CN1857218A - Slow released medicine containing antituberculotic - Google Patents
Slow released medicine containing antituberculotic Download PDFInfo
- Publication number
- CN1857218A CN1857218A CNA2006102003122A CN200610200312A CN1857218A CN 1857218 A CN1857218 A CN 1857218A CN A2006102003122 A CNA2006102003122 A CN A2006102003122A CN 200610200312 A CN200610200312 A CN 200610200312A CN 1857218 A CN1857218 A CN 1857218A
- Authority
- CN
- China
- Prior art keywords
- release
- sustained
- acid
- tuberculosis
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
The slow released implanting agent and injection containing antituberculotic are set or injected to local tuberculosis focus for maintaining the local effective medicine concentration while lowing the systemic toxicity. The slow released injection consists of slow released microsphere and solvent. The slow released microsphere includes antituberculotic selected from Cycloserine, Ofloxacin, Ciprofloxacin and Sparfloxacin and slow releasing supplementary material, and the solvent is special solvent containing suspending agent. The suspending agent is carboxymethyl cellulose sodium, etc. and has viscosity of 100-3000 cp at 20-30 deg.c. The slow releasing supplementary material is selected from EVAc, PLA, PLGA, etc. The slow released implanting agent may be prepared with slow released microsphere. The present invention has obvious and unique treating effect on various kinds of intractable tuberculosis.
Description
(I) technical field
The invention relates to a sustained release preparation containing an antituberculosis drug, belonging to the technical field of drugs. Specifically, the invention provides a sustained-release preparation containing cycloserine and/or quinolone antituberculosis drugs, which is mainly a sustained-release injection and a sustained-release implant. The sustained release preparation is mainly applied locally, and can obtain and maintain effective drug concentration at local tuberculosis focus.
(II) background of the invention
Tuberculosis represented by pulmonary tuberculosis is originally a disease which seriously affects the health of people, is widely popularized all over the world, takes hundreds of millions of people, is called as white plague, and has a theory of 'ten knots and nine deaths'. With the advent of anti-tuberculosis drugs such as streptomycin, tuberculosis became a treatable disease. However, the generation of tubercle bacillus resistance caused by the neglect of the severity, the obvious shortage of the related prevention and treatment and the non-standard treatment becomes the most troublesome problem for successfully treating the disease.
Because of its very high infectivity, its incidence has increased worldwide at a rate of 1% each year. Of the three diseases identified by the world health organization that require significant global control, tuberculosis is second only to aids, preceded by malaria. One person is infected by tubercle bacillus every second in the world, 3 to 4 people die due to tuberculosis every minute, and about 300 million people die of tuberculosis every year in the world at present. The current prevalence of tuberculosis in China is very serious, and the tuberculosis becomes one of 22 tuberculosis high-load countries in the world; at present, about six million tuberculosis patients account for one third of the worldwide sick people, and the second place in China is just next to India; drug resistant patients account for one fourth of the world in China. At least 150 new patients occur in China every year, wherein more than 65 infectious patients occur, the number of deaths caused by tuberculosis is as high as twenty-five thousand every year, and most of the deaths are young and middle-aged. It has become the number one killer as a single infectious disease. Tuberculosis requires more than six months of continuous medication to obtain a more satisfactory prognosis. Because the treatment time is long, a patient may forget to take the medicine quantitatively in time, and the drug resistance is often caused. The treatment of drug-resistant tuberculosis patients is prolonged in time on one hand, and the application cost of the combination chemotherapy of a plurality of drugs is high on the other hand. For example, more than twenty-three thousand yuan is needed in China. Therefore, the research and development of new and effective preparations or methods for preventing and treating tuberculosis has become an urgent problem worldwide.
At present, a plurality of new antitubercular drugs have already shown good curative effect, but the effect on multidrug-resistant tuberculosis (MDR-TB) is not ideal enough. Because it is difficult to achieve effective bactericidal concentrations with conventional therapeutic administration for many chronic lesions, particularly localized lesions. There are many side effects caused by increasing dosage or taking the medicine for a long time.
Disclosure of the invention
The invention provides a sustained-release preparation containing an anti-tuberculosis drug aiming at the defects of the prior art, in particular to a sustained-release preparation containing a cycloserine and/or quinolone drugs for the anti-tuberculosis drug, which is mainly a sustained-release injection and a sustained-release implant.
As a common antituberculotic drug, cycloserine and/or quinolone drugs are mainly orally taken preparations abroad, and even general injections are not ideal enough because effective drug concentration cannot be obtained at a focus part. And the obvious systemic toxicity and the generation of drug resistance in the application process greatly limit the application of the drug.
The invention discovers that the anti-tuberculosis drugs are prepared into sustained-release preparations (mainly sustained-release injection and sustained-release implant), which not only can greatly improve the local drug concentration, reduce the concentration of the drugs in the circulatory system and reduce the toxicity of the drugs to normal tissues, but also can greatly facilitate the application of the drugs, reduce the treatment course, shorten the treatment time, reduce the complications of the drugs, reduce the cost of patients and reduce the drug tolerance. The above unexpected findings constitute the 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 antituberculotic drug
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 antituberculotic is selected from cycloserine and/or quinolone drugs; the sustained-release auxiliary material is selected from one or the combination of polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dipolymer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue; the suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
Quinolones such as, but not limited to, ofloxacin, ciprofloxacin, sparfloxacin. The antituberculotic of the present invention may be selected from one or more of cycloserine and/or quinolone drugs.
The proportion of the anti-tuberculosis drug in the composition 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 antituberculous sustained-release microspheres are preferably as follows:
2-50% of antituberculotic drug
Sustained release auxiliary materials 50-98%
0.0 to 30 percent of suspending agent
The sustained release adjuvant is selected from polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimmer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene vinyl acetate copolymer, polylactic acid, polyglycolic acid and glycolic acid copolymer, hyaluronic acid, collagen or gelatin.
The most preferable effective components and weight percentages in the sustained-release microspheres are as follows:
(1) 5-40% cycloserine, ofloxacin, ciprofloxacin or sparfloxacin;
(2) a combination of 5-40% cycloserine and 5-40% ofloxacin, ciprofloxacin or sparfloxacin;
(3) a combination of 5-40% ofloxacin and 5-40% ciprofloxacin or sparfloxacin; or
(4) A combination of 5-40% ciprofloxacin and 5-40% sparfloxacin.
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; or
(5) 55-90% EVAc.
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 as a suspending agent are prepared into a sustained-release injection. The concentration of sodium carboxymethylcellulose in the solvent may be 0.1-5%, but is preferably 0.5-3%, and most preferably 1-2%.
The molecular weight peak of polylactic acid may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and most preferably 30,000-50,000; the molecular weight of polyglycolic acid may be, but is not limited to, 5000-; the polyhydroxy acids can be selected singly or in multiple ways. When selected alone, polylactic acid (PLA) or a copolymer of hydroxycarboxylic acid and glycolic acid (PLGA) is preferred, and the molecular weight of the copolymer may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and is most preferably 30,000-50,000; when more than one choice is selected, the polymer or the composite polymer or copolymer of different polymers is preferred, and the composite polymer or copolymer of polylactic acid or sebacic acid with different molecular weight is most preferred, such as, but not limited to, polylactic acid with molecular weight of 1000 to 30000 mixed with polylactic acid with molecular weight of 20000 to 50000, polylactic acid with molecular weight of 10000 to 30000 mixed with PLGA with molecular weight of 30000 to 80000, polylactic acid with molecular weight of 20000 to 30000 mixed with sebacic acid, PLGA with molecular weight of 30000 to 80000 mixed with sebacic acid.
Among the various polymers, preferred are polylactic acid, sebacic acid, and a mixture or copolymer of polylactic acid and sebacic acid, and the mixture or copolymer can be selected from, but not limited to, PLA, PLGA, a mixture of glycolic acid and hydroxycarboxylic acid, and a mixture or copolymer of sebacic acid and an aromatic polyanhydride or an aliphatic polyanhydride. The blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), di-fatty acid-sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid-sebacic acid) [ P (FA-SA) ], and the like. The content of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization is 10-60 wt% and 20-90 wt%, respectively, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
In addition to the above-mentioned adjuvants, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176 and 4789724 and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luoming and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.
In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. The sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.
In the slow release injection, the drug slow release system can be prepared into microspheres, submicron spheres, micro emulsion, nanospheres, granules or spherical pellets, and then the injection is prepared after the drug slow release system is mixed with an injection solvent. The suspension type sustained-release injection is preferably selected from various sustained-release injections, the suspension type sustained-release injection is a preparation obtained by suspending a drug sustained-release system containing an anti-tuberculosis 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 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.
Therefore, another form of the sustained-release agent of the present invention is a sustained-release implant. The active ingredients of the antituberculous 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, granules, 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:
2-50% of antituberculotic drug
Sustained release auxiliary materials 50-98%
0.0 to 30 percent of suspending agent
The effective components and the weight percentage of the sustained-release implant are most preferably as follows:
(1) 5-40% cycloserine, ofloxacin, ciprofloxacin or sparfloxacin;
(2) a combination of 5-40% cycloserine and 5-40% ofloxacin, ciprofloxacin or sparfloxacin;
(3) a combination of 5-40% ofloxacin and 5-40% ciprofloxacin or sparfloxacin; or
(4) A combination of 5-40% ciprofloxacin and 5-40% sparfloxacin.
The sustained-release auxiliary materials in the antituberculous sustained-release microspheres of the invention preferably have the following weight percentages:
(1) 55-95% PLA;
(2) 50-98% PLGA;
(3) 50-95% of polifeprosan;
(4) 55-90% of a copolymer of di-fatty acid and sebacic acid; or
(5) 55-90% EVAc.
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 tuberculosis of human and animals, mainly sustained-release injections or sustained-release implants. The prepared medicinal preparation can be used for treating systemic tuberculosis such as pulmonary tuberculosis, but is preferably used for treating local lesions. Common local lesions or so-called extrapulmonary tuberculosis mainly include: tuberculosis bulb, lymphoid tuberculosis, bone joint tuberculosis, synovial tuberculosis, tuberculous osteomyelitis, renal tuberculosis, skin tuberculosis, intestinal tuberculosis, mammary tuberculosis, genital tuberculosis (fallopian tube, endometrium, testis, epididymis), anal tuberculosis, thyroid tuberculosis, pericardial tuberculosis, chest wall tuberculosis, tuberculosis fistula, pleural tuberculosis, etc. In addition, local lesions include chronic fibrocavitary tuberculosis and chronic lesions caused by or combined with tuberculosis, such as: but are not limited to, severe bedsores, refractory skin ulcers, diabetic foot, femoral head necrosis, and senile prostate diseases.
The administration route depends on various factors, and in order to obtain an effective concentration at the site of tuberculosis, the drug may be administered via various routes, such as subcutaneous, intraluminal (e.g., intraperitoneal, thoracic and intraspinal), peri-or intralesional injection or placement, intra-lymph node and intra-medullary injection, but the sustained-release implant is preferably locally injected (sustained-release injection) or placed (sustained-release implant) at the lesion. Can be injected or placed during or before surgery; can be used for interventional therapy by bronchofiberscope and other instruments, such as pulmonary tuberculosis cavity; or percutaneous puncture intralesional administration intervention treatment; injection or placement in joint cavities; can be applied simultaneously with or separately from systemic chemotherapy, but preferably has a period of one week to several months before and after topical application.
The dosage to be administered varies depending on the composition of the drug, but the total amount of the drug may vary from 10% to 200% of the daily dose by the conventional route. For example, cycloserine is 0.5 to 20 mg/kg, ofloxacin is 0.75 to 30 mg/kg or 0.1 to 1.6g/d, and ciprofloxacin is 0.1 to 3 g/d. When the two drugs are used in combination, the dosage of each drug does not exceed 100% of the daily dose of the drug administered by its conventional route. For example, cycloserine is 2.5 to 10 mg/kg, ofloxacin is 7.5 to 15 mg/kg or 0.6 to 0.8g/d, and ciprofloxacin is 1.0 to 1.5 g/d. If the lesion is not completely cleared or improved, it is considered that the sustained-release agent is placed or injected again after 20 to 40 days. In order to prevent the spread of tubercle bacillus in focus, systemic administration should be added before and after each local administration.
The sustained-release injection or the sustained-release implant prepared by the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic drugs, anticoagulant drugs, hemostatic drugs 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 antituberculotic drug (cycloserine)
White rats were used as test subjects, and were grouped to receive the same amount of cycloserine (10 mg) in the following different ways: group 1, common cycloserine injection was intraperitoneally injected; group 2, common cycloserine injections were subcutaneously injected into the costal region; group 3, cycloserine sustained release injection subcutaneously injected in the quaternary rib area; and in group 4, the cycloserine sustained-release implant is subcutaneously placed in the costal part. The drug concentration at the local administration site was measured after one week, two weeks, and three weeks, respectively. The results show that the difference of the local drug concentration is obvious after different modes of application, the local administration can be obviously improved, and the effective drug concentration of the administration part can be effectively maintained. Wherein the effect of local placement of the sustained-release implant and injection of the sustained-release injection is the best. However, local injection of sustained release injections is most convenient and easy to handle. 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 after application of antituberculotic drugs in different modes
Using white rat as test object, 2X 105Each tubercle bacillus was injected into its femoral bone marrow cavity and given equivalent cycloserine treatment one week later according to the cohort of trial 1 (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 cycloserine sustained-release injection and placed with the cycloserine sustained-release implant has the best effect, the local red and swollen part begins to be obviously reduced in the first week after the treatment, and all animals do not die. In the group of normal cycloserine injections injected into the abdominal cavity, 70% of animals died within 20 days; in the group of local injections of the common cycloserine injection, 20% of the animals died within 20 days, but 50% of the animals died within 30 days. The comparison of antibacterial effects shows that the difference of the effects after different modes of application is obvious, the effective drug concentration of the part where the sustained-release implant is placed can be obviously improved and effectively maintained by local administration, and the effect of locally placing the sustained-release implant and injecting the sustained-release injection is the best. However, the operation of injecting the sustained-release injection is most convenient and easy. Not only has good curative effect, but also has little toxic and side effect.
Experiment 3 comparison of the in vivo bacteriostatic action of cycloserine applied in different ways
The test 2 was repeated using white rats as test subjects, and the results are shown in Table 1
TABLE 1
| Test set (n) | Is treated by | Animal mortality (%) | P value |
| 1(10) | Control | 0 | |
| 2(10) | Common cycloserine injection for intraperitoneal injection | 90 | |
| 3(10) | Local injection common cycloserine injection | 60 | ＜0.05 |
| 4(10) | Local injection cycloserine sustained-release injection | 20 | ＜0.01 |
| 5(10) | Local placed cycloserine slow release implant | 10 | ＜0.01 |
The results show that the antituberculotic cycloserine has different bacteriostatic effects when being administered by different routes, and has good local application effect (P is less than 0.05), wherein the effect of local injection of the cycloserine sustained-release injection and the local cyclic serine sustained-release implant is better.
Experiment 4 comparison of the in vivo bacteriostatic action of cycloserine applied in different ways
The test 3 was repeated with the white rat as the test subject, but the animals were observed to 60 days after the administration, and the results are shown in Table 2
TABLE 2
| Test set (n) | Is treated by | Animal mortality (%) | P value |
| 1(10) | Control | 0 | |
| 2(10) | Common cycloserine injection for intraperitoneal injection | 100 | |
| 3(10) | Local injection common cycloserine injection | 80 | |
| 4(10) | Local injection cycloserine slow releaseInjection preparation | 50 | |
| 5(10) | Local placed cycloserine slow release implant | 30 | ＜0.01 |
The results show that the antituberculosis drug cycloserine has different bacteriostatic effects when administered by different routes, and has good local application effect, wherein the effect of local injection of the cycloserine sustained-release injection and local placement of the cycloserine sustained-release implant is better. But the effect of the local placement of the cycloserine sustained-release implant is better than that of the local injection of the cycloserine sustained-release injection (P is less than 0.01).
Experiment 5 comparison of the in vivo bacteriostatic action of cycloserine applied in different ways
The test 3 was repeated with the white rat as the test subject, but the animals were observed to 60 days after the administration, and the results are shown in Table 3
TABLE 3
| Test set (n) | Is treated by | Animal mortality (%) | P value |
| 1(10) | Control | 0 | |
| 2(10) | Common ofloxacin injection for intraperitoneal injection | 80 | |
| 3(10) | General ofloxacin injection for local injection | 60 | |
| 4(10) | Local injection ofloxacin slow release injection | 30 | |
| 5(10) | Local placed ofloxacin slow release implant | 10 | ＜0.01 |
Experiment 6 comparison of the in vivo bacteriostatic action of cycloserine applied by different ways
The test 3 was repeated with the white rat as the test subject, but the animals were observed to 60 days after the administration, and the results are shown in Table 4
TABLE 4
| Test set (n) | Is treated by | Animal mortality (%) | P value |
| 1(10) | Control | 0 | |
| 2(10) | Common intra-annular saxatilis injection for intraperitoneal injection | 90 | |
| 3(10) | Local injection common intra-annular Saxing injection | 60 | |
| 4(10) | Local ciprofloxacin slow-release injection | 40 | |
| 5(10) | Local-placed ciprofloxacin slow-release implant | 20 | ＜0.01 |
The results of experiments 5 and 6 show that the antituberculotic drugs have different antibacterial effects when administered by different routes, and have good local application effect, wherein the local injection of the sustained-release injection and the local placement of the sustained-release implant have better effects. But the effect of the local placement of the sustained-release implant is better than that of the local injection of the sustained-release injection (P is less than 0.01).
The same significant therapeutic effects are seen with topically placed and topically injected sparfloxacin.
Test 7 synergistic Effect of different combinations of drugs
Take 2X 105After culturing the tubercle bacillus for 24 hours, treating the tubercle bacillus with different drugs with the same concentration (5ug/ml) for 24 hours, detecting the cell growth inhibition rate (%), and the results are shown in Table 5
TABLE 5 synergistic effect of different drug combinations (% inhibition)
| Cyclic serine | Ofloxacin | Ciprofloxacin | Sparfloxacin hydrochloride | Cycloserine + ofloxacin | Cycloserine + intra-cycle saxasin | Cycloserine + sparfloxacin |
| 58 | 68 | 60 | 62 | 94 | 90 | 92 |
Experiment 7 shows that the antituberculosis drugs cycloserine and quinolone drugs have obvious bacteriostatic action when being applied independently, but the combined application effect is good (P is less than 0.01).
In conclusion, the slow release agent for local placement and local injection of cycloserine or quinolone drugs has obvious inhibition effect on bacterial growth, and the obvious treatment effect is related to the effective drug concentration locally obtained. Therefore, the effective component of the sustained release agent is cycloserine or any one of quinolone drugs and the combination thereof.
The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein suspension injection formed by combining with special solvent containing suspending agent is preferred.
The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.
(IV) detailed description of the preferred embodiments
Example 1.
90, 90 and 80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is respectively put into three containers of (A), (B) and (C), then 100 ml of dichloromethane is added into each copolymer, after dissolving and mixing evenly, 10m of cycloserine, l0mg ofloxacin, l0mg cycloserine and l0mg ofloxacin are respectively added, after shaking up again, the microspheres for injection containing 10% of cycloserine, 10% of ofloxacin, 10% of cycloserine and 10% of ofloxacin 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 300-600 cp (at 20-30 deg C). The slow release injection has the release time in vitro physiological saline of 15-20 days and the release time under the skin of a mouse of about 30-40 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 anti-tuberculosis active ingredients and the weight percentage thereof are as follows:
(1) 5-40% cycloserine, ofloxacin, ciprofloxacin or sparfloxacin;
(2) a combination of 5-40% cycloserine and 5-40% ofloxacin, ciprofloxacin or sparfloxacin;
(3) a combination of 5-40% ofloxacin and 5-40% ciprofloxacin or sparfloxacin; or
(4) A combination of 5-40% ciprofloxacin and 5-40% sparfloxacin.
Example 3.
70mg of polylactic acid (PLGA, 75: 25) with a molecular weight peak of 65000 is respectively put into three containers, namely, a container (A), a container (B) and a container (C), then 100 ml of dichloromethane is added into each container, after the materials are dissolved and uniformly mixed, 30mg of cycloserine, 30mg of ciprofloxacin, 15mg of cycloserine and 15mg of ciprofloxacin are respectively added into the three containers, after the materials are uniformly shaken again, the microspheres for injection containing 30% of cycloserine, 30% of ciprofloxacin, 15% of cycloserine and 15% of ciprofloxacin 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 300-600 cp (at 20-30 deg C). The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 4
The steps of the method for processing the sustained-release injection are the same as those of the example 3, but the difference is that the anti-tuberculosis active ingredients and the weight percentage thereof are as follows:
(1) 5-40% cycloserine, ofloxacin, ciprofloxacin or sparfloxacin;
(2) a combination of 5-40% cycloserine and 5-40% ofloxacin, ciprofloxacin or sparfloxacin;
(3) a combination of 5-40% ofloxacin and 5-40% ciprofloxacin or sparfloxacin; or
(4) A combination of 5-40% ciprofloxacin and 5-40% sparfloxacin.
Example 5.
Putting 70mg of ethylene-vinyl acetate copolymer (EVAc) into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 20mg of cycloserine and 10mg of sparfloxacin, shaking up again, and preparing the microspheres for injection containing 20% of cycloserine and 10% of sparfloxacin 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 slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 6.
The procedure of the process for preparing the sustained-release injection is the same as that of example 5, except that the antituberculous active ingredient contained therein is:
10-20% cycloserine and 10-20% ofloxacin, ciprofloxacin or sparfloxacin.
Example 7.
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 20mg of ofloxacin and 10mg of ciprofloxacin are added, after the mixture is shaken again, the microspheres for injection containing 20% of ofloxacin and 10% of ciprofloxacin are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 8.
The procedure of the process for preparing the sustained-release injection is the same as that of example 7, except that the antituberculous active ingredient contained therein is:
10-20% of ofloxacin and 10-20% of ciprofloxacin or sparfloxacin.
Example 9
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 15mg of ofloxacin and 15mg of sparfloxacin are added, the mixture is shaken again and then the spray drying method is used for preparing the microsphere for injection containing 15% of ofloxacin and 15% of sparfloxacin. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose, 15 percent of sorbitol and 0.2 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 10
The procedure of the process for preparing the sustained-release injection is the same as that of example 9, except that the antituberculous active ingredient contained therein is:
a combination of 15% ofloxacin and 15% sparfloxacin.
Example 11
70mg of a polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is placed into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed uniformly, 10mg of ciprofloxacin and 20mg of sparfloxacin are added, the mixture is shaken again uniformly, and then the spray drying method is used for preparing the microspheres for injection containing 10% of ciprofloxacin and 20% of sparfloxacin. 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 about 30-40 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 anti-tubercular active ingredient contained therein was:
10-20% ciprofloxacin and 10-20% sparfloxacin.
Example 13
70mg of polylactic acid (PLGA, 50: 50) with a molecular weight peak of 45000 is put into a container, 100 ml of dichloromethane is added, 10mg of cycloserine and 20mg of rifapentine are added after being dissolved and mixed evenly, and the microspheres for injection containing 10% of cycloserine and 20% of rifapentine are prepared by a spray drying method after being shaken again. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 15-25 days in vitro physiological saline and the release time of about 35-50 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 anti-tuberculosis active ingredients and the weight percentage are as follows:
(1) 5-40% cycloserine, ofloxacin, ciprofloxacin or sparfloxacin;
(2) a combination of 5-40% cycloserine and 5-40% ofloxacin, ciprofloxacin or sparfloxacin;
(3) a combination of 5-40% ofloxacin and 5-40% ciprofloxacin or sparfloxacin; or
(4) A combination of 5-40% ciprofloxacin and 5-40% sparfloxacin.
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 a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000;
b) a copolymer (PLGA) of polyglycolic acid and glycolic acid with a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
c) ethylene vinyl acetate copolymer (EVAc);
d) p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) copolymer (polifeprosan) 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer-sebacic acid) copolymer;
g) poly (fumaric acid-sebacic acid) copolymer;
h) xylitol, oligosaccharide, chondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin or albumin glue.
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 (10)
1. The slow release preparation containing the anti-tuberculosis medicine is characterized by being mainly used for local tuberculosis focus, so that the anti-tuberculosis medicine is released locally on the tuberculosis focus, and the systemic toxicity of the anti-tuberculosis medicine is reduced while the local effective medicine concentration is effectively obtained and maintained.
2. The sustained-release antituberculotic drug formulation according to claim 1, characterized in that it is a sustained-release injection, consisting of the following components:
(A) a sustained release microsphere comprising:
1-70% of antituberculotic drug
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 anti-tuberculosis active ingredient is cycloserine and/or quinolone drugs;
the suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), and is selected from one or more of sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40 and Tween-80.
3. The antituberculous sustained-release injection according to claim 2, characterized in that the quinolone drug is selected from one of ofloxacin, ciprofloxacin, sparfloxacin or a combination thereof.
4. The antituberculous sustained-release injection according to claim 2, characterized in that the antituberculous sustained-release injection comprises the following active antituberculous components in percentage by weight:
(1) 5-40% cycloserine, ofloxacin, ciprofloxacin or sparfloxacin;
(2) a combination of 5-40% cycloserine and 5-40% ofloxacin, ciprofloxacin or sparfloxacin;
(3) a combination of 5-40% ofloxacin and 5-40% ciprofloxacin or sparfloxacin; or
(4) A combination of 5-40% ciprofloxacin and 5-40% sparfloxacin.
5. The antituberculous sustained-release injection according to claim 2, characterized in that the sustained-release excipients are selected from one or a combination of the following:
a) polylactic acid;
b) copolymers of polyglycolic acid and glycolic acid;
c) polifeprosan;
d) ethylene vinyl acetate copolymers;
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer-sebacic acid) copolymer;
g) poly (fumaric acid-sebacic acid) copolymer;
h) xylitol, oligosaccharide, chondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin or albumin glue.
6. The antituberculous sustained-release injection according to claim 2, characterized in that the suspending agents used are respectively one of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20;
f) (iodine) glycerol, dimethicone, propylene glycol or carbomer;
g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;
h) 5-20% of mannitol and 0.1-0.5% of Tween 80; or
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.
7. The sustained-release antituberculotic drug formulation according to claim 1, characterized in that it is a sustained-release implant consisting of the following components:
(1) 1-70% of antituberculotic drug
(2) Sustained release auxiliary materials 30-99%
(3) 0.0 to 30 percent of suspending agent
The above are weight percentages
8. The anti-tuberculosis slow-release implant according to claim 7, characterized in that the anti-tuberculosis slow-release implant comprises the following anti-tuberculosis active ingredients in percentage by weight:
(1) 5-40% cycloserine, ofloxacin, ciprofloxacin or sparfloxacin;
(2) a combination of 5-40% cycloserine and 5-40% ofloxacin, ciprofloxacin or sparfloxacin;
(3) a combination of 5-40% ofloxacin and 5-40% ciprofloxacin or sparfloxacin; or
(4) A combination of 5-40% ciprofloxacin and 5-40% sparfloxacin.
9. The antituberculous sustained release implant according to claim 7, characterized in that the sustained release excipients are selected from one or a combination of the following:
a) polylactic acid;
b) copolymers of polyglycolic acid and glycolic acid;
c) polifeprosan;
d) ethylene vinyl acetate copolymers;
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer-sebacic acid) copolymer;
g) poly (fumaric acid-sebacic acid) copolymer;
h) xylitol, oligosaccharide, chondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin or albumin glue.
10. The slow release implant of claim 9, wherein the slow release excipients comprise:
a) the molecular weight peak value of the polylactic acid is selected from 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
b) in the copolymer of polyglycolic acid and glycolic acid, the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
c) in polifeprosan, the ratio of p-carboxyphenylpropane to sebacic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.
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| CNA2006102003122A CN1857218A (en) | 2006-04-04 | 2006-04-04 | Slow released medicine containing antituberculotic |
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| CNA2008103004121A Division CN101254169A (en) | 2006-04-04 | 2006-04-04 | Sustained-release agent containing tuberculosis-resistance medicament |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20090284A1 (en) * | 2009-02-26 | 2010-08-27 | Consiglio Nazionale Ricerche | USE OF INHIBITORS OF SERINA PALMITOILTRASFERASI FOR THE PREVENTION AND DECELERATION OF HEREDITIC RETINAL DEGENERATIONS AND RELATIVE COMPOSITIONS |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20090284A1 (en) * | 2009-02-26 | 2010-08-27 | Consiglio Nazionale Ricerche | USE OF INHIBITORS OF SERINA PALMITOILTRASFERASI FOR THE PREVENTION AND DECELERATION OF HEREDITIC RETINAL DEGENERATIONS AND RELATIVE COMPOSITIONS |
| WO2010097201A1 (en) * | 2009-02-26 | 2010-09-02 | Universita' Degli Studi Di Milano | Serine palmitoyltransferase inhibitors for preventing and delaying retinitis pigmentosa |
| CN102333527A (en) * | 2009-02-26 | 2012-01-25 | 米兰大学 | Serine palmitoyltransferase inhibitors for the prevention and delay of retinitis pigmentosa |
| CN102333527B (en) * | 2009-02-26 | 2014-04-16 | 米兰大学 | Serine palmitoyltransferase inhibitors for preventing and delaying retinitis pigmentosa |
| US9114119B2 (en) | 2009-02-26 | 2015-08-25 | Universita' Degli Studi Di Milano | Use of serine palmitoyl transferase inhibitors for preventing and delaying inherited retinal degenerations and compositions thereof |
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