight loss platform before about 155 ℃, which is in the error range with the result that the sample contains 5.5 crystal water (the theoretical value is 4.35%); infrared spectrum (v)^KBr _max cm^-1)：3422.2，2927.9，1639.7，1564.3，1401.8，1309.4，1155.0，1071.4，1040.2，938.4，593.2；MS ESI(m/z)：2023.40[M+8H-7Na]⁺(ii) a Sugammadex sodium content (HPLC method): measured value: 95.23%, theoretical value: 95.65 percent.

Example 6 preparation of sugammadex sodium 6 hydrate (lambda type compound)

Adding 8g of sugamonic acid and a proper amount of water into a 250ml three-neck flask, stirring, introducing nitrogen for protection, heating to 30-40 ℃, stirring, adding a 3M sodium hydroxide solution to adjust the pH value of the solution to be about 9.9, stirring to dissolve, then adding 100ml of ethanol, 30ml of methanol and 10ml of isopropanol, standing at about 0 ℃, fully precipitating the precipitate, performing suction filtration, washing with a small amount of cold ethanol for 2 times, performing suction filtration, spreading the obtained solid, and performing forced air drying at about 70 ℃ in an oven for about 2.5 hours to obtain 7.0g of white-like solid; and (3) identification: HPLC: the HPLC main peak retention time in the content determination is consistent with that of the anhydrous sodium sugammadex; the moisture content of the sample was 4.79% as determined by the Karl method, and the plateau weight loss was about 4.83% (see FIG. 6) as measured by the thermogravimetric analysis, before about 130 ℃The corresponding endothermic peak (DTA) is arranged under a weight loss platform, which is within an error range with the result that the sample contains 6 crystal water (theoretical value is 4.73 percent); infrared spectrum (v)^KBr _max cm^-1)：3440.6，2928.6，1640.5，1563.2，1401.9，1309.8，1154.7，1070.9，1040.4，939.2，594.0；MS ESI(m/z)：2023.40[M+8H-7Na]⁺(ii) a X powder diffraction (see figure 7): measured at diffraction angle 2 θ, in the range of 3-60 °, there are a number of distinct characteristic peaks (powder X-ray diffraction) around: 5.83,7.22,8.34,9.12,9.88,10.45,11.10,11.70,13.13,13.68,15.36,15.70,16.59,17.53,18.38,18.84,19.60,20.68,21.93,22.75,23.50,24.08,25.41, 30.21; sugammadex sodium content (HPLC method): measured value: 94.92%, theoretical value: 95.27 percent.

Example 7 preparation of sugammadex sodium 6.5 hydrate (kappa type Compound)

Adding 8g of sugamonic acid and a proper amount of water into a 250ml three-neck flask, stirring, introducing nitrogen for protection, heating to about 40 ℃, stirring, adding a 3M sodium hydroxide solution to adjust the pH value of the solution to about 9.6, stirring to dissolve, then adding 60ml of acetone, 10ml of methanol and 100ml of ethanol, cooling to below 5 ℃, standing until precipitates are fully separated out, performing suction filtration, washing with a small amount of cold methanol for 3 times, performing suction filtration, spreading the obtained solid, and performing forced air drying in an oven at about 66 ℃ for about 3 hours to obtain 7.1g of white-like solid; and (3) identification: HPLC: the HPLC main peak retention time in the content determination is consistent with that of the anhydrous sodium sugammadex; the moisture content is 5.13% by Karl method, the thermal analysis shows that the platform weight loss is about 5.17% (see figure 8), the corresponding endothermic peak (DTA) is provided under the weight loss platform before about 142 ℃, and the result (theoretical value is 5.10%) of the sample containing 6.5 crystal water is in an error range; infrared spectrum (v)^KBr _max cm^-1)：3440.3，2929.8，1639.7，1563.5，1401.1，1309.6，1154.2，1071.4，1040.2，938.7，593.4；MS ESI(m/z)：2023.40[M+8H-7Na]⁺(ii) a Sugammadex sodium content (HPLC method): measured value: 94.48%, theoretical value: 94.90 percent.

Example 8 preparation of sodium sugammadex 12 hydrate (u type compound)

In a 250ml three-necked flask, 8g of sugamogluconic acid was added and water was addedStirring, introducing nitrogen for protection, heating to about 45 ℃, stirring, adding 3M sodium hydroxide solution to adjust the pH value of the solution to about 9.6, stirring to dissolve, adding 50ml of acetone, 60ml of methanol and 50ml of isopropanol, cooling to below 5 ℃, standing, fully precipitating a precipitate, performing suction filtration, washing with a small amount of cold ethanol for 3 times, performing suction filtration, spreading the obtained solid, and performing forced air drying at about 50 ℃ in an oven for about 2 hours to obtain 6.8g of white-like solid; and (3) identification: HPLC: the HPLC main peak retention time in the content determination is consistent with that of the anhydrous sodium sugammadex; the specific rotation is +121.5 degrees; the Karl method determines that the water content is 9.07%, and the thermal analysis shows that the platform weight loss is about 9.12% (see figure 9), and the corresponding endothermic peak (DTA) is arranged under the weight loss platform before about 142 ℃, which is in an error range with the result that the sample contains 12 crystal water (theoretical value is 9.03%); infrared spectrum (v)^KBr _max cm^-1)：3422.0，2926.5，1640.3，1565.8，1401.2，1340.1，1217.3，1155.9，1071.5，1040.2，938.6，593.3；MS ESI(m/z)：2023.40[M+8H-7Na]⁺(ii) a Sugammadex sodium content (HPLC method): measured value: 90.45%, theoretical value: 90.97 percent.

Example 9 preparation of sodium sugammadex 14.5 hydrate (

Compound of type (II)

Adding 8g of sugamonic acid and a proper amount of water into a 250ml three-neck flask, stirring, introducing nitrogen for protection, heating to about 40 ℃, stirring, adding 4M sodium hydroxide solution to adjust the pH value of the solution to about 9.5, stirring to dissolve, adding 60ml of acetonitrile and 100ml of methanol, cooling to below 5 ℃, standing until a precipitate is fully precipitated, performing suction filtration, washing a small amount of ethanol for 2 times, performing suction filtration, adding a proper amount of methanol and water (95: 5) into the flask, heating and stirring to dissolve the obtained solid, adding 150ml of acetonitrile and ethanol (1:1) for recrystallization, standing below 5 ℃, standing until a crystal is fully precipitated, performing suction filtration, washing the solid with a small amount of ethanol, performing suction filtration, spreading the obtained solid, and performing forced air drying at about 28 ℃ for about 10 hours in an oven to obtain 7.5g of white-like solid; and (3) identification: HPLC: the HPLC main peak retention time in the content determination is consistent with that of the anhydrous sodium sugammadex;the Karl method determines that the water content is 10.68%, and the thermal analysis shows that the platform weight loss is about 10.71% (see figure 10), and the corresponding endothermic peak (DTA) is provided under the weight loss platform before about 148 ℃, which is in an error range with the result that the sample contains 14.5 crystal water (the theoretical value is 10.71%); MS ESI (m/z): 2023.40[ M +8H-7Na]⁺。

Example 10 preparation of sugammadex sodium 9 hydrate (compound type τ)

Adding 8g of sugamonic acid and a proper amount of water into a 250ml three-neck flask, stirring, introducing nitrogen for protection, heating to about 40 ℃, stirring, adding a 4M sodium hydroxide solution to adjust the pH value of the solution to about 9.5, stirring to dissolve, adding 20ml of acetone and 120ml of ethanol, cooling to below 5 ℃, standing until a precipitate is fully separated out, performing suction filtration, washing with a small amount of cold ethanol and acetone for 3 times, performing suction filtration, spreading the obtained solid, and performing forced air drying at about 55 ℃ in an oven for about 3 hours to obtain 7.1g of white-like solid; and (3) identification: HPLC: the HPLC main peak retention time in the content determination is consistent with that of the anhydrous sodium sugammadex; the specific rotation is +121.5 degrees; the moisture content is 7.10% by Karl method, the thermal analysis is that the platform weight loss is about 7.18%, and the corresponding endothermic peak (DTA) is arranged under the weight loss platform before about 142 ℃, which is in the error range with the result that the sample contains 9 crystal water (the theoretical value is 6.93%); infrared spectrum (v)^KBr _max cm^-1)：3440.2，2927.3，1639.6，1564.1，1401.9，1309.2，1154.7，1071.4，1040.8，938.9，593.2；MS ESI(m/z)：2023.40[M+8H-7Na]⁺(ii) a Sugammadex sodium content (HPLC method): measured value: 92.64%, theoretical value: 93.07 percent.

EXAMPLE 11 preparation of Shugammadex sodium Crystal hydrate lyophilized powder for injection (prescription: 100 bottles)

Prescription: the sugammadex sodium crystal hydrate (the weight of the main medicine is calculated by the sugammadex sodium) is 10g, sorbitol is 5g, EDTA disodium is 0.05g, about 1M lactic acid and disodium hydrogen phosphate solution are added into a proper amount of water for injection to 200 ml;

taking the sugammadex sodium crystal hydrate, sorbitol and EDTA disodium according to the prescription amount, adding about 200ml of water for injection into a liquid preparation tank, stirring to dissolve, adjusting the pH to 7.5-8.5 by using about 1M of lactic acid and disodium hydrogen phosphate solution, adding 0.01% (W/V) of activated carbon, stirring for 30min, filtering by using a 0.22 micron microporous filter membrane, subpackaging according to 100mg of the weight of the main drug per bottle, freezing at-45 to-35 ℃ for about 4 hours, vacuum freeze-drying at-45 to-10 ℃ for about 10 hours, vacuum-drying at-10 to-20 ℃ for about 6 hours, plugging, and rolling an aluminum cover to obtain the finished product.

EXAMPLE 12 preparation of crystalline hydrate of sugammadex sodium lyophilized powder for injection (prescription: 100 bottles)

Prescription: 5g of sugammadex sodium crystalline hydrate (the weight of the main drug is calculated by sugammadex sodium), 5g of mannitol, 0.1g of EDTA calcium sodium 4 hydrate, about 1M lactic acid and sodium hydroxide solution, a proper amount of water for injection added to 100 ml;

taking the formula amount of the sugammadex sodium crystal hydrate, mannitol and EDTA calcium sodium, adding a proper amount of water for injection, stirring to dissolve, adjusting the pH value to about 8.0 by using about 1M of lactic acid and sodium hydroxide solution, adding the water for injection to 100ml, adding 0.002% (W/V) of activated carbon, stirring for 20min, filtering by using a 0.22-micron microporous filter membrane, taking the solution by using a 1ml pipette, subpackaging according to the amount of the liquid 1 ml/bottle, freezing at-45 to-35 ℃ for about 4 hours, freezing and drying at-45 to-10 ℃ for about 10 hours in vacuum, drying at-10 to-20 ℃ for about 6 hours in vacuum, pressing and rolling an aluminum cap to obtain a finished product.

EXAMPLE 13 preparation of injection of New Compound Shubiglucose sodium (prescription: 100)

Prescription: 50g of sugammadex sodium crystalline hydrate (the weight of the main drug is calculated by sugammadex sodium), 5g of sorbitol, 0.1g of EDTA calcium sodium 4 hydrate, 5g of trehalose, a proper amount of 2M malic acid solution and 1M sodium hydroxide solution, and the total amount of water for injection is 500ml

The preparation process comprises the following steps: weighing or preparing raw and auxiliary materials according to a prescription, stirring and dissolving the components of the prescription amount with a proper amount of fresh water for injection in a liquid preparation tank, uniformly mixing, adjusting the pH value to 7.6 with a proper amount of malic acid solution and sodium hydroxide solution, adding the water for injection to the full amount, uniformly stirring, circularly filtering a 0.22 mu m microporous filter membrane, filling and sealing the filtrate according to 5 ml/piece, sterilizing the injection at 115 ℃ for 30min, cooling, and checking to obtain the injection.

EXAMPLE 14 preparation of injection of New Compound Shubiglucose sodium (prescription: 200)

Prescription: the sugammadex sodium crystal hydrate (weight calculated by anhydrous substance) of the invention is 10g, sorbitol is 3g, EDTA calcium sodium 4 hydrate is 0.1g, trehalose is 5g, 2M citric acid solution and 1M sodium hydroxide solution are proper, and water for injection is added to the total amount of 200ml

The preparation process comprises the following steps: weighing or preparing raw and auxiliary materials according to a prescription, stirring and dissolving the components of the prescription amount in a liquid preparation tank by using a proper amount of fresh water for injection in sequence, uniformly mixing, adjusting the pH value to 7.5 by using a proper amount of citric acid solution and sodium hydroxide solution, supplementing the water for injection to the full amount, uniformly stirring, filtering twice by using a 0.22 mu m microporous filter membrane, filling the filtrate into an ampoule by using 2ml of injection extraction solution according to 2 ml/ampoule, sealing, and inspecting to obtain the injection.

EXAMPLE 15 preparation of injection of New Compound Shubiglucose sodium (prescription: 200)

Prescription: the sugammadex sodium crystal hydrate (weight calculated by anhydrous substance) of the invention is 20g, sorbitol is 3g, EDTA calcium sodium 4 hydrate is 0.1g, L-malic acid is 2g, glycine is 10g, 2M L-malic acid solution and 1M sodium hydroxide solution are proper, and water for injection is added to the total amount of 400ml

The preparation process comprises the following steps: weighing or preparing raw and auxiliary materials according to a prescription, stirring and dissolving the components of the prescription amount in a liquid preparation tank by using a proper amount of fresh water for injection in sequence, uniformly mixing, adjusting the pH value to 7.5 by using a proper amount of L-malic acid solution and sodium hydroxide solution, adding the water for injection to the full amount, uniformly stirring, filtering twice by using a 0.22 mu m microporous filter membrane, taking the solution from the filtrate by using a 2ml pipette according to 2 ml/ampoule, sealing, and inspecting to obtain the compound injection.

EXAMPLE 16 preparation of lyophilized powder for injection of a New Compound of Sugammadex sodium (prescription: 200 bottles)

Prescription: the new compound of sugammadex sodium of the invention (calculated by weight of anhydrous substance) is 20g, sorbitol is 10g, EDTA calcium sodium 4 hydrate is 0.1g, 2M lactic acid solution and 1M sodium hydroxide solution are proper, and water for injection is added to the total amount of 600ml

The preparation process comprises the following steps: weighing or preparing raw and auxiliary materials according to a prescription, stirring and dissolving the components of the prescription amount in a liquid preparation tank by using a proper amount of fresh water for injection in sequence, uniformly mixing, adjusting the pH value to 7.6 by using a proper amount of lactic acid solution and sodium hydroxide solution, adding the water for injection to the full amount, uniformly stirring, filtering twice by using a 0.22 mu m microporous filter membrane, filling the filtrate into an ampoule by using 3ml of injection extraction solution according to the volume of 3ml, freezing at-45 to-30 ℃ for about 4 hours, vacuum freeze-drying at-45 to-10 ℃ for about 16 hours, vacuum-drying at-10 to-25 ℃ for about 6 hours, plugging, and rolling an aluminum cover to obtain a finished product.

EXAMPLE 17 infusion preparation of sodium chloride of New Compound of sugammadex sodium

20g of sugammadex sodium crystal hydrate, 65g of sodium chloride, 5g of citric acid and 0.2g of EDTA calcium sodium 4 hydrate are put into a liquid preparation tank, 8000M of water for injection is added, 1M of citric acid and sodium citrate solution is used for adjusting the pH value to be within the range of 7.5-8.0, the mixture is stirred to be completely dissolved, the water for injection is added to 10000ml, 0.005% of active carbon is added, the mixture is heated and stirred for about 10-30 minutes, the mixture is filtered and decarburized, then the mixture is filtered by an ultrafiltration membrane for intercepting the relative molecular mass of 8000 and 20000, the filtrate is filled into a 50ml or 100ml or 200ml glass bottle, and nitrogen gas is filled, the stopper is added, the cover is rolled, the sterilization, the cooling and the inspection are carried out, thus obtaining the sugammadex sodium sugammadex.

Example 18: preparation of Shugeng sodium hydrate capsule (prescription 1000 granules)

Prescription: sugammadex sodium hydrate 10g

Microcrystalline cellulose 40g

Magnesium stearate 0.5g

The prescription amount of the sugammadex sodium hydrate (weight based on anhydrous substance) and magnesium stearate of the invention are sieved by a 100-mesh sieve, fully mixed and filled into a No. 2 capsule.

Example 19: shugeng glucose sodium hydrate tablet (prescription 100 tablets)

Sieving the prescription dose of the sugammadeca sodium hydrate (calculated by anhydrous substance weight), instant sorbitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate with a 100-mesh sieve, uniformly mixing, pressing into large tablets, grinding the tablets into granules with 18-24-mesh sieve, adding the magnesium stearate with the 100-mesh sieve, uniformly mixing, and tabletting.

The present invention has been described in detail with reference to the specific embodiments and examples, but it should be understood that the scope of the present invention is not limited thereto, and it will be apparent to those skilled in the art that various modifications, improvements, substitutions and combinations can be made to the technical solution of the present invention and the embodiments thereof without departing from the spirit and scope of the present invention, and these are within the scope of the present invention. It should be understood, however, that the drawings and detailed description thereto are not intended to limit the invention to the particular form disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present invention as defined by the appended claims.

Claims (11)

1. Novel compounds of muscle relaxant antagonism characterized by: the new muscle relaxation antagonistic compound is sugammadex sodium crystal hydrate with molecular formula of C₇₂H₁₀₄Na₈O₄₈S₈·nH₂O, wherein n is 3.5, 5, 5.5, 6.5, 7, 7.5, 9, 12, 14.5.

2. Novel compounds of muscle relaxation antagonism according to claim 1, characterized by: the new compound for muscle relaxation antagonism is sugammadex sodium 3.5, 5, 5.5, 6.5, 9, 14.5 hydrate.

3. Novel compounds of muscle relaxation antagonism according to claim 1, characterized by: the new compound for muscle relaxation antagonism is sugammadex sodium 6 hydrate.

4. Novel compounds of muscle relaxation antagonism according to claims 1,3, characterized by: measured by powder X-ray diffractometry, at a diffraction angle 2 theta, in a measurement range of 3-60 DEG, at the following 2 theta values, ranging between + -0.2 DEG, there are corresponding characteristic values: 5.83,7.22,8.34,9.12,9.88,10.45,11.10,11.70,13.13,13.68,15.36,15.70,16.59,17.53,18.38,18.84,19.60,20.68,21.93,22.75,23.50,24.08,25.41, 30.21.

5. Novel compounds of muscle relaxation antagonism according to claim 1, characterized by: the new compound for muscle relaxation antagonism is sugammadex sodium 7 hydrate.

6. Novel compounds of muscle relaxation antagonism according to claims 1, 5 characterized by: measured by powder X-ray diffractometry, at a diffraction angle 2 theta, in a measurement range of 3-60 DEG, at the following 2 theta values, ranging between + -0.2 DEG, there are corresponding characteristic values: 6.32,8.27, 11.46, 13.76, 14.69, 16.27, 17.24, 17.81, 18.93, 20.42, 21.38, 22.40, 22.97, 24.32, 26.48.

7. Novel compounds of muscle relaxation antagonism according to claim 1, characterized by: the new compound for muscle relaxation antagonism is sugammadex sodium 7.5 hydrate.

8. Novel compounds of muscle relaxation antagonism according to claims 1, 7, characterized by: measured by powder X-ray diffractometry, at a diffraction angle 2 theta, in a measurement range of 3-60 DEG, at the following 2 theta values, ranging between + -0.2 DEG, there are corresponding characteristic values: 5.56,7.13,7.77,8.76, 10.12, 11.75, 12.63, 15.73, 16.28, 16.82, 17.13, 17.59, 18.81, 19.94, 20.51, 21.57, 22.18, 23.06, 24.09, 24.65, 26.51, 27.87.

9. Novel compounds of muscle relaxation antagonism according to any one of claims 1 to 8, characterized by: the pharmaceutical composition is used for preparing a pharmaceutical composition containing the novel compound with muscle relaxant antagonism, and the pharmaceutical composition is used for preparing solid preparations, suppositories, injections, ointments, gels, emulsions and pharmaceutically acceptable preparations, wherein the injections are selected from but not limited to sterile powder injections, freeze-dried powder injections, large infusion solutions and small water injection preparations, and the solid preparations are selected from but not limited to tablets, capsules, granules, pellets and vaginal effervescent tablets.

10. A novel compound of muscle relaxant antagonism or a pharmaceutical composition thereof according to any one of claims 1 to 9, wherein: for the preparation of a medicament for the treatment or prevention of reversal of induced neuromuscular anesthesia.

11. A process for the preparation of a novel compound of muscle relaxant antagonism according to claims 1-10 characterised in that: the preparation method comprises the following steps:

in a reaction vessel, adding sugamonic acid, adding water and/or an organic solvent C₁-C₆Is selected from low molecular alcohol (such as methanol, ethanol, isopropanol, n-butanol, etc.), C₂-C₈Low molecular ether (selected from but not limited to diethyl ether, tetrahydrofuran, isopropyl ether, methyl tetrahydrofuran, etc.), C₂-C₆Stirring at 10-80 deg.C, adding one or more of sodium hydroxide solution or sodium carbonate solution, water and C₁-C₆Low molecular alcohol of (2), C₂-C₈Low molecular ether of (2), C₃-C₈Stirring one or more solutions of organic solvents such as low molecular ketone, reacting for 0.2-2 hr, adding organic solvent C₁-C₆Low molecular alcohol of (2), C₂-C₈Low molecular ether of (2), C₂-C₆Standing at below 25 deg.C to separate out solid, filtering, and adding C₁-C₆Low molecular alcohol of (2), C₂-C₈Low molecular ether of (2), C₃-C₈Low molecular ketone of (2), C₂-C₆Low molecular nitrile of (2), C₂-C₈Low molecular ester of (2), C₁-C₆Washing one or more of the low molecular weight halogenated hydrocarbons for 1-3 times, filtering, and mixing the obtained solid with water and C₁-C₆Low molecular alcohol of (2), C₂-C₈Low score of (2)Daughter ether, C₃-C₈Low molecular ketone of (2), C₁-C₆Low molecular halogenated hydrocarbon of C₂-C₆Low molecular nitrile of (2), C₂-C₈One or more of low molecular weight ester and dimethylformamide as crystallization solvent, filtering, standing below 25 deg.C to precipitate crystals, filtering, and adding organic solvent C1-C6 low molecular weight alcohol, C2-C8 lower ether, C3-C8 low molecular weight ketone, C3-C8₂-C₈Washing one or more of low molecular ester and C1-C6 lower halogenated hydrocarbon, filtering, and drying to obtain new muscle relaxation antagonistic compound;

or recrystallizing anhydrous sugammadex or amorphous sugammadex according to the above operation, washing with the above organic solvent, filtering, and drying to obtain new compound with muscle relaxation resistance;

wherein, the organic solvent C₁-C₆The low molecular alcohol of (1) is selected from but not limited to methanol, ethanol, isopropanol and butanol; c₂-C₆The low molecular nitrile of (a) is selected from, but not limited to, acetonitrile; c₂-C₈The low molecular ether or low molecular ether of (2) is selected from but not limited to diethyl ether, isopropyl ether, tetrahydrofuran, methyl tetrahydrofuran; c₁-C₆The lower halogenated hydrocarbon is selected from but not limited to dichloromethane, chloroform, dichloroethane; c₂-C₈The low molecular ester is selected from but not limited to butyl acetate, ethyl acetate and ethyl formate; c₃-C₈The low molecular ketone is selected from but not limited to acetone, butanone and isohexanone.

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