CN1552339A - Methyleritrocina injection - Google Patents

Abstract

A methyl erythromycin injection contains insoluble or slightly soluble methyl erythromycin moleculae and amphiprotic moleculae, which are dispersed in aqueous solution. Its advantages are high stability in aqueous solution and low irritation to blood vessel.

Description

Clarithromycin preparation for injection

Technical field

The present invention relates to a kind of antibiotic formulations, particularly a kind of injection macrolide antibiotics preparation.

Background technology

Erythromycin belongs to macrolide antibiotics, and macrolide antibiotics belongs to the trophophase antibacterial, by hindering the synthetic antibacterial action of bringing into play of bacterioprotein.The antimicrobial spectrum of macrolide antibiotics is wider, gram positive bacteria and gram negative bacteria are had stronger inhibitory action, and chlamydia, mycoplasma, rickettsia, spirillum, actinomycetes, the long bacterium of slave, minority mycobacteria and ameba also have inhibitory action.Clinically, macrolide antibiotics is widely used in treating mycoplasma pneumonia, conjunctiva class, urinary system infection, respiratory infection, skin and soft tissue infection, pertussis etc.Macrolide antibiotic commonly used comprises erythromycin, erythromycin, Roxithromycin, azithromycin, reaches dirithromycin etc.

Macrolide antibiotics is usually oral administration administration clinically, then needs drug administration by injection for severe infections and patient that can not oral drugs.In the injection macrolide antibiotics of Ying Yonging, injection erythromycin, injection azithromycin and injection erythromycin are arranged clinically.But, the general insoluble or slightly soluble of macrolide antibiotics (acidity is between pH5～8) in the aqueous solution under the physiological condition, in order to make the injecting drug use of aqueous solution, normally make it soluble in water this class medicine and weak acid such as formation salt such as lactobionic acid, lactic acid, then through intravenously administrable.Because macrolide antibiotics is fat-soluble stronger usually, therefore its injection has the zest that differs in size to blood vessel, in the infusion of drug process, can cause the pain of patient infusion position blood vessel, sometimes be difficult to tolerance or even cause phlebitis, all can cause this badness reaction as injection erythromycin, injection erythromycin etc.Obviously, this untoward reaction has greatly limited the injection use clinically of this type of medicine.

For overcoming the blood vessel irritation of injecting drug use, generally be medicine to be made preparations such as liposome, Emulsion, cyclodextrin, avoid medicine to contact with the direct of blood vessel.But because the macrolide antibiotics molecular proportion is bigger, and in aqueous solution its molecule instability, be unsuitable for preparing cyclodextrin clathrate or injectable emulsion.In addition, because the clinical consumption of macrolide antibiotics generally than higher, is generally more than 150mg/ person-time,, and certain difficulty in process is arranged if use liposomal encapsulated technology then can cause too high cost.Based on these considerations, United States Patent (USP) (patent No. 5,085,864) has disclosed erythromycin and cholate (glycodeoxycholate) has been formed complex, make medicine be dissolved in the method that is used to inject behind the water, this patent claims this method can reduce the blood vessel irritation of erythromycin.Chinese patent (application number 00112690.3) discloses and has contained injection of erythromycin and preparation method thereof, problems such as this method utilizes the polyvinylpyrrolidone of macromolecule and poloxamer to wrap up the clathrate that micromolecular erythromycin forms molecular capsule, and insufferable zest of patient and medicine dissolubility and stability in aqueous solution is lower when solving intravenous drip.But these methods still have, and volume is excessive, effectively degerming, maybe can not stablize problems such as preservation.

In sum, develop and a kind ofly can reduce its zest, increase its stability and cheaper macrolide antibiotics preparation of cost in aqueous solution blood vessel, significant clinically.

Summary of the invention

In order to overcome the problems referred to above in the present technology, the purpose of this invention is to provide and a kind ofly reduce its zest, increase its stability in aqueous solution and clarithromycin preparation for injection with low cost blood vessel.

For achieving the above object, clarithromycin preparation for injection of the present invention is with insoluble under physiological condition or be slightly soluble in the erythromycin molecule of aqueous solution and amphiphatic molecule forms complex, and this complex is stable with particulate form, be scattered in equably in water or the aqueous buffer solution and form.

Erythromycin among the present invention is its analog such as erythromycin, dirithromycin, Roxithromycin or other macrolide antibiotics also.

Amphiphatic molecule among the present invention is cholesterol derivative, lecithin and derivant thereof, and cholesterol derivative includes, but are not limited to cholesterol sodium sulfate, cholesterol sodium phosphate, cholesterol sodium sulfonate etc.

Erythromycin molecule and amphiphilic molar ratio are 1: 0.5～1: 5 among the present invention, and prepared compound particles size is 10～600nm.

Be appreciated that the present invention can add one or more excipient substances or other according to different needs and can make all kinds of preparations or all kinds of compound preparation for the medicine that forms the stable and uniform system in preparation; The concentrating or dilute preparation, be dried to powder formulation and lyophilized formulations is made in lyophilization of liquid preparation, stored frozen preparation, variable concentrations of also can be as required said preparation being made different size with the permission degree.

Compared with prior art, the present invention adopts erythromycin or its analog, need not increase under its water miscible prerequisite, make non-covalent bonded thermodynamically stable complex with possess hydrophilic property and lipophilic amphiphatic molecule, the characteristics of this complex are to be nano-scale particle in water.In composite structure, with in the drug molecule to the lipotropy structure division of vascular stimulation and amphiphilic lipotropy part inwardly, and jointly outwardly to the non-stimulated hydrophilic group of blood vessel and amphiphilic hydrophilic parts, both guaranteed the high stability of this complex in aqueous solution, the zest of having avoided the lipotropy part of antibiotic molecule to be caused again to blood vessel.

In the erythromycin molecule, hydrophilic parts is arranged, the lipotropy part is also arranged.The common lipotropy of erythromycin molecule is stronger, and it forms after the salt in the water soluble with acid in water, but its lipotropy does not change.Cholesterol is a lipophilic molecules, can form hydrophilic radical after the cholesterol molecule is derived and becomes amphiphatic molecule, and its amphoterisation method is with the salify of deriving of the hydroxyl in the molecule, can be made into sulfate, phosphate and sulfonate etc. usually.Nontoxic, non-irritating characteristics that cholesterol derivative has.The cholesterol molecule of erythromycin molecule and amphoterisation is by the hydrophobic force of lipotropy part and the polarity affinity that may also pass through hydrophilic parts in water, and formation is according to the polymolecular complex of certain molecule mole ratio, this complex evenly and stably is scattered in the water with colloidal form, this dispersion can dilute, concentrates, dissolve and dilute after lyophilizing and the lyophilizing, all presents stable and outward appearance dispersing character uniformly.

United States Patent (USP) (patent No. 5,194,266) uses cholesterol sodium sulfate and amphotericin B to form complex under its specific process conditions, and (the complex particle size distribution can improve the half lethal dose of amphotericin B to mice after 50～250nm); United States Patent (USP) (the patent No. 4,822,777) (the complex particle size distribution can significantly improve common amphotericin B animal dis motility rate and its toxicity of reduction to fungal infection after 100～400nm) to use cholesterol sodium sulfate and amphotericin B to form complex under its specific process conditions; United States Patent (USP) (the patent No. 5,077,057) under its specific process conditions, use cholesterol sodium sulfate and antibiotic except that amphotericin B or antiviral drugs to form in the extension claim of stablizing non-covalent bonded complex (this extension claim contain covered all water soluble drugs), requiring employed antibiotic or antiviral drugs is water soluble, with and technological requirement use extruder (extruder) to carry out the adjustment of complex particle diameter with specific pore.The process conditions of above-mentioned patent, the water solublity of medicine is required or medicine object etc. all is different from content of the present invention.

The specific embodiment

Embodiment 1:

The heating for dissolving in an amount of ethanol with 0.5g cholesterol sodium sulfate and 0.8g erythromycin, remove ethanol, the complex that forms is scattered in the buffer of pH7.0 with the nanometer machine, makes the suspension that the granular size meansigma methods is 110nm, the concentration that contains of this suspension is 10mg/ml.

Embodiment 2:

0.5g cholesterol sodium sulfate and 0.8g erythromycin are dissolved in the dimethyl sulfoxide, with this solution, in the buffer of pH7.2, be dispersed into the suspension that the granular size meansigma methods is 100nm, suspension is little blue color, opalescence, remove dimethyl sulfoxide, make complex, this complex is added lactose again, make the concentration of 10mg/ml, lyophilization forms white block dried frozen aquatic products, adds water for injection during use and redissolves.

Embodiment 3:

0.5g Roxithromycin and 0.75g cholesterol sodium phosphate are dissolved in the ethanol under slight fever, with adding under this solution stirring in the buffer of pH7.0, form dispersion, remove ethanol, this dispersion is dispersed into the dispersion that the granular size meansigma methods is 70nm with the nanometer machine, and drug level is 10mg/ml.

Embodiment 4:

0.5g cholesterol sodium sulfonate and the heating of 0.75g erythromycin are dissolved in ethanol, and ethanol is removed in decompression, is dispersed into the dispersion that mean diameter is 110nm in the buffer of pH7.0, and it is 10mg/ml that dispersion contains concentration.

Embodiment 5:

0.4g cholesterol sodium sulfonate and the heating of 0.65g dirithromycin are dissolved in the ethanol, and ethanol is removed in decompression, and the gained solid disperses in the buffer of pH7.5, make that to contain concentration be 10mg/ml, mean diameter is the homogeneous dispersion of 106nm, adds lactose 2g, lyophilization.

The vascular stimulation test of rabbit

According to preparing macrolide antibiotic-cholesterol sodium sulfate complex in the foregoing description, and with these complex as the test medication, carry out the blood vessel irritation experiment with rabbit.Get healthy rabbits, the male and female dual-purpose, 5 every group, in the intravenous injection trial drug 2mg/ml diluent 5ml/kg that picks up the ears, once a day, continuous 5 days, other picked up the ears intravenous injection with volume 5% glucose injection (contrast medication).Whether perusal every day medicine-feeding part has cosmetic variation such as the congestion of blood vessel, surrounding tissue edema during the administration.The perusal standards of grading see Table 1, the results are shown in Table 3.Put to death animal in 2 hours after the last administration, get injection site and surrounding tissue, with 10% formaldehyde fixed, section, HE dyeing, microscopically is observed and is had or not pathological changes such as the congestion of blood vessel, surrounding tissue edema, presses methods of marking and judges the blood vessel irritation extent of reaction.Standards of grading see Table 2, the results are shown in Table 3.

Table 1. perusal irritant test standards of grading

The scoring of observation index basis for estimation

The congestion of blood vessel normal 0

Congested 1

Blood vessel lines unclear 2

Blood vessel is aubergine 3

The surrounding tissue edema does not have edema 0

Slight edema 1

Obvious edema 2

Serious edema 3

The result judges: the slight zest in≤0.5 nonirritant≤2.5

≤ 4.5 moderate zests≤6.0 severe zests

Table 2. blood vessel irritation om observation standards of grading

The scoring of observation index basis for estimation

Congestion of blood vessel endothelium and tube wall complete 0

Vessel endothelium and induced endothelial 1

Thrombosis 2 in the blood vessel

Angiorrhexis 3

Surrounding tissue edema normal 0

Edema 1

Hemorrhage 2

Inflammatory cell infiltration 3

The result judges: the slight zest in≤0.5 nonirritant≤2.5

≤ 4.5 moderate zests≤6.0 severe zests

Table 3. vein blood vessel irritant test check result (X ± SD)

The group perusal stimulates the score histopathology to stimulate score

5% glucose solution 00

Erythromycin cholesterol sodium sulfate complex 0.6 ± 0.5 1.2 ± 1.1

Lactobionic acid erythromycin 0.8 ± 0.4 5.0 ± 0

Erythromycin cholesterol sodium sulfate complex 0.4 ± 0.2 0.8 ± 0.4

Although show with reference to the preferred embodiments of the present invention before this and described the present invention, but it will be understood by those skilled in the art that can according to the present invention make on the various forms and details on variation and can not break away from the spirit and scope that appending claims of the present invention limits.

Claims (10)

1, a kind of clarithromycin preparation for injection, it is characterized in that, form complex by erythromycin molecule and amphiphatic molecule insoluble under physiological condition or that be slightly soluble in aqueous solution, this complex is stable with particulate form, be scattered in equably in water or the aqueous buffer solution and form.

2, clarithromycin preparation for injection as claimed in claim 1 is characterized in that, described amphiphatic molecule is cholesterol derivative or lecithin and derivant thereof.

3, clarithromycin preparation for injection as claimed in claim 2 is characterized in that, described cholesterol derivative is cholesterol sodium sulfate, cholesterol sodium phosphate or cholesterol sodium sulfonate.

4, clarithromycin preparation for injection as claimed in claim 1 is characterized in that, erythromycin molecule and amphiphilic molar ratio are 1: 0.5～1: 5.

5, clarithromycin preparation for injection as claimed in claim 1 is characterized in that, this compound particles size is 10～600nm.

6, clarithromycin preparation for injection as claimed in claim 1, it is characterized in that can add one or more excipient substances or other in said preparation according to different needs can make all kinds of preparations or all kinds of compound preparation for the medicine that forms the stable and uniform system.

7, clarithromycin preparation for injection as claimed in claim 1, it is characterized in that the concentrating or dilute preparation, be dried to powder formulation and lyophilized formulations is made in lyophilization of liquid preparation, stored frozen preparation, variable concentrations of can be as required said preparation being made different size with the permission degree.

8, the application of the described clarithromycin preparation for injection of claim 1.

9, a kind of injection macrolide antibiotics preparation, it is characterized in that, form complex by macrolide antibiotics molecule and amphiphatic molecule insoluble under physiological condition or that be slightly soluble in aqueous solution, this complex is stable with particulate form, be scattered in equably in water or the aqueous buffer solution and form.

10, injection macrolide antibiotics preparation as claimed in claim 9 is characterized in that, described macrolide antibiotics molecule is erythromycin, dirithromycin or Roxithromycin.