CN101283971A - Sustained-release injection containing antibiotic lincomycin and application thereof - Google Patents
Sustained-release injection containing antibiotic lincomycin and application thereof Download PDFInfo
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Abstract
The invention provides a sustained-release injection or sustained-release implant containing lincomycin antibiotic. The sustained-release injection comprises sustained-release microspheres and solvent. The microspheres contain sustained-release adjuvants and antibiotics, and the solvent is a special solvent containing suspending agent such as sodium carboxymethylcellulose and having viscosity of 100-3000cp (20-30 DEG C); and the sustained-release adjuvants are selected from poly(ethylene-co-vinylacetate) (EVAc), polifeprosan, poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), sebacic acid copolymer, albumin glue and gelatin. The sustained-release implant is made from microspheres or by other methods. The sustained-release implant or injection can be locally placed or injected into foci to locally sustained-release of drug for more than 10 days, so as to obtain and maintain local drug effective concentration while remarkably reduce the systemic toxicity of the drug. The sustained-release injection has distinct and unique therapeutic effect on local infection diseases caused by Staphylococci, Streptococci, Peptostreptococcus, Propionibacterium acnes, Enterobacter, Mycobacterium tuberculosis, Gonococcus or Meningococcus, such as chronic osteomyelitis, severe decubital ulcer, refractory skin ulcer, diabetic foot, femoral head necrosis, abscess, etc.
Description
(1) technical field
The present invention relates to a kind of contain antibiotic slow releasing injection and application thereof, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of antibiotic slow releasing injection and sustained-release implant of containing.This slow releasing agent topical application is main, can and keep active drug concentration in the local acquisition of bacterial infection.
(2) background technology
Along with antibiotic appearance, bacterial infection has become a kind of medicable disease.Yet because treatment is lack of standardization, treatment time is longer, and many patients may just forget quantitatively medication in time, thereby often cause chemical sproof generation.Much the bacterial infection that should cure shows effect repeatedly becomes chronic lesion.And the drug resistance patient or repeatedly the treatment of the chronic lesion of outbreak on the one hand will make spinning out of treatment time, be exactly Application and Development or the use in conjunction that causes multiple potent antibiotics on the other hand, consequently expense costliness, new Resistant strain are constantly improved constantly by cultivation, effective dose, thereby form vicious cycle.Therefore, new effective treatment Resistant strain and the preparation of chronic and refractory infection or the world subject that method has become eager solution of research and development.
At present, have many new antibacterials to demonstrate curative effect preferably, yet to a lot of chronic lesions, particularly local lesion, the routine treatment administration is difficult to obtain effective bacteriocidal concentration.Escalated dose or take medicine for a long time and have a lot of side effect again.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of contain antibiotic slow releasing injection and application thereof are provided, particularly, is a kind of slow releasing injection and sustained-release implant.
Antibacterials are mainly oral formulations, can not obtain active drug concentration in lesions position.Even general injection is also not ideal enough.Because dose deficiency, single drug, irregular factor such as take medicine not only can not reach effective blood concentration, are not enough to thorough kill bacteria, and lure that fastbacteria survives or impel bacterial dissociation into.Depending merely on increases the restriction that dosage can be subjected to general toxic reaction again.
The present invention finds, antibiotic medicine made slow releasing agent (being mainly slow releasing injection and sustained-release implant) is local to be placed or injection not only can greatly improve partial drug level, reduces the concentration of medicine in blood circulation, reduce the toxicity of medicine to normal structure, can also greatly make things convenient for medicinal application, reduce the course of treatment, shorten treatment time, reduce medicine complication, reduce patient expense, reduce the single medicine consumption, strengthen therapeutic effect, reduce drug resistance.Drug-resistant bacteria is particularly merged the therapeutic effect that bacterial infection local lesion or chronic infection have remarkable uniqueness, effectively overcome the limitation of systemic administration.
With the tuberculous cavity is example, because the barrier action of tuberculous cavity wall, hole wall peripheral vessels rareness, sclerosis even closure in addition are difficult to infiltrate in the cavity through the antibacterials of conventional approach (oral or intramuscular injection or drop) application.Drug level in the cavity is very low, does not have sterilization or bacteriostasis, causes that on the contrary fastbacteria produces.Placing or inject slow releasing pharmaceutical through the skin puncture under iconography technology such as ultrasound wave and/or CT help not only can inject medicine in the cavity more exactly, also can medicine be confined to tens of skies in the wall of hole, thereby directly effectively kill the bacterium in the wall of hole by release mechanism; In addition, caseous focus is softening, sphacelus comes off discharge because the medicine that discharges to the corrosion function of hole wall, can impel; During partial operation also can by means of puncture needle or corresponding utensil (as but be not limited to bronchoscope, cystoscope, peritoneoscope, articular cavity mirror etc.) local kitchen range is removed.Moreover, local repeated multiple times puncture also can weaken the barrier action of empty wall.So the medicine that not only helps in the blood enters focus, also helps the hypertrophy of granulation tissue and the purification in cavity.Same case includes but not limited to chronic osteomyelitis, deep abscess, peritoneal abscess, arthritis etc.
In addition, existing antibiotic is of a great variety, is not that all antibiotic all can be made into slow releasing preparation, and different antibiotic must be selected suitable slow-release auxiliary material when making slow releasing preparation.Therefore, the present invention is based on above unexpected the discovery, and from hundreds of antibacterials, successfully filter out effective antimicrobial component that can be applicable to slow release by follow-up a large amount of research, from hundreds of slow-release auxiliary material, successfully filter out the slow release composition that can be applicable to antibiotic sustained release.Discharge mensuration inside and outside the final body and filter out effective combination.Thereby constitute main contents of the present invention.
A kind of form of medicinal slow release agent of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow releasing injection is grouped into by following one-tenth:
(a) sustained-release microparticle, the one-tenth following by percentage by weight is grouped into:
Antibiotic effective ingredient 1-70%
Slow-release auxiliary material 30-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(b) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Slow-release auxiliary material is selected from polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), sodium carboxymethyl cellulose, hydroxy methocel, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The available antibiotic effective ingredient of the present invention is, but be not limited to apramycin (Apramycin), avilamycin (Avilamycin (GP)), pirlimycin (Pirlimycin), danofloxacin (Danofloxacin), spectinomycin (Spectinomycin), polymyxin B (Polymyxin B), grace promise mycin (Enrofloxacin), difloxacin (Difloxacin), Florfenicol (Florfenicol), bambermycin (Flavomycin), chlortetracycline (Chlortetracycline), carbadox (Carbodox), lincomycin (Lincomycin), tiamulin (Tiamulin), cloxacillin (Cloxacilin), marbofloxacin (Marbofloxacin), Premafloxacin (Premafloxacin), doxycycline (Doxycycline), streptomycin (Streptomycin), penicillin/novobiocin (Penicillin/Novobiocin), penicillin, novobiocin, Sarafloxacin (Sarafloxacin), Salinomycin (Salinomycin (GP)), tylosin (Tylosin), tylosin tartrate (Tylosin tartrate), cefalexin (Cephalexin), ceftiofur (Ceftiofur), neomycin (Neomycin), novobiocin (Novobiocin), ibafloxacin (Ibafloxacin), gentamycin sulfate, trimethoxy joint diamidogen is had a liking for eyelash/sulfalene.
The available antibiotics of the present invention also is selected from the salt or the ester of said medicine, as, but be not limited to, hydrochloric acid, sulphuric acid, acetic acid, lactic acid, tartaric acid, malic acid, coloured glaze are clapped acid, phosphoric acid, the acid of nitrogen Australia, sulfinic acid, formic acid, toluenesulfonic acid, Loprazolam, nitric acid, benzoic acid, citric acid, maleic acid, nitrogen iodic acid, alkanoic acid, fluorenes methyl ester, peopentyl ester, ester salt etc.Salt trends towards more being soluble in the aqueous solvent or other proton solvent of corresponding free alkali form.Avirulence medicinal basic addition salts comprises the salt such as alkali such as sodium, potassium, calcium, amine.Those skilled in the art know many avirulent pharmaceutically acceptable addition salts.
The effective ingredient of medicinal slow release agent of the present invention is the combination of any one or two kinds of medicines of above-mentioned any one or more than one medicine and other any apoplexy due to endogenous wind.
Above-mentioned antibacterials shared ratio in slow releasing agent is decided because of concrete condition, can be 1%-70%, is good with 2%-50%, and 5%-40% is best.
Antibacterials and in slow releasing agent shared percentage by weight be preferably:
(1) 2-50% apramycin, avilamycin, danofloxacin, lincomycin, spectinomycin, doxycycline or streptomycin;
(2) 2-50% penicillin, difloxacin, chlortetracycline, carbadox, cloxacillin, marbofloxacin or Premafloxacin;
(3) 2-50% pirlimycin, Sarafloxacin, grace promise mycin, tylosin, cefalexin, ceftiofur or neomycin; Or
(4) 2-50% Salinomycin, novobiocin, ibafloxacin, gentamycin sulfate, sulfadiazine or sulfafurazole.
But the most preferably combination of the medicine of different mechanism of action, for: a kind of or its combination in apramycin, avilamycin, pirlimycin, danofloxacin, spectinomycin, grace promise mycin, difloxacin, chlortetracycline, carbadox, lincomycin, cloxacillin, marbofloxacin, Premafloxacin, doxycycline, streptomycin, penicillin, Sarafloxacin, Salinomycin, tylosin, cefalexin, ceftiofur, neomycin, novobiocin, ibafloxacin, gentamycin sulfate, sulfadiazine, the sulfafurazole.
Above-mentioned antibacterials shared ratio in slow releasing agent is decided because of concrete condition, can be 1%-70%, is good with 2%-50%, and 5%-40% is best.
The effective ingredient in the antimicrobial sustained-release microsphere of the present invention and the percentage by weight of slow-release auxiliary material are preferably as follows:
Antibacterials 2-50%
Slow-release auxiliary material 50-98%
Suspending agent 0.0-30%
Slow-release auxiliary material is selected from one of copolymer, sodium carboxymethyl cellulose, hydroxy methocel, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and albumin glue of polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, polyglycolic acid and hydroxyacetic acid or its combination.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release micro-spheres of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%; Or
(6) sodium carboxymethyl cellulose of 40-95%, hydroxy methocel, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
Above sustained-release micro-spheres is made slow releasing injection with the solvent that contains sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 or soil temperature 80 suspending agents.Wherein the concentration of sodium carboxymethyl cellulose in solvent can be 0.1-5%, but is preferred with 0.5-3%, with 1-2% for most preferably.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Except that above-mentioned adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain antimicrobial component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or.
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.
Microsphere also can be used for preparing other slow releasing injection, as gel injection, gel rubber sustained-release injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is
The Polyethylene Glycol of 1000-15000 (PEG) is as the hydrophilic block of micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through local injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.The method of making gel injection is arbitrarily.
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) is 10/90-90/10 (weight) with the blend ratio of polyglycolic acid, preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Another form of slow releasing agent of the present invention is that slow releasing agent is a sustained-release implant.The effective ingredient of antibiotic implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.
The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.The volume size depends on factors such as the position, size of focus.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.
The most preferred dosage form of sustained-release implant is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
The effective ingredient and the percentage by weight of sustained-release implant of the present invention are preferably as follows:
Antibacterials 2-50%
Slow-release auxiliary material 50-98%
Suspending agent 0.0-30%
The percentage by weight of antibiotic effective one-tenth in sustained-release implant is 1-50%, is preferred with 2-50%, and 5-40% is for most preferably.
Antibiotic effective ingredient is preferably in the sustained-release implant of the present invention:
(1) 2-50% apramycin, avilamycin, danofloxacin, lincomycin, spectinomycin, doxycycline or streptomycin;
(2) 2-50% penicillin, difloxacin, chlortetracycline, carbadox, cloxacillin, marbofloxacin or Premafloxacin;
(3) 2-50% pirlimycin, Sarafloxacin, grace promise mycin, tylosin, cefalexin, ceftiofur or neomycin; Or
(4) 2-50% Salinomycin, novobiocin, ibafloxacin, gentamycin sulfate, sulfadiazine or sulfafurazole.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release implant of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%; Or
(6) sodium carboxymethyl cellulose of 40-95%, hydroxy methocel, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue.
In addition, selected adjuvant also can be above-mentioned any one above combination.
The present invention can be used to prepare the pharmaceutical preparation of the various bacterial infections for the treatment of people and animal, is mainly slow releasing injection or sustained-release implant.Though the drug prepared preparation can be used for the treatment of the infection that staphylococcus, Streptococcus, Peptostreptococcus, mucositis mora bacterium, propionibacterium acnes, escherichia coli, citron Bacillus, Klebsiella, Enterobacter, Serratia, Proteus (proteus mirabilis, proteus vulgaris), morgan's bacillus genus, Providian Bordetella, hemophilus influenza, Bacteroides, tubercule bacillus, gonococcus or meningococcus cause.Responsive microbial infection, as, but be not limited to folliculitis, furuncle, carbuncle, the infectiousness impetigo, erysipelas, cellulitis, lymphatic vessel (knot) inflammation, pyogenic paronychia, subcutaneous abscess, hidradenitis, infectious sebaceous cyst, chronic Pyoderma, intra-abdominal abscess, abscess in the thoracic cavity, appendicitis, mastitis, mammary abscess, perianal abscess, secondary infection such as wound or operation wound, pharyngolaryngitis, the throat abscess, acute/chronic bronchitis, tonsillitis, peritonsillitis, peritonsillar abscess, bronchiectasis (during infection), the chronic respiratory system diseases secondary infection, pneumonia, pulmonary suppuration disease, otitis media, sinusitis, renal abscess, the internal organs peripheral abscess, pyelonephritis, cystitis, cholecystitis, liver abscess, adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, palpebral abscess, dacryocystisis, meibomitis, periodontitis, pericoronitis, ganathitis, arthritis, joint abscess, osteomyelitis, the tuberculosis abscess, purulent meningitis.Preparation of the present invention can be used for the treatment of systemic infection, but with the treatment local lesion serve as preferred.Common local lesion also comprises chronic pathological changes that chronic disease causes or that merge, as: but be not limited to chronic osteomyelitis, serious symptom decubital ulcer, intractable cutaneous ulcer, diabetic foot, femur head necrosis and old prostate class disease etc.
Route of administration depends on multiple factor.For obtaining valid density at diseased region, medicine can give through number of ways, the administration of for example oral, rectum, through mucous membrane, percutaneous or enteral; That non-intestinal transmission comprises is intramuscular, subcutaneous, the injection in the marrow, and in the sheath, in directly injection, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), focus week or the intralesional injection of intraventricular, intravenous, endoperitoneal, intranasal, ophthalmic or the placement, lymph node and in the bone marrow.But with focus local injection (slow releasing injection) or placement (sustained-release implant) serves as preferred.Can or place in when operation or perioperatively injection; Can be through apparatus interventional therapys such as fibre bronchus mirrors, as treatment pulmonary abscess; But also percutaneous puncture intralesional administration interventional therapy; But also intraarticular injection or placement; Can separate application with systemic chemotherapy while or front and back, but the whole body antibacterial therapy of a couple of days is preferably arranged before and after the topical application.
Drug dose is different different because of the medicine composition, does not wait but a kind of medicine total amount can be 10% to 200% of conventional route day dosage.If focus is not removed fully or improved, can consider to place once more after 10 to 20 days or the injection slow releasing agent.For preventing that the intralesional bacterium from sending out, should suitably be equipped with the whole body administration before and after each topical.
Also can add other medicinal ingredient in slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to hormone, antalgica, anticoagulant medicine, hemorrhage etc.
Sustained-release micro-spheres also can be used for preparing other preparation, as, but be not limited to tablet, pill, dragee, capsule, liquid, gel, syrup, mud agent, ointment, suspension etc.
By following test and embodiment technical method of the present invention is further described:
The local drug concentration that test 1, different modes are used after the antibacterials (lincomycin) compares
With the rat is subjects, will accept equivalent lincomycin (10 milligrams) through following different modes respectively after its grouping: group 1, the common lincomycin injection of lumbar injection; Group 2, the common lincomycin injection of hypochondrium subcutaneous injection; Group 3, hypochondrium subcutaneous injection lincomycin slow releasing injection; Group 4, hypochondrium subcutaneous placement lincomycin sustained-release implant.Measure topical place drug level after one week, two weeks, three weeks respectively.The result shows, the local drug concentration significant difference after different modes is used, and topical can obviously improve, and effectively keeps the active drug concentration of medicine-feeding part.It is best with the effect of injection slow releasing injection wherein to place sustained-release implant with the part.Yet, local injection slow releasing injection operation most convenient, easy.This discovery constitutes key character of the present invention.Following correlation test has further confirmed this point.
The interior bacteriostasis of body that test 2, different modes are used after the antibacterials compares
With the rat is subjects, with 2 * 10
5Individual staphylococcus aureus is injected in its femur bone marrow intracavity, and the grouping (10/group) according to test 1 after the week gives the treatment of equivalent danofloxacin.Check inflammatory activity such as local redness subsequently, put to death animal after 30 days and get local bone marrow inspection bacterium.The result shows that injection danofloxacin slow releasing injection and placement danofloxacin sustained-release implant group effect are best, and first week beginning after treatment of local redness is obviously dwindled, and all animals do not have death.In the common danofloxacin injection of lumbar injection (i.p.) group, dead in 70% animal 20 days; In the common danofloxacin injection of local injection group, dead in 20% animal 20 days, but dead in 70% animal 30 days.Relatively fungistatic effect shows, the difference between the effects after different modes is used is remarkable, and topical can obviously improve and effectively keep the active drug concentration at position, place, and it is best with the effect of injection slow releasing injection wherein to place sustained-release implant with the part.But, injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
Above result shows, the antibacterials danofloxacin is through the bacteriostasis difference of different approaches administration, is (P＜0.01), wherein local injection danofloxacin slow releasing injection and local better effects if of placing the danofloxacin sustained-release implant well with the effect of topical application.
The vivo bacteria corrosion action of test 3, medicine relatively
With the rat is subjects, with 2 * 10
5Individual staphylococcus is injected in its femur bone marrow intracavity, and a week back grouping (10/group) also contains the sustained-release implant treatment of different pharmaceutical.Check inflammatory activity such as local redness subsequently, put to death animal after 30 days and get local bone marrow inspection bacterium.The result shows, compares with whole body administration group with matched group, and the sustained-release implant that contains grace promise mycin, difloxacin, lincomycin, cloxacillin, marbofloxacin, Premafloxacin or doxycycline all has better therapeutic effect (P＜0.05).Wherein, slow-release auxiliary material is polifeprosan (to carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA) copolymer, p-CPP: SA is 30: 70).
The vivo bacteria corrosion action of test 4, medicine relatively
With the rat is subjects, with 2 * 10
5Individual bacillus is injected in its femur bone marrow intracavity, and a week back grouping (10/group) also contains the slow releasing injection treatment of different pharmaceutical.Check inflammatory activity such as local redness subsequently, put to death animal after 30 days and get local bone marrow inspection bacterium.The result shows, compares with whole body administration group with matched group, and the slow releasing injection that contains streptomycin, penicillin, Sarafloxacin, Salinomycin, tylosin, cefalexin or ceftiofur all has better therapeutic effect (P＜0.01).Wherein, slow-release auxiliary material is polifeprosan (to carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA) copolymer, p-CPP: SA is 20: 80).The result shows that the proportion of composing of copolymer obviously influences the release of medicine.
The vivo bacteria corrosion action of the grace promise mycin sustained-release implant that test 5, different molecular weight polylactic acid are made relatively
With the rat is subjects, with 2 * 10
5Individual staphylococcus aureus is injected in its femur bone marrow intracavity, and a week back grouping (10/group) also contains equivalent grace promise mycin sustained-release implant treatment by polylactic acid (PLA) carrying of different molecular weight (MW).Check inflammatory activity such as local redness subsequently, put to death animal after 30 days and get local bone marrow inspection bacterium.The result shows, compare with whole body administration group, the bacteriostatic rate increases with the polylactic acid molecule amount and improves, and is followed successively by 58% (MW:5000), 66% (MW:15000), 80% (MW:25000), 88% (MW:40000) and 92% (MW:60000), and the P value is all less than 0.01.
The vivo bacteria corrosion action of the grace promise mycin sustained-release implant that test 6, different molecular weight polylactic acid are made relatively
With the rat is subjects, with 2 * 10
5Individual staphylococcus aureus is injected in its femur bone marrow intracavity, and a week back grouping (10/group) also contains equivalent grace promise mycin sustained-release implant treatment by polylactic acid (PLA) carrying of different molecular weight (MW).Check inflammatory activity such as local redness subsequently, put to death animal after 30 days and get local bone marrow inspection bacterium.The result shows, compare with whole body administration group, the bacteriostatic rate increases with the polylactic acid molecule amount and improves, and is followed successively by 70% (MW:5000), 78% (MW:15000), 86% (MW:25000), 90% (MW:40000) and 96% (MW:60000), and the P value is all less than 0.01.
The vivo bacteria corrosion action of the difloxacin slow releasing injection that test 7, different molecular weight polylactic acid are made relatively
With the rat is subjects, with 2 * 10
5Individual staphylococcus aureus is injected in its femur bone marrow intracavity, and a week back grouping (10/group) also contains by the equivalent grace promise mycin slow releasing injection of polylactic acid (PLA) carrying of different molecular weight (MW) (viscosity is 600cp (20 ℃-30 ℃ time)) treatment.Check inflammatory activity such as local redness subsequently, put to death animal after 30 days and get local bone marrow inspection bacterium.The result shows, compare with whole body administration group, the bacteriostatic rate increases with the polylactic acid molecule amount and improves, and is followed successively by 64% (MW:5000), 72% (MW:15000), 84% (MW:25000), 92% (MW:40000) and 96% (MW:60000), and the P value is all less than 0.01.
Same effect also sees difloxacin, lincomycin, cloxacillin, marbofloxacin, Premafloxacin or doxycycline slow releasing injection.
That pays special attention to is simple to operation, the good reproducibility of slow releasing agent of the present invention, particularly slow releasing injection.Good effect not only, toxic and side effects is little.
Same effect also sees the slow releasing injection of streptomycin, penicillin, Sarafloxacin, Salinomycin, tylosin, cefalexin or ceftiofur.
Optimum slow-release auxiliary material is a polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), sodium carboxymethyl cellulose, hydroxy methocel, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination.
Optimum suspending agent is one of methylcellulose, hydroxy methocel, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80 or its combination.
In a word, local placement or the single antibacterials slow releasing agent of local injection all have the obvious suppression effect to bacteria growing, community's notable synergistic of two or more medicine, the therapeutical effect that is shown is all relevant with its local active drug concentration that obtains with potentiation.Therefore, the effective ingredient of slow releasing agent of the present invention is the combination of one or more medicines.
The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with (suspendible) injection (comprising gel injection) that is combined to form with the special solvent that contains suspending agent wherein.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
With 90,90 and 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer put into (first), (second) and (the third) three container respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, add 10mg danofloxacin, 10mg cefalexin, 20mg tylosin respectively, shake up the back contains 10% danofloxacin, 10% cefalexin and 20% with spray drying method for preparation tylosin injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The viscosity of injection is 300cp-600cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 5-10 days, is about 10-20 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained antibiotic effective ingredient and percentage by weight thereof are:
(1) 2-50% apramycin, avilamycin, danofloxacin, lincomycin, spectinomycin, doxycycline or streptomycin;
(2) 2-50% penicillin, difloxacin, chlortetracycline, carbadox, cloxacillin, marbofloxacin or Premafloxacin;
(3) 2-50% pirlimycin, Sarafloxacin, grace promise mycin, tylosin, cefalexin, ceftiofur or neomycin; Or
(4) 2-50% Salinomycin, novobiocin, ibafloxacin, gentamycin sulfate, sulfadiazine or sulfafurazole.
Embodiment 3.
With 70mg molecular weight peak value 10000 polylactic acid (PLGA, 75: 25) put into (first), (second) and (the third) three container respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, adding 30mg lincomycin, 30mg doxycycline, 15mg woods respectively in three containers can mould and 15mg doxycycline, shake up again the back contain 30% lincomycin, 30% doxycycline, 15% woods with spray drying method for preparation can be mould and the injectable microsphere of 15% doxycycline.Dried microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The viscosity of injection is 400cp-600cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 7-15 days, is about 15-25 days at the subcutaneous drug release time of mice.
Embodiment 4
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained antibiotic effective ingredient and percentage by weight thereof are:
(1) 5-40% apramycin, avilamycin, danofloxacin, lincomycin, spectinomycin, doxycycline or streptomycin;
(2) 5-40% penicillin, difloxacin, chlortetracycline, carbadox, cloxacillin, marbofloxacin or Premafloxacin;
(3) 5-40% pirlimycin, Sarafloxacin, grace promise mycin, tylosin, cefalexin, ceftiofur or neomycin; Or
(4) 5-40% Salinomycin, novobiocin, ibafloxacin, gentamycin sulfate, sulfadiazine or sulfafurazole.
Embodiment 5.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of Sarafloxacins and 10 milligrams of tylosins, shake up the back contains 20% Sarafloxacin and 10% tylosin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 7-14 days, is about 15-30 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained antibiotic effective ingredient is:
The Salinomycin of 2-50%, novobiocin, ibafloxacin, gentamycin sulfate, sulfadiazine or sulfafurazole.
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg Salinomycin and 10mg sulfadiazine, shake up the back contains 20% Salinomycin and 10% sulfadiazine with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 5-10 days, is about 10-20 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained antibiotic effective ingredient is:
The pirlimycin of 5-40%, Sarafloxacin, grace promise mycin, tylosin, cefalexin, ceftiofur or neomycin.
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg grace promise mycin and 15mg streptomycin, shake up the back again and contain 15% grace promise mycin and 15% streptomycin injectable microsphere with spray drying method for preparation.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 7-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 10
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained antibiotic effective ingredient is:
The penicillin of 5-40%, difloxacin, chlortetracycline, carbadox, cloxacillin, marbofloxacin or Premafloxacin.
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg apramycin and 10mg spectinomycin and 10mg danofloxacin, shake up the back contains 10% apramycin and 10% spectinomycin and 10% danofloxacin with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 12
The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained antibiotic effective ingredient is:
The combination of the penicillin of the apramycin of 10-20%, avilamycin, danofloxacin, lincomycin, spectinomycin, doxycycline or streptomycin and 10-20%, difloxacin, chlortetracycline, carbadox, cloxacillin, marbofloxacin or Premafloxacin.
Embodiment 13
With 70mg molecular weight peak value 15000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg danofloxacin and 15mg tylosin, shake up the back contains 15% danofloxacin and 15% tylosin with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 15-20 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained antibiotic effective ingredient and percentage by weight are:
(1) 5-40% apramycin, avilamycin, danofloxacin, lincomycin, spectinomycin, doxycycline or streptomycin;
(2) 5-40% penicillin, difloxacin, chlortetracycline, carbadox, cloxacillin, marbofloxacin or Premafloxacin;
(3) 5-40% pirlimycin, Sarafloxacin, grace promise mycin, tylosin, cefalexin, ceftiofur or neomycin; Or
(4) 5-40% Salinomycin, novobiocin, ibafloxacin, gentamycin sulfate, sulfadiazine or sulfafurazole.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) the molecular weight peak value is the polylactic acid (PLA) of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) ethylene vinyl acetate copolymer (EVAc);
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) sodium carboxymethyl cellulose, hydroxy methocel, xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin glue.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-10, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20;
F) (iodine) glycerol, simethicone, propylene glycol or carbomer;
G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
H) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
Above embodiment only is used for explanation, and is not limitation application of the present invention.
The present invention disclosed and the protection the content see claim.
Claims (2)
1. one kind contains antibiotic slow releasing injection, it is characterized in that the following one-tenth of this slow releasing injection is grouped into:
(A) sustained-release micro-spheres comprises:
Antibiotic
Slow-release auxiliary material
With
(B) solvent is for common solvent or contain the special solvent of suspending agent;
Wherein,
Described slow releasing injection consist of following combination:
Antibiotic is 30% lincomycin, and slow-release auxiliary material is 10000 polylactic acid for the molecular weight peak value, and solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose;
Below all be weight percentage.
2. the slow releasing injection according to claim 1, it is characterized in that the sustained-release micro-spheres in this slow releasing injection is used to prepare sustained-release implant, the whole body that is used for effectively obtaining and reduces medicine when keeping the local active drug concentration of focus distributes, and is used for the treatment of the acute and chronic infection of the humans and animals that sensitive bacterial causes.
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| CNA2008103015751A CN101283971A (en) | 2006-05-17 | 2006-05-17 | Sustained-release injection containing antibiotic lincomycin and application thereof |
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| CNA2008103015751A CN101283971A (en) | 2006-05-17 | 2006-05-17 | Sustained-release injection containing antibiotic lincomycin and application thereof |
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| CNA2006102004591A Division CN1879604A (en) | 2006-05-17 | 2006-05-17 | An antibiotics-containing sustained releasing injection and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756909A (en) * | 2010-03-18 | 2010-06-30 | 青岛康地恩药业有限公司 | Lung-targeting ceftiofur microsphere and preparation method thereof |
| CN111973613A (en) * | 2020-07-30 | 2020-11-24 | 瑞普（天津）生物药业有限公司 | Compound spectinomycin powder injection and preparation method thereof |
-
2006
- 2006-05-17 CN CNA2008103015751A patent/CN101283971A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756909A (en) * | 2010-03-18 | 2010-06-30 | 青岛康地恩药业有限公司 | Lung-targeting ceftiofur microsphere and preparation method thereof |
| CN111973613A (en) * | 2020-07-30 | 2020-11-24 | 瑞普（天津）生物药业有限公司 | Compound spectinomycin powder injection and preparation method thereof |
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