CN100551376C - A kind of antibiotic slow releasing preparation of topical application - Google Patents
A kind of antibiotic slow releasing preparation of topical application Download PDFInfo
- Publication number
- CN100551376C CN100551376C CNB2006102004750A CN200610200475A CN100551376C CN 100551376 C CN100551376 C CN 100551376C CN B2006102004750 A CNB2006102004750 A CN B2006102004750A CN 200610200475 A CN200610200475 A CN 200610200475A CN 100551376 C CN100551376 C CN 100551376C
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- acid
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Landscapes
- Medicinal Preparation (AREA)
Abstract
A kind of antibiotic slow releasing preparation of topical application is slow releasing injection or sustained-release implant, injection is made up of sustained-release micro-spheres and solvent, sustained-release micro-spheres contains slow-release auxiliary material and is selected from beta-lactamase inhibitor or tetracycline antibiotics, solvent is the special solvent that contains suspending agents such as sodium carboxymethyl cellulose, and viscosity is 100cp-3000cp (20 ℃-30 ℃ time); Slow-release auxiliary material is selected from EVAc, polifeprosan, PLA, PLGA, decanedioic acid copolymer, albumin glue, gelatin etc.; Sustained-release implant prepares by sustained-release micro-spheres or through methods such as fusions.This agent is placed in the part or injection can about 10 days, obviously reduce its general toxicity in the slow release of affected area with medicine when effectively obtaining and keeping local kitchen range active drug concentration.The therapeutic effect that the infection, particularly local lesion that staphylococcus, Streptococcus, propionibacterium acnes, tubercule bacillus, gonococcus or meningococcus etc. are caused such as chronic osteomyelitis, serious symptom decubital ulcer, diabetic foot, femur head necrosis and various abscess etc. have remarkable uniqueness.
Description
(I) technical field
The invention relates to a sustained-release preparation of locally applied antibiotics, belonging to the technical field of medicines. Specifically, the invention provides a slow release injection and a slow release implant containing tetracycline antibiotics or beta-lactamase inhibitors. The sustained release preparation is mainly applied locally, and can obtain and maintain effective drug concentration locally in bacterial infection.
(II) background of the invention
With the advent of antibiotics, bacterial infection became a treatable disease. However, the treatment is not standard, the treatment time is long, and a patient forgets to take the medicine quantitatively in time, so that the drug resistance is generated. Many of the bacterial infections cured by the method repeatedly attack to become chronic lesions. The treatment of drug-resistant patients or recurrent chronic lesions leads, on the one hand, to a prolonged period of treatment and, on the other hand, to the development and use or combined use of a plurality of potent antibiotics, with the result that the costs are high, new drug-resistant strains are continuously cultivated and the effective dose is continuously increased, thus forming a vicious circle. Therefore, research and development of new effective agents or methods for treating drug-resistant strains and chronic persistent infections have become an urgent problem worldwide.
At present, a plurality of new antibacterial drugs have shown good curative effect, but for many chronic lesions, especially for local lesions, the effective bactericidal concentration is difficult to obtain by the conventional therapy administration. There are many side effects caused by increasing dosage or taking the medicine for a long time.
Disclosure of the invention
Aiming at the defects of the prior art, the invention provides a slow release agent containing tetracycline antibiotics or beta-lactamase inhibitors. In particular to a slow release injection and a slow release implant containing antibiotics, which belong to the antibiotic slow release preparation for local application.
The antibacterial drug is mainly an oral preparation, and the effective drug concentration can not be obtained at the focus part. Even a general injection is not ideal enough. Due to the factors of insufficient dosage, single administration, irregular administration and the like, the traditional Chinese medicine composition can not reach effective blood concentration and can not thoroughly kill bacteria, and can induce drug-resistant bacteria to survive or promote bacterial variation. Increasing the dose alone can be limited by systemic toxic effects. The above disadvantages are particularly manifested in the treatment of local infections, including various chronic inflammations and pyogenic infections.
The invention discovers that the tetracycline antibiotics or beta-lactamase inhibitors are prepared into sustained-release agents (mainly sustained-release injection and sustained-release implant) for local placement or injection, so that the local drug concentration can be greatly improved, the concentration of the drugs in a circulatory system can be reduced, the toxicity of the drugs to normal tissues can be reduced, the drug application can be greatly facilitated, the treatment course can be reduced, the treatment time can be shortened, the complications of the drugs can be reduced, the cost of patients can be reduced, the single drug dosage can be reduced, the treatment effect can be enhanced, and the drug tolerance can be reduced. Has obvious and unique treatment effect on drug-resistant bacteria, particularly on local focus or chronic infection caused by combined bacterial infection, and effectively overcomes the limitation of systemic medication.
In the case of the tubercular cavity, the antibacterial agent applied by the conventional route (oral or intramuscular injection or drip) hardly penetrates into the cavity due to the barrier effect of the wall of the tubercular cavity and the rarity, hardening, even closing of the blood vessels around the cavity wall. The drug concentration in the cavity is very low, so that the drug does not play a role in sterilization or bacteriostasis, but causes drug-resistant bacteria to be generated. The slow-release medicine is placed or injected through skin puncture under the assistance of imaging technologies such as ultrasonic waves and/or CT (computed tomography) and the like, so that the medicine can be accurately injected into the cavity, and can be limited in the cavity wall for tens of days through a slow-release mechanism, and therefore bacteria in the cavity wall can be directly and effectively killed; in addition, the released medicine can erode the cavity wall, so that the softening of a cheese lesion and the falling and discharging of necrotic substances can be promoted; local lesions can also be cleared during local procedures by means of a puncture needle or corresponding instrument (such as, but not limited to, bronchoscope, cystoscope, laparoscope, arthroscope, etc.). Moreover, repeated local punctures can also weaken the barrier function of the cavity wall. Therefore, the medicine in the blood can enter the focus, and the proliferation of granulation tissue and the purification of cavities are facilitated. The same cases include, but are not limited to, chronic osteomyelitis, deep abscess, celiac abscess, arthritis, and the like.
In addition, the existing antibiotics are various in types, not all the antibiotics can be prepared into sustained-release preparations, and different antibiotics must be prepared into sustained-release preparations by selecting proper sustained-release auxiliary materials. Therefore, based on the above unexpected findings, the present invention successfully screens out effective antibacterial ingredients suitable for sustained release from hundreds of antibacterial drugs through subsequent extensive studies, and successfully screens out sustained release ingredients suitable for sustained release of antibiotics from hundreds of sustained release excipients. Finally, effective combinations are screened out through in vivo and in vitro release measurement. Thus constituting the main subject of the present invention.
One form of the drug sustained release preparation is sustained release injection, which consists of sustained release microspheres and a solvent. Specifically, the sustained-release injection consists of the following components:
(a) the sustained-release particles comprise the following components in percentage by weight:
1-70% of antibacterial active ingredient
Sustained release auxiliary materials 30-99%
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(b) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the viscosity range IV (dl/g) of the sustained-release auxiliary material is 0.1-0.8, and the sustained-release auxiliary material is selected from racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycollic acid copolymer (D, L-PLGA), monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), polyethylene glycol/polylactic acid (PLA-PEG-PLA), polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), carboxyl-terminated polylactic acid (PLA-COOH), carboxyl-terminated polylactic acid/glycollic acid copolymer (PLGA-COOH), polifeprosan, difatty fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], poly (FA-sebacic acid) ], and the like, Ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), Polydioxanone (PDO), polytrimethylene carbonate (PTMC), sodium carboxymethylcellulose, hydroxymethylcellulose, xylitol, oligosaccharides, chondroitin, chitin, hyaluronic acid, collagen, gelatin, protein glue or a combination thereof; the suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
The antibacterial active ingredients of the invention can be selected from tetracycline antibiotics and beta-lactamase inhibitors. A tetracycline antibiotic selected from one of demeclocycline, methacycline hydrochloride, doxycycline, tetracycline hydrochloride, doxycycline, guanmecycline, lysitetracycline, hydropyracycline, minocycline hydrochloride, demeclocycline, minocycline, oxytetracycline hydrochloride, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, or a combination thereof. Wherein preferably mecycline, methacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysitetracycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin salts or esters; a beta-lactamase inhibitor: sulbactam, sultamicin tosylate, clavulanate potassium (clavulanate potassium), ticarcillin, clavulanic acid, sulbactam sodium, telavastin, and Terminalia minactins for injection or a combination thereof. Wherein, sulbactam, sultamicin, potassium clavulanate (potassium clavulanate), ticarcillin, clavulanic acid, sulbactam sodium, tazobactam, timentin and salt or ester thereof are preferred.
The antibiotic useful in the present invention is also selected from the group consisting of salts and esters of the above drugs, such as, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, thiopamoic acid, phosphoric acid, azathionic acid, sulfinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, maleic acid, azoodic acid, alkanoic acids, fluorenylmethyl ester, pivaloyl ester, ester salts, and the like. Salts tend to be more soluble in the aqueous or other protic solvents of the corresponding free base form. Non-toxic pharmaceutically acceptable base addition salts include salts with bases such as sodium, potassium, calcium, amines, and the like. Those skilled in the art are aware of many non-toxic pharmaceutically acceptable addition salts.
The active ingredients of the drug sustained release preparation are the combination of any one or more than one drug and any one or two drugs in other any classes.
The proportion of the antibacterial agent in the sustained-release agent is determined by specific conditions, and can be 1-70%, preferably 2-50%, and most preferably 5-40%.
The weight percentages of the effective components and the sustained-release auxiliary materials in the antibacterial sustained-release microspheres are preferably as follows:
2 to 50 percent of antibacterial drug
Sustained release auxiliary materials 50-98%
0.0 to 30 percent of suspending agent
The slow release auxiliary material is preferably selected from one or the combination of polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dipolymer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene-vinyl acetate copolymer, polylactic acid, copolymer of polyglycolic acid and glycolic acid, sodium carboxymethyl cellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue.
The sustained-release injection and the weight percentage thereof are most preferably as follows:
(1) 2-50% demeclocycline, methacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, or nystatin, or
(2) 2-50% sulbactam, sultamicin, clavulanate potassium (clavulanate potassium), ticarcillin, clavulanic acid, sulbactam sodium, telavan or timentin.
The most preferable sustained-release auxiliary materials in the sustained-release microspheres and the weight percentage thereof are as follows:
(1) 55-90% PLA;
(2) 50-90% PLGA;
(3) 50-85% of polifeprosan;
(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;
(5) 55-90% EVAc;
(6) 40-95% of sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue; or
(7) Racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.
The sustained-release microspheres and a solvent containing sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, a surface active substance, Tween 20, Tween 40 or Tween 80 suspending agent are prepared into the sustained-release injection. The concentration of sodium carboxymethylcellulose in the solvent may be 0.1-5%, but is preferably 0.5-3%, and most preferably 1-2%.
Among the various polymers, preferred are polylactic acid, sebacic acid, and a mixture or copolymer of polylactic acid and sebacic acid, and the mixture or copolymer can be selected from, but not limited to, PLA, PLGA, a mixture of glycolic acid and hydroxycarboxylic acid, and a mixture or copolymer of sebacic acid and an aromatic polyanhydride or an aliphatic polyanhydride. The blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), di-fatty acid-sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid-sebacic acid) [ P (FA-SA) ], and the like. The content of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization is 10-60 wt% and 20-90 wt%, respectively, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
The molecular weight peak of polylactic acid may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and most preferably 5,000-30,000; the molecular weight of polyglycolic acid may be, but is not limited to, 5000-; the polyhydroxy acids can be selected singly or in multiple ways. When selected alone, polylactic acid (PLA) or a copolymer of hydroxycarboxylic acid and glycolic acid (PLGA) is preferred, and the molecular weight of the copolymer may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and is most preferably 30,000-50,000; when more than one choice is selected, the polymer or the composite polymer or copolymer of different polymers is preferred, and the composite polymer or copolymer of polylactic acid or sebacic acid with different molecular weight is most preferred, such as, but not limited to, polylactic acid with molecular weight of 1000 to 30000 mixed with polylactic acid with molecular weight of 20000 to 50000, polylactic acid with molecular weight of 10000 to 30000 mixed with PLGA with molecular weight of 30000 to 80000, polylactic acid with molecular weight of 20000 to 30000 mixed with sebacic acid, PLGA with molecular weight of 30000 to 80000 mixed with sebacic acid. The polylactic acid used is preferably L-polylactic acid (L-PLA). The viscosity range IV (dl/g) of the L-polylactic acid (L-PLA) is 0.2-0.8, the glass transition temperature range is 55-65 ℃, and the melting point is 175-185 ℃.
In addition to the above-mentioned adjuvants, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176 and 4789724 and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luoming and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.
In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. The sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.
In the slow release injection, the drug slow release system can be prepared into microspheres, submicron spheres, micro emulsion, nanospheres, granules or spherical pellets, and then the injection is prepared after the drug slow release system is mixed with an injection solvent. The suspension type sustained-release injection is preferably selected from various sustained-release injections, the suspension type sustained-release injection is a preparation obtained by suspending a drug sustained-release system containing an antibacterial component in an injection, the used auxiliary materials are one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvents are, but not limited to, distilled water, water for injection, physiological saline, absolute ethanol or buffers formulated with various salts. The suspending agent is intended to effectively suspend the microspheres containing the drug, thereby facilitating injection.
The suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
The content of the suspending agent in the common solvent depends on the characteristics of the suspending agent, and can be 0.1-30% according to the specific situation. Preferably, the suspending agent consists of:
A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80; or
B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or (b).
C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
The method of preparation of the sustained release injection is arbitrary and can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray drying to prepare microspheres, dissolving in combination with freezing (drying) and pulverizing to form fine powders, liposome-encapsulating, and emulsifying. Among them, a dissolving method (i.e., solvent evaporation method), a drying method, a spray drying method and an emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections, and the method is arbitrary. The microspheres used may have a particle size in the range of 5-400um, preferably 10-300um, most preferably 20-200 um.
The microspheres can also be used for preparing other sustained-release injections, such as gel injections, gel sustained-release injections and block copolymer micelle injections. The block copolymer micelle is formed by a hydrophobic-hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. Of these, polyethylene glycol (PEG) having a molecular weight of 1000-15000 is preferable as the hydrophilic block of the micelle copolymer, and biodegradable polymers such as PLA, polylactide, polycaprolactone and copolymers thereof (molecular weight 1500-25000) are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be locally injected. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly. The method for preparing the gel injection is arbitrary, but the polymer material used is preferably a polylactic acid-containing hydrogel, such as, but not limited to, racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycolic acid copolymer (D, L-PLGA), monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), polyethylene glycol/polylactic acid (PLA-PEG-PLA), polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), carboxyl-terminated polylactic acid (PLA-COOH), carboxyl-terminated polylactic acid/glycolic acid copolymer (PLGA-COOH), etc. Wherein the viscosity IV (DL/g) of the racemic polylactic acid DL-PLA is 0.5-8, and the glass transition temperature is 50-60 ℃; the ratio of DL-LA to GA in the racemic polylactic acid/glycolic acid copolymer is 90/10, 80/20, 75/25, 60/40 and 50/50, the glass transition temperature range is 40-60 ℃, and the viscosity range IV (DL/g) is 0.15-2.0; the viscosity range IV (dl/g) of the monomethyl polyethylene glycol/polylactic acid and the monomethyl polyethylene glycol/polylactic acid/glycollic acid copolymer is 0.1-0.4; the viscosity range IV (dl/g) of the monomethyl polyethylene glycol/polylactic acid (MPEG-PLA) and the monomethyl polyethylene glycol/polylactic acid copolymer is 0.1-0.5; the viscosity range IV (dl/g) of the polyethylene glycol/polylactic acid and the polyethylene glycol/polylactic acid copolymer is 0.1-0.5; the viscosity IV (dl/g) of the carboxyl-terminated polylactic acid is 0.5-8, and the glass transition temperature is 50-65 ℃; the viscosity range IV (dl/g) of the carboxyl-terminated polylactic acid/glycollic acid copolymer is 0.1-1.0, and the glass transition temperature range is 45-55 ℃.
The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).
The preparation of injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.
The sustained-release microspheres can also be used for preparing sustained-release implants, the used pharmaceutical excipients can be any one or more of the above pharmaceutical excipients, but water-soluble high molecular polymers are taken as the main choice, and in various high molecular polymers, polylactic acid, sebacic acid, a mixture or copolymer of high molecular polymers containing polylactic acid or sebacic acid are taken as the first choice, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, a mixture of PLA and PLGA, and a mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride. The blending ratio of polylactic acid (PLA) to polyglycolic acid is 10/90 to 90/10 (by weight), preferably 25/75 to 75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and lactic acid in copolymerization are respectively 10-90% and 90-10% by weight. The aromatic polyanhydride is represented by p-carboxyphenylpropane (p-CPP), the content of the p-carboxyphenylpropane (p-CPP) and sebacic acid in copolymerization is respectively 10-60% and 20-90% by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
Another form of the sustained-release agent of the present invention is a sustained-release implant. The effective components of the antibacterial implant can be uniformly packaged in the whole pharmaceutic adjuvant, and also can be packaged in the center of a carrier support or on the surface of the carrier support; the active principle can be released by direct diffusion and/or by degradation via polymers.
The slow release implant is characterized in that the slow release auxiliary material contains any one or more of the other auxiliary materials besides the high molecular polymer. The added pharmaceutic adjuvants are collectively called as additives. The additives can be classified into fillers, pore-forming agents, excipients, dispersants, isotonic agents, preservatives, retarding agents, solubilizers, absorption enhancers, film-forming agents, gelling agents, etc. according to their functions.
The main components of the sustained-release implant can be prepared into various dosage forms. Such as, but not limited to, capsules, sustained release formulations, implants, sustained release implants, and the like; in various shapes such as, but not limited to, granules, pills, tablets, powders, spheres, chunks, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred. The size of the volume depends on the location and size of the lesion. It can be in the form of rod of 0.1-5mm (thick) × 1-10mm (long), or in the form of sheet.
The optimal dosage form of the sustained-release implant is biocompatible, degradable and absorbable sustained-release implant, and can be prepared into various shapes and various dosage forms according to different clinical requirements. The packaging method and procedure for its main ingredients are described in detail in US patent (US5651986) and include several methods for preparing sustained release formulations: such as, but not limited to, (i) mixing a carrier support powder with a drug and then compressing into an implant, a so-called mixing process; (ii) melting the carrier support, mixing with the drug to be packaged, and then cooling the solid, the so-called melt process; (iii) dissolving the carrier support in a solvent, dissolving or dispersing the drug to be packaged in a polymer solution, and then evaporating the solvent and drying, the so-called dissolution method; (iv) spray drying; and (v) freeze-drying method.
The active ingredients and the weight percentage of the slow release implant are preferably as follows:
2 to 50 percent of antibacterial drug
Sustained release auxiliary materials 50-98%
0.0 to 30 percent of suspending agent
The weight percentage of the antibacterial effective component in the sustained-release implant is 1-50%, preferably 2-50%, and most preferably 5-40%.
The antibacterial active ingredients in the sustained-release implant are preferably:
(1) 2-50% demeclocycline, methacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, or nystatin, or
(2) 2-50% sulbactam, sultamicin, clavulanate potassium (clavulanate potassium), ticarcillin, clavulanic acid, sulbactam sodium, telavan or timentin.
The sustained-release auxiliary materials in the sustained-release implant and the weight percentage thereof are most preferably as follows:
(1) 55-90% PLA;
(2) 50-90% PLGA;
(3) 50-85% of polifeprosan;
(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;
(5) 55-90% EVAc; or
(6) 40-95% of sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue.
In addition, the selected adjuvants can be a combination of any one or more of the above.
The invention can be used for preparing pharmaceutical preparations for treating various bacterial infections of human and animals, and is mainly a sustained-release injection or a sustained-release implant. The prepared pharmaceutical preparation can be used for treating infection caused by staphylococcus, streptococcus, peptostreptococcus, catarrh moraxella, propionibacterium acnes, escherichia coli, citrobacter, klebsiella, enterobacter, serratia, proteus (proteus mirabilis, proteus vulgaris), morganella, providencia, haemophilus influenzae, bacteroides, mycobacterium tuberculosis, gonococcus or meningococcus. Infection caused by sensitive bacteria, such as, but not limited to, folliculitis, furuncle, carbuncle, infective impetigo, erysipelas, cellulitis, lymphangitis, suppurative paronychia, subcutaneous abscess, hidradenitis, infective atheroma, chronic abscess, intraperitoneal abscess, intrathoracic abscess, appendicitis, mastitis, mammary abscess, perianal abscess, secondary infection such as trauma or surgical wound, pharyngolaryngitis, laryngopharyngeal abscess, acute and chronic bronchitis, tonsillitis, peritonsillar abscess, bronchiectasis (when infected), secondary infection of chronic respiratory system disease, pneumonia, lung suppuration, otitis media, sinusitis, renal abscess, perianal abscess, pyelonephritis, cystitis, cholecystitis, hepatic abscess, adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, blepharitis, dacryocystitis, abscess, and abscess, Meibomitis, periodontitis, pericoronitis, maxitis, arthritis, joint abscess, osteomyelitis, tuberculosis abscess, and suppurative meningitis. The formulations of the invention may be used for the treatment of systemic infections, but treatment of local lesions is preferred. Common local lesions also include chronic lesions caused by or combined with chronic diseases such as: but are not limited to, chronic osteomyelitis, severe bedsores, refractory skin ulcers, diabetic foot, femoral head necrosis, and senile prostate diseases.
The route of administration depends on a variety of factors. To achieve an effective concentration at the site of the lesion, the drug may be administered by a variety of routes, such as oral, rectal, transmucosal, transdermal, or enteral administration; parenteral delivery includes intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intrapericardiac, intravenous, intraperitoneal, intranasal, intraocular injections, intracavitary (e.g., intra-articular, intraperitoneal, thoracic, and spinal), peri-or intralesional injections or placements, intranodal, and intramedullary. But is preferably locally injected (slow release injection) or placed (slow release implant) on the lesion. Can be injected or placed during or before surgery; can be used for interventional therapy via bronchofiberscope and other instruments, such as lung abscess treatment; or percutaneous puncture intralesional administration intervention treatment; injection or placement in joint cavities; can be applied simultaneously with or separately from systemic treatment, but preferably several days before and after topical application.
The dosage of a drug varies depending on the composition of the drug, but the total amount of one drug may vary from 10% to 200% of the daily dose of a conventional route. If the lesion is not completely cleared or improved, it is considered that the sustained-release preparation is placed or injected again after 10 to 20 days. In order to prevent bacterial dissemination in the focus, systemic administration should be properly matched before and after each local administration.
Other medicinal components such as, but not limited to, hormones, analgesic drugs, anticoagulant drugs, hemostatic drugs and the like can also be added into the sustained-release injection or the sustained-release implant prepared by the invention.
The sustained release microspheres can also be used to prepare other formulations such as, but not limited to, tablets, pills, dragees, capsules, liquids, drops, sprays, gels, syrups, slurries, ointments, suspensions, and the like.
The technical process of the invention is further described by the following tests and examples:
test 1 comparison of local drug concentrations after different modes of application of antibacterial drug (minocycline)
Rats were assigned to receive equal amounts of minocycline (10 mg) in different ways: group 1, normal minocycline injection was injected intraperitoneally; group 2, injections of ordinary minocycline injection subcutaneously on the scaly side; group 3, minocycline slow release injections subcutaneously into the scaly area; group 4, minocycline sustained release implants were placed subcutaneously in the scaly area. The drug concentration at the local administration site was measured after one week, two weeks, and three weeks, respectively. The results show that the difference of the local drug concentration is obvious after different modes of application, the local administration can be obviously improved, and the effective drug concentration of the administration part can be effectively maintained. Wherein the effect of local placement of the sustained-release implant and injection of the sustained-release injection is the best. However, local injection of sustained release injections is most convenient and easy to handle. This finding constitutes an important feature of the present invention. This is further confirmed by the following correlation tests.
Experiment 2 comparison of in vivo antibacterial Effect of different modes of application of antibacterial drugs
Using white rat as test object, 2X 105One staphylococcus aureus was injected into their femoral bone marrow cavity and one week later an equal amount of doxycycline treatment was given per trial 1 cohort (10/cohort). Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results show that the group injected with the doxycycline sustained-release injection and placed with the doxycycline sustained-release implant has the best effect, the local redness begins to obviously shrink in the first week after the treatment, and all animals do not die. In the group of normal doxycycline injections for intraperitoneal injection (i.p.), 70% of animals die within 20 days; in the group of local injections of ordinary doxycycline injections, 20% of animals died within 20 days, but 70% of animals died within 30 days. The comparison of antibacterial effects shows that the difference of the effects after different modes of application is obvious, the effective drug concentration of the part where the sustained-release implant is placed can be obviously improved and effectively maintained by local administration, and the effect of locally placing the sustained-release implant and injecting the sustained-release injection is the best. However, the operation of injecting the sustained-release injection is most convenient and easy. Not only has good curative effect, but also has little toxic and side effect.
The results show that the antibacterial effect of the antibacterial drug doxycycline administered by different routes is different, the effect of local application is good (P is less than 0.01), wherein the effect of local injection of the doxycycline sustained-release injection and local placement of the doxycycline sustained-release implant is better.
Test 3 comparison of in vivo antibacterial Effect of drugs
Using white rat as test object, 2X 105Each staphylococcus was injected into the femoral bone marrow cavity, grouped (10/group) one week later and treated with a slow release implant containing different drugs. Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results show that compared with the control group and the systemic administration group, the sustained-release implant containing demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultamicin, potassium clavulanate, ticarcillin, clavulanic acid, sulbactam sodium, telavant or timentin has better treatment effect (P is less than 0.05). Wherein the sustained release adjuvant is polifeprosan (p-CPP) and Sebacic Acid (SA) copolymer, and the ratio of p-CPP to SA is 30: 70).
The slow release auxiliary material with the same action effect is one or the combination of difatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dipolymer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue.
Test 4 comparison of in vivo antibacterial Effect of drugs
Using white rat as test object, 2X 105The bacilli were injected into their femoral bone marrow cavities, grouped one week later (10/group) and treated with slow release injections containing different drugs. Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results showed that containing demeclocycline, methacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysitetracycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, desoxyoxytetracycline, doxycyclineThe slow release injection (with the viscosity of 200-600cp) of the doxycycline hydrochloride, the oxytetracycline hydrochloride, the nystatin, the sulbactam, the sultam, the clavulanate potassium, the ticarcillin, the clavulanic acid, the sulbactam sodium, the tazobactam or the timentin has better treatment effect (P is less than 0.01). Wherein the sustained release adjuvant is polifeprosan (p-CPP) and Sebacic Acid (SA) copolymer, and the ratio of p-CPP to SA is 20: 80). The results show that the composition ratio of the copolymer significantly affects the release of the drug.
Experiment 5, comparison of in vivo antibacterial action of Metacycline sustained release implant prepared from polylactic acid with different molecular weights
Using white rat as test object, 2X 105Several staphylococcus aureus bacteria were injected into their femoral bone marrow cavities, grouped after one week (10/group) and given treatments with sustained release implants containing equal amounts of metacycline carried by polylactic acid (PLA) of different Molecular Weights (MW). Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results showed that the bacterial inhibition increased with increasing polylactic acid molecular weight, 58% (MW: 5000), 66% (MW: 15000), 80% (MW: 25000), 88% (MW: 40000) and 92% (MW: 60000) in this order, and the P value was less than 0.01, as compared to the systemic administration group.
The same results are seen with sustained release implants of demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultamicin, clavulanate potassium, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin, or timentin.
Test 6, comparison of in vivo antibacterial action of Sutalicillin sustained-release implant made of polylactic acid with different molecular weights
Using white rat as test object, 2X 105Staphylococcus aureus was injected into the bone marrow cavity of femur, divided into groups (10/group) one week later and given with different groupsTreating with equivalent amount of sultamicin sustained release implant carried by polylactic acid (PLA) with Molecular Weight (MW). Inflammation changes such as local redness and swelling were then examined and thirty days later animals were sacrificed and local bone marrow was examined for bacteria. The results showed that the bacterial inhibition increased with increasing polylactic acid molecular weight, and that the P value was less than 0.01, in the order of 69% (MW: 5000), 80% (MW: 15000), 87% (MW: 25000), 92% (MW: 40000) and 98% (MW: 60000), as compared with the systemic administration group.
The same results are seen with sustained release implants of demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultamicin, clavulanate potassium, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin, or timentin.
Experiment 7, comparison of in vivo antibacterial action of ticarcillin sustained release injection prepared from polylactic acid with different molecular weights
Using white rat as test object, 2X 103Staphylococcus aureus was injected into the femoral bone marrow cavity, divided into groups (10 groups) one week later and administered with a sustained release injection containing an equivalent amount of ticarcillin carried by polylactic acid (PLA) of different Molecular Weights (MW) (viscosity 600cp (20 ℃ -30 ℃) for treatment, then examined for inflammatory changes such as local redness and swelling, and animals were sacrificed thirty days later and examined for local bone marrow bacteria, the results showed that the bacterial inhibition rate increased with increasing polylactic acid molecular weight, in the order of 62% (MW: 5000), 70% (MW: 15000), 85% (MW: 25000), 92% (MW: 40000) and 97% (MW: 60000), and the P value was less than 0.01, as compared to the systemic administration group.
The same effect can be seen in dimecycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultamicin, clavulanate potassium, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin or timentin sustained release injection.
Particularly, the sustained-release preparation, particularly the sustained-release injection, has simple and convenient operation and good repeatability. Not only has good curative effect, but also has little toxic and side effect.
The most suitable sustained-release auxiliary material is one or the combination of polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dipolymer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue.
The most suitable suspending agent is one or more of methylcellulose, hydroxymethyl cellulose, sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, or their combination.
In a word, the single antibacterial drug sustained-release preparation placed or injected locally has obvious inhibition effect on the growth of bacteria, the combination of two or more than two drugs has obvious synergy, and the shown treatment effect and the synergy are related to the effective drug concentration obtained locally. Therefore, the effective component of the sustained-release agent is the combination of one or more than one medicine.
The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein the (suspension) injection (including gel injection) formed by combining with special solvent containing suspending agent is preferred.
The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.
(IV) detailed description of the preferred embodiments
Example 1.
90, 80 and 70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is respectively placed into three containers of (A), (B) and (C), then 100 ml of dichloromethane is added into each copolymer, after dissolving and mixing uniformly, 10mg of demeclocycline, 20mg of metacycline and 30mg of doxycycline are respectively added, after shaking uniformly again, the microspheres for injection containing 10% of demeclocycline, 20% of metacycline and 30% of doxycycline are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 15 percent of mannitol to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 450-600 cp (at 20-30 deg C). The slow release injection has the release time in vitro physiological saline of 5-15 days and the release time under the skin of a mouse of about 12-20 days.
Example 2.
The steps of the method for processing the sustained-release injection are the same as the example 1, but the difference is that the contained antibacterial active ingredients and the weight percentage thereof are as follows: 2-50% demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultam, clavulanate, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin, or timentin.
Example 3.
70mg of polylactic acid (PLGA, 75: 25) with the molecular weight peak value of 10000 is respectively put into three containers of (A), (B) and (C), then 100 ml of dichloromethane is added into each container, after dissolving and mixing evenly, 30mg of doxycycline, guanmincycline or lysine tetracycline is respectively added into the three containers, after shaking evenly again, the microspheres for injection containing 30% of doxycycline, guanmincycline or lysine tetracycline are prepared by a spray drying method. Suspending the dried microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 400-600 cp (at 20-30 deg C). The slow release injection has the release time in vitro physiological saline of 7-15 days and the release time under the skin of a mouse of about 15-25 days.
Example 4
The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is that the contained antibacterial active ingredients and the weight percentage thereof are as follows: 5-40% demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultam, clavulanate, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin, or timentin.
Example 5.
Putting 80mg of ethylene vinyl acetate copolymer (EVAc) into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 20mg of hydrogen pyridine tetracycline or 20mg of minocycline, shaking uniformly again, and preparing microspheres for injection containing 20% of hydrogen pyridine tetracycline or 20% of minocycline by using a spray drying method. Then suspending the microspheres in injection containing 5-15% of sorbitol to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 380cp-560cp (at 20 ℃ -30 ℃). The slow release injection has the release time in vitro physiological saline of 7-14 days and the release time under the skin of a mouse of about 15-30 days.
Example 6.
The procedure of the process for preparing a sustained-release injection is the same as in example 5, except that the antibacterial active ingredient contained therein is: 20-30% demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultam, clavulanate, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin, or timentin.
Example 7.
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, 30mg of minocycline, oxytetracycline or oxytetracycline is added after the mixture is dissolved and mixed evenly, and the mixture is shaken up again and then is prepared into the sustained-release microspheres for injection containing 30% of minocycline, oxytetracycline or oxytetracycline by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 400-600 cp (at 20-30 deg C). The slow release injection has the release time in vitro physiological saline of 6-12 days and the release time under the skin of a mouse of about 15-22 days.
Example 8.
The procedure of the process for preparing a sustained-release injection is the same as in example 7, except that the antibacterial active ingredient contained therein is: 10-30% demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultam, clavulanate, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin, or timentin.
Example 9
Putting 85mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer into a container, adding 100 ml of dichloromethane, dissolving and mixing uniformly, adding 15mg of oxytetracycline, nystatin or sulbactam, shaking uniformly again, and preparing the sustained-release microspheres for injection containing 15% of oxytetracycline, nystatin or sulbactam by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose, 15 percent of sorbitol and 0.2 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The viscosity of the injection is 300-550 cp (at 20-30 deg C). The slow release injection has a release time of 7-15 days in vitro physiological saline and a release time of about 20-30 days under the skin of a mouse.
Example 10
The procedure of the process for preparing a sustained-release injection is the same as in example 9, except that the antibacterial active ingredient contained therein is: 15% demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultam, clavulanate, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin, or timentin.
Example 11
90mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 10mg of sultamicin, potassium clavulanate or ticarcillin is added, after the mixture is shaken again, the injection sustained-release microspheres containing 10% of sultamicin, potassium clavulanate or ticarcillin are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 10-15 days in-vitro physiological saline and the drug release time of about 20-30 days under the skin of a mouse.
Example 12
The procedure for preparing a sustained-release implant was the same as in example 11, except that the antibacterial active ingredient contained therein was: 20% demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultam, clavulanate, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin, or timentin.
Example 13
70mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak value of 15000 is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 30mg of clavulanic acid, tazobactam or timentin is added, after the mixture is shaken again evenly, the microspheres for injection containing 30% of clavulanic acid, tazobactam or timentin are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 10-15 days in vitro physiological saline and the release time of 15-20 days under the skin of a mouse.
Example 14
The steps of the method for processing the sustained-release implant are the same as those of the examples 11 and 13, but the difference is that the sustained-release implant comprises the following antibacterial active ingredients in percentage by weight: 20-30% demeclocycline, metacycline, doxycycline, tetracycline, doxycycline, guanmecycline, lysinocycline, hydropyracycline, minocycline, demeclocycline, minocycline, oxytetracycline, doxycycline hydrochloride, oxytetracycline hydrochloride, nystatin, sulbactam, sultam, clavulanate, ticarcillin, clavulanic acid, sulbactam sodium, telpatatin, or timentin.
Example 15
The procedure of processing into sustained release preparation is the same as that of examples 1-14, except that the sustained release excipient is one or a combination of the following:
a) polylactic acid (PLA) with the molecular weight peak value of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000;
b) a copolymer (PLGA) of polyglycolic acid and glycolic acid with a peak molecular weight of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of the polyglycolic acid to the glycolic acid is 50-95: 50-50;
c) ethylene vinyl acetate copolymer (EVAc);
d) p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) copolymer (polifeprosan) 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer-sebacic acid) copolymer;
g) poly (fumaric acid-sebacic acid) copolymer;
h) sodium carboxymethylcellulose, hydroxymethyl cellulose, xylitol, oligosaccharide, chondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin or albumin glue; or
i) Racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.
Example 16
The procedure for preparing a sustained release injection is the same as in examples 1 to 10, except that the suspending agent used is one or a combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20;
f) (iodine) glycerol, dimethicone, propylene glycol or carbomer;
g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;
h) 5-20% of mannitol and 0.1-0.5% of Tween 80; or
i)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.
Claims (1)
1. A sustained release preparation for topical application of antibiotics is characterized in that the sustained release preparation is a sustained release injection, and comprises the following components:
(A) a sustained release microsphere comprising:
antibiotic
Sustained release excipients
And
(B) a solvent;
wherein,
the antibiotic is tetracycline antibiotic;
the suspending agent in the solvent is one or the combination of mannitol, sodium carboxymethylcellulose, sorbitol and tween 80;
the slow release injection comprises the following components:
(1) the antibiotic is 10% demeclocycline, 20% metacycline or 30% doxycycline, the slow release auxiliary material is polifeprosan with the ratio of p-carboxyphenylpropane to sebacic acid being 20: 80, and the solvent is normal saline containing 15% mannitol;
(2) the antibiotic is 30% guanmecycline or 30% lysine tetracycline, the slow release auxiliary material is polylactic acid with the molecular weight of 10000, and the solvent is normal saline containing 1.5% sodium carboxymethylcellulose;
(3) the antibiotic is 20% of hydropyrazine or 20% of minocycline, the slow release auxiliary material is ethylene-vinyl acetate copolymer, and the solvent is injection containing 5-15% of sorbitol;
(4) the antibiotic is 30% minocycline or 30% oxytetracycline, the slow release auxiliary material is polifeprosan with the ratio of p-carboxyphenylpropane to sebacic acid being 20: 80, and the solvent is normal saline containing 1.5% of sodium carboxymethylcellulose and 0.5% of Tween 80;
(5) the antibiotic is 15% nystatin, the slow release auxiliary material is polifeprosan with the ratio of p-carboxyphenylpropane to sebacic acid being 20: 80, the solvent is normal saline containing 1.5% of sodium carboxymethylcellulose, 15% of sorbitol and 0.2% of tween 80;
the weight percentage of the antibiotic is based on the microsphere, and the volume weight ratio of the suspending agent is based on the solvent.
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| CN102274158B (en) * | 2010-09-21 | 2012-08-22 | 河南科技大学 | Prulifloxacin liposome gel and preparation method thereof |
| CN102247318B (en) * | 2010-09-28 | 2013-01-09 | 佛山市南海东方澳龙制药有限公司 | Oxytetracycline uterus injectant and preparation method thereof |
| CN102018953B (en) * | 2010-11-18 | 2013-05-01 | 南京碧迪可医药科技有限公司 | Pharmaceutical composition containing nocathiacin antibiotics |
| CN105056242A (en) * | 2015-09-09 | 2015-11-18 | 上海市徐汇区牙病防治所 | External nano drug carrier system for carrying medicament for resisting periodontal pathogens |
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