CN1883706A

CN1883706A - Topically applied sustained-release antibiotic preparation

Info

Publication number: CN1883706A
Application number: CN 200610200474
Authority: CN
Inventors: 孙晋海
Original assignee: Jinan Kangquan Medicine Science and Technology Co Ltd
Current assignee: Jinan Kangquan Medicine Science and Technology Co Ltd
Priority date: 2006-05-22
Filing date: 2006-05-22
Publication date: 2006-12-27

Abstract

Disclosed is a topical applicated antibiotics slow release agent as a slow release injection or a slow release implantation agent, comprising slow release microspheres and menstruum. Said release microsphere comprises slow release assist materials and antibiotics, and said menstruum is a special menstruum comprising suspending agents of sodium carboxymethylcellulose, etc, with a viscosity of 100cp-3000cp(at 20-30 DEG C). Said slow release assist materials are selected from the group of EVAc, polifeprosan, PLA, PLGA, sebacic acid copolymer, albumen glue, gelatin, and etc. Said slow release implantation agent is prepared with slow release microspheres or by melt method, etc. The disclosed slow release agent can release drugs for 10 days by topical applicated or injected at a focus, decreasing whole body toxicity obviously while obtaining and sustaining effective topical drug concentration at the focus.

Description

Antibiotic sustained release agent for local application

(I) technical field

The invention relates to an antibiotic sustained release agent for local application, belonging to the technical field of medicaments. Specifically, the invention provides a slow release injection and a slow release implant containing antibiotics. The sustained release preparation is mainly applied locally, and can obtain and maintain effective drug concentration locally in bacterial infection.

(II) background of the invention

With the advent of antibiotics, bacterial infection became a treatable disease. However, the treatment is not standard, the treatment time is long, and a patient forgets to take the medicine quantitatively in time, so that the drug resistance is generated. Many of the bacterial infections cured by the method repeatedly attack to become chronic lesions. The treatment of drug-resistant patients or recurrent chronic lesions leads, on the one hand, to a prolonged period of treatment and, on the other hand, to the development and use or combined use of a plurality of potent antibiotics, with the result that the costs are high, new drug-resistant strains are continuously cultivated and the effective dose is continuously increased, thus forming a vicious circle. Therefore, research and development of new effective agents or methods for treating drug-resistant strains and chronic persistent infections have become an urgent problem worldwide.

At present, a plurality of new antibacterial drugs have shown good curative effect, but for many chronic lesions, especially for local lesions, the effective bactericidal concentration is difficult to obtain by the conventional therapy administration. There are many side effects caused by increasing dosage or taking the medicine for a long time.

Disclosure of the invention

The invention provides a sustained-release antibiotic preparation for local application aiming at the defects of the prior art, in particular to a sustained-release injection and a sustained-release implant.

The antibacterial drug is mainly an oral preparation, and the effective drug concentration can not be obtained at the focus part. Even a general injection is not ideal enough. Due to the factors of insufficient dosage, single administration, irregular administration and the like, the traditional Chinese medicine composition can not reach effective blood concentration and can not thoroughly kill bacteria, and can induce drug-resistant bacteria to survive or promote bacterial variation. Increasing the dose alone can be limited by systemic toxic effects. The above disadvantages are particularly manifested in the treatment of local infections, including various chronic inflammations and pyogenic infections.

The invention discovers that the local placement or injection of the sustained release preparation (mainly sustained release injection and sustained release implant) prepared from the antibiotic drug not only can greatly improve the local drug concentration, reduce the concentration of the drug in a circulatory system and reduce the toxicity of the drug to normal tissues, but also can greatly facilitate the drug application, reduce the treatment course, shorten the treatment time, reduce the complications of the drug, reduce the cost of patients, reduce the dosage of single drug, enhance the treatment effect and reduce the drug tolerance. Has obvious and unique treatment effect on drug-resistant bacteria, particularly on local focus or chronic infection caused by combined bacterial infection, and effectively overcomes the limitation of systemic medication.

In the case of the tubercular cavity, the antibacterial agent applied by the conventional route (oral or intramuscular injection or drip) hardly penetrates into the cavity due to the barrier effect of the wall of the tubercular cavity and the rarity, hardening, even closing of the blood vessels around the cavity wall. The drug concentration in the cavity is very low, so that the drug does not play a role in sterilization or bacteriostasis, but causes drug-resistant bacteria to be generated. The slow-release medicine is placed or injected through skin puncture under the assistance of imaging technologies such as ultrasonic waves and/or CT (computed tomography) and the like, so that the medicine can be accurately injected into the cavity, and can be limited in the cavity wall for tens of days through a slow-release mechanism, and therefore bacteria in the cavity wall can be directly and effectively killed; in addition, the released medicine can erode the cavity wall, so that the softening of a cheese lesion and the falling and discharging of necrotic substances can be promoted; local lesions can also be cleared during local procedures by means of a puncture needle or corresponding instrument (such as, but not limited to, bronchoscope, cystoscope, laparoscope, arthroscope, etc.). Moreover, repeated local punctures can also weaken the barrier function of the cavity wall. Therefore, the medicine in the blood can enter the focus, and the proliferation of granulation tissue and the purification of cavities are facilitated. The same cases include, but are not limited to, chronic osteomyelitis, deep abscess, celiac abscess, arthritis, and the like.

In addition, the existing antibiotics are various in types, not all the antibiotics can be prepared into sustained-release preparations, and different antibiotics must be prepared into sustained-release preparations by selecting proper sustained-release auxiliary materials. Therefore, based on the above unexpected findings, the present invention successfully screens out effective antibacterial ingredients suitable for sustained release from hundreds of antibacterial drugs through subsequent extensive studies, and successfully screens out sustained release ingredients suitable for sustained release of antibiotics from hundreds of sustained release excipients. Finally, effective combinations are screened out through in vivo and in vitro release measurement. Thus constituting the main subject of the present invention.

One form of the drug sustained release preparation is sustained release injection, which consists of sustained release microspheres and a solvent. Specifically, the sustained-release injection consists of the following components:

(a) the sustained-release particles comprise the following components in percentage by weight:

1-70% of antibacterial active ingredient

Sustained release auxiliary materials 30-99%

0.0 to 30 percent of suspending agent

The above are weight percentages

And

(b) the solvent is common solvent or special solvent containing suspending agent.

Wherein,

the viscosity range IV (dl/g) of the sustained-release auxiliary material is 0.1-0.8, and the sustained-release auxiliary material is selected from one or the combination of polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dipolymer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue; the suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.

The antibacterial active ingredient of the invention can be selected from, but is not limited to, beta-lactam antibiotics selected from Aztreonam (thiaximo monoamide, AZACTAM, Aztreonam), carumonam sodium, imipenem (lmipenm), Cilastatin (Cilastatin), meropenem, 7? Amido-3-alkoxycarbonyl (and 3-keto) -1-carba (1-dethia) -3-ceph-4-carboxylic acid and derivatives thereof and related 3-substituted compounds; (ii) an amidol antibiotic selected from the group consisting of chloramphenicol, thiamphenicol, succinchloramphenicol, palmitomycin (type B), lincomycin, Virginiamycin (Virginiamycin), clindamycin, enantiotropium, and zetidic acid; sulfonamides selected from the group consisting of vitreosulfazole, Sulfamethazine (Sulfadimethoxine), Trimethoprim, sulfadimidine, Sulfamethazine/olmeprin (Sulfadimethoxine/Ormetoprim), Sulfachlorpyridazine (Sulfachlorpyridazine), Sulfadiazine (Sulfamethazine), Sulfathiazole (Sulfathiazole), Sulfisoxazole (sulfadoxazole), Trimethoprim/Sulfadiazine (Trimethoprim/Sulfadiazine), and pirimidyl acid; and other antibiotics such as, but not limited to, vancomycin hydrochloride, norvancomycin hydrochloride, lincomycin, clindamycin, lincomycin hydrochloride, clindamycin hydrochloride, fosfomycin, polymyxin B, colistin, neomycin, bacitracin, sodium fusidate, polymyxin B and E, polymyxin B sulfate, polymyxin E sulfate, teicoplanin, stalobacin H and I, antibiotics of the macromycin (macrotelolide) class, reesoridicin, aminocyclitols, Polaramycin (Polaramycin).

Preferred antibacterial agents are aztreonam, carumonam sodium, imipenem, cilastatin, meropenem, chloramphenicol, thiamphenicol, jimycin, virginiamycin, clindamycin, antipyroxin, trimethoprim, sulfadimidine, olmeprin, sulfachlorpyridazine, sulfadiazine, sulfathiazole, sulfaisoxazole, vancomycin, norvancomycin, lincomycin, clindamycin, fosfomycin, polymyxin B, colistin, neomycin, bacitracin, sodium fusidate, teicoplanin, liuyangmycin or polacrycin and salts or esters thereof.

The antibiotic useful in the present invention is also selected from the group consisting of salts and esters of the above drugs, such as, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, thiopamoic acid, phosphoric acid, azathionic acid, sulfinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, maleic acid, azoodic acid, alkanoic acids, fluorenylmethyl ester, pivaloyl ester, ester salts, and the like. Salts tend to be more soluble in the aqueous or other protic solvents of the corresponding free base form. Non-toxic pharmaceutically acceptable base addition salts include salts with bases such as sodium, potassium, calcium, amines, and the like. Those skilled in the art are aware of many non-toxic pharmaceutically acceptable addition salts.

The active ingredients of the drug sustained release preparation are the combination of any one or more than one drug and any one or two drugs in other any classes.

The proportion of the antibacterial agent in the sustained-release agent is determined by specific conditions, and can be 1-70%, preferably 2-50%, and most preferably 5-40%.

The antibacterial drugs and the weight percentage of the antibacterial drugs in the sustained release agent are preferably as follows:

(1) 2-50% of a beta-lactam antibiotic selected from aztreonam, carumonam sodium, imipenem, cilastatin, meropenem or 7? Amido-3-alkoxycarbonyl (and 3-keto) -1-carba (1-dethia) -3-ceph-4-carboxylic acid;

(2) 2-50% of an amide alcohol antibiotic selected from chloramphenicol, thiamphenicol, lincomycin, virginiamycin, clindamycin, phenytoin or zetidic acid;

(3) 2-50% of a sulfa drug selected from boscalid sulfathiazole, trimethoprim, sulfamethazine, sulfamonomethoxine, olmeprin, sulfachlorpyridazine, sulfadiazine, sulfathiazole, sulfisoxazole or trimethoprim; or

(4) 2-50% of other antibiotics selected from vancomycin, norvancomycin, lincomycin, clindamycin, fosfomycin, polymyxin B, colistin, neomycin, bacitracin, sodium fusidate, teicoplanin, liuyangmycin, reesei-shaddock, aminocyclitols or polacrycin.

The weight percentages of the effective components and the sustained-release auxiliary materials in the antibacterial sustained-release microspheres are preferably as follows:

2 to 50 percent of antibacterial drug

Sustained release auxiliary materials 50-98%

0.0 to 30 percent of suspending agent

The slow release auxiliary material is selected from one or the combination of polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dipolymer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene-vinyl acetate copolymer, polylactic acid, polyglycolic acid and glycolic acid copolymer, sodium carboxymethyl cellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue.

The most preferable sustained-release auxiliary materials in the sustained-release microspheres and the weight percentage thereof are as follows:

(1) 55-90% PLA;

(2) 50-90% PLGA;

(3) 50-85% of polifeprosan;

(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;

(5) 55-90% EVAc; or

(6) 40-95% of sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue.

The sustained-release microspheres and a solvent containing sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, a surface active substance, Tween 20, Tween 40 or Tween 80 suspending agent are prepared into the sustained-release injection. The concentration of sodium carboxymethylcellulose in the solvent may be 0.1-5%, but is preferably 0.5-3%, and most preferably 1-2%.

Among the various polymers, preferred are polylactic acid, sebacic acid, and a mixture or copolymer of polylactic acid and sebacic acid, and the mixture or copolymer can be selected from, but not limited to, PLA, PLGA, a mixture of glycolic acid and hydroxycarboxylic acid, and a mixture or copolymer of sebacic acid and an aromatic polyanhydride or an aliphatic polyanhydride. The blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), di-fatty acid-sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid-sebacic acid) [ P (FA-SA) ], and the like. The content of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization is 10-60 wt% and 20-90 wt%, respectively, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.

The molecular weight peak of polylactic acid may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and most preferably 5,000-30,000; the molecular weight of polyglycolic acid may be, but is not limited to, 5000-; the polyhydroxy acids can be selected singly or in multiple ways. When selected alone, polylactic acid (PLA) or a copolymer of hydroxycarboxylic acid and glycolic acid (PLGA) is preferred, and the molecular weight of the copolymer may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and is most preferably 30,000-50,000; when more than one choice is selected, the polymer or the composite polymer or copolymer of different polymers is preferred, and the composite polymer or copolymer of polylactic acid or sebacic acid with different molecular weight is most preferred, such as, but not limited to, polylactic acid with molecular weight of 1000 to 30000 mixed with polylactic acid with molecular weight of 20000 to 50000, polylactic acid with molecular weight of 10000 to 30000 mixed with PLGA with molecular weight of 30000 to 80000, polylactic acid with molecular weight of 20000 to 30000 mixed with sebacic acid, PLGA with molecular weight of 30000 to 80000 mixed with sebacic acid. The polylactic acid used is preferably L-polylactic acid (L-PLA). The viscosity range IV (dl/g) of the L-polylactic acid (L-PLA) is 0.2-0.8, the glass transition temperature range is 55-65 ℃, and the melting point is 175-185 ℃.

In addition to the above-mentioned adjuvants, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176 and 4789724 and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luoming and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.

In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. The sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.

In the slow release injection, the drug slow release system can be prepared into microspheres, submicron spheres, micro emulsion, nanospheres, granules or spherical pellets, and then the injection is prepared after the drug slow release system is mixed with an injection solvent. The suspension type sustained-release injection is preferably selected from various sustained-release injections, the suspension type sustained-release injection is a preparation obtained by suspending a drug sustained-release system containing an antibacterial component in an injection, the used auxiliary materials are one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvents are, but not limited to, distilled water, water for injection, physiological saline, absolute ethanol or buffers formulated with various salts. The suspending agent is intended to effectively suspend the microspheres containing the drug, thereby facilitating injection.

The suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.

The content of the suspending agent in the common solvent depends on the characteristics of the suspending agent, and can be 0.1-30% according to the specific situation. Preferably, the suspending agent consists of:

A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80; or

B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or (b).

C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.

The method of preparation of the sustained release injection is arbitrary and can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray drying to prepare microspheres, dissolving in combination with freezing (drying) and pulverizing to form fine powders, liposome-encapsulating, and emulsifying. Among them, a dissolving method (i.e., solvent evaporation method), a drying method, a spray drying method and an emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections, and the method is arbitrary. The microspheres used may have a particle size in the range of 5-400um, preferably 10-300um, most preferably 20-200 um.

The microspheres can also be used for preparing other sustained-release injections, such as gel injections, gel sustained-release injections and block copolymer micelle injections. The block copolymer micelle is formed by a hydrophobic-hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. Of these, polyethylene glycol (PEG) having a molecular weight of 1000-15000 is preferable as the hydrophilic block of the micelle copolymer, and biodegradable polymers such as PLA, polylactide, polycaprolactone and copolymers thereof (molecular weight 1500-25000) are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be locally injected. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly. The method for preparing the gel injection is arbitrary, but the polymer material used is preferably a polylactic acid-containing hydrogel, such as, but not limited to, racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycolic acid copolymer (D, L-PLGA), monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), polyethylene glycol/polylactic acid (PLA-PEG-PLA), polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), carboxyl-terminated polylactic acid (PLA-COOH), carboxyl-terminated polylactic acid/glycolic acid copolymer (PLGA-COOH), etc. Wherein the viscosity IV (DL/g) of the racemic polylactic acid DL-PLA is 0.5-8, and the glass transition temperature is 50-60 ℃; the ratio of DL-LA to GA in the racemic polylactic acid/glycolic acid copolymer is 90/10, 80/20, 75/25, 60/40 and 50/50, the glass transition temperature range is 40-60 ℃, and the viscosity range IV (DL/g) is 0.15-2.0; the viscosity range IV (dl/g) of the monomethyl polyethylene glycol/polylactic acid and the monomethyl polyethylene glycol/polylactic acid/glycollic acid copolymer is 0.1-0.4; the viscosity range IV (dl/g) of the monomethyl polyethylene glycol/polylactic acid (MPEG-PLA) and the monomethyl polyethylene glycol/polylactic acid copolymer is 0.1-0.5; the viscosity range IV (dl/g) of the polyethylene glycol/polylactic acid and the polyethylene glycol/polylactic acid copolymer is 0.1-0.5; the viscosity IV (dl/g) of the carboxyl-terminated polylactic acid is 0.5-8, and the glass transition temperature is 50-65 ℃; the viscosity range IV (dl/g) of the carboxyl-terminated polylactic acid/glycollic acid copolymer is 0.1-1.0, and the glass transition temperature range is 45-55 ℃.

The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).

The preparation of injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.

The sustained-release microspheres can also be used for preparing sustained-release implants, the used pharmaceutical excipients can be any one or more of the above pharmaceutical excipients, but water-soluble high molecular polymers are taken as the main choice, and in various high molecular polymers, polylactic acid, sebacic acid, a mixture or copolymer of high molecular polymers containing polylactic acid or sebacic acid are taken as the first choice, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, a mixture of PLA and PLGA, and a mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride. The blending ratio of polylactic acid (PLA) to polyglycolic acid is 10/90 to 90/10 (by weight), preferably 25/75 to 75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and lactic acid in copolymerization are respectively 10-90% and 90-10% by weight. The aromatic polyanhydride is represented by p-carboxyphenylpropane (p-CPP), the content of the p-carboxyphenylpropane (p-CPP) and sebacic acid in copolymerization is respectively 10-60% and 20-90% by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.

Another form of the sustained-release agent of the present invention is a sustained-release implant. The effective components of the antibacterial implant can be uniformly packaged in the whole pharmaceutic adjuvant, and also can be packaged in the center of a carrier support or on the surface of the carrier support; the active principle can be released by direct diffusion and/or by degradation via polymers.

The slow release implant is characterized in that the slow release auxiliary material contains any one or more of the other auxiliary materials besides the high molecular polymer. The added pharmaceutic adjuvants are collectively called as additives. The additives can be classified into fillers, pore-forming agents, excipients, dispersants, isotonic agents, preservatives, retarding agents, solubilizers, absorption enhancers, film-forming agents, gelling agents, etc. according to their functions.

The main components of the sustained-release implant can be prepared into various dosage forms. Such as, but not limited to, capsules, sustained release formulations, implants, sustained release implants, and the like; in various shapes such as, but not limited to, granules, pills, tablets, powders, spheres, chunks, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred. The size of the volume depends on the location and size of the lesion. It can be in the form of rod of 0.1-5mm (thick) × 1-10mm (long), or in the form of sheet.

The optimal dosage form of the sustained-release implant is biocompatible, degradable and absorbable sustained-release implant, and can be prepared into various shapes and various dosage forms according to different clinical requirements. The packaging method and procedure for its main ingredients are described in detail in US patent (US5651986) and include several methods for preparing sustained release formulations: such as, but not limited to, (i) mixing a carrier support powder with a drug and then compressing into an implant, a so-called mixing process; (ii) melting the carrier support, mixing with the drug to be packaged, and then cooling the solid, the so-called melt process; (iii) dissolving the carrier support in a solvent, dissolving or dispersing the drug to be packaged in a polymer solution, and then evaporating the solvent and drying, the so-called dissolution method; (iv) spray drying; and (v) freeze-drying method.

The active ingredients and the weight percentage of the slow release implant are preferably as follows:

2 to 50 percent of antibacterial drug

Sustained release auxiliary materials 50-98%

0.0 to 30 percent of suspending agent

The weight percentage of the antibacterial effective component in the sustained-release implant is 1-50%, preferably 2-50%, and most preferably 5-40%.

The antibacterial active ingredients in the sustained-release implant are preferably:

(1) 2-50% aztreonam, carumonam sodium, imipenem, cilastatin, meropenem or 7? Amido-3-alkoxycarbonyl (and 3-keto) -1-carba (1-dethia) -3-ceph-4-carboxylic acid;

(2) 2-50% of chloramphenicol, thiamphenicol, lincomycin, virginiamycin, clindamycin, pravastatin or zetidic acid;

(3) 2-50% of vitreosil, trimethoprim, sulfamethazine, sulfamonomethoxine, olmeprin, sulfachlorpyridazine, sulfadiazine, sulfathiazole, sulfamethoxazole or trimethoprim; or

(4) 2-50% of vancomycin, norvancomycin, lincomycin, clindamycin, fosfomycin, polymyxin B, colistin, innovatomycin, neomycin, bacitracin, sodium fusidate, teicoplanin, liuyangmycin, reeves shad mycin, aminocyclitols antibiotic or polacrycin.

The sustained-release auxiliary materials in the sustained-release implant and the weight percentage thereof are most preferably as follows:

(1) 55-90% PLA;

(2) 50-90% PLGA;

(3) 50-85% of polifeprosan;

(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;

(5) 55-90% EVAc;

(6) 40-95% of sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue; or

(7) Racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.

In addition, the selected adjuvants can be a combination of any one or more of the above.

The invention can be used for preparing pharmaceutical preparations for treating various bacterial infections of human and animals, and is mainly a sustained-release injection or a sustained-release implant. The prepared pharmaceutical preparation can be used for treating infection caused by staphylococcus, streptococcus, peptostreptococcus, catarrh moraxella, propionibacterium acnes, escherichia coli, citrobacter, klebsiella, enterobacter, serratia, proteus (proteus mirabilis, proteus vulgaris), morganella, providencia, haemophilus influenzae, bacteroides, mycobacterium tuberculosis, gonococcus or meningococcus. Infection caused by sensitive bacteria, such as, but not limited to, folliculitis, furuncle, carbuncle, infective impetigo, erysipelas, cellulitis, lymphangitis, suppurative paronychia, subcutaneous abscess, hidradenitis, infective atheroma, chronic abscess, intraperitoneal abscess, intrathoracic abscess, appendicitis, mastitis, mammary abscess, perianal abscess, secondary infection such as trauma or surgical wound, pharyngolaryngitis, laryngopharyngeal abscess, acute and chronic bronchitis, tonsillitis, peritonsillar abscess, bronchiectasis (when infected), secondary infection of chronic respiratory system disease, pneumonia, lung suppuration, otitis media, sinusitis, renal abscess, perianal abscess, pyelonephritis, cystitis, cholecystitis, hepatic abscess, adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, blepharitis, dacryocystitis, abscess, and abscess, Meibomitis, periodontitis, pericoronitis, maxitis, arthritis, joint abscess, osteomyelitis, tuberculosis abscess, and suppurative meningitis. The formulations of the invention may be used for the treatment of systemic infections, but treatment of local lesions is preferred. Common local lesions also include chronic lesions caused by or combined with chronic diseases such as: but are not limited to, chronic osteomyelitis, severe bedsores, refractory skin ulcers, diabetic foot, femoral head necrosis, and senile prostate diseases.

The route of administration depends on a variety of factors. To achieve an effective concentration at the site of the lesion, the drug may be administered by a variety of routes, such as oral, rectal, transmucosal, transdermal, or enteral administration; parenteral delivery includes intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intrapericardiac, intravenous, intraperitoneal, intranasal, intraocular injections, intracavitary (e.g., intra-articular, intraperitoneal, thoracic, and spinal), peri-or intralesional injections or placements, intranodal, and intramedullary. But is preferably locally injected (slow release injection) or placed (slow release implant) on the lesion. Can be injected or placed during or before surgery; can be used for interventional therapy via bronchofiberscope and other instruments, such as lung abscess treatment; or percutaneous puncture intralesional administration intervention treatment; injection or placement in joint cavities; can be applied simultaneously with or separately from systemic treatment, but preferably several days before and after topical application.

The dosage of a drug varies depending on the composition of the drug, but the total amount of one drug may vary from 10% to 200% of the daily dose of a conventional route. If the lesion is not completely cleared or improved, it is considered that the sustained-release preparation is placed or injected again after 10 to 20 days. In order to prevent bacterial dissemination in the focus, systemic administration should be properly matched before and after each local administration.

Other medicinal components such as, but not limited to, hormones, analgesic drugs, anticoagulant drugs, hemostatic drugs and the like can also be added into the sustained-release injection or the sustained-release implant prepared by the invention.

The sustained release microspheres can also be used to prepare other formulations such as, but not limited to, tablets, pills, dragees, capsules, liquids, drops, sprays, gels, syrups, slurries, ointments, suspensions, and the like.

The technical process of the invention is further described by the following tests and examples:

test 1 comparison of local drug concentrations after different modes of application of antibacterial drug (meropenem)

White rats were used as test subjects and were grouped to receive equal amounts of meropenem (10 mg) in the following different ways: group 1, general meropenem injection was intraperitoneally injected; group 2, common meropenem injections were subcutaneously injected in the quaternary rib area; group 3, meropenem sustained release injection was subcutaneously injected in the scaly area; group 4, meropenem sustained release implant was placed subcutaneously in the tuberosity. The drug concentration at the local administration site was measured after one week, two weeks, and three weeks, respectively. The results show that the difference of the local drug concentration is obvious after different modes of application, the local administration can be obviously improved, and the effective drug concentration of the administration part can be effectively maintained. Wherein the effect of local placement of the sustained-release implant and injection of the sustained-release injection is the best. However, local injection of sustained release injections is most convenient and easy to handle. This finding constitutes an important feature of the present invention. This is further confirmed by the following correlation tests.

Experiment 2 comparison of in vivo antibacterial Effect of different modes of application of antibacterial drugs

Using white rat as test object, 2X 10⁵One staphylococcus aureus was injected into the femoral bone marrow cavity and one week later an equivalent amount of vancomycin treatment was given per trial 1 group (10/group). Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results show that the group injected with the vancomycin sustained release injection and placed with the vancomycin sustained release implant has the best effect, the local red and swollen part begins to be obviously reduced in the first week after the treatment, and all animals do not die. In the intraperitoneal injection (i.p.) group of common vancomycin injections, 70% of animals die within 20 days; in the group of the local injection of the ordinary vancomycin injection, 20% of animals died within 20 days, but 70% of animals died within 30 days. The comparison of antibacterial effects shows that the difference of the effects after different modes of application is obvious, and the local administration can obviously improve and effectively maintain the effective drug concentration of the part, whereinThe effect of local placement of the sustained-release implant and injection of the sustained-release injection is best. However, the operation of injecting the sustained-release injection is most convenient and easy. Not only has good curative effect, but also has little toxic and side effect.

The results show that the antibacterial effect of the antibacterial vancomycin is different when the antibacterial vancomycin is administrated by different routes, the local application effect is good (P is less than 0.01), and the effect of locally injecting the vancomycin sustained release injection and locally placing the vancomycin sustained release implant is better.

Test 3 comparison of in vivo antibacterial Effect of drugs

Using white rat as test object, 2X 10⁵Each staphylococcus was injected into the femoral bone marrow cavity, grouped (10/group) one week later and treated with a slow release implant containing different drugs. Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results show that compared with the control group and the systemic administration group, the sustained-release implant containing aztreonam, carumonam sodium, imipenem, cilastatin, meropenem, chloramphenicol, thiamphenicol, lincomycin, virginiamycin, clindamycin, enantiotropium, trimethoprim, sulfadimidine, olmeprin, sulfachlorpromazine, sulfadiazine, sulfathiazole, sulfaisoxazole, vancomycin, norvancomycin, lincomycin, clindamycin, fosfomycin, polymyxin B, colistin, innovation mycin, neomycin, bacitracin, sodium fusidate, teicoplanin, yang liumycin or polamycin has better treatment effect (P is less than 0.05). Wherein the sustained release adjuvant is polifeprosan (p-CPP) and Sebacic Acid (SA) copolymer, and the ratio of p-CPP to SA is 30: 70).

Test 4 comparison of in vivo antibacterial Effect of drugs

Using white rat as test object, 2X 10⁵The individual bacilli are injected into the bone marrow cavity of femur, and divided into groups (10 per group) one week later and treated with slow-release injection containing different drugs. Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results show thatIn comparison with the control group and the group administered systemically, do the control group contain aztreonam, carumonam sodium, imipenem, cilastatin, meropenem, or 7? The slow release injection of amido-3-alkoxycarbonyl (and 3-keto) -1-carba (1-dethia) -3-cephem-4-carboxylic acid has better therapeutic effect (P is less than 0.01). Wherein the sustained release adjuvant is polifeprosan (p-CPP) and Sebacic Acid (SA) copolymer, and the ratio of p-CPP to SA is 20: 80). The results show that the composition ratio of the copolymer significantly affects the release of the drug.

Experiment 5, comparison of in vivo antibacterial action of lincomycin sustained-release implant prepared from polylactic acid with different molecular weights

Using white rat as test object, 2X 10⁵Several staphylococcus aureus bacteria were injected into their femoral bone marrow cavities, grouped (10/group) one week later and treated with sustained release implants containing equal amounts of lincomycin carried by polylactic acid (PLA) of different Molecular Weights (MW). Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results showed that the bacterial inhibition increased with increasing polylactic acid molecular weight, 58% (MW: 5000), 66% (MW: 15000), 80% (MW: 25000), 88% (MW: 40000) and 92% (MW: 60000) in this order, and the P value was less than 0.01, as compared to the systemic administration group.

Similar results are seen with sustained release implants of chloramphenicol, thiamphenicol, lincomycin, virginiamycin, clindamycin, epidothiamine or zetidine.

Experiment 6, comparison of in vivo antibacterial action of sulfadiazine sustained-release implant prepared from polylactic acid with different molecular weights

Using white rat as test object, 2X 10⁵Several staphylococcus aureus bacteria were injected into their femoral bone marrow cavities, grouped after one week (10/group) and treated with sustained release implants containing equal amounts of sulfadiazine carried by polylactic acid (PLA) of different Molecular Weights (MW). Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results showed that the bacterial inhibition rate increased with increasing polylactic acid molecular weight, 70% (MW: 5000), 78% (MW: 5000) in this order, as compared to the systemic administration group: 15000) 86% (MW: 25000) 90% (MW: 40000) And 96% (MW: 60000) The P values are all less than 0.01.

The same results are seen with sustained release implants of vitronectin, trimethoprim, sulfamethazine, sulfamonomethoxine, olmeprin, sulfachlorpyridazine, sulfadiazine, sulfathiazole, sulfisoxazole or trimethoprim.

Experiment 7, comparison of in vivo antibacterial action of clindamycin sustained-release injection prepared from polylactic acid with different molecular weights

Using white rat as test object, 2X 10⁵Staphylococcus aureus was injected into the femoral bone marrow cavity and grouped (10/group) one week later and treated with sustained release injections (viscosity 600cp (20 ℃ -30 ℃)) containing equal amounts of clindamycin loaded by polylactic acid (PLA) of different Molecular Weights (MW). Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results showed that the bacterial inhibition increased with increasing polylactic acid molecular weight, 64% (MW: 5000), 72% (MW: 15000), 84% (MW: 25000), 90% (MW: 40000) and 95% (MW: 60000), all with a P value of less than 0.01, compared to the systemic group.

The same effect can be seen in vancomycin, norvancomycin, lincomycin, clindamycin, fosfomycin, polymyxin B, colistin, neomycin, bacitracin, sodium fusidate, teicoplanin, liuyangmycin, reeves shaddock mycin, aminocyclitols antibiotics or polacrycin sustained release injection.

Particularly, the sustained-release preparation, particularly the sustained-release injection, has simple and convenient operation and good repeatability. Not only has good curative effect, but also has little toxic and side effect.

The same effects can also be seen in sustained release injections of aztreonam, carumonam sodium, imipenem, cilastatin and meropenem.

The most suitable sustained-release auxiliary material is one or the combination of polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dipolymer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue.

The most suitable suspending agent is one or more of methylcellulose, hydroxymethyl cellulose, sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, or their combination.

In a word, the single antibacterial drug sustained-release preparation placed or injected locally has obvious inhibition effect on the growth of bacteria, the combination of two or more than two drugs has obvious synergy, and the shown treatment effect and the synergy are related to the effective drug concentration obtained locally. Therefore, the effective component of the sustained-release agent is the combination of one or more than one medicine.

The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein the (suspension) injection (including gel injection) formed by combining with special solvent containing suspending agent is preferred.

The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.

(IV) detailed description of the preferred embodiments

Example 1.

90, 90 and 80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is respectively put into three containers of (A), (B) and (C), then 100 ml of dichloromethane is added into each copolymer, after dissolving and mixing evenly, 10mg of aztreonam, 10mg of meropenem and 20mg of vancomycin are respectively added, after shaking up again, the microspheres for injection containing 10% of aztreonam, 10% of meropenem and 20% of vancomycin are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 15 percent of mannitol to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 450-600 cp (at 20-30 deg C). The slow release injection has the release time in vitro physiological saline of 5-10 days and the release time under the skin of a mouse of about 10-20 days.

Example 2.

The steps of the method for processing the sustained-release injection are the same as the example 1, but the difference is that the contained antibacterial active ingredients and the weight percentage thereof are as follows: 2-50% of aztreonam, carumonam sodium, imipenem, cilastatin, meropenem, chloramphenicol, thiamphenicol, lincomycin, virginiamycin, clindamycin, antipyroxin, trimethoprim, sulfadimidine, olmeprin, sulfachlorpyridazine, sulfadiazine, sulfathiazole, sulfaisoxazole, vancomycin, norvancomycin, lincomycin, clindamycin, fosfomycin, polymyxin B, colistin, novobiocin, neomycin, bacitracin, sodium fusidate, teicoplanin, liuyangmycin or polacrycin.

Example 3.

70mg of polylactic acid (PLGA, 75: 25) with the molecular weight peak value of 10000 is respectively put into three containers, namely, a container (A), a container (B) and a container (C), then 100 ml of dichloromethane is added into each container, after the materials are dissolved and uniformly mixed, 30mg of imipenem, 30mg of lincomycin, 15mg of imipenem and 15mg of lincomycin are respectively added into the three containers, the materials are shaken up again, and then the spray drying method is used for preparing the microspheres for injection containing 30% of imipenem, 30% of lincomycin, 15% of imipenem and 15% of lincomycin. Suspending the dried microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 400-600 cp (at 20-30 deg C). The slow release injection has the release time in vitro physiological saline of 7-15 days and the release time under the skin of a mouse of about 15-25 days.

Example 4

The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is that the contained antibacterial active ingredients and the weight percentage thereof are as follows:

(1) 2-50% aztreonam, carumonam sodium, imipenem, cilastatin, meropenem, or 7 β -acylamino-3-alkoxycarbonyl (and 3-keto) -1-carba (1-dethia) -3-ceph-4-carboxylic acid;

Example 5.

Putting 70mg of ethylene vinyl acetate copolymer (EVAc) into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 20mg of cilastatin and 10mg of meropenem, shaking up again, and preparing microspheres for injection containing 20% of cilastatin and 10% of meropenem by using a spray drying method. Then suspending the microspheres in injection containing 5-15% of sorbitol to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 300-550 cp (at 20-30 deg C). The slow release injection has the release time in vitro physiological saline of 7-14 days and the release time under the skin of a mouse of about 15-30 days.

Example 6.

The procedure of the process for preparing a sustained-release injection is the same as in example 5, except that the antibacterial active ingredient contained therein is: 2-50% aztreonam, carumonam sodium, imipenem, cilastatin, meropenem or 7? Amido-3-alkoxycarbonyl (and 3-keto) -1-carba (1-dethia) -3-ceph-4-carboxylic acid.

Example 7.

70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing evenly, 20mg of thiamphenicol and 10mg of virginiamycin are added, after shaking up again, injection microspheres containing 20% of thiamphenicol and 10% of virginiamycin are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 400-600 cp (at 20-30 deg C). The slow release injection has the release time in vitro physiological saline of 6-12 days and the release time under the skin of a mouse of about 14-21 days.

Example 8.

The procedure of the process for preparing a sustained-release injection is the same as in example 7, except that the antibacterial active ingredient contained therein is: 2-50% of chloramphenicol, thiamphenicol, lincomycin, virginiamycin, clindamycin, prantazone or zetidic acid.

Example 9

70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 15mg of trimethoprim and 15mg of sulfathiazole are added, after the mixture is shaken again evenly, microspheres containing 15% of trimethoprim and 15% of sulfathiazole for injection are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose, 15 percent of sorbitol and 0.2 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 400-650 cp (at 20-30 deg C). The slow release injection has a release time of 7-15 days in vitro physiological saline and a release time of about 20-30 days under the skin of a mouse.

Example 10

The procedure of the process for preparing a sustained-release injection is the same as in example 9, except that the antibacterial active ingredient contained therein is: 5-40% of boscalid sulfathiazole, trimethoprim, sulfamethazine, sulfamonomethoxine, olmeprin, sulfachlorpyridazine, sulfadiazine, sulfathiazole, sulfamethoxazole or trimethoprim.

Example 11

90mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 10mg of vancomycin or 10mg of lincomycin or 10mg of neomycin is added, after the mixture is shaken up again, the microspheres for injection containing 10% of vancomycin and 10% of lincomycin or 10% of neomycin are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 10-15 days in-vitro physiological saline and the drug release time of about 20-30 days under the skin of a mouse.

Example 12

The procedure for preparing a sustained-release implant was the same as in example 11, except that the antibacterial active ingredient contained therein was: 20% of vancomycin, norvancomycin, lincomycin, clindamycin, fosfomycin, polymyxin B, colistin, innovatomycin, neomycin, bacitracin, sodium fusidate, teicoplanin, liuyangmycin, reeves shaddock, aminocyclitols antibiotic or polamycins.

Example 13

Putting 70mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak value of 15000 into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 30m of meropenem or 30mg of tylosin, shaking up again, and preparing microspheres for injection containing 30% of danofloxacin or 30% of tylosin by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 10-15 days in vitro physiological saline and the release time of 15-20 days under the skin of a mouse.

Example 14

The steps of the method for processing the sustained-release implant are the same as those of the examples 11 and 13, but the difference is that the sustained-release implant comprises the following antibacterial active ingredients in percentage by weight:

(1) 20-30% aztreonam, carumonam sodium, imipenem, cilastatin, meropenem, or 7? Amido-3-alkoxycarbonyl (and 3-keto) -1-carba (1-dethia) -3-ceph-4-carboxylic acid;

(2) 20-30% of chloramphenicol, thiamphenicol, lincomycin, virginiamycin, clindamycin, pravastatin or zetidic acid;

(3) 20-30% of boscalid sulfathiazole, trimethoprim, sulfamethazine, sulfamonomethoxine, olmeprin, sulfachlorpyridazine, sulfadiazine, sulfathiazole, sulfamethoxazole or trimethoprim;

(4) 20-30% of vancomycin, norvancomycin, lincomycin, clindamycin, fosfomycin, polymyxin B, colistin, innovatomycin, neomycin, bacitracin, sodium fusidate, teicoplanin, liuyangmycin, reeves shaddock, aminocyclitols antibiotic or polacrycin.

Example 15

The procedure of processing into sustained release preparation is the same as that of examples 1-14, except that the sustained release excipient is one or a combination of the following:

a) polylactic acid (PLA) with the molecular weight peak value of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000;

b) a copolymer (PLGA) of polyglycolic acid and glycolic acid with a peak molecular weight of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of the polyglycolic acid to the glycolic acid is 50-95: 50-50;

c) ethylene vinyl acetate copolymer (EVAc);

d) p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) copolymer (polifeprosan) 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid) copolymer;

g) poly (fumaric acid-sebacic acid) copolymer;

h) sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin or albumin glue; or

(5) 55-90% EVAc;

Example 16

The procedure for preparing a sustained release injection is the same as in examples 1 to 10, except that the suspending agent used is one or a combination of the following:

a) 0.5-3.0% carboxymethylcellulose (sodium);

b) 5-15% mannitol;

c) 5-15% sorbitol;

d) 0.1-1.5% of surface active substances;

e) 0.1-0.5% tween 20;

f) (iodine) glycerol, dimethicone, propylene glycol or carbomer;

g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;

h) 5-20% of mannitol and 0.1-0.5% of Tween 80; or

i)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.

The above examples are intended to illustrate, but not limit, the application of the invention.

The invention is disclosed and claimed.

Claims

1. A slow-release antibiotic preparation for local application is characterized in that the slow-release antibiotic preparation is a slow-release injection and comprises the following components:

(A) a sustained release microsphere comprising:

1 to 70 percent of antibiotic

Sustained release auxiliary materials 30-99%

0.0 to 30 percent of suspending agent

The above are weight percentages

And

Wherein,

the antibiotic is selected from the group consisting of antibacterial agents selected from aztreonam, carumonam sodium, imipenem, cilastatin, meropenem, chloramphenicol, thiamphenicol, lincomycin, virginiamycin, clindamycin, antipyroxin, trimethoprim, sulfadimidine, olmeprin, sulfachlorpyridazine, sulfadiazine, sulfathiazole, sulfaisoxazole, vancomycin, norvancomycin, lincomycin, clindamycin, fosfomycin, polymyxin B, colistin, neomycin, bacitracin, fusidic acid sodium, teicoplanin, liuyangmycin or polacrycin and salts or esters thereof.

The viscosity range IV (dl/g) of the sustained-release auxiliary material is 0.1-0.8, and the sustained-release auxiliary material is selected from one or the combination of the following materials:

a) polylactic acid;

b) copolymers of polyglycolic acid and glycolic acid;

c) polifeprosan;

d) ethylene vinyl acetate copolymers;

e) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid) copolymer;

g) poly (fumaric acid-sebacic acid) copolymer;

h) sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or protein gel; or

i) Racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.

The suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), and is selected from sodium carboxymethyl cellulose, hydroxymethyl cellulose, iodine glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40, Tween-80, or their combination.

2. The sustained-release injection according to claim 1, wherein the sustained-release injection is used for effectively obtaining and maintaining the local effective drug concentration of the lesion while reducing the systemic distribution of the drug, and is used for treating acute and chronic infections of humans and animals caused by sensitive bacteria.

3. The sustained-release injection according to claim 1, wherein the sustained-release excipient comprises:

a) the molecular weight peak value of the polylactic acid is selected from 5000-10000, 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

b) in the copolymer of polyglycolic acid and glycolic acid, the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 5000-10000, 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

c) in polifeprosan, the ratio of p-carboxyphenylpropane to sebacic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.

4. A sustained-release injection as claimed in claim 2, wherein the suspending agents used are each one of the following:

a) 0.5-3.0% carboxymethylcellulose (sodium);

b) 5-15% mannitol;

c) 5-15% sorbitol;

d) 0.1-1.5% of surface active substances;

e) 0.1-0.5% tween 20;

f) (iodine) glycerol, dimethicone, propylene glycol or carbomer;

g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;

h) 5-20% of mannitol and 0.1-0.5% of Tween 80; or

5. The sustained-release injection of claim 1, wherein the sustained-release microspheres in the sustained-release injection are used to prepare a sustained-release implant for reducing the systemic distribution of the drug while effectively obtaining and maintaining the local effective drug concentration at the lesion site, and for treating acute and chronic infections in humans and animals caused by sensitive bacteria.

6. The antibacterial sustained-release implant according to claim 5, characterized in that the antibacterial active ingredients and the weight percentages thereof of the antibacterial sustained-release implant are:

(3) 2-50% of vitreosil, trimethoprim, sulfamethazine, sulfamonomethoxine, olmeprin, sulfachlorpyridazine, sulfadiazine, sulfathiazole, sulfamethoxazole or trimethoprim;

7. The antibacterial sustained-release implant according to claim 5, wherein the sustained-release excipient is selected from one or a combination of the following:

a) polylactic acid;

b) copolymers of polyglycolic acid and glycolic acid;

c) polifeprosan;

d) ethylene vinyl acetate copolymers;

e) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid) copolymer;

g) poly (fumaric acid-sebacic acid) copolymer;

8. The antibacterial sustained-release implant according to claim 7, characterized in that the sustained-release excipients include:

(1) the molecular weight peak value of the polylactic acid is selected from 5000-10000, 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

(2) in the copolymer of polyglycolic acid and glycolic acid, the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 5000-10000, 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

(3) in polifeprosan, the ratio of p-carboxyphenylpropane to sebacic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.

9. The susceptible bacteria of claims 2 and 5 are Staphylococcus, Streptococcus, Peptostreptococcus, Moraxella catarrhalis, Propionibacterium acnes, Escherichia coli, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus (Proteus mirabilis, Proteus vulgaris), Morganella, providencia, Haemophilus influenzae, Bacteroides, Mycobacterium tuberculosis, gonococcus or meningococcus.

10. The acute and chronic infections according to claims 2 and 5 are folliculitis, furuncle, carbuncle, infective impetigo, erysipelas, cellulitis, lymphangitis, suppurative paronychia, subcutaneous abscess, hidradenitis, infective atheroma, chronic abscess, intraperitoneal abscess, intrathoracic abscess, appendicitis, mastitis, mammary abscess, perianal abscess, secondary infection such as trauma or surgical trauma, pharyngolaryngitis, abscess, acute and chronic bronchitis, tonsillitis, peritonsillar inflammation, peritonsillar abscess, bronchiectasis complicated infection, secondary infection of chronic respiratory system diseases, pneumonia, lung suppuration, otitis media, sinusitis, renal abscess, perivisceral abscess, pyelonephritis, cystitis, cholecystitis, liver abscess, adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, eyelid abscess, perianal abscess, etc, Dacryocystitis, meibomitis, periodontitis, pericoronitis, maxitis, arthritis, joint abscess, osteomyelitis, tuberculous abscess, suppurative meningitis, chronic osteomyelitis, severe decubital ulcer, intractable skin ulcer, diabetic foot, femoral head necrosis and senile prostatitis.