CN1843360A - Slow release injection containing cefradine - Google Patents
Slow release injection containing cefradine Download PDFInfo
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- CN1843360A CN1843360A CNA2006102004888A CN200610200488A CN1843360A CN 1843360 A CN1843360 A CN 1843360A CN A2006102004888 A CNA2006102004888 A CN A2006102004888A CN 200610200488 A CN200610200488 A CN 200610200488A CN 1843360 A CN1843360 A CN 1843360A
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Abstract
Disclosed is a slow release injection containing cephalosporin, which comprises slow release microballoons and dissolvent, wherein the slow release microballoons include slow release auxiliary materials and cephalosporin, the dissolvent being specific one containing suspension adjuvant such as sodium carboxymethyl cellulose, the slow release auxiliary materials are selected from EVAc, PLA, PLGA, sebacylic acid copolymer, albumen glue or gelatin, the slow release microballoons can also be made into slow release implantation agent or ointment.
Description
(1) technical field
The present invention relates to a kind of slow releasing injection that contains cephalosporin, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection and sustained-release implant that contains cephalosporin.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 the appearance of antibiotics, 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 to cause multiple potent cephalosporin and other antibiotic Application and Development or use in conjunction 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, many new antibacterials, particularly cephalosporin are arranged, demonstrated 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 slow releasing injection and application thereof that contains cephalosporin is provided, particularly, is a kind of slow releasing injection and sustained-release implant.
Antibiotic comprises that cephalosporin is 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, cephalosporin 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 chronic abscess is example, because the barrier action of inflammatory reaction around it, the antibacterials of using through conventional approach (oral or intramuscular injection or drop) are difficult to infiltrate into intralesional.Drug level in the pus is very low, does not have sterilization or bacteriostasis, causes that on the contrary fastbacteria produces.Under iconography technology such as ultrasound wave and/or CT help, place or inject slow releasing pharmaceutical and not only medicine can be injected more exactly intralesional through the skin puncture, also can medicine be confined in the kitchen range a couple of days by tens of days, thereby directly effectively kill the antibacterial in the kitchen range by release mechanism; In addition, because the medicine that discharges, can impel the discharge that comes off of the sphacelus of focus to the corrosion function in kitchen range week; 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 kitchen range wall.So the medicine that not only helps in the blood enters focus, also helps the hypertrophy of granulation tissue and the purification of local kitchen range.Same case includes but not limited to chronic osteomyelitis, deep abscess, peritoneal abscess, arthritis, abscess of pleural cavity etc.
In addition, existing cephalosporin is of a great variety, is not that all cephalosporins all can be made into slow releasing preparation, and different cephalosporins 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-cephalosporin 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 the cephalosporin slow 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 1-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-25%
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 range of viscosities IV (dl/g) is 0.1～0.8, be selected from poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), 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), PPDO (PDO), PTMC (PTMC), 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 cephalosporin of the present invention is selected from cephalosporin or its salt or ester, as, but be not limited to 6315-S, Latamoxef Sodium, Flumarin, cefalexin, cefalexin fluorenes methyl ester, cefprozil, Cefpodoxime Proxetil, cefuroxime, Cefuroxime Sodium, cefmenoxime, cefaclor, cefradine, cefclidin, cefixime, cefixime sodium, cefathiamidine, cefmetazole, Cefminox sodium, cefonicid sodium, cefoperazone sodium, cefpiramide, cefpiramide sodium, cefadroxil, ceftriaxone sodium, cefalotin, cephalothin sodium (pioneer I), cefaloridine (pioneer II), ceftiofur, Ceftiofur sodium, ceftiofur hydrochloride, cefotaxime sodium, ceftazidime, cefotetan, Cefotetan Disodium, cefoxitin sodium, cefotiam, cefotiam hexetil, ceftizoxime, ceftizoxime sodium, cefazolin, Cefazolin sodium, cefroxadine, T-1982, loracarbefabid, cefepime, cefepime hydrochloride, Cefpodoxime Proxetil, ceftibuten, FK-482, Cefodizime, cefaloglycin, cephalo Luo Qi, cefamandole, cefamandole nafate, cefpirome, Cefpirome Sulfate, Ro-15-8075, cefteram pivoxil, cefditoren, cefoxitin sodium, cefacetrile, cefuzonam, vinyl pyrrolidine cephalosporins, the position replaces between 7-[() phenylglycine] 1-carbon generation-1-desulfuration cephalosporin, sodium fusidate, lincomycin hydrochloride, avocin.
The available cephalosporin 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.
Above-mentioned antibacterials shared ratio in slow releasing agent is decided because of concrete condition, can be 1%-60%, is good with 2%-50%, and 5%-40% is best.
Antibacterials and in slow releasing agent shared percentage by weight be preferably:
(1) flomoxef of 2-50%, latamoxef, Flumarin, cefalexin, cefprozil, cefuroxime, cefmenoxime, cefaclor, cefradine, cefixime, cefathiamidine, cefmetazole, cefminox;
(2) cefonicid of 2-50%, cefoperazone, cefpiramide, cefadroxil, ceftriaxone, cefalotin, cefaloridine, cefotaxime, ceftazidime, cefotetan, cefoxitin, cefotiam;
(3) ceftizoxime of 2-50%, cefazolin, cefroxadine, cefbuperazone, loracarbefabid, cefepime, ceftibuten, FK-482, Cefodizime, cefaloglycin, cephalo Luo Qi; Or
(4) cefamandole of 2-50%, cefpirome, cefetamet, cefditoren, cefacetrile, cefuzonam, fusidic acid.
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:
Antibiotic effective ingredient 2-50%
Slow-release auxiliary material 50-98%
Suspending agent 0.0-30%
Slow-release auxiliary material is selected from poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and albumin glue 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%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
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.
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.
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.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.
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 hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the 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, granule, 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:
Antibiotic effective ingredient 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) flomoxef of 2-50%, latamoxef, Flumarin, cefalexin, cefprozil, cefuroxime, cefmenoxime, cefaclor, cefradine, cefixime, cefathiamidine, cefmetazole, cefminox;
(2) cefonicid of 2-50%, cefoperazone, cefpiramide, cefadroxil, ceftriaxone, cefalotin, cefaloridine, cefotaxime, ceftazidime, cefotetan, cefoxitin, cefotiam;
(3) ceftizoxime of 2-50%, cefazolin, cefroxadine, cefbuperazone, loracarbefabid, cefepime, ceftibuten, FK-482, Cefodizime, cefaloglycin, cephalo Luo Qi; Or
(4) cefamandole of 2-50%, cefpirome, cefetamet, cefditoren, cefacetrile, cefuzonam, fusidic acid.
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%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
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 of various bacterium, preferred pathogenic bacterium are gram-positive bacterium, as staphylococcus class and hammer mushroom etc.; Gram negative bacteria is as the eisseria class; Filament shape antibacterial comprises defence line mushroom and strepto-mushroom; Bacillus comprises shaft-like mushroom, citron Bacillus, Enterobacter, rod-like stem mushroom and clostridium class, Escherichia class, Shigella class, Yersinia class, Salmonella class, Klebsiella class, aquatic Pseudomonas class, haemophilus class, pasteurella class, Rhodopseudomonas class, cloth Pu Shi Bacillus class, Agrobacterium class, Bordetella class and Streptobacillus class; Spirillum class, campylobacter class, vibrio class; Comprise Dermacentroxenus class and chlamydiaceae class with intracellular antibacterial.Highly preferred pathogenic bacterium are the staphylococcus aureus and the staphylococcus saprophyticus of staphylococcus; The streptococcus pyogenes of Streptococcus, streptococcus agalactiae and streptococcus pneumoniae; Peptostreptococcus; Bacillus pyocyaneus; The escherichia coli of Enterobacter; Anthrax bud robe bacillus, corynebacterium diphtheriae, aerogenesis cottonrose hibiscus film clostridium, bacillus botulinus, clostridium tetani, Diplococcus gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, invade the lung legionella, colon bacillus, Yersinia pestis, hemophilus influenza, helicobacter pylori, embryo's Campylobacter, vibrio cholera, vibrio parahaemolytious, Treponoma palladium, actinomyces israelii, Rickettsia prowazekii, Rickettsia rickettsii, the sand holes chlamydia, chlamydia psittaci, Bacillus abortus, Agrobacterium tumefaciens, mucositis mora bacterium, propionibacterium acnes, Proteus (proteus mirabilis, proteus vulgaris), morgan's bacillus belongs to, the Providian Bordetella, Bacteroides, tubercule bacillus, the infection that causes.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 formed different differently because of medicine, does not wait but a kind of medicine total amount can be 1% to 200% of conventional route day dosage, or 1-1000mg/kg, can be once or for several times.Conventional route day as cefalexin is adult's 1～2g/ day, to divide and take for 3～4 times to dosage; Children's 25～50mg/kg divides and takes for 3～4 times; Cefalotin intramuscular, intravenous injection or intravenous drip, adult's 2g～6g/ day, 2～4 times/day.Child 50mg～100mg/kg every day, 2～4 times/day.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 (cefalexin) compares
With the rat is subjects, will accept equivalent cefalexin (20 milligrams) through following different modes respectively after its grouping: group 1, the common cefalexin injection of lumbar injection; Group 2, the common cefalexin injection of hypochondrium subcutaneous injection; Group 3, hypochondrium subcutaneous injection cefalexin slow releasing injection; Group 4, hypochondrium subcutaneous placement cefalexin 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.
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 cefalotin.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 cefalotin slow releasing injection and placement cefalotin 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 cefalotin injection of lumbar injection (i.p.) group, dead in 60% animal 20 days; In the common cefalotin injection of local injection group, dead in 30% 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, cefalotin is through the bacteriostasis difference of different approaches administration, is (P＜0.01), the wherein better effects if of local injection cefalotin slow releasing injection and local placement head spore thiophene sustained-release implant well with the effect of topical application.This discovery constitutes key character of the present invention.Following correlation test has further confirmed this point.
The vivo bacteria corrosion action of test 3, medicine 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 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, compare with whole body administration group with matched group, the sustained-release implant of fluorine-containing oxygen cephalo, latamoxef, Flumarin, cefalexin, cefprozil, cefuroxime, cefmenoxime, cefaclor, cefradine, cefixime, cefathiamidine, cefmetazole or cefminox all has better therapeutic effect (P＜0.01).
Used 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) in this experiment.Measuring the residual in vivo result of antibiotics shows: the about 15, the 3rd day the about 40%, the 5th day 80-90% of release in the 1st day.
The vivo bacteria corrosion action of test 4, medicine relatively
With the rat is subjects, with 2 * 10
5Individual bacterium 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, compare with whole body administration group with matched group, the slow releasing injection that contains cefonicid, cefoperazone, cefpiramide, cefadroxil, ceftriaxone, cefalotin, cefaloridine, cefotaxime, ceftazidime, cefotetan, cefoxitin or cefotiam 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).In the presentation of results polifeprosan to the speed of the scale effect drug release of carboxy phenyl propane and certain herbaceous plants with big flowers diacid.
Same result also sees ceftizoxime, cefazolin, cefroxadine, cefbuperazone, loracarbefabid, cefepime, ceftibuten, FK-482, Cefodizime, cefaloglycin or cephalo Luo Qi.
The vivo bacteria corrosion action of the cefpirome 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 cefpirome 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 68% (MW:5000), 76% (MW:15000), 84% (MW:25000), 90% (MW:40000) and 94% (MW:60000), and the P value is all less than 0.01.
It is cefamandole, cefetamet, cefditoren, cefacetrile, cefuzonam or the fusidic acid slow releasing agent that adjuvant is made that same result also sees with polylactic acid.
The vivo bacteria corrosion action of the amoxycillin antibiotics 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 amoxycillin antibiotics sustained-release implant treatment by polylactic acid (PLA, molecular weight peak value the are 20000) 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 68% (MW:5000), 76% (MW:15000), 84% (MW:25000), 90% (MW:40000) and 94% (MW:60000), and the P value is all less than 0.01.
The bacteriostatic rate is 70-96% (P＜0.01).
The vivo bacteria corrosion action of the carbenicillin sodium 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 carbenicillin sodium 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, compares with whole body administration group, and the bacteriostatic rate is 80-100% (P＜0.01).Same effect also sees sodium nafcillin, antibiotics sodium (potassium), carboxylic benzyl antibiotics, carbenicillin sodium, ammonia benzyl antibiotics, ammonia benzyl antibiotics trihydrate, amoxycillin antibiotics, amoxycillin antibiotics trihydrate, Piperacillin-tazobactam mixt., talampicillin, ticarcillin sodium, Lengmpicillin Hydrochloride, Primaxin, epicillin, Carindaillin Sodium, methoxy benzene antibiotics, ethoxy Cai antibiotics, benzyl star antibiotics 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.
Discover that further optimum slow-release auxiliary material is a poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, 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.In existing numerous cephalosporin, be not that all cephalosporins all can be made into slow releasing preparation, different cephalosporins must be selected suitable slow-release auxiliary material when making slow releasing preparation.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 flomoxef, 10mg cefalotin, 20mg cefazolin respectively, shake up the back contains 10% flomoxef, 10% cefalotin and 20% with spray drying method for preparation cefazolin 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 350cp-550cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 7-14 days, is about 15-25 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) flomoxef of 2-50%, latamoxef, Flumarin, cefalexin, cefprozil, cefuroxime, cefmenoxime, cefaclor, cefradine, cefixime, cefathiamidine, cefmetazole or cefminox;
(2) cefonicid of 2-50%, cefoperazone, cefpiramide, cefadroxil, ceftriaxone, cefalotin, cefaloridine, cefotaxime, ceftazidime, cefotetan, cefoxitin or cefotiam;
(3) ceftizoxime of 2-50%, cefazolin, cefroxadine, cefbuperazone, loracarbefabid, cefepime, ceftibuten, FK-482, Cefodizime, cefaloglycin or cephalo Luo Qi; Or
(4) cefamandole of 2-50%, cefpirome, cefetamet, cefditoren, cefacetrile, cefuzonam or fusidic acid.
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, in three containers, add 30mg cefalexin, 30mg cefaclor, 30mg cefuroxime respectively, shake up the back contains 30% cefalexin, 30% cefaclor, 30% cefuroxime with spray drying method for preparation injectable microsphere again.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 500cp-650cp (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: the flomoxef of 2-50%, latamoxef, Flumarin, cefalexin, cefprozil, cefuroxime, cefmenoxime, cefaclor, cefradine, cefixime, cefathiamidine, cefmetazole or cefminox.
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 cefalotin and 10 milligrams of cefotaximes, shake up the back contains 20% cefalotin and 10% cefotaxime 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 5-12 days, is about 14-22 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 cefonicid of 2-50%, cefoperazone, cefpiramide, cefadroxil, ceftriaxone, cefalotin, cefaloridine, cefotaxime, ceftazidime, cefotetan, cefoxitin or cefotiam.
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 30: 70) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 30mg cefazolin or 30mg cephalo Luo Qi, shake up the back contains 30% cefazolin or 30% cephalo Luo Qi 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 ceftizoxime of 2-50%, cefazolin, cefroxadine, cefbuperazone, loracarbefabid, cefepime, ceftibuten, FK-482, Cefodizime, cefaloglycin or cephalo Luo Qi.
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 cefpirome and 15mg cefditoren, shake up the back again and contain 15% cefpirome and 15% cefditoren 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 cefamandole of 2-50%, cefpirome, cefetamet, cefditoren, cefacetrile, cefuzonam or fusidic acid.
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 40: 60) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the 30mg cefalexin, shake up the back contains 30% cefalexin 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 7-15 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 flomoxef of 10-30%, latamoxef, Flumarin, cefalexin, cefprozil, cefuroxime, cefmenoxime, cefaclor, cefradine, cefixime, cefathiamidine, cefmetazole or cefminox.
Embodiment 13
With 85mg molecular weight peak value is that 15000 polylactic acid (PLGA, 25: 75) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds the 15mg cefalotin, shakes up the back contains 15% cefalotin 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) 20% flomoxef, latamoxef, Flumarin, cefalexin, cefprozil, cefuroxime, cefmenoxime, cefaclor, cefradine, cefixime, cefathiamidine, cefmetazole or cefminox;
(2) 20% cefonicid, cefoperazone, cefpiramide, cefadroxil, ceftriaxone, cefalotin, cefaloridine, cefotaxime, ceftazidime, cefotetan, cefoxitin or cefotiam;
(3) 20% ceftizoxime, cefazolin, cefroxadine, cefbuperazone, loracarbefabid, cefepime, ceftibuten, FK-482, Cefodizime, cefaloglycin or cephalo Luo Qi; Or
(4) 20% cefamandole, cefpirome, cefetamet, cefditoren, cefacetrile, cefuzonam or fusidic acid.
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) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin glue;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.。
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 (10)
1. a slow releasing injection and application thereof that contains cephalosporin is characterized in that this slow releasing injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Cp-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-25%
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 one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of sodium carboxymethyl cellulose, hydroxy methocel, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
2. the slow releasing injection according to claim 1, the whole body that it is characterized in that this slow releasing injection is used for effectively obtaining and reduce 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.
3. the slow releasing injection according to claim 1 is characterized in that the cephalosporin selection is from flomoxef, latamoxef, Flumarin, cefalexin, cefprozil, cefuroxime, cefmenoxime, cefaclor, cefradine, cefixime, cefathiamidine, cefmetazole, cefminox, cefonicid, cefoperazone, cefpiramide, cefadroxil, ceftriaxone, cefalotin, cefaloridine, cefotaxime, ceftazidime, cefotetan, cefoxitin, cefotiam, ceftizoxime, cefazolin, cefroxadine, cefbuperazone, loracarbefabid, cefepime, ceftibuten, FK-482, Cefodizime, cefaloglycin, cephalo Luo Qi, cefamandole, cefpirome, cefetamet, cefditoren, cefacetrile, cefuzonam or fusidic acid and salt thereof or ester.
4. the slow releasing injection according to claim 1 is characterized in that in the slow-release auxiliary material:
A) the molecular weight peak value of polylactic acid is selected from 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000;
B) in the copolymer of polyglycolic acid and hydroxyacetic acid, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, and the molecular weight peak value is 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000;
C) in the polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
5. the slow releasing injection according to claim 1 is characterized in that used suspending agent is respectively one of following:
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.
6. the medicament slow release 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.
7. the antimicrobial sustained-release implant according to claim 6, the percentage by weight that it is characterized in that antibiotic effective ingredient in the antimicrobial sustained-release implant is 2-50%.
8. the antimicrobial sustained-release implant according to claim 6 is characterized in that slow-release auxiliary material is selected from poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination.
9. described according to Claim 8 described antimicrobial sustained-release implant is characterized in that in the slow-release auxiliary material:
(1) the molecular weight peak value of polylactic acid is selected from 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000;
(2) in the copolymer of polyglycolic acid and hydroxyacetic acid, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, and the molecular weight peak value is 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000;
(3) in the polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
10. be staphylococcus, Streptococcus, Peptostreptococcus, propionibacterium acnes, escherichia coli, citron Bacillus, Enterobacter, Serratia, Proteus, morgan's bacillus genus, Providian Bordetella, hemophilus influenza, Bacteroides, tubercule bacillus, gonococcus or meningococcus according to claim 2 and 6 described sensitive bacterials; Described acute and chronic infection is a folliculitis, furuncle, carbuncle, the infectiousness impetigo, erysipelas, cellulitis, lymphangitis, the lymph duct ligation, 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, the infection that bronchiectasis merges, 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, chronic osteomyelitis, the serious symptom decubital ulcer, intractable cutaneous ulcer, diabetic foot, femur head necrosis and old prostatitis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006102004888A CN1843360A (en) | 2006-05-24 | 2006-05-24 | Slow release injection containing cefradine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006102004888A CN1843360A (en) | 2006-05-24 | 2006-05-24 | Slow release injection containing cefradine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1843360A true CN1843360A (en) | 2006-10-11 |
Family
ID=37062346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006102004888A Pending CN1843360A (en) | 2006-05-24 | 2006-05-24 | Slow release injection containing cefradine |
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| Country | Link |
|---|---|
| CN (1) | CN1843360A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101810584A (en) * | 2010-04-12 | 2010-08-25 | 海南美大制药有限公司 | Microsphere injection of medicinal composition of cefotiam hydrochloride and anhydrous sodium carbonate |
| CN101822644A (en) * | 2010-04-12 | 2010-09-08 | 陶灵刚 | Micro-balloon injection for pharmaceutical composition of cefmenoxime hydrochloride / anhydrous sodium carbonate |
| CN105663058A (en) * | 2016-02-01 | 2016-06-15 | 济南康和医药科技有限公司 | Cefditoren pivoxil nanoparticle pharmaceutical preparation and preparation method |
| CN106581005A (en) * | 2016-12-17 | 2017-04-26 | 郑州郑先医药科技有限公司 | Western medicinal composition for treating amygdalitis |
| CN109010297A (en) * | 2018-10-25 | 2018-12-18 | 苏州东瑞制药有限公司 | A kind of cefprozil tablet and preparation method thereof |
| CN109053768A (en) * | 2018-08-07 | 2018-12-21 | 中国医药集团总公司四川抗菌素工业研究所 | A kind of preparation method of unformed cefditoren |
| CN112274644A (en) * | 2020-10-28 | 2021-01-29 | 陕西秦岭七药协同创新中心有限公司 | Medicine for treating spinal and osteoarthropathy and relieving pain thereof |
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2006
- 2006-05-24 CN CNA2006102004888A patent/CN1843360A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101810584A (en) * | 2010-04-12 | 2010-08-25 | 海南美大制药有限公司 | Microsphere injection of medicinal composition of cefotiam hydrochloride and anhydrous sodium carbonate |
| CN101822644A (en) * | 2010-04-12 | 2010-09-08 | 陶灵刚 | Micro-balloon injection for pharmaceutical composition of cefmenoxime hydrochloride / anhydrous sodium carbonate |
| CN101810584B (en) * | 2010-04-12 | 2012-05-09 | 海南美大制药有限公司 | Microsphere injection of medicinal composition of cefotiam hydrochloride and anhydrous sodium carbonate |
| CN105663058A (en) * | 2016-02-01 | 2016-06-15 | 济南康和医药科技有限公司 | Cefditoren pivoxil nanoparticle pharmaceutical preparation and preparation method |
| CN106581005A (en) * | 2016-12-17 | 2017-04-26 | 郑州郑先医药科技有限公司 | Western medicinal composition for treating amygdalitis |
| CN109053768A (en) * | 2018-08-07 | 2018-12-21 | 中国医药集团总公司四川抗菌素工业研究所 | A kind of preparation method of unformed cefditoren |
| CN109010297A (en) * | 2018-10-25 | 2018-12-18 | 苏州东瑞制药有限公司 | A kind of cefprozil tablet and preparation method thereof |
| CN112274644A (en) * | 2020-10-28 | 2021-01-29 | 陕西秦岭七药协同创新中心有限公司 | Medicine for treating spinal and osteoarthropathy and relieving pain thereof |
| CN112274644B (en) * | 2020-10-28 | 2021-12-07 | 陕西秦岭七药协同创新中心有限公司 | Medicine for treating spinal and osteoarthropathy and relieving pain thereof |
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