CN101301269A

CN101301269A - Sustained-release agent containing sulbenicillin and uses thereof

Info

Publication number: CN101301269A
Application number: CNA2008103015662A
Authority: CN
Inventors: 孔庆忠; 贺润平; 栾永祖
Original assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Current assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Priority date: 2006-05-24
Filing date: 2006-05-24
Publication date: 2008-11-12

Abstract

A sustained release preparation containing sulbenicillin consists of sustained release microsphere and dissolvant, wherein the sustained release microsphere contains sustained release auxiliary materials and penicillins antibiotic; the dissolvant is special dissolvant containing suspending agents such as sodium carboxymethyl cellulose, and the viscosity of the dissolvant is 100 to 3,000 cp (at a temperature of between 20 and 30 DEG C); the sustained release auxiliary materials are selected from EVAc, Polifeprosan, PLA, PLGA, sebacic acid copolymer, albumin glue and gelatin, etc.; the sustained release microsphere can also be made into a sustained release implantation agent. The sustained release implantation agent and sustained release injection can be partly placed or injected into a bacteria focus so as to slowly release medicine over local bacteria focus for 5 to more than 30 days, thereby obviously reducing whole-length toxicity while effectively obtaining and maintaining the effective drug concentration of local focus. The sustained release preparation has remarkable and unique therapeutic effects in curing infections caused by staphylococcus, streptococcus, peptostreptococcus, propionibacterium acnes, enterobacter, tubercle bacillus, gonococcus or meningococcus, etc., and local focuses in particular such as chronic osteomyelitis, severe bedsore, intractable skin ulcer, diabetic foot, femoral head necrosis and various abscesses.

Description

Sulbenicillin-containing sustained release agent and application thereof

(I) technical field

The invention relates to a sustained release agent containing penicillin antibiotics and application thereof, belonging to the technical field of medicaments. Specifically, the invention provides a sustained-release injection and a sustained-release implant containing penicillin 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 penicillin, 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 prolonged treatment times and on the other hand to the development and use or combined use of a number of potent penicillin antibiotics and other antibiotics, with the result that expensive, 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 slow release injection containing penicillin antibiotics and application thereof, and particularly relates to a slow release injection and a slow release implant.

Antibiotics, including penicillin antibiotics, are mainly oral preparations, and effective drug concentration cannot 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 invention discovers that the local placement or injection of the penicillin antibiotic drugs prepared into the sustained release agent (mainly comprising sustained release injection and sustained release implant) can greatly improve the local drug concentration, reduce the concentration of the drugs in a circulatory system, reduce the toxicity of the drugs to normal tissues, greatly facilitate the drug application, reduce the treatment course, shorten the treatment time, reduce the complications of the drugs, 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 chronic abscesses, antibacterial drugs applied by conventional routes (oral or intramuscular injection or drip) are difficult to penetrate into the lesions due to the barrier effect of their peripheral inflammatory reactions. The concentration of the drug in pus is very low, which can not play the role of sterilization or bacteriostasis, but can cause the generation of drug-resistant bacteria. The slow-release medicine is placed or injected through skin puncture under the assistance of imaging technologies such as ultrasonic waves and/or CT and the like, so that the medicine can be accurately injected into a focus, and the medicine can be limited in the focus for days to tens of days through a slow-release mechanism, so that bacteria in the focus can be directly and effectively killed; in addition, due to the erosion effect of the released medicine on the periphery of the focus, the necrotic substances of the focus can be promoted to fall off and be discharged; 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 partial punctures can also weaken the barrier function of the wall of the cooktop. Therefore, the medicine in the blood can enter the focus, and the proliferation of granulation tissue and the purification of local focus are facilitated. The same cases include, but are not limited to, chronic osteomyelitis, deep abscess, celiac abscess, arthritis, pleural abscess, etc.

In addition, the existing penicillin antibiotics are various in types, not all penicillin antibiotics can be prepared into sustained release preparations, and different penicillin antibiotics need to be selected from proper sustained release auxiliary materials when being prepared into sustained release preparations. 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 penicillin antibiotics from hundreds of sustained release excipients. Finally, the effective combination is screened out by in-vitro release measurement of the organism. 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 racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycollic 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/glycollic acid copolymer (PLGA-COOH), polifeprosan, difatty fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], poly (FA-sebacic acid) ], and the like, Ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin, albumin glue or their combination; 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 penicillin antibiotics used in the invention are selected from: penicillin (Penicilin), Penicillin V, carboxythicillin, procaine Penicillin, metconazole Penicillin, carbapenem antibiotics, penem antibiotics, thiomycin, sulbenicillin sodium, furacilin, ticarcillin, fluoropiperazine Penicillin, oxypiperazine Penicillin, mecillin, potassium metacillin, apacillin sodium, pimecrillin, azlocillin sodium, aspoxicillin, amlodipine Penicillin sodium, azido Penicillin, flucloxacillin sodium, penicillanic acid, sodium vatopeem sodium, oxacillin sodium, 1, 3, 4-thiacarbapenem compounds, methicillin, cloxacillin sodium, oxacillin sodium, oxacillin V, hexacillin, cyclohexylpenicillin, oxacillin V, oxacillin, oxa, Sulbenicillin, carfilcillin, cainacillin, mezlocillin sodium, maytansillin, moxicillin (amicinalin, Mecillinam, Amdinocillin, cocactin), nafcillin sodium, penicillin sodium (potassium), carbenicillin sodium, ampicillin trihydrate, amoxicillin trihydrate, tazocillin, phthalammin, ticarcillin sodium, ampicillin hydrochloride, imipenem, epicillin, mepiquat, methicillin, ethoxycai penicillin, benzathine penicillin, cefazolin, sulbactam sodium.

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 of the invention are any one or the combination of more than one drug.

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 penicillin, penicillin V, carboxythicillin, procaine penicillin, metschnipulin, carbapenem penicillin, penem antibiotic, thiomycin, sulbenicillin sodium, furbenicillin, ticarcillin, fluoropiperazine penicillin, oxypiperazine penicillin, mecillin, hydracillin, and hydracillin potassium;

(2) 2-50% of apacillin sodium, pimecrillin, azlocillin sodium, aspoxicillin, amlodipine sodium, azidocillin, flucloxacillin sodium, penicillanic acid, vatrocillin sodium, oxacillin sodium, 1, 3, 4-thiadiazole carbapenem compound, methicillin or cloxacillin sodium;

(3) 2-50% oxacillin, oxacillin sodium, cloxacillin sodium, ampicillin, amoxicillin, piperacillin sodium, seabavancin V, ciclacillin, sulbenicillin, carbenicillin, cainsillin, mezlocillin sodium, maytansicillin or moxillin; or

(4) 2-50% nafcillin sodium, penicillin sodium (potassium), carbenicillin sodium, ampicillin trihydrate, amoxicillin trihydrate, tazocillin, phthalammin, ticarcillin sodium, ampicillin hydrochloride, imibencarb, epicillin, doxycycline, methicillin, ethoxycai penicillin, benzathine, cefazolin or sulbactam sodium.

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 active ingredient

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 racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid/glycollic acid copolymer, polifeprosan, difatty acid and sebacic acid copolymer, poly (erucic acid dimmer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene-vinyl acetate copolymer, polylactic acid, polyglycolic acid and glycolic acid copolymer, 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;

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

(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid and carboxyl-terminated polylactic acid/glycollic acid copolymer.

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%.

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.

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.

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.

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 active ingredient

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% penicillin, penicillin V, carboxythicillin, procaine penicillin, metschnipulin, carbapenem penicillin, penem penicillin, thiomycin, sulbenicillin sodium, furbenicillin, ticarcillin, flupiperacillin, piperacillin, mecillin, hydracillin, or potassium natacillin;

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; or

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

(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic 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 intraventricular, intravenous, intraperitoneal, intranasal, intraocular injections, intracavitary (e.g., intraperitoneal, thoracic, and intravertebral), 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 chemotherapy, but preferably several days before and after topical application.

The dosage of the 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, or 1 to 1000 ten thousand units. The daily dosage of the penicillin sodium in a conventional way is 80-320 ten thousand units per 1 day of human by intramuscular injection; the daily dose of the children is 3-5 ten thousand units/kg, and the administration is divided into 2-4 times. Intravenous drip is suitable for patients with serious diseases, such as infectious endocarditis and purulent meningitis. 1 day of an adult is 240-2000 ten thousand units, 1 day of a child is 20-40 ten thousand units/kg, and at least one infusion is added for intermittent rapid drip infusion for 4-6 times; the daily dosage of the amoxicillin is 1-4 g/day for adults, and the daily dosage is 3-4 times. The dosage for children is as follows: 50-100 mg/kg per day for 3-4 times. 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, 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 (ampicillin)

Rats were used as test subjects and were grouped to receive equal amounts of ampicillin (50 mg) in the following different ways: group 1, the common ampicillin injection is injected into the abdominal cavity; group 2, the injection of ampicillin in general was injected subcutaneously into the Quiba; group 3, ampicillin sustained release injection was subcutaneously injected into the quaternaries; and 4, placing an ampicillin sustained-release implant under the skin of the quaternary costal part. 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.

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 bone marrow cavity of their femur and one week later an equivalent amount of carbenicillin treatment was given in groups (10/group) of trial 1. 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 of the injection of the carbenicillin sustained-release injection and the placement of the carbenicillin 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 ordinary carbenicillin injection, 70% of animals 2Death within 0 day; in the group of the local injection of the ordinary carbenicillin injection, 20% of the animals died within 20 days, but 70% of the animals died within 30 days. The comparison of antibacterial effects shows that the difference of the effects after different modes of application is obvious, the effective drug concentration of the part where the sustained-release implant is placed can be obviously improved and effectively maintained by local administration, and the effect of locally placing the sustained-release implant and injecting the sustained-release injection is the 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 drug carbenicillin has different antibacterial effects when administered by different routes, and has good local application effect (P is less than 0.01), wherein the local injection of the carbenicillin sustained release injection and the local placement of the carbenicillin sustained release implant have better effects. This finding constitutes an important feature of the present invention. This is further confirmed by the following correlation tests.

Test 3 comparison of in vivo antibacterial Effect of drugs

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 slow release implants 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 penicillin, penicillin V, carboxythicillin, procaine penicillin, metschnixin, carbapenem penicillin antibiotics, penem penicillin antibiotics, thienamycin, sulbenicillin sodium, furacilin, ticarcillin, flupiperacillin, oxypiperazine penicillin, mecillin, natacillin or potassium natacillin has better treatment effect (P is less than 0.05)

The slow release auxiliary material used in the experiment is polifeprosan (p-carboxyphenylpropane (p-CPP) and Sebacic Acid (SA) copolymer, wherein the ratio of p-CPP to SA is 30: 70). Penicillin is released in vivo as: 18% (day 1), 30% (day 2), 50% (day 3), 75% (day 4), 90% (day 5), 98% (day 7), 100% (day 10).

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 that compared with the control group and the systemic administration group, the sustained-release injection containing oxacillin, oxacillin sodium, cloxacillin sodium, ampicillin, amoxicillin, piperacillin sodium, sapacinomycin V, cyclohexylcillin, sulbenicillin, carpoxicillin, carbanilin, mezlocillin sodium, mettanocillin and moxillin has better treatment 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 ratio of p-carboxyphenylpropane and sebacic acid in polifeprosan significantly affects the release of the drug.

The same results are seen for apacillin sodium, pimecrillin, azlocillin sodium, aspoxicillin, amlodipine sodium, azidocillin, flucloxacillin sodium, penicillanic acid, vatrocillin sodium, oxacillin sodium, 1, 3, 4-thiadiazolecarbonene compounds, methicillin or cloxacillin sodium.

Experiment 5, comparison of in vivo antibacterial action of ticarcillin sustained release implant 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 divided into groups (10/group) one week later and treated with an equivalent amount of ticarcillin sustained release implant carried by polylactic acid (PLA, molecular weight peak 10000) 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, in order of 6, compared to the systemic administration group0% (MW: 10000), 74% (MW: 20000), 82% (MW: 30000) and 95% (MW: 60000), all with a P value less than 0.05.

Similar results are seen for nafcillin sodium, penicillin sodium (potassium), carbenicillin sodium, ampicillin trihydrate, amoxicillin trihydrate, tazocillin, phthalazinone, ticarcillin sodium, ampicillin hydrochloride, imicarb, epicillin, dipalmycin, methicillin, ethoxycai penicillin, benzathine, cefazolin or sulbactam sodium.

Experiment 6, comparison of antibacterial action in vivo of amoxicillin 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 amoxicillin 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, which was 66% (MW: 10000), 72% (MW: 20000), 80% (MW: 30000) and 92% (MW: 60000) in this order, and the P value was less than 0.05, compared to the systemic administration group.

Experiment 7, comparison of in vivo antibacterial action of carbenicillin sodium 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) after one week and given a sustained release injection containing equal amounts of carbenicillin sodium carried by polylactic acid (PLA) of different Molecular Weights (MW) (viscosity 600cp (20 ℃ -30 ℃) for treatment. then, inflammation changes such as local redness and swelling were examined, and animals were sacrificed and local bone marrow examined for bacteria thirty days later.25000) 88% (MW: 40000) And 90% (MW: 60000) The P values are all less than 0.01.

The same effects can be seen in nafcillin sodium, penicillin sodium (potassium), carbenicillin sodium, ampicillin trihydrate, amoxicillin trihydrate, tazocillin, phthalein ampicillin, ticarcillin sodium, ampicillin hydrochloride, imibenecin, epicillin, milbemycin, methicillin, ethoxycai penicillin, and benzathine 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.

Further research shows that the most suitable sustained-release excipients are racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, terminal carboxyl polylactic acid/glycolic acid copolymer, polifeprosan, copolymer of di-fatty acid and sebacic acid (PFAD-SA), poly (erucic aciddipolymer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), copolymer of polyglycolic acid and glycolic acid (PLGA), sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, One or the combination of 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. In the existing penicillin antibiotics, not all penicillin antibiotics can be prepared into a sustained release preparation, and proper sustained release auxiliary materials are required to be selected when different penicillin antibiotics are prepared into the sustained release preparation. 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 placed 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 carbothiofuran penicillin, 10mg of flucloxacillin and 20mg of mezlocillin are respectively added, after shaking evenly again, the microspheres for injection containing 10% of carbothiofuran penicillin, 10% of flucloxacillin and 20% of mezlocillin 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 350-550 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 14-22 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:

(3) 2-50% oxacillin, oxacillin sodium, cloxacillin sodium, amoxicillin, piperacillin sodium, Haibamicin V, ciclacillin, sulbenicillin, carbenicillin, cairinin, mezlocillin sodium, maytansicillin or moxiflorin; or

Example 3.

70mg of polylactic acid (PLGA, 75: 25) with the molecular weight peak value of 10000 is respectively put into three containers of (A), (B) and (C), then 100 ml of dichloromethane is added into each container, after the mixture is dissolved and mixed evenly, 30mg of ampicillin, 30mg of carbenicillin and 30mg of mezlocillin are respectively added into the three containers, after the mixture is shaken again, the microspheres for injection containing 30% of ampicillin, 30% of carbenicillin and 30% of mezlocillin are prepared by a spray drying method. 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) 5-40% of penicillin, penicillin V, carboxythicillin, procaine penicillin, metschnipulin, carbapenem penicillin, penem antibiotic, thiomycin, sulbenicillin sodium, furbenicillin, ticarcillin, flupiperacillin, piperacillin, mecillin, hydracillin or potassium natacillin;

(2) 5-40% of apacillin sodium, pimecrillin, azlocillin sodium, aspoxicillin, amlodipine sodium, azidocillin, flucloxacillin sodium, penicillanic acid, vatrocillin sodium, oxacillin sodium, 1, 3, 4-thiadiazole carbapenem compound, methicillin or cloxacillin sodium;

(3) 5-40% oxacillin, oxacillin sodium, cloxacillin sodium, amoxicillin, piperacillin sodium, Haibamicin V, ciclacillin, sulbenicillin, carbenicillin, cairinin, mezlocillin sodium, maytansicillin or moxiflorin; or

(4) 5-40% nafcillin sodium, penicillin sodium (potassium), carbenicillin sodium, ampicillin trihydrate, amoxicillin trihydrate, tazocillin, phthalazinone, ticarcillin sodium, ampicillin hydrochloride, imibencarb, epicillin, doxycycline, methicillin, ethoxycai penicillin, benzathine, cefazolin or sulbactam sodium.

Example 5.

70mg of ethylene vinyl acetate copolymer (EVAc) is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 20mg of sulbenicillin and 10mg of ticarcillin are added, the mixture is shaken up again, and then the spray drying method is used for preparing the microspheres for injection containing 20% of sulbenicillin and 10% of ticarcillin. Then suspending the microspheres in injection containing 5-15% of sorbitol to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time in vitro physiological saline of 5-12 days and the release time under the skin of a mouse of about 14-22 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: 10-30% of penicillin, penicillin V, carboxythicillin, procaine penicillin, metconazole penicillin, carbapenem penicillin, penem antibiotic, thiomycin, sulbenicillin sodium, furbenicillin, ticarcillin, flupiperacillin, piperacillin, mecillin, hydracillin or potassium.

Example 7.

70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 30: 70) copolymer is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 20mg of pivampicillin and 10mg of flucloxacillin are added, the mixture is shaken up again and evenly, and then the spray drying method is used for preparing the microspheres for injection containing 20% of pivampicillin and 10% of flucloxacillin. 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 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 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: 5-40% of apacillin sodium, pimecrillin, azlocillin sodium, aspoxicillin, amlodipine sodium, azidocillin, flucloxacillin sodium, penicillanic acid, vatrocillin sodium, oxacillin sodium, 1, 3, 4-thiadiazole carbapenem compound, methicillin or cloxacillin sodium.

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 piperacillin and 15mg of mezlocillin are added, the mixture is shaken up again, and the microspheres containing 15% of piperacillin and 15% of mezlocillin 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 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: 10-30% of oxacillin, oxacillin sodium, cloxacillin sodium, amoxicillin, piperacillin sodium, Haibamicin V, cyclohexylcillin, sulbenicillin, carbenicillin, cairinin, mezlocillin sodium, maytansicillin or moxiflorin in combination with 10-30% of nafcillin sodium, penicillin sodium (potassium), carbenicillin sodium, ampicillin trihydrate, amoxicillin trihydrate, tazocillin, phthalazinone, ticarcillin sodium, ampicillin hydrochloride, imipenem, epicillin, metribumycin, methicillin, ethoxycai penicillin, benzathine penicillin, cefazolin or sulbactam sodium.

Example 11

70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, 30mg of amoxicillin is added after the mixture is dissolved and mixed evenly, and the microspheres for injection containing 30% amoxicillin are prepared by a spray drying method after the mixture is shaken again and evenly. 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: 10-30% of oxacillin, oxacillin sodium, cloxacillin sodium, amoxicillin, piperacillin sodium, seabamycin V, ciclacillin, sulbenicillin, carfillin, carindicillin, mezlocillin sodium, maytansillin, moxillin, nafcillin sodium, penicillin sodium (potassium), carbenicillin sodium, ampicillin trihydrate, amoxicillin trihydrate, tazocillin, phthalazinone, ticarcillin sodium, ampicillin hydrochloride, imicarb, epicillin, metribuzin, methicillin, ethoxycai penicillin, benzathine, cefazolin or sulbactam sodium.

Example 13

Putting 85mg 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 15mg of benzathine, shaking uniformly again, and preparing the microspheres for injection containing 15% of benzathine by using 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% of penicillin, penicillin V, carboxythicillin, procaine penicillin, metaxacin, carbapenem antibiotics, penem antibiotics, thiomycin, sulbenicillin sodium, furbenicillin, ticarcillin, flupiperacillin, oxapiperacillin, mecillin, hydracillin, or hydracillin potassium;

(2) 20% of apacillin sodium, pimecrillin, azlocillin sodium, aspoxicillin, amlodipine, flucloxacillin, penicillanic acid, valacilin sodium, oxacillin sodium, methicillin or cloxacillin sodium;

(3) 20% oxacillin, cloxacillin, amoxicillin, piperacillin sodium, ciclacillin, sulbenicillin, carbenicillin, cairinin, mezlocillin, maytansicillin or moxillin; or

(4) 20% nafcillin sodium, carbenicillin sodium, ampicillin trihydrate, amoxicillin trihydrate, tazocillin, phthalacillin, ticarcillin sodium, ampicillin hydrochloride, imibenicillin, epicillin, milbemycin, methicillin, ethoxycai penicillin, benzathine, cefazolin or sulbactam sodium.

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

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.

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 injection containing penicillin antibiotics and application thereof are characterized in that the slow release injection comprises the following components:

(A) a sustained release microsphere comprising:

penicillin antibiotics

Sustained release excipients

And

(B) the menstruum is common menstruum or special menstruum containing a suspending agent;

wherein,

the slow release injection is prepared from the following components in parts by weight:

the penicillin antibiotic is 20% sulbenicillin and 10% ticarcillin, the slow release auxiliary material is para-carboxyphenylpropane and polifeprosan with the sebacic acid being 20: 80, and the dissolvent is injection containing 5-15% sorbitol;

the above are all weight percentages.

2. The sustained-release injection according to claim 1, wherein the sustained-release microspheres in the sustained-release injection are used for preparing a sustained-release implant for effectively obtaining and maintaining the local effective drug concentration of the focus while reducing the systemic distribution of the drug, and for treating acute and chronic infections of human and animals caused by sensitive bacteria.