CN117083288A - Sulfate of polymyxin derivative and pharmaceutical composition thereof - Google Patents

Sulfate of polymyxin derivative and pharmaceutical composition thereof Download PDF

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CN117083288A
CN117083288A CN202280007209.3A CN202280007209A CN117083288A CN 117083288 A CN117083288 A CN 117083288A CN 202280007209 A CN202280007209 A CN 202280007209A CN 117083288 A CN117083288 A CN 117083288A
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dab
thr
sulfate
phe
methylheptanoyl
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陈庆财
陈虹宇
陈京顺
宗在伟
卢斌
杨奇珍
李明月
张佳伟
鲁晶晶
周宇智
孙敏
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Nanjing Hairun Pharmaceutical Co ltd
Jiangsu Aosaikang Pharmaceutical Co Ltd
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Nanjing Hairun Pharmaceutical Co ltd
Jiangsu Aosaikang Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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Abstract

The sulfate of polymyxin derivative, more specifically, a 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate with a mass percent of 12.1% -15.1%, preferably, the salt is in an amorphous crystalline form, and compared with salts such as acetate, trifluoroacetate and the like, the sulfate of the product has good stability, good solubility and small hygroscopicity, and is very favorable for preparing pharmaceutical preparations; in addition, the invention also provides an injection composition of the polymyxin derivative sulfate, which comprises the compound A sulfate, a pharmaceutically acceptable carrier and a pH regulator.

Description

Sulfate of polymyxin derivative and pharmaceutical composition thereof Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a sulfate of a polymyxin derivative and a pharmaceutical composition thereof.
Background
In 2017, WHO issues a key pathogen list for developing new antibiotics in the first place, wherein the important importance of class 1 (critical) comprises 3 types of carbapenem drug resistant Acinetobacter baumannii, carbapenem drug resistant Pseudomonas aeruginosa and carbapenem drug resistant and third generation cephalosporin resistant Enterobacteriaceae bacteria, and the multidrug resistant gram-negative bacteria have drug resistance to carbapenem antibiotics, so that new antibiotics are needed in clinic for treating the serious drug resistant bacteria.
Polymyxin has good curative effects on the negative bacteria, so polymyxin becomes a final defense line for treating multi-drug resistant gram negative bacteria. Polymyxin was first reported in 1947 as a cyclic antibacterial lipopeptide of different structural types produced by fermentation of different Paenibacillus polymyxa, including polymyxin B, E, A, C, D, F, K, M, P, S and T, etc. Among them, polymyxin B and polymyxin E are clinically used.
The common structural characteristics of polymyxin antibiotics are: consists of a cyclic heptapeptide, a linear tripeptide and an N-fatty acyl chain connected with the linear tripeptide, wherein the heptapeptide ring is formed by condensing an amino acid L-Dab (alpha, gamma-diaminobutyric acid) at the 4 th position and an amino acid L-Thr (or L-Leu) at the 10 th position. Polymyxins of the same type structure generally contain more than two different components depending on the N-substituted fatty acyl chain or the amino acid at position 7. At the beginning of the 50 s of the 20 th century, polymyxin B was applied soon, and serious adverse effects including significant nephrotoxicity were found to occur with systemic administration, with a gradual decrease in clinical use after the 70 s of the 20 th century. Recent clinical studies have found that the incidence of CMS-induced acute kidney injury in patients is as high as 60.4% and that polymyxin B has a incidence of 41.8% and that the nephrotoxicity of polymyxin severely limits clinical use. Therefore, there is an urgent need to develop novel high-efficiency, low-toxicity polymyxin derivatives.
Many structural modifications have been made at present, but the problems that the antibacterial activity is not compatible with nephrotoxicity and neurotoxicity exist, and the modification result is often unsatisfactory.
WO2018108154A1 prepares a modified chain having an increased or decreased side chain acyl chain (modified R 0 ) Hydrophobic new derivatives, basic amino acids or polar amino acids substituted for amino acids at position 1 and/or 3 (R is altered 1 、R 3 ) New derivatives of (2) and/or 10 amino acids are replaced by hydrophobic amino acids or polar amino acids (R is changed 2 、R 9 ) New derivatives of (2) substitution of hydrophobic or basic or polar amino acids for amino acids at position 5 and/or 8 and/or 9 (change R 4 、R 7 、R 8 ) New derivatives of (2) substitution of hydrophobic amino acids or polar amino acids for amino acids at position 6 and/or 7 (modification of R 5 、R 6 ) Is a novel derivative of (a). By changing the amino number or hydrophobicity of the polymyxin molecule, the antibacterial spectrum is enlarged or the antibacterial activity is improved or the nephrotoxicity is reduced. After structural and toxicity studies of the system, the inventors have obtained detailed structure-activity and toxicity relationships and have surprisingly found that the compound 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr]Has the characteristics of high antibacterial activity and low nephrotoxicity, and is a novel polymyxin derivative.
In the invention, 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] is simply referred to as a compound A, and the structure is as follows:
surprisingly, it has been found that the sulphate salt of the compound 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] has a number of advantages over its acetate salt, its trifluoroacetate salt. The research shows that the sulfate of 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] has good stability, good solubility and small hygroscopicity, and is very favorable for preparing medicinal preparations.
Disclosure of Invention
In a first aspect, the present invention provides a 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate having a mass percentage of sulphate of 12.1% to 15.1%.
Preferably, the present invention relates to a 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate having a mass percentage of sulphate of 13.6% -14.6%.
Preferably, the 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate of the present invention has a mass% of sulphate of 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9, 15.0% or 15.1%.
Preferably, a 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate having a mass percentage of sulphate of 12.1% to 15.1%, characterised in that the salt is in amorphous crystalline form.
In a second aspect, the invention provides a pharmaceutical composition comprising a 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate salt as described in any one of the preceding claims and a pharmaceutically acceptable carrier.
In a third aspect, the present invention provides the use of a 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate as described in any of the preceding claims in the manufacture of an antibacterial medicament.
Preferably, the present invention relates to the use of 6-methylheptanoyl-Dab-Thr-D-Ser-loop (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate salt of any of the above-mentioned claims for the preparation of an antibacterial agent against "superbacteria" carrying the NDM-1 gene.
Preferably, 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate may be administered orally or parenterally.
Preferably, parenteral administration forms are injection administration, including injection needles, injection powder needles and small infusion solutions.
In a fourth aspect, the invention provides a method of preparing a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate of any of the foregoing, the method comprising combining the 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate of any of the foregoing with a pharmaceutically acceptable carrier.
The term "pharmaceutically acceptable" as used herein is within the scope of sound medical judgment and is suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio. "pharmaceutically acceptable" is also commonly referred to as "pharmaceutically acceptable".
Compared with the prior art, the 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate with the mass percent of sulfate radical of 12.1 to 15.1 percent; preferably, 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate having a mass percentage of sulphate of 12.1% to 15.1%, said salt being in amorphous crystalline form, the effect of the product being:
(1) The stability under acid-base, oxidation, high temperature and illumination conditions is better than that of other salts;
(2) Is very soluble in water;
(3) Salts of polymyxin compounds are very hygroscopic and wet, but in the research of the product, we find that the hygroscopicity of the sulfate of the compound A is unexpectedly small compared with other salts, and because the variable range of the acid radical content of the product obtained by the same process is smaller, the sulfate prepared by the process has more advantages on the stability of the salt content and the stability of the corresponding quality;
therefore, the sulfate of the compound A is safe, effective and controllable in quality in the preparation and use processes, and is more beneficial to preparing the pharmaceutical preparation.
In a specific embodiment of the pharmaceutical composition provided in the second aspect of the present invention is an injectable composition comprising a pH adjuster. The invention provides a compound A sulfate injection composition and a preparation method thereof, which solve the defect of unstable solution state of a compound A sulfate preparation, and obtain a stable preparation finished product through freeze-drying after pH control.
More specifically, the invention discloses an injection composition of polymyxin derivative sulfate, which is characterized in that: the composition comprises a compound A sulfate, a pharmaceutically acceptable carrier and a pH regulator, wherein the compound A sulfate has sulfate radical with the mass percent of 12.1-15.1%, and preferably, the compound A sulfate has sulfate radical with the mass percent of 13.6-14.6%. More specifically, compound a sulfate is concerned with a sulfate of 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9, 15.0% or 15.1% by mass.
The pH regulator is water-soluble regulator selected from H 2 SO 4 Sulfuric acid solution, HCl, hydrochloric acid solution, HAc, acetic acid solution, H 3 PO 4 Phosphoric acid solution.
Preferably, when the pH adjustor is selected from sulfuric acid solution, hydrochloric acid solution, acetic acid solution, phosphoric acid solution, the concentration of the pH adjustor is 5 to 15mg/ml, preferably 10 to 15mg/ml.
The pH regulator regulates the pH of the solution to 1.0-5.0, preferably to 2.0-4.0, preferably to 3.0-4.0.
Preferably, the pharmaceutically acceptable carrier is selected from the group consisting of: mannitol, sucrose, lactose, glucose, sorbitol, trehalose.
Preferably, the content of the compound A sulfate unit preparation is 5-30 mg/ml, preferably 9.5-26.25 mg/ml, more preferably 23.75-26.25 mg/ml, and more specifically 5mg/ml, 6mg/ml, 7mg/ml, 8mg/ml, 9mg/ml, 10mg/ml, 11mg/ml, 12mg/ml, 13mg/ml, 14mg/ml, 15mg/ml, 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 21mg/ml, 22mg/ml, 23mg/ml, 24mg/ml, 25mg/ml, 26mg/ml, 27mg/ml, 28mg/ml, 29mg/ml, 30mg/ml, based on the compound A sulfate.
Preferably, the content of the pharmaceutical carrier unit preparation in the prescription is 10-50 mg/ml, preferably 20-40 mg/ml, preferably 20-30 mg/ml, more specifically, the content of the pharmaceutical carrier unit preparation is 10mg/ml, 15mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 35mg/ml, 40mg/ml, 45mg/ml, 50mg/ml.
The composition is a water injection, freeze-dried powder and sterile powder.
Preferably, the composition is lyophilized after sterile filtration.
Preferably, the pre-lyophilization composition solution has a volume of 1-10ml, more specifically, the pre-lyophilization composition solution has a volume of 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml.
More specifically, the invention discloses an injection composition of polymyxin derivative sulfate, which is characterized in that: the composition comprises a compound A sulfate, mannitol and a pH regulator, wherein the compound A sulfate has a sulfate radical with a mass percentage of 13.6-14.6%. More specifically, the sulfate of compound a has a sulfate content of 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6% by mass.
The pH regulator is sulfuric acid solution with concentration of 5-15 mg/ml, preferably 10-15 mg/ml.
The pH regulator regulates the pH value of the solution to 3.0-4.0.
The content in the prescription is 5-30 mg/ml, preferably 9.5-26.25 mg/ml, more preferably 23.75-26.25 mg/ml, and more specifically 5mg/ml, 6mg/ml, 7mg/ml, 8mg/ml, 9mg/ml, 10mg/ml, 11mg/ml, 12mg/ml, 13mg/ml, 14mg/ml, 15mg/ml, 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 21mg/ml, 22mg/ml, 23mg/ml, 24mg/ml, 25mg/ml, 26mg/ml, 27mg/ml, 28mg/ml, 29mg/ml, 30mg/ml, based on the sulfate of the compound A.
The content of mannitol unit preparation in the prescription is 10-50 mg/ml, preferably 20-30 mg/ml, more specifically, the content of the pharmaceutically acceptable carrier unit preparation is 10mg/ml, 15mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 35mg/ml, 40mg/ml, 45mg/ml, 50mg/ml.
Preferably, the pre-lyophilization composition solution has a volume of 1-10ml, more specifically, the pre-lyophilization composition solution has a volume of 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml.
The invention also discloses a preparation process of the injection composition of the compound A sulfate, which comprises the following steps: adding water for injection in an amount of 60-90% (illustratively, 80%) of the total volume of the preparation into a dosing container at room temperature, adding a prescribed amount of a pharmaceutically acceptable carrier, stirring to dissolve completely, adding a prescribed amount of a sulfate of compound A, and stirring to dissolve completely; regulating pH value with pH regulator, adding injectable water to full amount, detecting intermediate, aseptically filtering, bottling in penicillin bottle, half-packing into box, and freeze drying.
Preferably, the volume of the filling solution is 1-10ml, more specifically, the volume of the filling solution is 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml.
Drawings
Fig. 1: example 1X-ray powder diffraction pattern (XRD) of compound a sulfate salt.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer.
DCM: dichloromethane (dichloromethane)
DMF: n, N-dimethylformamide
DIEA: n, N-diisopropylethylamine
OAll allyl group
PIP: piperidine compounds
TFA: trifluoroacetic acid
TIS: triisopropylsilane
Example 1 preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate having a mass percentage of sulfate of 13.6% -14.6%
Preparation of resin peptide:
2g (1.12 mmol,0.56 mmol/g) of 2-chlorotrityl chloride resin (2-CTC) was taken and placed in a polypeptide reaction flask, and 20mL of DCM was added to the flask, followed by stirring and swelling for 30min, followed by suction filtration and washing once with 20mL of DCM to complete the resin swelling.
Fmoc-Dab (NH) was weighed 2 ) 1.40g (3.36 mmol,3.0 eq) of the OAll HCl amino acid and 1.30g (10.08 mol,9.0 eq) of DIEA were dissolved in 12mLDCM, added to the polypeptide reaction flask, reacted for 2h at 30℃with stirring, the reaction solution was drained and the resin was washed 3 times with 16mL DCM each.
16mL of DCM solution containing 15% methanol and 5% DIEA was added, the reaction was stirred at 30℃for 30min, the resin was blocked, suction filtration was performed, each of 16mL of DCM and DMF was alternately washed 3 times, 5min+15min of Fmoc protecting group was removed with 20% PIP/DMF solution twice, each of 16mL was alternately washed 4 times, each of 16mL of DCM/DMF.
Sequentially completing the steps of Fmoc-Dab (Boc) -OH, fmoc-Thr (tBu) -OH, fmoc-D-Phe-OH, fmoc-Dab (Boc) -OH, fmoc-Dab (Dde) -OH, fmoc-D-Ser (tBu) -OH, fmoc-Thr (tBu) -OH, fmoc-Dab (Boc) -OH, 6-methylheptanoic acid, hydrazine hydrate removal allyl, fmoc-Thr (tBu) -OH, tetra-triphenylphosphine palladium removal Dde protecting group, peptide chain cyclization and the like, and completing the synthesis of the resin peptide, and drying to obtain 3.6g of the resin peptide.
Preparing a crude product:
the dried resin peptide was added to the lysate (95% TFA,2.5% H) 2 O，2.5% Tis) 18mL (5V/M), and the mixture was stirred at 30℃for 2 hours and filtered to obtain a filtrate. The resin was washed 3 times with 2mL of lysate each and the filtrates were combined.
Slowly adding the filtrate into 96mL of methyl tertiary butyl ether, stirring while adding, precipitating a large amount of white solid, stirring for 10min, carrying out suction filtration, respectively pulping and washing the filter cake with 20mL of methyl tertiary butyl ether for 3 times, carrying out suction filtration, and drying under reduced pressure at 30 ℃ to obtain 1.0g of crude product, wherein the yield is about 77%.
Preparing a sulfate finished product:
to the crude product, 2mL of water, 2mL of acetonitrile and 1.0g of ammonium sulfate were added, and after filtration of the solution, 20mL of water was added for dilution.
Purifying, salt exchanging and enriching crude products through a DAC-100 middle-high pressure liquid phase:
primary purification: purifying by preparative high performance liquid chromatography, wherein the filler is reverse phase C18 with a size of 10 μm, mobile phase A is (0.3% ammonium sulfate+0.1% sodium bisulfate)/water solution, mobile phase B is acetonitrile, the detection wavelength is 214nm, gradient eluting as shown in the following table 1, collecting the corresponding main peak components, mixing the components with HPLC purity of more than 95%, concentrating to remove acetonitrile, and purifying for the second time.
Table 1: gradient of elution for primary purification
And (3) secondary purification: purifying by preparative high performance liquid chromatography, wherein the filler is reverse phase C18 with a size of 10 μm, the mobile phase A is 0.2% ammonium acetate/water solution, the mobile phase B is acetonitrile, gradient eluting as shown in the following table 2, collecting main peak components at a wavelength of 214nm, mixing components with HPLC purity of more than 98%, concentrating to remove acetonitrile, and changing salt.
Table 2: gradient of elution for secondary purification
Preparation of sulfate: purified by preparative high performance liquid chromatography with a packing of 10 μm reversed phase C18, mobile phase a of 1% ammonium sulfate/water solution and mobile phase B of acetonitrile, gradient eluted by table 3 below:
table 3: sulfate preparation elution gradient
The first 60min is the process of changing the sulfate into sulfate in the preparation column, and the second 60min is the process of eluting the product from the preparation column. And collecting main peaks in the elution process at the wavelength of 214nm to obtain eluent, fully concentrating, removing acetonitrile as much as possible, improving the concentration before freeze-drying, wherein the concentration of sulfate before freeze-drying is about 80mg/mL, and freeze-drying by the freeze-drying process shown in the following table 4 to obtain 0.30g of sulfate product of white solid, wherein the total yield is 20%. HPLC purity 99.540%, 1 H NMR(500MHz,D 2 O):δ7.29(t,J＝10Hz,2H),7.24-7.19(m,3H),4.65-4.61(m,2H),4.43-4.40(m,1H),4.38-4.34(m,2H),4.29-4.23(m,3H),4.19-4.10(m,5H),4.07-4.06(m,1H),3.85-3.76(m,2H),3.29-3.23(m,1H),3.10-2.93(m,10H),2.79-2.73(m,1H),2.67-2.61(m,1H),2.23(t,J＝10Hz,3H),2.18-2.09(m,3H),2.07-1.96(m,2H),1.92-1.86(m,2H),1.85-1.75(m,11H),1.52-1.46(m,2H),1.44-1.38(m,1H),1.23-1.17(m,2H),1.13-1.06(m,9H),0.75(d,J＝5Hz,6H),0.70(t,J＝10Hz,3H)，MS(m/z):1164.6689[M+H] + theoretical value of 1164.6663[ M+H ]] + The structure is characterized as the sulfate of compound a.
Table 4: freeze-drying process
Sulfate was measured by "ion chromatography" according to the fourth code 0513 of the chinese pharmacopoeia 2020 edition:
test solution: taking a proper amount of compound A sulfate, precisely weighing, adding water for dissolving and diluting to prepare a solution containing about 0.25mg of compound A sulfate in each 1 ml.
Control solution: the ammonium sulfate reference substance is taken in proper amount, precisely weighed and diluted by the diluent to prepare a solution with the concentration of about 0.06mg of sulfate radical in each 1 ml.
Chromatographic conditions: using anion exchange chromatography column (Dionex IonPac AS15 column, or equivalent performance chromatography column); the detector is a conductivity detector; the detection mode is inhibition conductance detection; column temperature is 30 ℃; taking 30mmol/L potassium hydroxide solution as eluent; the flow rate is 1.0ml per minute; the sample volume was 25. Mu.l.
Assay: precisely measuring the sample solution and the reference substance solution, respectively injecting into ion chromatograph, and recording chromatogram.
Limit: calculated as peak area according to the external standard method. The optimized process of the embodiment 1 is repeated for a plurality of times, and the obtained product contains 13.6% -14.6% of sulfate radicals, has small variable range and controllable quality.
The X-ray powder diffraction pattern is shown in figure 1 (copper target), which shows an amorphous crystalline form.
In addition, compound A free base and compound A sulfate with the sulfate radical of 13.6-14.6% prepared in example 1 (the target proportion is converted when the mol ratio is needed) are weighed, the weighed sample is dissolved in 50ml of purified water according to each gram, the dissolved sample is transferred into a freeze-drying bottle, and the freeze-drying treatment is carried out, so that the compound A sulfate with the sulfate radical of 2.5-3.5% and the sulfate radical of 9.5-10.5% is respectively prepared.
Example 2 preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] acetate with 15.0% to 25.0% acetate by mass
With reference to the procedure described in example 1, mobile phase A "1% ammonium sulfate/water solution" during the preparation and purification was modified to "1% ammonium acetate", and the other procedure was unchanged, to obtain 0.32g of acetate as a white solid product with a total yield of 20%. HPLC purity 99.638%; warp yarn 1 H NMR(500MHz,D 2 O) and MS are characterized as acetates of compound a.
The acetic acid content is determined by high performance liquid chromatography (acetic acid determination method in the synthetic polypeptide of the four-part general rule 0872 of the year 2020 edition of Chinese pharmacopoeia):
about 20mg of acetate of the compound A is precisely weighed, placed in a 10ml measuring flask, added with diluent (mobile phase A-methanol (95:5)) to be dissolved and diluted to scale, shaken uniformly to serve as a sample solution, measured by referring to an acetic acid measuring method (general rule 0872 of four parts of Chinese pharmacopoeia 2020 edition) in synthetic polypeptide, the process of the embodiment 2 is repeated for a plurality of times, and the obtained product contains 15.0% -25.0% of acetic acid, has a large variable range and is detected to be in an amorphous crystal form by an X-ray powder diffraction pattern.
Example 3 preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] trifluoroacetate salt with mass% of trifluoroacetate salt of 24.0% -31.0%
With reference to the method described in example 1, mobile phase A "1% ammonium sulfate/water solution" in the course of preparation and purification was modified to "1% aqueous solution of trifluoroacetic acid and 1% aqueous ammonia", and the other methods were unchanged, to obtain 0.35g of trifluoroacetate as a white solid product with a total yield of 20%. HPLC purity of 99.408%, via 1 H NMR(500MHz,D 2 O) and MS are characterized as the trifluoroacetate salt of compound a.
The trifluoroacetic acid content was measured by referring to high performance liquid chromatography (high performance liquid chromatography of the fourth edition of chinese pharmacopoeia 2020 edition, general rule 0512):
test solution: and (3) taking a proper amount of compound A trifluoroacetate, precisely weighing, adding a diluent (0.5% phosphoric acid solution) for dissolving and diluting to prepare the compound A trifluoroacetate with the concentration of about 1mg per 1 ml.
Control solution: taking a proper amount of sodium trifluoroacetate reference substance, precisely weighing, adding a diluent for dissolving and diluting to prepare a solution with the concentration of about 0.35mg in each 1ml serving as the reference substance solution.
Chromatographic conditions: linear gradient elution was performed using octadecylsilane chemically bonded silica as the packing material (Waters Atlantis T, 4.6mm×250mM,5 μm or column with comparable performance), 10mM potassium dihydrogen phosphate solution (pH adjusted to 2.5 with phosphoric acid) as mobile phase a, acetonitrile as mobile phase B, following table 5; the flow rate is 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength is 210mn; the sample volume was 10. Mu.l.
Table 5: trifluoroacetic acid content determination elution gradient
Assay: precisely measuring the control solution and the sample solution, respectively injecting into a liquid chromatograph, and recording chromatograms.
Limit: the process of example 3 was repeated a number of times to obtain a product containing 24.0% -31.0% trifluoroacetic acid with a large variable range, which was detected as amorphous crystalline form by X-ray powder diffraction pattern.
Example 4 solubility experiment
Salts of Compound A were prepared as in examples 1-3, sampled, and the solubility of the samples in methanol, acetonitrile and water was examined, respectively, and the results are shown in Table 6.
The operation method comprises the following steps:
solubility in water: weighing about 1g, placing into a 10ml test tube with a stopper scale, and adding less than 1ml of water;
solubility in methanol: weighing about 10mg, placing into 100ml test tube with plug scale, and adding 100ml water;
solubility in acetonitrile: weighing about 10mg, placing into 100ml test tube with plug scale, and adding 100ml water;
the above sample after solvent addition was vigorously shaken at 25.+ -. 2 ℃ for 30 seconds every 5 minutes, and the dissolution was observed within 30 minutes, i.e., no visually visible solute particles were considered to be completely dissolved.
Table 6: solubility test results
The results show that the three salts of compound a have similar solubilities and are all very soluble in water.
Example 5 stability experiment
Salts of compound a were prepared as in examples 1-3, sampled, and examined for stability under alkaline damage, acid damage, high temperature liquid damage, oxidative damage, high temperature solids, light liquids conditions:
(1) Preparation of test solution:
unbroken: taking about 10mg of a sample to be tested, precisely weighing, placing into a 10ml measuring flask, adding water for dissolving and diluting to a scale, and shaking uniformly to obtain the product;
alkali destruction: taking about 10mg of a test sample, precisely weighing, placing in a 10ml measuring flask, adding 1ml of 0.05M NaOH solution, shaking to dissolve, standing at room temperature for 45min, adding 1ml of 0.05M HCl solution for neutralization, diluting with water to scale, and shaking to obtain the final product;
acid damage: taking about 10mg of a test sample, precisely weighing, placing in a 10ml measuring flask, adding 1ml of 0.5M HCl solution, shaking to dissolve, standing in a water bath at 60 ℃ for 2 hours, adding 1ml of 0.5M NaOH solution for neutralization, diluting with water to a scale, and shaking uniformly to obtain the product;
high temperature liquid destruction: taking about 10mg of a test sample, precisely weighing, placing in a 10ml measuring flask, adding 5ml of water, shaking to dissolve, standing at 80 ℃ in water bath for 2h, diluting with water to a scale, and shaking uniformly to obtain the final product;
oxidative destruction: taking about 10mg of a test sample, precisely weighing, placing in a 10ml measuring flask, adding 5ml of 3% hydrogen peroxide, shaking to dissolve, performing water bath at 50 ℃ for 3 hours, diluting with water to a scale, and shaking uniformly to obtain the product;
high temperature solids destruction: taking about 10mg of a test sample, precisely weighing, placing in a 10ml measuring flask, carrying out water bath at 80 ℃ for 4 hours, standing at room temperature, adding water for dissolution, diluting to a scale, and shaking uniformly to obtain the product;
illumination solid destruction: taking about 10mg of a sample to be tested, precisely weighing, placing in a 10ml measuring flask, standing for 48 hours at 5000 lx+/-500 lx, adding water for dissolving and diluting to a scale, and shaking uniformly to obtain the product;
destruction of the illuminating liquid: about 10mg of the sample is taken, precisely weighed, placed in a 10ml measuring flask, added with about 5ml of water, shaken to dissolve, placed for 48 hours at 5000 lx+/-500 lx, diluted to a scale with water, and shaken uniformly to obtain the product.
(2) The detection method comprises the following steps:
the measurement was performed by referring to high performance liquid chromatography (the fourth edition of chinese pharmacopoeia 2020 edition, general rule 0512).
Chromatographic conditions: linear gradient elution was performed using octadecylsilane chemically bonded silica as packing material (ACE EXCEL 5 c18-AR,4.6mm x 250mm,5 μm or column with comparable performance), 0.05% phosphoric acid solution as mobile phase a, acetonitrile as mobile phase B, following table 7; the flow rate is 1.0ml per minute; the column temperature is 30 ℃; the temperature of the sample tray is 5 ℃; the detection wavelength is 214nm; the sample volume was 10. Mu.l.
Assay: precisely measuring the solution of the sample, injecting into a liquid chromatograph, and recording the chromatogram.
Table 7: stability detection method elution gradient
The stability test results are shown in table 8 below:
table 8: stability test results
The three salts of the compound A are sensitive to alkali damage, acid damage and oxidation damage, are stable to high-temperature solid, light solid and light liquid, and the sulfate of the compound A has better stability to oxidation damage and high-temperature liquid damage.
In summary, the sulfate stability of compound a is better than acetate and trifluoroacetate.
Example 5 hygroscopicity test
(1) Taking a dry glass weighing bottle with a plug, placing the bottle in a proper constant temperature dryer (with an ammonium sulfate saturated solution placed at the lower part) at 25+/-1 ℃ one day before the test, precisely weighingWeight (m) 1 )。
(2) A proper amount of the sample is taken and spread in the weighing bottle, and the weight (m 2 )。
(3) The weighing bottle is opened and placed under the constant temperature and humidity condition for 24 hours together with the bottle cap.
(4) The lid of the weighing flask was closed, and the weight (m 3 )。
(5) Calculation formula
The results of the moisture wicking test are shown in table 9 below:
table 9: results of moisture permeability test
The hygroscopicity of the compound a sulfate is significantly lower than acetate and trifluoroacetate, which is more conducive to sample storage and transport.
Example 6 comparison of Mass changes of solutions before and after Sterilization
Table 10: formulation recipe:
the process method comprises the following steps:
adding injection water (the temperature is below 25 ℃) of which the total volume is 80 percent into a batching container, adding mannitol with the prescription amount, stirring to dissolve completely, adding sulfate raw material (sulfate compound A prepared according to the method of the example 1, with the weight percent of sulfate radical of 13.6-14.6) with the prescription amount, and stirring to dissolve completely; adjusting pH with dilute sulfuric acid solution (10 mg/ml), adding injectable water to full volume, filling into 10ml ampoule bottles after intermediate content is qualified, sterilizing four prescriptions at 121deg.C for 8 min, sterilizing 5 bottles at 121deg.C for 15min, and comparing the quality difference of prescriptions before and after sterilization.
Compound a sulfate was prepared according to the recipe of examples 6-1 to 6-4, sampled, and examined for quality change before and after sterilization of the comparative solution:
(1) Preparation of test solution:
taking 20mg of the content of the product, precisely weighing, placing into a 10ml measuring flask, adding water for dissolving and diluting to a scale, and shaking uniformly to obtain the product; solution stability: the solution was stable by standing at 10℃for 48 hours.
(2) The detection method comprises the following steps:
the measurement was performed by referring to high performance liquid chromatography (the fourth edition of chinese pharmacopoeia 2020 edition, general rule 0512).
Chromatographic conditions: linear gradient elution was carried out using octadecylsilane chemically bonded silica as the filler (ACE UltraCore 5 SuperC18, 250 mm. Times.4.6 mm,5 μm or a column of comparable potency), 10mmol/L sodium sulfate solution (pH adjusted to 2.3 with phosphoric acid) as mobile phase A, acetonitrile as mobile phase B, as follows; the flow rate is 1.0ml per minute; the column temperature is 30 ℃; the temperature of the sample tray is 10 ℃; the detection wavelength is 214nm; the sample volume was 10. Mu.l.
Table 11: linear gradient elution conditions
Assay: precisely measuring the solution of the sample, injecting into a liquid chromatograph, and recording the chromatogram.
The mass change of the comparative solution before and after sterilization is shown in table 12 below:
the results show that the product is not suitable for adopting a terminal sterilization method, and is lyophilized after sterile filtration in order to improve the stability of the product.
Example 7 investigation of the stability of the intermediate solutions of the present products under different pH conditions
Table 13: prescriptions of different lot numbers
Adding injection water (the temperature is below 25 ℃) of which the total volume is 80 percent into a batching container, adding mannitol with the prescription amount, stirring to dissolve completely, adding sulfate raw material (sulfate compound A prepared according to the method of the example 1, with the weight percent of sulfate radical of 13.6-14.6) with the prescription amount, and stirring to dissolve completely; the pH was adjusted with a dilute sulfuric acid solution (10 mg/ml), and water for injection was added to the total amount. The stability of the intermediate solution of the product at each pH was examined.
The detection method is the same as in example 6.
Table 14: stability test results
The result shows that the product is unstable under the condition of pH of 2.0, and the pH is relatively stable within the range of 3.0-5.0.
Example 8 quality comparison of the products with different mannitol levels and different pH values
Table 15: prescription of prescription
Adding injection water (the temperature is below 25 ℃) of which the total volume is 80 percent into a batching container, adding mannitol with the prescription amount, stirring to dissolve completely, adding sulfate raw material (sulfate compound A prepared according to the method of the example 1, with the weight percent of sulfate radical of 13.6-14.6) with the prescription amount, and stirring to dissolve completely; the pH was adjusted with a dilute sulfuric acid solution (10 mg/ml), and water for injection was added to the total amount. After the intermediate is detected to be qualified, the intermediate is filled in a penicillin bottle, half-packed into a box, and freeze-dried (the freeze-drying condition is the same as that of example 6) to obtain each prescription sample.
Detection same as in example 6
Table 16: results of investigation on stability of freeze-dried preparation samples with different pH values
The results show that the products of the examples 8-1 and 8-2 are stable within the pH range of 3.0-4.0, and the mannitol can reduce the water content of the products and improve the stability after being used.
Example 9
Table 17: prescription of prescription
Adding 80% of water for injection (the temperature is below 25 ℃) which is used for preparing the total volume into a batching container according to the prescription of examples 9-1-4, adding mannitol with the prescription amount, stirring to dissolve completely, adding the sulfate raw material (the sulfate of the compound A prepared according to the method of example 1, with the weight percentage of sulfate of 13.6% -14.6%) with the prescription amount, stirring to dissolve completely; the pH was adjusted with a dilute sulfuric acid solution (10 mg/ml), and water for injection was added to the total amount.
After the intermediate products of all prescriptions are detected to be qualified, corresponding valve liquid medicine is started to pass through a redundant terminal sterilization filter element and is filtered to a buffer receiving tank, and the following conditions are adopted for freeze-drying:
and (5) placing the liquid medicine filled with the half-pressed plug into a freeze-drying box, and closing the box door.
And (3) starting up for refrigeration, setting the inlet temperature of the heat conduction oil to be reduced to-45 ℃ for 1 hour, and preserving heat for 2-4 hours after the inlet temperature of the heat conduction oil reaches-45 ℃. And closing the cold valve of the plate, and opening the vacuum pump to vacuumize when the cold trap temperature reaches-45 ℃ and the heat preservation time reaches the requirement.
Heating to-10 ℃ for the first time, and preserving heat for 3-9 h;
heating to 10 ℃ for the second time, and preserving heat for 2-4 hours;
heating to 35 ℃ for the third time, and preserving heat for 3-6 hours.
And (5) plugging, putting the mixture into a filtered sterile air outlet box, and shutting down the box.
EXAMPLE 10 stability results of sulphate at different concentrations
Samples containing sulfate radicals with different concentrations are prepared respectively, and placed for 3 months (package: medicinal low-density polyethylene bag plus aluminum foil bag package) under the conditions of 25+/-2 ℃ and 60+/-5% RH before lofting, the sulfate radical content and related substances are inspected, and the stability is evaluated. The results of related substances are different before the sample is lofted in different batches, but less than 3% of the total impurities are within the limit. The test was carried out as in example 6. The results show that the higher the sulfate content (13.6% -14.6%), the smaller the total impurities after 3 months of standing, the more stable the sample.
Table 18: results of stability test of sulfate samples of Compound A containing sulfate groups at different concentrations
EXAMPLE 11 long-term test results
Samples were prepared according to examples 9-4, and the stability was evaluated by examining sulfate content and related substances before lofting and at 25 ℃ ± 2 ℃ and RH60% ± 5% for 3 months and 6 months (inner package: medium borosilicate glass tube injection bottle and halogenated butyl rubber stopper (bromination)). The test was carried out as in example 6.

Claims (20)

  1. 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate having a mass percentage of sulfate of 12.1% -15.1%.
  2. 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate having a mass percentage of sulfate of 13.6% -14.6%.
  3. 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate having a mass percentage of sulphate of 12.1% to 15.1%, characterised in that the salt is in amorphous crystalline form.
  4. A pharmaceutical composition comprising the 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate of any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
  5. Use of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate as claimed in any one of claims 1 to 3 in the manufacture of an antibacterial medicament.
  6. Use of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate salt according to any one of claims 1 to 3 for the manufacture of an antibacterial medicament against "superbacteria" carrying the NDM-1 gene.
  7. The use according to claim 5, wherein 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate is administered orally.
  8. The use according to claim 5, wherein the 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate is administered parenterally.
  9. The use as claimed in claim 8, wherein the parenteral administration is in the form of injection, including water injection needles, powder injection needles and small infusion solutions.
  10. A method of preparing a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate of any one of claims 1 to 3, the method comprising combining the 6-methylheptanoyl-Dab-Thr-D-Ser-ring (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate of any one of claims 1 to 3 with a pharmaceutically acceptable carrier.
  11. The pharmaceutical composition of claim 4, wherein: the pharmaceutical composition is an injection composition and further comprises a pH regulator.
  12. The pharmaceutical composition of claim 11, wherein the pH modifier is a water-soluble modifier selected from the group consisting of H 2 SO 4 Sulfuric acid solution, HCl, hydrochloric acid solution, HAc, acetic acid solution, H 3 PO 4 Phosphoric acid solution.
  13. Pharmaceutical composition according to claim 11, wherein when the pH adjusting agent is selected from the group consisting of sulfuric acid solution, hydrochloric acid solution, acetic acid solution, phosphoric acid solution, the pH adjusting agent concentration is 5-15 mg/ml, preferably 10-15 mg/ml.
  14. The pharmaceutical composition according to claim 11, wherein the pH adjuster adjusts the pH of the solution to 1.0-5.0, preferably the pH of the solution to 3.0-4.0.
  15. The pharmaceutical composition of claim 11, wherein the pharmaceutically acceptable carrier is selected from one or more of mannitol, sucrose, lactose, glucose, sorbitol, trehalose.
  16. Pharmaceutical composition according to claim 11, wherein the 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulphate unit formulation content is 5 to 30mg/ml, preferably 9.5 to 26.25mg/ml, more preferably 23.75 to 26.25mg/ml.
  17. Pharmaceutical composition according to claim 11, wherein the amount of pharmaceutically acceptable carrier unit formulation is from 10 to 50mg/ml, preferably from 20 to 30mg/ml.
  18. The pharmaceutical composition of claim 11, wherein the composition is a water needle, a lyophilized powder, a sterile powder.
  19. The pharmaceutical composition of claim 11, wherein the composition is lyophilized after sterile filtration.
  20. The process for preparing a pharmaceutical composition according to claim 11, comprising the steps of: adding water for injection with the total volume of 60-90% into a batching container at room temperature, adding a medicinal carrier with the prescription amount, stirring to dissolve completely, adding 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo (4-10) [ Dab-D-Phe-Thr-Dab-Thr ] sulfate with the prescription amount, and stirring to dissolve completely; regulating pH value with pH regulator, adding injectable water to full amount, detecting intermediate, aseptically filtering, bottling in penicillin bottle, half-packing into box, and freeze drying.
CN202280007209.3A 2021-03-31 2022-03-30 Sulfate of polymyxin derivative and pharmaceutical composition thereof Pending CN117083288A (en)

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US10047126B2 (en) * 2014-04-01 2018-08-14 Monash University Polymyxin derivatives as antimicrobial compounds
EP3224273A1 (en) * 2014-11-26 2017-10-04 New Pharma Licence Holdings Limited Compounds
FI126143B (en) * 2015-01-15 2016-07-15 Northern Antibiotics Oy Polymyxin derivatives and uses thereof
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