WO2001047542A1

WO2001047542A1 - Vancomycin preparations

Info

Publication number: WO2001047542A1
Application number: PCT/JP2000/009438
Authority: WO
Inventors: Tomio Watanabe; Rieko Hamano; Norifumi Miyamoto
Original assignee: Meiji Seika Kaisha, Ltd.
Priority date: 1999-12-28
Filing date: 2000-12-28
Publication date: 2001-07-05
Also published as: AU2231601A

Abstract

Vancomycin preparations (in particular, freeze dried preparations) produced by a conventional production process without resort to any organic solvents so as to prevent vancomycin from chemical decomposition, having a high stability and a high solubility and showing a relieved renal toxicity. These preparations contain vancomycin or pharmaceutically acceptable salts thereof and polyethylene glycol.

Description

Description Thin preparation Background of the invention

Field of the invention

The present invention relates to a 'preparation, and more particularly, to a freeze-dried vancomycin preparation having excellent stability and solubility, and further having reduced renal toxicity.

Related technology

Vancomycin is a glycopeptide antibiotic derived from Streptomyces orien talis and is mainly effective against Gram-negative bacteria. When vancomycin is used as an injection, its mineral acid salt is often used in the form of a powder or lyophilized form and dissolved before administration.

However, when vancomycin mineral salts are stored for a long period of time, chemical decomposition proceeds, resulting in coloration and reduced antibacterial properties. For this reason, methods such as replacing the inside of the vial containing vancomycin with an inert gas such as nitrogen and lowering the storage temperature have been conventionally used.

In Japanese Patent Application Laid-Open No. Hei 11-80022, the use of amino acids, and in Japanese Patent Application Laid-Open No. 3-193375, the use of sugar alcohols has attempted to stabilize each. However, the effect was not enough. In addition, the solubility, which is a characteristic of the lyophilized formulation, was not sufficient, and it was not instantaneously dissolved in water for injection, and preparation of the drug solution was troublesome. In Patent Nos. 2,888,390 and 2,893,934, an organic solvent such as ethanol, n-propanol, or isopropyl acetate is freeze-dried together with vancomycin to form a readily soluble lyophilized formulation. Although attempts have been made, this drug, which is used as an injection, suffered from residual solvent problems and was of low practicality.

In addition, vancomycin hydrochloride may cause renal disorders such as acute renal failure and interstitial nephritis as side effects, and it is necessary to administer it carefully, such as by conducting periodic tests. Was.

From the above, it can be said that the development of a vancomycin formulation with high stability, excellent solubility, and low toxicity to the kidney has been awaited.

Summary of the Invention

The present invention relates to a vancomycin preparation which suppresses the chemical decomposition of vancomycin by a normal production method that does not use an organic solvent or the like in which a residual solvent is problematic, has stable and good solubility, and further has reduced toxicity to kidneys. In particular, it aims to provide a freeze-dried preparation of vancomycin.

The present inventors have surprisingly found that combining vancomycin with polyethylene glycol stabilizes vancomycin and improves the solubility of the preparation. We have also surprisingly found that the resulting composition has reduced kidney toxicity. The present invention is based on these findings.

A formulation according to the present invention is a vancomycin formulation comprising vancomycin or a pharmaceutically acceptable salt thereof and polyethylene glycol.

The formulation according to the present invention is advantageous in that it can be easily prepared, the chemical degradation of vancomycin during storage is suppressed, the stability and solubility are excellent, and the toxicity to the kidney is reduced.

Detailed description of the invention

Vancomycin used in the present invention can be produced, for example, by the method described in US Pat. No. 3,670,999. Alternatively, commercially available pharmaceutical grade drug substances can be used. Since the free base of vancomycin is poorly soluble in water, it is not preferable as it is as an API for injection. The free base is converted into a water-soluble salt and then supplied as an API for injection. Accordingly, the pharmaceutically acceptable salts of vancomycin used in the present invention include water-soluble salts, for example, water-soluble inorganic salts such as hydrochloride and sulfate, and water-soluble organic salts. Particularly, hydrochloride is preferable.

The average molecular weight of the polyethylene glycol used in the present invention (measured by the average molecular weight test described in Macrogol 400, 13th revised edition, Japanese Pharmacopoeia) is from 300 to 200,000. Preferably, those having an average molecular weight of 300 to 200, more preferably those having an average molecular weight of 400 are preferably used. Can be. Specifically, PEG 300, PEG 600, PEG 1000, PEG 1 540, PEG 2000 _S PEG 4000, PE G 6000 PEG 20000 (all manufactured by Wako Pure Chemical Industries, Ltd.), Macrogol 300, Macrogol 400, McGol 600, Macro Goal 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macrogol 20000 (all manufactured by Nippon Oil & Fats). The amount of polyethylene glycol is usually 4 to 50 parts by weight, preferably 6 to 40 parts by weight, and more preferably 8 to 25 parts by weight, based on 100 parts by weight of vancomycin. Although the stability increases with the increase in the amount of polyethylene glycol, sufficient stability can be ensured by adding up to 50 parts.

In addition, various additives can be added to increase the solubility of the lyophilized preparation or to adjust the pH or osmotic pressure as an injection. These additives are not particularly limited as long as they are substances and addition amounts usually used as additives for pharmaceuticals. For example, the following additives may be added as needed.

Examples of the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, malic acid, tartaric acid, succinic acid or salts thereof, sodium hydroxide, potassium hydroxide and the like.

Further, salts such as sodium chloride and chlorinated glucose, sugars such as sucrose and glucose, and sugar alcohols such as mannitol, sorbitol and xylitol may be added as an osmotic pressure adjusting agent.

As a method for preparing the freeze-dried preparation of the present invention, vancomycin or a pharmaceutically acceptable salt thereof, polyethylene glycol, a sugar alcohol, and various additives such as a pH adjuster, if necessary, are dissolved in an aqueous medium, Perform aseptic filtration using a membrane filter. Next, the sterile solution is dispensed into vials, trays, etc., and prepared by the usual freeze-drying method.

By enclosing the preparation according to the present invention and a solution in a multi-chamber container having a partition capable of communicating, a vancomycin infusion kit that can be stably stored and can be easily prepared at the time of use can also be provided.

Example

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto. Example 1

A 5 OmL solution was prepared by adding 500 mg of vancomycin hydrochloride and 10 Omg of polyethylene glycol (Macrogol 400) as a stabilizer per 5 mL of water for injection. This solution was aseptically filtered through a membrane filter (0.22 m), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. Following the normal freeze-drying method, cool to --40 ° C, freeze and hold for 2 hours, then reduce the water content under 10 OmT 0 rr or less, at -10 ° C for 20 hours, and at 40 ° C for 10 hours. Was dried by sublimation, the vacuum was released with nitrogen gas, and the mixture was sealed to give a freeze-dried preparation.

Example 2

5 OmL was prepared by adding 50 Omg of vancomycin hydrochloride and 10 Omgs of polyethylene glycol (Macrogol 400) as a stabilizer per 100 mL of mannitol per 5 mL of water for injection. The solution was aseptically filtered through a membrane filter one (0. 22 urn), this _c filled with each drug solution 5mL vial having an inner volume of about 15 mL, in accordance with conventional freeze drying method, freeze and cooled to one 40 ° C And hold for 2 hours, under reduced pressure of 10 OmTorr or less, — Sublimate moisture at 10 ° C for 20 hours and further at 40 ° C for 10 hours, dry, release the vacuum with nitrogen gas, stopper tightly and freeze-dried It was decided.

Example 3

A 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride, 40 mg of polyethylene glycol (Macrogol 400) as a stabilizer, and 10 Omg of mannitol per 5 mL of water for injection. This solution was aseptically filtered through a membrane filter (0.22 IJL m), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. This was subjected to the same operation as in Example 1 to obtain a lyophilized preparation.

Example 4

A 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride per 5 mL of water for injection and 80 mg of polyethylene glycol (Macrogol 400) 80 mg _s mannitol as a stabilizer. This solution was aseptically filtered through a membrane filter (0.22 µm), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. This was subjected to the same operation as in Example 1 to obtain a lyophilized preparation. 0 Example 5

A 5 OmL solution was prepared by adding 500 mg of vancomycin hydrochloride, 120 mg of polyethylene glycol (Macrogol 400) as a stabilizer, and 100 mg of mannitol per 5 mL of water for injection. This solution was aseptically filtered through a membrane filter (0.22 Mm), and 5 mL each of the drug solution was filled into a vial having an internal volume of about 15 mL. C This was obtained in the same manner as in Example 1 to obtain a freeze-dried preparation.

Example 6

A 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride, 100 mg of polyethylene glycol (Macrogol 400) as a stabilizer, and 300 mg of mannitol per 5 mL of water for injection. The solution was aseptically filtered through a membrane filter evening scratch (0. 22 um), this _c filled by chemical 5 mL of the vial having an inner volume of about 15 mL, to give a freeze-dried preparation in the same manner as in Example 1 Was.

Example 7

A 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride, 100 mg of polyethylene glycol (Macrogol 400) as a stabilizer, and 200 mg of mannitol per 5 mL of water for injection. This solution was aseptically filtered through a membrane filter (0.22; m), and 5 mL each of the drug solution was filled into a vial with an internal volume of about 15 mL. C This was then freeze-dried in the same manner as in Example 1. I got

Example 8

A 5 OmL solution was prepared by adding 50 Omg of vancomycin hydrochloride and 10 Omg of polyethylene glycol (Macrogol 400) as a stabilizer per 150 mL of water for injection. This solution was aseptically filtered through Yuichi Membrane Filler (0.22 μm), and 5 mL each of the drug solution was filled into a vial with an internal volume of about 15 mL. _{C The} freeze-dried preparation was obtained in the same manner as in Example 1. .

Comparative Example 1

Vancomycin hydrochloride (50 Omg) and L-arginine (18 Omg) as a stabilizer were dissolved per 5 mL of water for injection, and hydrochloric acid was added to adjust the pH to 4, to thereby prepare 5 OmL. This solution was aseptically filtered through a membrane filter (0.22 μm), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. This is the same as in Example 1. A freeze-dried preparation was obtained in the same manner as in b.

Comparative Example 2

5 OmL of a solution prepared by dissolving 500 mg of vancomycin hydrochloride and 10 Omg of D-mannitol as a stabilizer per 5 mL of water for injection was prepared. This solution was aseptically filtered through a membrane filter (0.22 UL), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. This was used to obtain a lyophilized preparation in the same manner as in Example 1 _c Comparative Example 3

50 mL of a solution in which 50 Omg of vancomycin hydrochloride was dissolved per 5 mL of water for injection was prepared. This solution was aseptically filtered through a membrane filter (0.22 / m), and each 5 mL of the drug solution was filled into a vial having an internal volume of about 15 mL. A lyophilized preparation was obtained in the same manner as in Example 1.

Test example 1

The preparations of the present invention obtained in Examples 1 to 8 and the preparations obtained in Comparative Examples 1 to 3 were stored under accelerated conditions of 40 ° C. for 1, 2, and 3 months, respectively. After the storage period has elapsed, weigh the titer equivalent to 10 Omg of vancomycin hydrochloride, add mobile phase A, dissolve to make exactly 1 OmL, and purify the purity of vancomycin by high performance liquid chromatography (HP LC) under the following conditions. Was determined.

High pressure pump system: Shimadzu LC-10 AT type

Detector: Torizu S-PD-10A

Detection wavelength: 280 nm

Data processing device: Shimadzu C-R7A type

Column used: GL Science Inertsil ODS-3 (5 ^ m 4.6x250 awake) Mobile phase composition:

A; Triethylamine buffer / acetonitrile / tetrahydrofuran mixture (92: 7: 1)

B; Triethylamine buffer / acetonitrile / tetrahydrofuran mixture (70: 29: 1)

Triethylamine buffer: Add 2000 mL of water to 4 mL of triethylamine, mix and adjust the pH to 3.2 with phosphoric acid. Solution A and Solution B are sent according to Table 1 below. The linear gradient was performed for 12 to 20 minutes and 22 to 23 minutes.

Flow rate: about 2mL / min

Holding time: about 9 minutes

Test medium composition: Mobile phase A Triethylamine buffer / acetonitrile

/ Tetrahydrofuran mixture (92: 7: 1) Next, the residual ratio of vancomycin B was determined by the following equation. The results are shown in Table 2. Vancomycin B peak area

Vancomycin B (%) = X 100

Total beak area Vancomycin B (%)

Survival rate (%) = 100

Vancomycin B (%)

(Remaining ratio for vancomycin B immediately after production)

Vancomycin B retention rate at 40 ° C storage (%)

Comparison was made with Comparative Example 1 (formulation containing arginine as a stabilizer), Comparative Example 2 (formulation containing D-mannitol as a stabilizer), and Comparative Example 3 (formulation without additives). Thus, it was confirmed that all of the formulations containing the polyethylene glycol of the present invention had a high residual ratio and were stable.

Test example 2

1 OmL of water for injection was injected into each vial of each of the preparations of the present invention obtained in Examples 1 to 8 and the preparations obtained in Comparative Examples 1 to 3, and the time required for dissolution was measured. Table 3 shows the results.

Dissolution test results

◎: Dissolved within 10 seconds after adding water for injection

溶解: Dissolve 10 to 30 seconds after adding water for injection

Δ: Dissolve 30 seconds to 1 minute after adding water for injection

: Requires at least 1 minute for dissolution after adding water for injection. Comparative Example 1 (formulation containing arginine as stabilizer), Comparative Example 2 (formulation containing D-mannitol as stabilizer), and Comparative Example 3 ( It was confirmed that the solubility of each of the formulations containing the polyethylene glycol of the present invention was improved as compared with the formulation without the additive.

Test example 3

In male SD rats (6 weeks of age), the formulation of Example 1 and the formulation of Comparative Example 3 were prepared with physiological saline so that the dose was 1 OmL / kg, and 40 Omg / kg was intravenously administered. After 24 hours, renal light microscopy was performed. Table 4 shows the results.

-: No significant change Soil: Mild +: Moderate + +: Intensity Observed by light microscopy, as shown in Table 4, seriously significant findings were observed in Comparative Example 3 administration group compared to Example 1 administration group. Was.

From the above, it was confirmed that the addition of polyethylene glycol not only improved safety but also improved solubility and reduced renal toxicity.

Claims

The scope of the claims

1. A vancomycin preparation comprising vancomycin or a pharmaceutically acceptable salt thereof, and polyethylene glycol.

2. The preparation according to claim 1, wherein the polyethylene glycol is used in an amount of 4 to 50 parts by weight based on 100 parts by weight of vancomycin or a pharmaceutically acceptable salt thereof.

3. The formulation according to claim 1 or 2, wherein the polyethylene glycol has an average molecular weight of from 300 to 200,000.

4. The preparation according to any one of claims 1 to 3, which is a lyophilized preparation.