A vancomycin aqueous solution composition

Abstract

The present application relates to the technical field of medicine, in particular to a vancomycin aqueous solution composition. The pharmaceutical composition comprises vancomycin or a pharmaceutically acceptable salt thereof, N-methyl alanine and water. The N-methyl alanine can improve the stability of vancomycin in the aqueous solution.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a vancomycin aqueous solution composition. Background Technology

[0002] The chemical name of vancomycin hydrochloride is:

[0003] (3S-(3R*,6S*(S*),7S*,22S*,23R*,26R*,36S*,38aS*))-3-(2-Amino-2-oxoethyl)-44-((2-O-(3-amino-2,3,6-trideoxy-3-C-methyl-alpha-L- lyxo-hexopyranosyl)-beta-D-glucopyranosyl)oxy)-10,19-dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-7,22,28,30 ,32-pentahydroxy-6-((4-methyl-2-(methylamino)-1-oxopentyl)amino)-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-1H,16H-(1,6,9)oxadiazacyclohexadecino(4,5-m)(10,2,16)benzoxadiazacyclotetracosine-26-carboxylic acid; Molecular weight: 1485.7; Molecular formula: C 66 H 76 Cl3N9O 24 Chemical structural formula:

[0004]

[0005] Vancomycin hydrochloride is a glycopeptide antibiotic derived from Streptomyces or Solomonas. The mechanism of action of vancomycin hydrochloride is to bind with high affinity to alanylalanine at the peptidoglycan terminus of the precursor peptide of sensitive bacterial cell walls, thereby blocking the synthesis of peptidoglycan, a high-molecular-weight component of bacterial cell walls, and thus inhibiting bacterial cell wall synthesis. In addition, vancomycin may also alter bacterial cell membrane permeability and selectively inhibit RNA synthesis.

[0006] Vancomycin hydrochloride is characterized by its strong bactericidal effect against Gram-positive bacteria only. Bacteria do not develop resistance to this drug, and it exhibits no cross-resistance with other antibiotics. Clinically, it is mainly used for infections caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-sensitive methicillin-resistant coagulase-negative staphylococci (MRCNS), and vancomycin-sensitive penicillin-resistant Streptococcus pneumoniae (PRSP). It is the drug of choice for infections caused by methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulase-negative staphylococci.

[0007] However, vancomycin hydrochloride has poor stability, especially in aqueous solution. It can be observed to gradually turn red at room temperature. This may be due to the phenolic and diphenolic groups in the vancomycin molecule. Phenolic aqueous solutions are easily hydrated or oxidized to quinones when exposed to light, which turns red.

[0008] Meanwhile, vancomycin's structure consists of a heptapeptide containing one asparagine group, which is prone to degradation in aqueous solution. In aqueous solution, the asparagine side chain in its structure readily undergoes deamination, hydrolysis, and rearrangement reactions, leading to formulation instability. Vancomycin degrades into the following main degradation impurities: Des-(amide)-succinimide-vancomycin B (RS2), CDP-1 major((1.2M)-[L-β-Asp 3 ]vancomycin B, CDP-IM) and CDP-1minor ([L-β-Asp 3 [vancomycin B,CDP-Im].

[0009]

[0010] Des-(amide)-succinimide-vancomycin B (RS2)

[0011]

[0012] CDP-1m([L-β-Asp 3 vancomycin B (CDP-I minor)

[0013]

[0014] CDP-1M((1.2M)-[L-β-Asp 3 [vancomycin B, CDP-I major)

[0015] Vancomycin hydrochloride is available in various dosage forms, including lyophilized powder or cryosol for injection, oral dry mixtures and capsules, and ophthalmic vancomycin ointment (oil-based, anhydrous). Vancomycin is mostly available in anhydrous form. Due to the stability issues of vancomycin aqueous solutions, the preparation of directly usable vancomycin injections, vancomycin eye drops, and topical gels / emulsions / sprays presents significant challenges, limiting the development and use of other vancomycin dosage forms.

[0016] Existing vancomycin lyophilized powder injections require dispersion and dilution before use, making the process rather cumbersome. Although Baxter has developed vancomycin injection solution, it requires frozen storage and must be thawed into a solution before use, which is very inconvenient. Moreover, due to stability issues, diluted vancomycin injection solution should be used as soon as possible to prevent the formation of impurities and visible foreign matter after prolonged storage.

[0017] Staphylococcus aureus, especially methicillin-resistant Staphylococcus aureus (MRSA), is a major pathogen causing surgical site infections (SSIs) of trauma, chronic wounds, and surgical sites. Vancomycin can effectively inhibit MRSA, thus it holds promise as an effective drug for treating MRSA infections of the eye, ear, and other wounds and chronic wounds, as well as for preventing and reducing the risk of surgical site MRSA infections. However, the stability issues of vancomycin aqueous solutions limit the development of vancomycin ophthalmic preparations and vancomycin topical gels / emulsions / sprays. Although ophthalmic vancomycin ointments exist, they are administered using oil-based bases (petrolatum, liquid paraffin), making administration inconvenient and potentially affecting vision after application.

[0018] Therefore, it is necessary to achieve the stability of vancomycin in aqueous solution. A stable vancomycin solution makes it possible to develop ready-to-use vancomycin injections, ophthalmic preparations, otomic preparations, nasal preparations, etc., which helps reduce the workload of medical staff, reduce safety risks caused by instability, improve ease of use, expand the scope of vancomycin's application, and better exert the efficacy of vancomycin. Summary of the Invention

[0019] To address the problems existing in the prior art, the present invention provides a pharmaceutical composition comprising vancomycin or a pharmaceutically acceptable salt thereof, N-methylalanine, and water.

[0020] Using N-methylalanine can improve the stability of vancomycin in aqueous solution.

[0021] Preferably, the pharmaceutical composition contains:

[0022] The concentration of vancomycin or its pharmaceutically acceptable salt is 0.1-30% w / w, more preferably, the concentration of vancomycin or its pharmaceutically acceptable salt is 0.1-15% w / w.

[0023] The N-methylalanine concentration is 0.1-30% w / w, and more preferably, the N-methylalanine concentration is 0.1-15% w / w.

[0024] Preferably, the pH of the composition is 3-6. The pH can be adjusted using an acid or base, such as, but not limited to, hydrochloric acid, acetic acid, and sodium hydroxide.

[0025] The N-methylalanine is N-methyl-DL-alanine, N-methyl-D-alanine, or N-methyl-L-alanine. More preferably, the N-methylalanine is N-methyl-D-alanine.

[0026] Preferably, the molar ratio of the N-methyl-amino acid to vancomycin is (0.1-40):1, and more preferably, the molar ratio of the N-methyl-amino acid to vancomycin is (0.5-20):1.

[0027] In one embodiment of the present invention, the composition may contain pH adjusters, ion chelating agents, osmotic pressure regulators, preservatives, etc.

[0028] For example, the pH adjuster includes, but is not limited to, one or more of the following: acetic acid, sodium acetate, succinic acid, amino acids, malic acid, lactic acid, citric acid, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid, and boric acid.

[0029] For example, the ion chelating agent includes, but is not limited to, one or more of the following: disodium edetate, citric acid, etc.

[0030] For example, the preservatives include, but are not limited to, one or more of the following: benzalkonium chloride, cresol, phenol, p-hydroxybenzoate, benzyl alcohol, EDTA, etc.

[0031] For example, the osmotic pressure regulator includes, but is not limited to, sodium chloride, glucose, etc.

[0032] Another aspect of the invention provides the use of the pharmaceutical composition in the preparation of a medicament for treating or preventing bacterial infections, including staphylococcal infections.

[0033] Preferably, the bacterial infection is caused by methicillin-resistant Staphylococcus aureus (MRSA).

[0034] The pharmaceutical composition of the present invention, wherein vancomycin is stable after 10 days at 25°C / 60% RH.

[0035] The pharmaceutical composition of the present invention can significantly improve the stability of vancomycin gel formulations under conditions of 25°C / 60%RH, and remain stable for at least 30 days.

[0036] The pharmaceutical composition of the present invention can significantly improve the stability of vancomycin eye drop formulations under conditions of 25°C / 60%RH, and remain stable for at least 30 days.

[0037] The pharmaceutical composition of the present invention can significantly improve the stability of vancomycin injection formulation under conditions of 25°C / 60%RH, and remain stable for at least 30 days.

[0038] The vancomycin solution formulation of the present invention exhibits the same antibacterial activity as an aqueous vancomycin solution of the same concentration but without N-methyl-alanine.

[0039] The pharmaceutical formulations of the present invention can be administered in undiluted or diluted form before administration. They can be diluted using a 5% or 10% dextran solution or another injectable diluent or infusion solution. Routes of administration may include, but are not limited to, injection, infusion, inhalation, oral administration, ear, nasal administration, topical administration, ocular administration, vaginal administration, and rectal administration. The pharmaceutical formulations of the present invention can be delivered using needles / syringes, infusion sets, catheters, applicators, bottles, nebulizers, inhalation devices, or as wound dressings.

[0040] The pharmaceutical compositions of the present invention can be packaged in glass vials, syringes, dropper bottles, tubes, applicators, unit dispensers, infusion bags, nebulizers, inhalation devices, or other drug containers. Optionally, the pharmaceutical compositions may be protected by filling with an inert gas such as nitrogen.

[0041] The pharmaceutical composition of the present invention can be used to prepare dosage forms such as injections, ophthalmic preparations, otoscopic preparations, and nasal preparations.

[0042] The vancomycin pharmaceutical composition aqueous solution provided by this invention is stable under non-freezing conditions. Due to the presence of N-methyl-alanine, the physical and chemical degradation of vancomycin can be effectively inhibited. The vancomycin aqueous solution provided by this invention has excellent potential for developing commercially available vancomycin injections, ophthalmic preparations, otolytic preparations, nasal preparations, etc. Attached Figure Description

[0043] Figure 1 The HPLC chromatogram of the F-4 formulation after 10 days under 25℃ / 60%RH conditions is shown.

[0044] Figure 2 The HPLC chromatogram of the F-20 formulation after 10 days under 25℃ / 60%RH conditions.

[0045] Figure 3 The HPLC chromatogram of the F-25 formulation after 30 days under 25℃ / 60%RH conditions.

[0046] Figure 4 The HPLC chromatogram of the F-29 formulation after 30 days under 25℃ / 60%RH conditions.

[0047] Figure 5 The HPLC chromatogram of the F-32 formulation after 30 days under 25℃ / 60%RH conditions. Detailed Implementation

[0048] To better understand the technical solution of the present invention, the technical solution of the present invention will be further described below with reference to specific embodiments. The embodiments are only for the purpose of helping to understand the present invention and should not be regarded as specific limitations of the present invention.

[0049] The HPLC analysis conditions for the following examples are:

[0050] Column: Welch Ultimate XB-C18 (250×4.6mm, 5μm)

[0051] Detection wavelength: 280nm;

[0052] Column temperature: 30℃;

[0053] Flow rate: 2.0 ml / min;

[0054] Injection volume: 20 μl;

[0055] Mobile phase:

[0056] Solution A: Accurately measure 4.0 ml of triethylamine, add water to 2000 ml, and adjust the pH to 3.20 with phosphoric acid;

[0057] Solution B: Acetonitrile-tetrahydrofuran-Solution A = 55-10-935, pH adjusted to 3.20 with phosphoric acid;

[0058] Solution C: Acetonitrile-tetrahydrofuran-Solution A = 290-10-700, pH adjusted to 3.20 with phosphoric acid;

[0059] Elution gradient:

[0060]

[0061]

[0062] Example 1: Effect of different amino acids on the stability of vancomycin

[0063] A vancomycin hydrochloride aqueous solution was prepared, wherein the concentration of vancomycin hydrochloride was 5% w / w and the concentration of stabilizer (amino acid) was 0.25% w / w. After being placed at 25℃ / 60%RH for 10 days, the relevant substances were detected by HPLC. The different stabilizers (amino acids) used in the composition and the corresponding test results are shown in Table 1.

[0064] Table 1

[0065]

[0066]

[0067] This study found that alanine could slow down the degradation of vancomycin. Other amino acids had a lower effect or accelerated degradation. The HPLC chromatogram of F-4 (DL-alanine) is shown below. Figure 1 The corresponding data is shown in Table 2:

[0068] Table 2

[0069] Peak Name R RT min Area% Area 1 RS2 5.335 1.87 470871 2 CDP-1 8.749 0.76 191171 3 <![CDATA[ Vancomycin HCL]]> 10.589 93.24 23585597

[0070] Example 2: Effect of N-methyl-alanine on the stability of vancomycin

[0071] The experimental method is as described in Example 1, and the stabilizer (amino acid) and the corresponding test results are listed in Table 3.

[0072] Table 3

[0073]

[0074]

[0075] N-methyl-DL-alanine is a derivative of alanine, and its stabilizing effect on vancomycin is superior to that of alanine. The effect of N-methyl-D-alanine is particularly prominent. The HPLC spectrum of F-20 (N-methyl-DL-alanine) is shown below. Figure 2 The corresponding data is shown in Table 4:

[0076] Table 4

[0077] Peak Name R RT min Area% Area 1 RS2 5.332 1.12 280162 2 CDP-1 8.762 0.71 177973 3 <![CDATA[ Vancomycin HCL]]> 10.576 94.66 23824054

[0078] Example 3: Effect of N-methyl-alanine on the stability of vancomycin gel

[0079] Weigh the prescribed amount of N-methyl-alanine into a beaker, add the prescribed amounts of water and acetic acid, and stir until well mixed; weigh the prescribed amount of gelatin and add it to the above solution, stirring to dissolve; weigh the prescribed amount of vancomycin hydrochloride and stir to dissolve. Place under accelerated conditions of 25℃ / 60%RH, and after 30 days, take samples to detect related substances. Calculate the percentage of impurity peak areas using peak area normalization. The results are shown in Table 5.

[0080] Table 5

[0081]

[0082]

[0083] Experimental results show that N-methyl-D-alanine, under conditions of 25℃ / 60%RH, can significantly improve the stability of vancomycin gelatin gel formulations, maintaining stability for at least 30 days. The HPLC chromatogram of the F-25 formulation after 30 days under 25℃ / 60%RH conditions is shown in the image. Figure 3 The corresponding data is shown in Table 6.

[0084] Table 6

[0085] Peak Name R RT min Area% Area 1 RS2 4.594 0.219 58915 2 CDP-1 7.222 0.402 108293 3 <![CDATA[ Vancomycin HCL]]> 8.631 95.28 25694407

[0086] Example 4: Effect of N-methyl-alanine on the stability of vancomycin eye drops

[0087] Weigh the prescribed amount of N-methyl-alanine into a beaker, add the prescribed amount of water, and stir to mix thoroughly. Weigh the prescribed amounts of benzalkonium chloride and glycine, add them to the above solution, and stir to dissolve. Weigh the prescribed amount of vancomycin hydrochloride and stir to dissolve. Place the solution under accelerated conditions of 25℃ / 60%RH for 30 days, then take samples to detect related substances. Calculate the percentage of impurity peak areas using peak area normalization. The results are shown in Table 7.

[0088] Table 7

[0089]

[0090]

[0091] Experimental results show that N-methyl-D-alanine, under conditions of 25℃ / 60%RH, can significantly improve the stability of vancomycin eye drop formulations, maintaining stability for at least 30 days. The HPLC chromatogram of the F-29 formulation after 30 days under 25℃ / 60%RH conditions is shown in the image. Figure 4 The corresponding data is shown in Table 8.

[0092] Table 8

[0093] Peak Name R RT min Area% Area 1 RS2 5.304 1.20 295178 2 CDP-1 8.707 0.72 176521 3 <![CDATA[ Vancomycin HCL]]> 10.558 94.63 23334406

[0094] Example 5: Effect of N-methyl-alanine on the stability of vancomycin injection

[0095] Weigh the prescribed amount of N-methyl-alanine into a beaker, add the prescribed amount of water, and stir to mix thoroughly. Weigh the prescribed amounts of polyethylene glycol 400 and L-lysine hydrochloride, add them to the above solution, and stir to dissolve. Weigh the prescribed amount of vancomycin hydrochloride and stir to dissolve. Place the solution under accelerated conditions of 25℃ / 60%RH for 30 days, then take samples to detect related substances. Calculate the percentage of impurity peak areas using peak area normalization. The results are shown in Table 9.

[0096] Table 9

[0097]

[0098]

[0099] Experimental results show that N-methyl-D-alanine, under conditions of 25℃ / 60%RH, can significantly improve the stability of vancomycin injection formulations, maintaining stability for at least 30 days. The HPLC chromatogram of the F-32 formulation after 30 days under 25℃ / 60%RH conditions is shown in the image. Figure 5 The corresponding data is shown in Table 10.

[0100] Table 10

[0101] Peak Name R RT min Area% Area 1 RS2 5.336 1.15 283427 2 CDP-1 8.731 0.72 177649 3 <![CDATA[ Vancomycin HCL]]> 10.565 94.62 23387061

Claims

1. A pharmaceutical composition comprising vancomycin or a pharmaceutically acceptable salt thereof, N-methylalanine, and water; in, The concentration of the vancomycin or its pharmaceutically acceptable salt is 0.5-5% w / w; The concentration of the N-methylalanine is 0.33-1% w / w; The N-methylalanine is N-methyl-D-alanine; The pH of the pharmaceutical composition is adjusted to 3-6 using an acid or base.

2. The pharmaceutical composition according to claim 1, characterized in that, The acid is hydrochloric acid or acetic acid; the base is sodium hydroxide.

3. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is a vancomycin gel, the components of which are: vancomycin hydrochloride 1% w / w, N-methyl-D-alanine 0.33% w / w, gelatin 0.75% w / w, acetic acid 1.0% w / w, and the balance being water.

4. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is vancomycin eye drops, the components of which are: vancomycin hydrochloride 3% w / w, N-methyl-D-alanine 1.0% w / w, benzalkonium chloride 0.01% w / w, glycine 1.0% w / w, and the balance being water.

5. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is vancomycin injection, the components of which are: vancomycin hydrochloride 0.5% w / w, N-methyl-D-alanine 1.0% w / w, polyethylene glycol 400 1.8% w / w, L-lysine hydrochloride 1.26% w / w, and the balance being water.

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